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<urn:uuid:095e6079-abc0-4612-9edf-a63c2bce0ca7> | seed | The aim of treatment of postmenopausal osteoporosis is to reduce the frequency of vertebral and non-vertebral fractures (especially at the hip), which are responsible for morbidity associated with the disease. Results of large placebo controlled trials have shown that alendronate, raloxifene, risedronate, the 1—34 fragment of parathyroid hormone, and nasal calcitonin, greatly reduce the risk of vertebral fractures. Furthermore, a large reduction of non-vertebral fractures has been shown for alendronate, risedronate, and the 1—34 fragment of parathyroid hormone. Calcium and vitamin D supplementation is not sufficient to treat individuals with osteoporosis but is useful, especially in elderly women in care homes. Hormone replacement therapy remains a valuable option for the prevention of osteoporosis in early postmenopausal women. Choice of treatment depends on age, the presence or absence of prevalent fractures, especially at the spine, and the degree of bone mineral density measured at the spine and hip. Non-pharmacological interventions include adequate calcium intake and diet, selected exercise programmes, reduction of other risk factors for osteoporotic fractures, and reduction of the risk of falls in elderly individuals.
a Claude Bernard University of Lyon, France, and INSERM Research Unit 403, Lyon
Correspondence to:Prof Pierre D Delmas, Hópital E Herriot, Pavillon F, 69437 Lyon Cedex 03, France |
<urn:uuid:c6c89bfa-6be5-4b0b-9ddd-5e91936c093a> | seed | The human genome project-molecular biology’s international extravaganza that seeks to decode all of humankind’s estimated 100,000 genes-is on track to be completed in 2005. Researchers know that each of those genes contains a precise molecular script for making a different protein. But after spending several billion dollars on the Genome Project over a decade and a half, scientists will simply have gathered the cast of characters for another fundamental mystery: What in the heck do all these proteins do?
On biology’s stage, proteins are the leading players-as well as the producers and directors. Acting alone and in groups, proteins do just about everything in a cell, from shuttling urgent messages to controlling the cycle of growth and death. It’s the role of proteins that scientists need to know to unravel the secrets of life-and to develop potent new drugs. In fact, in one sense the Human Genome Project and its counterparts for other organisms, such as flies, worms, viruses, and bacteria, are simply precursors of a great Human Protein Project. Yet the efforts to decode the genes of less complex creatures are bringing advance notice of just how poorly lit the world of proteins really is.
Take baker’s yeast. A staple of genetics labs, researchers finished sequencing its genome-all 6,000 genes-in 1996. Each of the strings of genetic “letters” predicts the basic makeup of a protein. “But we still have no idea whatsoever what nearly half of those proteins do,” laments Roger Brent, a geneticist at the Molecular Sciences Institute in Berkeley, Calif. “And yeast is one of the most intensively studied organisms.”
Today’s research techniques are woefully inadequate for explaining the function of so many proteins. Typically researchers will breed “knock-out” mice missing a particular gene, then study what effect the loss of the corresponding protein has on the animal-an approach that is like trying to understand how a carburetor works by removing it and checking to see whether the car still runs. Thanks to the rapidly growing
availability of the DNA sequences of genes, scientists are gaining a neatly labeled inventory of parts. “What we need now are fast ways to find where and how all those parts fit,” says Brent. “We need to apply high-throughput approaches to studying proteins.”
The field developing these approaches is called “protein genomics,” or, more catchily, “proteomics,” and it’s one of the hottest areas of biotech. Over the past year, research in this sector has spawned an array of high-tech startups, including Genome Pharmaceuticals, a spin-out from Germany’s Max-Planck Institute, and Hybrigenics, a Paris-based venture. Established gene-hunting firms are also moving aggressively into proteomics. Cambridge, Mass.-based Millennium Pharmaceuticals, Genome Therapeutics, and Incyte Pharmaceuticals of Palo Alto, Calif. all have research groups. These genomics companies bring to the protein game qualities honed over half a decade of searching for genes: a taste for big projects and an aptitude for automated, high-speed science. |
<urn:uuid:9710b1a1-a56a-4aee-8410-52f80804a37c> | seed | of the known R genes, particularly those which confer protection from pathogen and nematode pests, are highly conserved in structure and function (Baker et al. 1997); that is, an R gene from one plant species will often function after transfer to another plant species. The N gene for resistance to tobacco mosaic virus in Nicotiana tabacum, for example, functions well after transfer to tomato (Whitham et al. 1996), and the Cf-9 gene for race-specific protection of tomato from the fungus Cladosporium fulvum is functional when transferred to tobacco and potato, as the gene triggers HR specifically in response to the C. fulvum avr9 avirulence protein (Hammond-Kosack et al. 1998).
Cloned R genes and pathogen avirulence genes make it possible to engineer natural resistance responses to a wide array of pathogens and pests. For example, combining an R gene with a corresponding avirulence gene under the control of appropriate regulatory genetic elements in transgenic pest-protected plants can facilitate activation of defense responses against pathogens that are normally not limited by that particular R gene.
Transfer of defense genes for specific degradative enzymes and inhibitors can also confer pest-protection. For example, constitutive or localized expression of a variety of genes that encode proteinase inhibitors, chitinases, and lectins in transgenic plants can provide protection against some chewing insects, sucking insects, or nematodes (Johnson et al. 1989; Kramer and Muthukrishnan 1997; Rao et al. 1998; Ryan 1990; Urwin et al. 1997). Transgenic modification of the production of defensive chemicals also will affect resistance to pests and pathogens (for example, Melanson et al. 1997).
Research focused on developing new ways to produce both conventional and transgenic pest-protected plants, is some of the most exciting in the field of plant biology. Through wide crosses and other nontransgenic techniques, plant resistance genes will continue to be transferred to crop species from species at greater and greater taxonomic distances. A number of genomics projects with model and crop plants are yielding data from which information about new R and defense genes can be obtained. That information could lead to identification and manipulation of resistance factors with unique specificities against important pests and pathogens. The signaling mechanisms whereby resistance responses are triggered by insects and pathogens are being unraveled. It might soon be possible to engineer plants with altered signaling components that result in resistance being triggered by a broader array of pests. Understanding how defensive secondary compounds and defense proteins are produced |
<urn:uuid:d2b9360f-37fc-4941-bf30-a88cc94190e4> | seed | Primary ovarian insufficiency (POI), also called premature ovarian failure, occurs when the ovaries stop working before a woman turns 40. Normally, the ovaries make the hormone estrogenand release a mature egg during each monthly cycle. In POI, the ovaries don’t produce normal amounts of estrogen and don’t produce and release an egg each month.
The most common signs of POI are irregular or missed menstrual periods, especially if a woman also has hot flashes. Periods may occur off and on, or may start again many years after POI is diagnosed. Due to the drop in estrogen levels, women with POI may also have menopause-like symptoms, including
In most cases the cause of POI is unknown. Women with certain genetic disorders, such as Turner syndrome and fragile X syndrome, are more likely to develop POI. Also, exposure to toxins (through chemotherapy and radiation therapy, for example) can damage genetic material in cells and lead to POI. Sometimes autoimmune disease—when your immune system attacks your own ovarian tissue—may be responsible for POI.
The risk of developing POI increases if you have a family history of the disorder.
The symptoms of POI are like the symptoms women have when they are going through menopause.
Because women with POI have low levels of estrogen at a young age, several health problems are more common than in women without POI:
If you have POI, you may also be more likely to develop other hormone-related disorders. Women with POI should be checked periodically for deficiencies in thyroid and adrenal gland hormones.
If you are younger than 40 and have stopped having periods or are having irregular ones, talk with your doctor to find the cause of the problem. Your doctor will ask about your menstrual history and any menopause-like symptoms you may be having. Blood tests will be done to check hormone levels and determine if your ovaries are working properly. Additional tests should also be done to check for possible genetic or autoimmune conditions that may be related to the ovarian failure.
Treatment depends on whether you have symptoms or are at risk for serious health problems. Hormone therapy (HT) is the most common treatment. HT combines estrogen and progesterone, another sex hormone. Together these two hormones mimic the natural balance of hormones in your body. HT relieves menopausal symptoms and also helps prevent osteoporosis. HT can be taken as a pill or applied to your skin as a gel, spray, or patch. Vaginal rings can also supply estrogen to the body.
In older, postmenopausal women, HT may increase risk of breast cancer, heart disease, and stroke. In younger women with POI, these risks are thought to be much lower, since it’s normal for women in this age group to have high estrogen levels. Usually, HT is stopped when a woman with POI reaches the age of natural menopause (around age 50).
If you cannot or do not want to take HT, you might benefit from non-hormonal treatments. In addition to medical treatment, you can lower your risk of osteoporosis and heart disease by eating a healthy diet and exercising regularly. |
<urn:uuid:4523276d-e7e3-4b12-8716-215c0878222b> | seed | organosulfur compound, also spelled organosulphur compound, also called organic sulfur compound, Encyclopædia Britannica, Inc.a subclass of organic substances that contain sulfur and that are known for their varied occurrence and unusual properties. They are found in diverse locations, including in interstellar space, inside hot acidic volcanoes, and deep within the oceans. Organosulfur compounds occur in the bodies of all living creatures in the form of certain essential amino acids (such as cysteine, cystine, and methionine, which are components of proteins), of the tripeptide glutathione, and of enzymes, coenzymes, vitamins, and hormones.
Typical organisms contain 2 percent sulfur dry weight. Coenzyme A (CoA), biotin, thiamin chloride (vitamin B1), α-lipoic acid, insulin, oxytocin, sulfated polysaccharides, and the nitrogen-fixing nitrogenase enzymes are but a few examples of important natural sulfur-containing compounds. Certain simple organosulfur compounds, such as thiols, are repugnant to humans and most higher animals even at extraordinarily low concentrations; they are used as defensive secretions by a variety of animal species and figure in unpleasant odours associated with polluted air and water, particularly that resulting from the use of sulfur-rich fossil fuels. However, related types of organosulfur compounds found in such foods as garlic, onion, chive, leek, broccoli, cabbage, radish, asparagus, mushroom, mustard, truffle, coffee, and pineapple are sources of olfactory and gustatory delight.
Mustard gas, or bis(β-chloroethyl) sulfide, (ClCH2CH2)2S, is a potent chemical warfare agent, whereas other sulfur compounds such as sulfanilamide (a sulfa drug), penicillin, and cephalosporin are valued antibiotics. Synthetic organosulfur compounds include polysulfones, inert polymers used in astronauts’ transparent face shields; polythiophenes, materials possessing the metal-like ability to conduct electricity; agricultural chemicals, insecticides, and organic solvents, such as dimethyl sulfoxide, CH3S(=O)CH3, and carbon disulfide, CS2; dyes; lubricating oil constituents; food additives; and substances used to make rayon. In chemical research, organosulfur compounds are valued reagents widely used for synthesizing new compounds. A global sulfur cycle exists that interconverts natural organosulfur compounds with either inorganic sulfide or sulfate ions. Sulfide or sulfate ions can also be formed in nature from elemental sulfur.
Differences between the chemistry of sulfur compounds and that of other common heteroatomic organic compounds (i.e., organic compounds containing elements other than carbon [C] and hydrogen [H], such as those of oxygen [O] and nitrogen [N]), are primarily due to the fact that sulfur is a member of the third period of elements, employing 3s, 3p, and sometimes 3d orbitals, which are significantly larger than the more compact 2s and 2p orbitals of second-period elements such as oxygen and nitrogen. The larger orbital size means that the outer valence electrons are more loosely held, being further removed from the influence of the positive nuclear charge. Such loosely held electrons are said to be more polarizable, allowing them to engage in bonding interactions with electrophilic partners more easily and earlier during the course of a reaction than in the case of lighter elements, where bonding interactions require close approach of partner atoms. In addition, in protic hydrogen-bonding solvents such as water and alcohols, sulfur is more weakly solvated than lighter heteroatoms. In these solvents, heavier heteroatoms such as sulfur show enhanced nucleophilicity compared with lighter heteroatoms because of their higher polarizability combined with decreased solvation (the solvation shell must be disrupted in reaching the transition state), despite the fact that stronger bonds are formed by the lighter heteroatoms. Thus, divalent sulfur compounds, such as thiols (containing an −SH group) and sulfides (containing an −S− group), readily bind to heavy metal ions such as silver (Ag), mercury (Hg), lead (Pb), and cadmium (Cd). Indeed, another name for thiol is mercaptan (from Latin mercurium captans, meaning “seizing mercury”), reflecting the use of thiols in treating mercury poisoning. Interactions between divalent sulfur and the metal ions iron (Fe), molybdenum (Mo), zinc (Zn), and copper (Cu) are crucial in metalloenzymes—for example, cytochrome C, in which the sulfur of methionine is coordinated to the iron in heme; the iron-sulfur proteins, in which cysteine sulfur is bound to iron; and molybdenum-containing enzymes, some of which involve dithiolate (two-sulfur) cofactors.
|R3S+||sulfonium salt||trimethylsulfonium salt|
|R2S+–CH2−||sulfonium ylide||dimethylsulfonium methylide|
|R3S+=O||oxosulfonium salt||trimethyloxosulfonium salt|
|R2S(O)+–CH2−||oxosulfonium ylide||dimethyloxosulfonium methylide|
|R4S=O||sulfurane oxide||tetramethylsulfurane oxide|
|R2C=S=O||thioketone S-oxide||thioacetone S-oxide (a sulfine)|
|R2C=SO2||thioketone S,S-dioxide||thioacetone S,S-dioxide (a sulfene)|
|RC(O)SR´||thioate ester||thioacetic acid methyl ester|
|RC(S)OR´||thionoate ester||thionoacetic acid methyl ester|
|RC(S)SR´||dithioate ester||dithioacetic acid methyl ester|
|RSOH||sulfenic acid||methanesulfenic acid|
|RSO2H||sulfinic acid||methanesulfinic acid|
|RSO3H||sulfonic acid||methanesulfonic acid|
|RSCl||sulfenyl chloride||methanesulfenyl chloride|
|RS(O)Cl||sulfinyl chloride||methanesulfinyl chloride|
|RSO2Cl||sulfonyl chloride||methanesulfonyl chloride|
|(RO)2S=O||sulfite ester||dimethyl sulfite|
|(RO)2SO2||sulfate ester||dimethyl sulfate|
It is useful to compare features of the compounds of sulfur (electron distribution 1s22s22p63s23p4) with those of oxygen, which lies directly above sulfur in the periodic table (electron distribution 1s22s22p4), and with those of the heavier member of the chalcogen family, selenium (electron distribution 1s22s22p63s23p64s23d104p4), which lies directly below sulfur. There are structural similarities, for example, between alcohols (R−OH), thiols (R−SH), and selenols (R−SeH), between hydroperoxides (R−OOH), sulfenic acids (R−SOH), and selenenic acids (R−SeOH), between ethers (R−O−R), sulfides (R−S−R), and selenides (R−Se−R), between ketones (R−C(=O)−R), thioketones (R−C(=S)−R), and selenoketones (R−C(=Se)−R), between peroxides (R−OO−R), disulfides (R−SS−R), and diselenides (R−SeSe−R), and between oxonium (R3O+), sulfonium (R3S+), and selenonium salts (R3Se+), where R represents a general carbon group—e.g., the methyl group, CH3, or the ethyl group, C2H5.
There are significant differences in the properties of these groups of related compounds. For example, thiols are somewhat stronger acids than the corresponding alcohols because the S−H bond is weaker than the O−H bond and because the larger sulfur atom better disperses the resulting negative charge as compared with oxygen. For the same reasons, selenols are even stronger acids than thiols. At the same time, SH hydrogen bonding is much weaker than OH hydrogen bonding, with the consequence that thiols are more volatile and have lower boiling points than the corresponding alcohols—for example, 6 °C (43 °F) for methanethiol compared with 66 °C (151 °F) for methanol. Compared with alcohols and ethers, low-molecular-weight thiols and selenols as well as sulfides and selenides have highly unpleasant and obnoxious odours, although the perception of the odour as unpleasant or pleasant can sometimes vary with the concentration of the particular compound. Disulfides and diselenides are far more stable than peroxides, and sulfonium and selenonium salts are much less reactive than oxonium salts; at the same time, simple thiocarbonyl (C=S) and selenocarbonyl (C=Se) compounds are much more reactive than simple carbonyl (C=O) compounds. In the case of the homologues of carbonyl compounds, the difference in reactivity is attributed to the poorer match in the size of the orbitals of the carbon and sulfur double bond (carbon 2p and sulfur 3p) or the carbon and selenium double bond (carbon 2p and selenium 4p) compared with the similar 2p orbitals used for the double bond between carbon and oxygen.
Both sulfur and selenium also have the ability to form compounds in which atoms of these elements have higher valences; these compounds have no counterpart in oxygen chemistry. In the case of sulfur, some examples are sulfoxides (R2S=O, typically written R2SO), sulfones (R2S(=O)2, typically written R2SO2), sulfonic acids (RSO3H), and oxosulfonium salts (R3S+=O). Analogs of the above sulfur compounds also exist for selenium. These higher-valence compounds of sulfur (or selenium) are stabilized through bonding involving 3d (or 4d) orbitals, not available to oxygen, as well as other factors associated with the larger size of sulfur and selenium as compared with oxygen. The longer, weaker bonds and higher degree of polarizability of selenium compared with sulfur lead to differences in properties and reactions of compounds of these two elements.
In addition to routine methods of analysis that can be used with all classes of organic compounds (see analysis), certain procedures reflect specific characteristics of sulfur. In a mass spectrometer, organosulfur compounds frequently produce strong molecular ions in which the charge is located predominantly on sulfur. The presence of sulfur is indicated by the occurrence of sulfur-34 (34S) isotope peaks, 4.4 percent of the abundance of 32S. Organically bound sulfur in the form of the natural isotope 33S can be directly examined by nuclear magnetic resonance (NMR) spectroscopy, although the low natural abundance (0.76 percent) and small magnetic and nuclear quadrupole moments make analysis more difficult than for protons (1H) or carbon-13 (13C). Levels of organosulfur compounds in crude petroleum as low as 10 parts per billion or less may have a detrimental effect on metallic catalysis or may cause unpleasant odours. These very low sulfur levels are detected using gas chromatographs with sulfur chemiluminescence or atomic-emission detectors with high sensitivity to detect sulfur compounds in the presence of other compounds.
Encyclopædia Britannica, Inc.Thiols, or sulfur analogs of alcohols, are sometimes referred to as mercaptans. In naming these compounds, the suffix -thiol is appended to the name of the appropriate hydrocarbon; e.g., CH3CH2CH2CH2SH is named butanethiol. The prefix mercapto- is placed before the name of a compound if the −SH group is to be named as a substituent, as in mercaptoacetic acid, HSCH2COOH. A third naming system uses the prefix thio- in front of the name of the corresponding oxygen compound, as, for example, thiophenol (C6H5SH), also called benzenethiol. A number of thiols are found in nature, such as cysteine and glutathione. In addition, 2-butenethiol is found in the defensive spray of the skunk, 2-propanethiol (allyl mercaptan) is found in the breath of people who have eaten garlic, and furfurylthiol contributes to the aroma of fresh coffee. Lower-molecular-weight thiols have strong, generally repugnant, skunky or rotten-egg-like odours, which can be detected by humans in air at very low concentrations—for example, 0.5 part per billion (0.5 × 10−9) in the case of ethanethiol or benzenethiol. For some thiols such as 4-mercapto-4-methylpentan-2-one (C6H12OS), which occurs in Sauvignon Blanc wines, the odour varies from pleasant at trace levels to unpleasant at higher levels. Because of their strong odours, thiols, such as 2-methyl-2-propanethiol, are used as odourants and warning agents for natural gas leaks. 2-Mercaptobenzothiazole is a thiol that finds use as an accelerator in the vulcanization of rubber (see below Disulfides and polysulfides and their oxidized products) and as a corrosion inhibitor, whereas 6-mercaptopurine has been employed in cancer therapy.
When long-chain alkanethiols are exposed to metallic gold, they bind to the gold surfaces, functioning as a type of “molecular alligator clip” and forming self-assembled monolayers (SAMs), of interest in the field of nanotechnology. SAMs can be formed on planar (two-dimensional) as well as particle (three-dimensional) surfaces. The ordering of long-chain alkanethiols is driven by the substantial gold-sulfur binding energy of approximately 160 kilojoules per mole (kJ/mol), as well as by the lateral van der Waals forces between the tethered alkyl chains (10–20 kJ/mol). Dipole interactions between polar end groups on alkyl chains can become important for functionalized thiols. Nanoparticles consisting of alkanethiolate monolayer-protected clusters (MPCs) in the form of ultrafine suspensions (colloids) of gold particles are 3-D analogs of the 2-D SAMs. The 2-D and 3-D SAMs can be prepared from ultraclean gold surfaces upon interaction with thiols (unprotected or S-acetyl or S-(N-ethyl)carbamoyl-protected) and disulfides, which are adsorbed about 40 percent more slowly than thiols. These sulfur compounds may have a wide range of alkane chain lengths (C3–C24) and diverse end-of-chain substituents, such as water-soluble groups (e.g., amino acids and polyethylene glycol), aromatic groups, silicon functionalities, fullerenes, porphyrins, ferrocene, crown ethers, and tetrathiofulvalenes, among others. There are many potential applications of SAMs and MPCs in fields ranging from materials science (e.g., nanoscale electronics, thin films, and electro-optics) to chemistry (e.g., catalysis, nanoreactors, and chemical sensors) to biology (e.g., membrane mimicry, biosensors, and drug delivery).
The interconversion of natural thiol pairs and disulfide groups constitutes a key oxidation-reduction reaction (or redox reaction) used in biochemistry; the redox potential, or tendency to attract electrons and thus become reduced, of the thiol-disulfide system is such that most disulfides are reducible by the biological reducing agent nicotinamide adenine dinucleotide (NADH), which has an optimum redox potential for this system. (See chemical reaction: Oxidation-reduction reactions for a discussion of redox reactions.) Proteins containing the mercapto (thiol) group from the component amino acid cysteine play key roles in many enzymatic processes. The cytoplasmic component glutathione (GSH), which also contains the mercapto group, is important in cellular oxidation and reduction, in nitric oxide (NO) transfer processes, and in protecting cells against damage from radicals. GSH reacts with NO to form the S-nitrosoglutathione (GSNO), which displays powerful antiplatelet aggregation properties and is therefore useful in coronary angioplasty operations. S-Nitrosothiols such as GSNO are found in vivo and play an important role as NO donors and in the transport and storage of NO, a small molecule that controls a remarkable range of physiological functions. In vivo release of NO from nitrosothiols may be catalyzed by copper ions. The selenium-containing enzyme glutathione peroxidase, which plays a crucial role in prevention of damage due to radicals derived from lipid hydroperoxides, is believed to function via formation of an intermediate with a sulfur-selenium bond that is significantly more reactive toward a thiol nucleophile than a sulfur-sulfur (disulfide) bond. Thus, the enzyme, which contains a selenocysteine (or selenol; RSeH) at its active site, is oxidized to a selenenic acid (RSeOH) in the course of reducing the hydroperoxide R′OOH. The selenenic acid is then converted by GSH to a selenyl sulfide (ESeSG), which reacts further with GSH to regenerate the enzyme RSeH. This reaction also gives glutathione disulfide (GSSG), which is reduced back to GSH, thereby continuing the cycle.
The sulfur in cysteine—and sulfur in other divalent sulfur compounds found in plants and animals—is ultimately derived from sulfate (−SO42−) in the soil, which is reduced in the cell. In plants and bacteria that utilize sulfate as a source of sulfur, the first step in the reduction process is the formation of adenosine phosphosulfate (APS), since direct reduction of sulfate itself is extremely difficult. The −OSO2O1− group of APS is reduced to a sulfite ion (SO32−) or a protein-bound sulfite, which is then further reduced to hydrogen sulfide (H2S), a direct precursor of cysteine and other natural organosulfur compounds.
In animals, sulfur-containing amino acids and other compounds are excreted as inorganic sulfate.
Thiols and thiol-derived compounds have several important roles in biology. As thiolate, RS−, they can function as bases, as ligands (e.g., in the binding of metals, as in hemoglobin), and as agents for the transfer of acetyl groups (e.g., in acetyl CoA) in lipid biosynthesis. In acetyl CoA, sulfur exists in the form of a derivative of a thiol, a thioester, CH3C(O)−SCoA; the (O) represents a (=O). The C(O)−S bond in this coenzyme is weaker than the corresponding C(O)−O bond in an ester. Furthermore, the thiolate anion (in this case, −SCoA) is a better leaving group than the analogous alkoxide anion (−OR) because in the larger sulfur atom the negative charge is spread over a larger volume of space. In general, the superior attacking-group (nucleophile) as well as leaving-group qualities of thiolate make it an excellent biocatalyst.
Low-molecular-weight thiols such as methanethiol (CH3SH) are found in crude petroleum. As such, they pose serious problems, associated not only with objectionable odours but also with their corrosive effect on equipment and their ability to poison (render nonfunctional) catalysts for air-pollution control or for other chemical processes. If they can be efficiently recovered from crude petroleum, these low-molecular-weight thiols can be used in the manufacture of agricultural chemicals and other chemical commodities.
Thiols were first prepared in the laboratory in 1834. They can be synthesized by several procedures, including reaction of an alkyl halide (RX, where X is a halogen) with the sulfur reagent thiourea, (NH2)2C=S, or with thiocyanate salts; reaction of organomagnesium (RMgX) or organolithium (RLiX) compounds with elemental sulfur; or addition of hydrogen sulfide or thioacetic acid (CH3C(O)SH) to alkenes (olefins). 1,2-Dithiols can be prepared by addition of thiocyanogen, (SCN)2, to olefins, followed by reduction. Aromatic thiols are frequently made from the reduction of arenesulfonyl chlorides (see below Other sulfinyl and sulfonyl compounds).
Similar to alcohols, thiols react with alkalies and other bases to form salts. In the presence of heavy metal salts (such as those of mercury, lead, silver, or copper), thiols form mercaptides (metal thiolates), which are insoluble in water but are frequently soluble in organic solvents. The formation of a black precipitate of lead mercaptide (or lead sulfide, PbS) upon the addition of lead salts to liquid petroleum products is the basis for the so-called doctor test for the detection of thiols.
Thiols form sulfides and thioesters in reactions analogous to those of alcohols. They react readily with aldehydes and ketones to form thioacetals and thioketals, respectively. Thioacetals and thioketals are more stable than the corresponding oxygen compounds and so are especially useful as protecting groups (temporarily suppressing the reactivity of the carbonyl group) as well as reagents in organic synthesis. Thiols are efficient radical scavengers (a radical X∙ abstracts a thiol hydrogen atom, giving a thiyl radical RS∙ and XH). The ability of thiols to serve as hydrogen atom donors makes them useful as radioprotective agents, especially since radiation can produce radicals; they are also useful as hydrogen atom donors in various other processes and synthetic reactions. Thiols add across to the multiple bond of unsaturated compounds, either under catalysis by light or acid or, in the case of unsaturated compounds activated by adjacent carbonyl groups, under catalysis by base. In all cases the products are sulfides.
Oxidation of thiols initially affords disulfides, which can also be formed by the combination of thiyl radicals. Sulfenic acids, R−SO−H, can be isolated as the first-formed oxidation product from sterically hindered thiols; these react further with thiols to form disulfides. There are a number of practical applications associated with the oxidation of thiols. Spills of obnoxious-smelling low-molecular-weight thiols are neutralized by oxidizing the thiols with sodium or calcium hypochlorite (bleach) solutions. Milder oxidants (e.g., 3 percent hydrogen peroxide, made alkaline with sodium bicarbonate, or 2 percent aqueous potassium iodate) have been used to deodorize pets that have encountered skunks. In petroleum refining, the process of “sweetening” involves oxidation of evil-smelling thiols in crude oil to more innocuous disulfides. Reaction of thiols (or disulfides) with chlorine yields sulfenyl chlorides (RSCl), which are useful reagents in synthesis reactions.
Encyclopædia Britannica, Inc.Sulfides, in which two organic groups are bonded to a sulfur atom (as in RSR′) are the sulfur analogs of ethers (ROR′). The organic groups, R and R′, may be both alkyl, both aryl, or one of each. If sulfur is simultaneously connected to different positions of the same carbon chain, a cyclic sulfide (a heterocycle) results. If no other functional group is present in the molecule, sulfides are named as such; e.g., ethyl methyl sulfide is CH3SC2H5. In molecules with other functional groups of higher priority, the sulfide group is designated by thio- (as in thiodiacetic acid, HO2CCH2SCH2CO2H) or by methylthio- (as in methylthioacetic acid, CH3SCH2CO2H). In saturated cyclic sulfides, the prefix thi- precedes the root associated with ring size; for example, thiirane, thietane, thiolane, and thiane for three-, four-, five-, and six-membered rings, respectively. Unsaturated cyclic sulfides, such as thiophene, which is very stable, are well known. Sulfides have low water solubility and are soluble in organic solvents. Similar to the thiols, lower-molecular-weight sulfides have strong, generally unpleasant odours. For example, allyl methyl sulfide is a major contributor to human “garlic breath.”
A variety of biologically important sulfides occur in nature. Acyclic examples include the essential amino acid methionine, which is involved in biological methyl transfer, and 2-phenylethyl methyl sulfide, C6H5CH2CH2SCH3, 5-methylthio-2,3-pentanedione, CH3C(O)C(O)CH2CH2SCH3, and di(3-methylbutyl)sulfide, ((CH3)2CHCH2CH2)2S, which are trail-marking secretions from the red fox, the striped hyena, and the polecat, respectively. Heterocyclic structures include, among others, the four-membered ring 2,2-dimethylthietane, from the mink; the five-membered rings from penicillin, biotin (involved in the biosynthesis of fatty acids and in carbon dioxide fixation), and thiamin (a coenzyme, as is biotin) and the terthienyl pesticide from marigold; and the six-membered ring 5-thio-d-mannose, a novel sugar having a sulfur atom in the ring instead of oxygen, isolated from an orange marine sponge, Clathria pyramida. In nature, sulfides can serve as ligands, as in cytochrome C, in which the sulfur of methionine is coordinated to the heme iron.
Most crude oils contain organosulfur compounds such as thiols, sulfides, and polysulfides, presumably formed from the reaction of hydrocarbons with elemental sulfur, in turn generated from microbial action on sulfate in rocks. As the oil ages, the thiols and sulfides are slowly converted into more stable compounds such as benzothiophene. Molybdenum-containing hydrodesulfurization catalysts are used in the removal of the undesirable sulfur compounds from petroleum, giving hydrocarbons and hydrogen sulfide as the final products. There is considerable interest in the use of monomeric and polymeric compounds made from heterocyclic sulfur compounds—such as thiophene, tetrathiafulvalene (TTF), and the bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) cation—as organic metals and superconductors (e.g., for use as switching elements and light-emitting diodes). Indeed, the 2000 Nobel Prize for Chemistry, awarded to American chemists Alan J. Heeger and Alan G. MacDiarmid and Japanese chemist Shirakawa Hideki, recognized the discovery of plastics that conduct electricity. Poly(phenylene sulfide) (PPS), a polymeric material derived from diphenyl sulfide, which has been known for more than 100 years, is used in electrical, electronic, and mechanical applications. Polythiophene conductors are of great interest for use in molecular electronic devices. Research has led to the preparation of macrocyclic α-conjugated oligothiophenes; for example, α-cyclothiophene, which has a perfect hexagonal “honeycomb” solid state structure.
A number of examples of syntheses of sulfides were described above as reactions of thiols. A unique synthesis of sulfides is illustrated by the reaction of ethylene with sulfur dichloride to form bis(β-chloroethyl) sulfide, known as sulfur mustard, or mustard gas, a blister-forming (vesicant) chemical warfare agent. This reaction has been applied to the synthesis of cyclic and bicyclic dichlorosulfides as well.
Like thiols, sulfides can form metal complexes, particularly in the case of cyclic polysulfides with crown etherlike structures, such as the hexathia-18-crown-6. Oxidation of sulfides yields sulfoxides or, under more vigorous conditions, sulfones; reaction with alkyl halides gives sulfonium salts; and reaction with halogen compounds produces halosulfonium salts. Halosulfonium ions and related species formed from sulfoxides are key intermediates in the synthesis of polysaccharides from 1-phenylthioglycosides, facilitating replacement of the phenylthio, PhS (or phenylsulfinyl, PhS(O)), group by a nucleophile from a second saccharide molecule, joining the saccharides in a process termed glycosylation. One-electron oxidation of sulfides gives radical cations, of importance in conducting materials; these radical cations can dimerize to give dithia dications, R2S+−S+R2, which can also be formed in reactions involving bis-sulfides, molecules with two spatially separated sulfide groups. With fluorinated reagents, diphenyl sulfide, (C6H5)2S, can be converted into the hexavalent sulfur compound tetrafluorodiphenylsulfur, (C6H5)2SF4. If one of the carbon groups, R, in a sulfide RSR′ is olefinic, aromatic, or acetylenic and the other group, R′, is a saturated carbon (e.g., methyl or ethyl), the bond to the saturated carbon can be cleaved with sodium or lithium metal in liquid ammonia—for example, RSR′ + Na/NΗ3→ RSNa + R′−H. Using Raney nickel (Ra-Ni; a type of active nickel), carbon-sulfur bonds in sulfides can be replaced by hydrogen—for example, RSR′ + Ra-Ni → R−H + R′−H. These reduction reactions are useful in synthesis or in determining the structure of an unknown organosulfur compound. Raney nickel desulfurization was a key step in first establishing the structure of penicillin. The high polarizability of sulfur stabilizes a negative charge on the carbon adjacent to divalent sulfur, as in RSCH2−(usually as α-lithium sulfides, RSCH2Li), which proves useful in organic synthesis through nucleophilic reaction with alkylating agents and carbonyl compounds.
Of particular value in this type of reaction is the 2-lithio derivative of the cyclic bis-sulfide 1,3-dithiane, widely used in the synthesis of ketones and aldehydes (the Corey-Seebach reaction, shown below). 1,3-Dithiane and other thioacetals can also be converted to olefins by the Takeda olefination reaction.
The cyclic sulfide thiophene undergoes reactions similar to those of benzene, although somewhat more easily.
Encyclopædia Britannica, Inc.A unique property of sulfur is the ability to form chains of sulfur atoms with organic groups at either end—e.g., RSnR′, where n can range from 2 to 20 or more. They are named by designating, in alphabetical order, the groups attached to sulfur, followed by the word sulfide, which is preceded by the prefix appropriate to the number of sulfur atoms, as in disulfide, trisulfide, tetrasulfide, and so forth or by use of dithio-, as in dithiodiacetic acid. Polysulfides are also named polysulfanes, with individual compounds being named trisulfane, tetrasulfane, and so on. A variety of disulfides occur in nature. The amino acid cystine, a disulfide, is an important component of many proteins; the sulfur-sulfur bond plays a key role in maintaining the molecules in shapes (so-called tertiary structures) essential for their biological activity. Interconversion of cysteine sulfhydryl (−SH) and cystine disulfide groups plays an important role in transport across cell membranes, in the immune process, and in blood clotting. The process of hair waving involves cleavage of the cystine disulfide link of keratine into the cysteine moiety, providing flexibility for the hair to assume the new wave or curl desired, followed by oxidative treatment to fix the hair in its new shape.
The coenzyme lipoic acid, a cyclic disulfide, is a growth factor—ubiquitously distributed in plants, animals, and microorganisms—and is used in photosynthesis and lipid and carbohydrate metabolism in plants and animals. It is involved in biological oxidations, where it oscillates between the oxidized cyclic form and the reduced acyclic dithiol form. Lipoic acid suffers from ring strain caused by repulsion of lone-pair electrons on adjacent sulfurs in the near planar ring, making it a better oxidizing agent than a six-membered cyclic disulfide, such as 1,2-dithiane, would be. At the same time, in the reduced dithiol form, the thiol groups are in sufficient proximity to facilitate reoxidation. Asparagusic acid (4-carboxy-1,2-dithiolane), found in asparagus roots, is considered to be a major factor in the natural resistance (i.e., survival in the soil) of this plant; 4-methylthio-1,2-dithiolane is a photosynthesis inhibitor from the stonewort. The characteristic flavour of the shiitake mushroom is due to the presence of the acyclic disulfide-sulfone CH3SO2CH2SCH2SCH2SSCH3 together with several cyclic polysulfides, including lenthionine; thiarubrine is a novel biologically active acetylenic cyclic disulfide found in plants related to marigolds. Dimethyl trisulfide (CH3SSSCH3), detectable at levels as low as 0.1 part per billion, is a key contributor to the flavour of beer, wine, whiskey, and various food products. It is also one of a number of organosulfur compounds present in coal.
When garlic cloves are distilled with water, garlic oil is isolated and is found to contain a mixture of compounds including diallyl disulfide, trisulfide, and polysulfides—e.g., (CH2=CHCH2)2Sn, where n = 2–8. None of these compounds occur naturally in garlic; rather, they are formed from the action of water and heat on allicin, a biologically active thiosulfinate, or disulfide S-oxide, CH2=CHCH2S(=O)SCH2CH=CH2, in turn formed enzymatically from sulfoxide precursors in the intact garlic bulb (see below Sulfoxides and sulfones: Reactions). Sulfurized olefins are used in extreme pressure lubrication, while a highly resistant sulfur cement and concrete can be prepared from cyclopentadiene Diels-Alder oligomers linked by polysulfide chains. Polysulfides with four or more sulfur atoms have a variety of useful properties and have been employed as industrial lubricants, sealants in the glass-insulation industry, and binders in solid propellants for rockets (e.g., Thiokol A, (CH2CH2S4)n). In the vulcanization of rubber, polyolefins are converted to an elastomeric substance with desirable mechanical properties by cross-linking the chains with two or more sulfur atoms.
Disulfides are generally prepared by oxidation of thiols, whereas polysulfides can be made by reaction of an excess of thiols with sulfur chlorides, SnCl2. Some cyclic disulfides and polysulfides can be prepared by reaction of elemental sulfur with unsaturated compounds; for example, the reaction of acetylene with sulfur yields a 1,2-dithiete, a four-membered ring compound with two sulfur atoms that exhibits aromatic stability similar to thiophenes. 1,2-Dithiins, six-membered ring disulfides found in thiarubrines, can be prepared by reaction of titanacyclopentadienes (formed in one step from acetylenes) with sulfur monochloride (S2Cl2) or thiocyanogen (SCN)2 and samarium iodide (SmI2).
Disulfides can be reduced to thiols both in the laboratory as well as in vivo (biologically). Biological reduction of thiols and the reverse process, oxidation of thiols to disulfides, are essential biochemical processes. Disulfides can be further oxidized to the S-oxides (thiosulfinates, RS(O)SR), the S,S-dioxides (thiosulfonates, RSO2SR), S,S′-disulfoxides (or α-disulfoxides, RS(O)S(O)R), and, ultimately, with cleavage of the sulfur-sulfur bond, to sulfonic acids, RSO3H. Polysulfides also undergo certain reactions of this kind. A number of the disulfide S-oxides are flavourants, formed on cutting plants of the Allium genus (onion and garlic) as well as cabbage, cauliflower, brussels sprouts, and so forth. With chlorine, disulfides give chlorinated cleavage products such as sulfenyl chlorides, RSCl, or, in the presence of water, RSO2Cl. The S−S bond can also be cleaved with alkyllithiums and other organometallic compounds to form sulfides.
Calichimicin (esperamicin) is a highly potent antitumour agent produced by bacteria of the Actinomycetales order and containing a pendant methyl trisulfide component (CH3SSS−). Acting much like a molecular “mouse trap,” cleavage of the sulfur-sulfur bond is thought to trigger a chain of events culminating in formation of a phenylene diradical, which removes hydrogen atoms from deoxyribonucleic acid (DNA). The initial sulfur-sulfur bond cleavage is favoured because this bond is significantly weaker in trisulfides than it is in disulfides.
Encyclopædia Britannica, Inc.The thiocarbonyl functional group (−C(=S)−), analogous to the carbonyl group, is found in thioaldehydes and thioketones, as well as in a variety of compounds with nitrogen or oxygen (or both) attached to the thiocarbonyl carbon (e.g., −XC(=S)Y−, where X and Y = N or O). These compounds are named by analogy with the corresponding oxygen compounds—e.g., thioacetone, CH3C(=S)CH3, or 2-propanethione. Many thiocarbonyl compounds tend to be deeply coloured and highly reactive, owing to the fact that the double bond (π bond) between carbon and sulfur uses orbitals of quite different sizes (2p on carbon and 3p on sulfur), which do not overlap well. The parent thiocarbonyl compound, thioformaldehyde (CH2=S), is extremely reactive and cannot be isolated. However, it is very stable in the gas phase in low concentrations and is formed when various small organosulfur compounds are heated to extremely high temperatures. Thioformaldehyde has been detected in interstellar space by radio astronomers. Carbon disulfide, S=C=S, is a common and important organic solvent and raw material containing a thiocarbonyl group; it is used in the manufacture of rayon. Isothiocyanates, R−N=C=S, have cumulated bonding similar to that in carbon disulfide. Allyl isothiocyanate, CH2=CHCH2N=C=S, gives horseradish its distinctive flavour; related compounds are found in mustard and radish. The dithiocarbamate thiuram, R2NC(S)SSC(S)NR2 (R = CH3), is used as an antioxidant and accelerator in rubber vulcanization and is also employed as an insect repellent and fungicide. The related compound disulfiram (Antabuse; R = CH2CH3) is used in treating alcoholism. A thioamide, ethionamide, is an important drug used in the treatment of tuberculosis, and other thioamides are used as peptide analogs and in peptide synthesis.
Thioketones are usually prepared through reaction of ketones with phosphorus sulfur reagents, such as Lawesson reagent, Ar2P2S4. Xanthates (from the Greek xanthos, meaning “yellow,” named for the colour of their copper salts), thiocarbonyl derivatives of carbonates, ROC(=S)OR, are prepared from alcohols and carbon disulfide. This reaction is used to produce a soluble form of cellulose that can be extruded into an acidic solution, which disrupts the xanthate group, regenerating the cellulose in the form of fibres (rayon) or films (cellophane). Thiourea, the diamide of thiocarbonic acid, is manufactured by heating ammonium thiocyanate, NH4SCN + heat → H2NC(=S)NH2. Thiourea can be used in syntheses of thiols that avoid formation of sulfide by-products. Divalent sulfur-containing derivatives of phosphoric acid, H3PO4, with P=S bonds have been used in pesticides (e.g., malathion and parathion), lubricant additives, and ore-flotation agents. They are generally synthesized from tetraphosphorus decasulfide (P4S10) or thiophosphoryl chloride (PSCl3).
Thioketones can be oxidized to give the corresponding thioketone S-oxides, also known as sulfines, such as thioacetone S-oxide, CH3C(=S=O)CH3. Thioformaldehyde readily trimerizes to 1,3,5-trithiane or polymerizes to poly(thioformaldehyde). The presence of a π bond in thioketones makes these compounds reactive in Diels-Alder reactions and related cycloaddition reactions. Similar to carbonyl compounds, thioketones can also undergo enolization (thioenolization), giving isomeric enethiols, which in some cases can be isolated. Thioenolization of thioacetone would give 2-propenethiol, CH3C(SH)=CH2. Thioketones reversibly add hydrogen sulfide to yield gem-dithiols (i.e., having both −SH groups on the same carbon)—for example, propane-2,2-dithiol, CH3C(SH)2CH3, in the case of thioacetone. It is probably the gem-dithiols rather than the thioketones themselves that are responsible for the extremely offensive smell associated with low-molecular-weight thioketones. Thionocarbonates of type ROC(S)OR′, derived from an alcohol ROH, are widely used in organic synthesis in a procedure that ultimately affords the deoxygenated product R−H (Barton-McCombie deoxygenation).
Encyclopædia Britannica, Inc.Two major groups of organosulfur compounds that have no counterparts among organic oxygen compounds are the sulfoxides and sulfones. If the bonding in these compounds is represented with doubly bonded structures—e.g., −S(=O)− for sulfoxide and −S(=O)2− for sulfone—the sulfur atoms “see” 10 and 12 valence electrons, respectively. This is more than the octet rule allows, but sulfur is not bound by the octet rule, because it can utilize 3d orbitals in its bonding, as would also be required in compounds such as sulfur hexafluoride (SF6). While there is some theoretical support for the expansion of the sulfur valence shell to accommodate more than eight electrons, the use of 3d orbitals in bonding schemes has been criticized because 3d orbitals are much higher in energy than the sulfur 3s and 3p orbitals. An alternative bonding model invokes polar bonding such as −S+(−O−)− for sulfoxide and −S2+(−O−)2− for sulfone. While it is clear that the polar resonance structures contribute to the overall bonding, it is probable that there is some contribution from sulfur 3d orbitals as well. It should be noted that the sulfoxide group also contains a lone pair of electrons on the sulfur atom, requiring that the sulfoxide group be nonplanar, similar to an amine, but quite different from the planar structure of a carbonyl group, −C(=O)−, to which a sulfoxide group is sometimes compared. An important consequence of the nonplanarity of the sulfoxide group is that sulfoxides of the type R(S=O)R′, where R and R′ are different, are chiral and can in fact be isolated in optically active form, with the sulfone group being tetrahedral. In contrast to amines but similar to phosphines, tricoordinate sulfur (trigonal pyramidal sulfur compounds with three ligands and a lone pair of electrons on sulfur—as found, for example, in sulfinyl chlorides, sulfite esters, sulfoxides, thiosulfinates, and sulfilimines) has a stable configuration, owing to longer bonds to sulfur (less crowding) and a greater amount of lone pair s-character (the percentage of s orbital in the total number of orbitals used in hybridization). Many optically active tricoordinate compounds occur in nature, and optically active sulfur compounds are widely used in the synthesis of other chiral compounds.
Sulfoxides are named by simply designating, in alphabetical order, the two organic groups attached to the −S(=O)− group, followed by the word sulfoxide (e.g., ethyl methyl sulfoxide, CH3S(O)C2H5), or by forming a prefix from the name of the simpler of the groups using the particle -sulfinyl- (e.g., 4-(methylsulfinyl)benzoic acid). The nomenclature of sulfones is similar to that of sulfoxides; the particle -sulfonyl- is used in complicated cases. Most sulfoxides are colourless liquids or solids with low melting points. The low-molecular-weight sulfoxide dimethyl sulfoxide (CH3S(=O)CH3, DMSO) is water soluble, exhibits low toxicity, and is an excellent solvent. It possesses the unusual ability to rapidly penetrate skin and can carry compounds through the skin in this way. It has some use in veterinary medicine, particularly in treating lameness in horses. Sulfones are usually colourless crystalline solids. Dimethyl sulfone is water soluble. The diaryl sulfones (p-H2NC6H4SO2C6H4NH2-p; e.g., dapsone) and related compounds have been used in the treatment of tuberculosis and leprosy. Polysulfone resins, which incorporate the −SO2C6H4− unit within a polymer, are used on a large scale for electrical and automotive parts and other applications requiring excellent thermal stability and resistance to oxidation.
Encyclopædia Britannica, Inc.Among compounds isolated from natural sources, S-alkyl cysteine S-oxides (such as S-1- and S-2-propenylcysteine S-oxides)—the precursors to the flavourants of plants of the genus Allium—were the first found to have optical activity at carbon as well as at another element (sulfur). A variety of other sulfoxides have since been isolated from natural sources, including sulforaphane (CH3S(O)(CH2)4NCS) from broccoli, reported to inhibit tumour growth, and zwiebelanes from onion extracts. DMSO is widely found at levels of three parts per million (ppm) or less and is a common component of natural waters, including seawater. Along with dimethyl sulfone, DMSO may be produced through algal metabolism. When found in rainwater, DMSO may result from oxidation of atmospheric dimethyl sulfide, (CH3)2S, which occurs as part of the natural transfer of sulfur of biological origin in the global sulfur cycle.
Sulfoxides are easily prepared by oxidation of sulfides with such reagents as sodium metaperiodate (NaIO4) or hydrogen peroxide (H2O2). Commercially, DMSO is made from air/nitric oxide-catalyzed oxidation of dimethyl sulfide, which in turn is a major by-product of the Kraft sulfate process for the manufacture of paper. More-vigorous oxidation of sulfides or sulfoxides—as, for example, with potassium permanganate, KMnO4—produces sulfones. Optically active sulfoxides can be prepared by oxidizing sulfides of type RSR′, where R ≠ R′, with optically active oxidants or microbiological oxidants. Alternatively, optically active sulfoxides can be prepared via reaction of optically active sulfinyl derivatives RS(=O)X, where X = O, N, or S, with reagents such as R′Li or R′MgBr. The solvent sulfolane (thiolane S,S-dioxide) is prepared by first reacting sulfur dioxide with butadiene to give sulfolene (a cyclic, unsaturated, five-membered ring sulfone), followed by hydrogenation to yield sulfolane.
Aromatic sulfones can also be made by the reaction of sulfonyl chlorides with aromatic hydrocarbons. Thiophene S-oxides and S,S-dioxides, formed by oxidation of thiophenes, are far more reactive than the parent thiophenes because of the loss of aromaticity resulting from replacement of one or both pairs of electrons on sulfur by oxygen.
Sulfoxides are easily reduced to sulfides with a variety of reducing agents such as lithium aluminum hydride. In contrast, removal of the sulfone oxygens is extremely difficult. The sulfinyl and sulfonyl groups resemble carbonyl groups in the acidifying effect on α-hydrogens (i.e., those hydrogens bonded to the carbon adjacent to the carbonyl or sulfonyl group). Thus, both DMSO and dimethyl sulfone (and related alkyl sulfoxides and sulfones) undergo loss of a proton to bases such as sodium hydride (NaH2), giving the corresponding salts—e.g., CH3S(O)CH2Na and CH3SO2CH2Na. These salts are useful as strong bases as well as reagents for organic synthesis. Sulfoxides undergo a variety of reactions, including both thermal- and enzyme-induced elimination of sulfenic acids; Pummerer rearrangement results in oxidation of the carbon atom adjacent to the sulfoxide group at the same time the sulfoxide is reduced to sulfide.
Ligand coupling reactions of sulfoxides, involving concerted intramolecular coupling of two groups bonded to sulfur, occur via a tetrasubstituted sulfurane intermediate with a trigonal pyramidal structure. Ortho-metallation of a chiral sulfoxide involves lithiation (replacement of an atom or group of atoms by lithium) of the aromatic ring ortho to the sulfoxide group, with coordination of lithium by sulfoxide oxygen. Subsequent reaction with aldehyde occurs in a manner minimizing steric hindrance.
DMSO finds considerable use in organic synthesis as a mild oxidant in a process termed Swern oxidation. Notable rearrangements of the sulfone group include the Ramberg-Bäcklund reaction and the Truce-Smiles rearrangement.
When a garlic clove is cut or crushed, S-2-propenylcysteine S-oxide (alliin) is transformed by the enzyme alliinase into the intermediate compound 2-propenesulfenic acid, CH2=CHCH2S−O−H, which immediately condenses to give the antibiotic substance allicin (allyl 2-propenethiosulfinate, formed at a level of roughly 0.4 percent of the weight of fresh cloves), a sulfinyl compound known as a thiosulfinate. Allicin is the principal flavourant of garlic and has antimicrobial, anticandidal (antiyeast), and antifungal properties; it also inhibits lipid synthesis in vitro. Allicin can be transformed into an unsaturated sulfoxide disulfide called ajoene, which has anticlotting (antithrombotic) properties. When an onion bulb is cut or crushed, an odourless substance in the bulb, S-1-propenylcysteine S-oxide, is similarly transformed into 1-propenesulfenic acid, CH3CH=CH−S−O−H, which rearranges to (Z)-propanethial S-oxide, CH3CH2CH=S+O−, the so-called lacrimatory factor, or tear-inducing substance, of the onion.
Encyclopædia Britannica, Inc.In sulfoxides, R−S(=O)−R′, and sulfones, R−S(=O)2−R′, groups R and R′ both contain a carbon atom bonded to sulfur. A variety of other organosulfur compounds are known of types R−S(=O)−X, Y−S(=O)−X, R−S(=O)2−X, and Y−S(=O)2−X, in which X and Y are elements other than carbon—e.g., oxygen, nitrogen, or a halogen. Three types of organosulfur oxyacids are possible: sulfenic acids, RSOH; sulfinic acids, RS(O)OH; and sulfonic acids, RSO2OH. These compounds are named by attaching the name of the alkane, arene, and so on, to the name for the acid, as in trichloromethanesulfenic acid, ethanesulfinic acid, and p-toluenesulfonic acid. The sulfonic acids are very strong—comparable to hydrochloric acid and other mineral acids—and are the most common of the sulfur-containing acids. The colourless and odourless sulfonic acids and their salts are water soluble. Sulfonic acid salts, particularly those of linear alkylbenzenesulfonates, are very useful and widely used as detergents and synthetic surfactants. Sulfonic acid groups can greatly enhance the water solubility of compounds, as seen with the sulfonic acid derivative of triphenyl phosphine (TPPTS), P(C6H4-m-SO3Na)3. Metal complexes of this compound are used as homogeneous catalysts for the syntheses of organic compounds in two-phase systems (e.g., in a mixture of water and an organic solvent) in industry and the laboratory. A few sulfonic acids occur naturally—for example, the essential nutrient taurine (2-aminoethanesulfonic acid; NH2CH2CH2SO3H), the echinosulfonic acids A–C, and the sulfobacins and other sulfonolipids. Sulfinic acids are weaker (having a pKa of roughly 2.2) and less stable than sulfonic acids. Sulfenic acids and their salts are unstable compounds, are weaker (pKa ≈ 5) than sulfinic acids, and are rarely isolated. Sulfenic acids containing one or three carbon atoms are key intermediates formed when onion, garlic, and related plants are cut or crushed (see above Sulfoxides and sulfones: Reactions).
Aromatic sulfonic acids and sulfonyl chlorides can be prepared by sulfonation of benzene derivatives with fuming sulfuric acid and chlorosulfonic acid, ClSO3H, respectively, while aliphatic sulfonic acids are prepared by vigorous oxidation of thiols or by reaction of amine sulfur trioxide complexes (e.g., Me3NSO3) with organolithium compounds. Trifluoromethanesulfonic acid (triflic acid; CF3SO3H), one of the strongest known organic acids, is manufactured by electrochemical fluorination of methanesulfonyl chloride or fluoride and is used as a polymerization catalyst, in fuel cells, in gasoline production, and in synthesis of organic and organometallic compounds. Reaction of sulfonyl chlorides with amino compounds, R′NH2, gives sulfonamides and related compounds, RSO2NHR′, whereas reaction of alcohols in the presence of tertiary amines yields sulfonates, RSO2OR′.
Carbanions attack sulfonyl chlorides at chlorine rather than sulfur, forming carbon-chlorine rather than carbon-sulfur bonds. Attack at sulfur can be realized by substituting sulfonyl fluorides, RSO2F, for sulfonyl chlorides. Aromatic sulfonyl chlorides can be reduced to aromatic thiols such as thiophenol with zinc metal-hydrochloric acid (Zn/HCl). Sulfinyl chlorides can be made by treating disulfides with chlorine in the presence of acetic anhydride. Sulfinyl chlorides react with amines and alcohols to yield sulfinamides (RS(O)NR′2) and sulfinates (RS(O)OR′), respectively. As previously noted (see above Disulfides and polysulfides and their oxidized products: Reactions), sulfenyl chlorides can be prepared by reaction of disulfides with equimolar quantities of chlorine. Sulfenyl chlorides readily add to olefins to produce chlorine-containing sulfides and react with amines to form sulfenamides, RSNR′2.
Sulfonylureas, RSO2NHC(O)NRR′, which are widely used herbicides, inhibit acetolactic synthase, a key plant enzyme. Anticlotting medical plastics have been prepared containing sulfonated polymers that bind heparin, a natural polysulfate. Sulfonamides, RSO2NH2, played an important role in the development of certain medicines. Sulfanilamide, p-aminobenzenesulfonamide, a compound used in the manufacture of azo dyes, was found to inhibit the growth of bacteria. This discovery led to the development of sulfa drugs, which still find some use today in the treatment of infections, although they have been largely replaced by newer antibiotics, to which bacteria are less resistant. Other sulfonamides include sildenafil (Viagra), a popular drug for the treatment of erectile dysfunction; piroxicam (Feldene), a cyclic sulfonamide used to treat arthritis; and acetazolamide (Diamox), a diuretic used in the treatment of glaucoma.
Esters of sulfuric acid—such as dimethyl sulfate, MeOSO2OMe, and diethyl sulfate, EtOSO2OEt, made from the alcohols methanol and ethanol, respectively, as well as sulfur trioxide/sulfuric acid—are important industrial chemicals used to introduce methyl (Me) and ethyl (Et) groups into organic molecules. Both dimethyl and diethyl sulfate are highly toxic. Esters of sulfurous acid known as dialkyl sulfites—dimethyl sulfite, MeOS(O)OMe, for example—can be made from alcohols and thionyl chloride: 2MeOH + Cl2S=O → MeOS(=O)OMe. Cyclic sulfite esters, made in a similar manner from 1,2-diols (1,2-dialcohols), and their oxidation products, cyclic sulfate esters, find considerable use in organic synthesis.
Optically active unsymmetrically substituted cyclic sulfites are especially useful in the synthesis of other optically active compounds.
Sulfides react with alkyl halides to give trivalent sulfonium salts, as in the case of trimethyl sulfonium bromide, (CH3)3S+Br−, formed from dimethyl sulfide and methyl bromide. The sulfonium salts are named by putting the names of the several alkyl groups before “sulfonium halide.” Similarly, sulfoxides can be converted into the corresponding oxosulfonium salts, as in the case of trimethyl oxosulfonium chloride, [(CH3)3S=O]+Cl−, converted from dimethyl sulfoxide and methyl chloride. Like sulfoxides, sulfonium and oxosulfonium salts are chiral and can be isolated in optically active form if the attached carbon groups are all different, as in RR′R″S+ and RR′R″S(=O)+. The first known optically active sulfur compounds were sulfonium salts, prepared in 1900. A number of sulfonium salts occur in nature; some examples include S-adenosyl methionine, a key biological source of the methyl group; thetin or 3-dimethylsulfonium propanoate, (CH3)2S+CH2CH2CO2−; and certain (2-hydroxyethyl)dimethylsulfoxonium salts, (CH3)2S+(O)CH2CH2OH. The latter two compounds occur in marine organisms. Thetin is an example of a zwitterion, a compound that is an internal ion pair; in the name of this compound, “dimethylsulfonium” precedes the name of the root compound. In the above examples of sulfonium salts, sulfur is bonded to three carbon groups, but sulfonium salts are known in which one or more of the carbon groups are replaced by other elements such as oxygen, nitrogen, sulfur, or a halogen.
Nucleophilic attack at the carbon bonded to sulfonium sulfur forms the basis of biological methylations, as illustrated by the reaction of S-adenosylmethionine.
Sulfonium and oxosulfonium salts react with bases, each losing a proton to give zwitterions of a special type, with the negative charge on the carbon adjacent to the positively charged sulfonium sulfur. These compounds are called sulfonium and oxosulfonium ylides, respectively—or, more broadly, sulfur ylides, by analogy with phosphorus ylides employed in the Wittig reaction. The structures of sulfonium ylides and oxosulfonium ylides are analogous to those of sulfoxides and sulfones, respectively. Stabilization of the negative charge on carbon is primarily due to the high polarizability of sulfur. While phosphorus ylides react with aldehydes and ketones to give olefins, sulfur ylides instead give epoxides (oxiranes). This is an important reaction in organic synthesis. If sulfur ylides derived from optically active sulfonium and oxosulfonium salt precursors are used, then optically active ylides can be prepared and these can be used in asymmetric syntheses of chiral epoxides and other products. Sulfonium and aminosulfoxonium ylides have also been used to synthesize “designer” polymers (e.g., polymers containing various groups not obtainable through conventional polymerization). Exposure of triaryl sulfonium salts to ultraviolet light releases protons. This process of photogeneration of acid has important applications.
In organosulfur compounds of type SR4 and SR6, analogous to the well-known fluorosulfur compounds SF4 and SF6, the valence of sulfur has been expanded beyond the normal octet to a dectet or dodecet, respectively. Pentacoordinate compounds SR4, called σ-sulfuranes, typically have four ligands and one lone pair of electrons and are classified as (10-S-4), in which, according to the Martin nomenclature scheme, the number preceding the central atom S refers to the total number of electrons shared by S, and the number following S, the number of ligands. These compounds adopt a trigonal bipyramidal structure in which the lone pair always occupies an equatorial position. (For a discussion of molecular shapes, see chemical bonding: Bonds between atoms.)
Among the four ligands, the two that are most electronegative take the apical positions (a), whereas the less-electronegative groups occupy the remaining two equatorial positions (e). The central sulfur in σ-sulfuranes is described as being part of a three-centre, four-electron bond. A related type of compound is the sulfurane S-oxide, classified as (10-S-5), formed by oxidation of a sulfurane. Hexacoordinate compounds SR6, with six ligands, called persulfuranes, have a square bipyramidal structure and are classified as (12-S-6). The σ-sulfuranes, sulfurane S-oxides, and persulfuranes are termed hypervalent compounds because their valences are expanded beyond eight. Because of this fact, these types of compounds are relatively unstable, with the central atom seeking to return to the octet state by extruding one or more ligands. For example, the σ-sulfurane (C6F5)4S, named tetrakis-(pentafluorophenyl)sulfurane, prepared at temperatures below 0 °C (32 °F), decomposes to C6F5C6F5 and C6F5SC6F5 upon warming. On the other hand, if protected from moisture, acyclic and cyclic dialkyloxysulfuranes of type R2(R′O)2S are stable at room temperature and find utility as reagents in organic synthesis. |
<urn:uuid:816fc151-3d37-4edc-87b0-e964dab664c9> | seed | On March 13, 1996, a gunman shot and killed sixteen kindergartners and one adult at a primary school in Dunblane, Scotland. Other children who witnessed the massacre experienced post-traumatic stress disorder (PTSD), an anxiety disorder that persists for months or even years after a traumatic event or series of events. Likewise, many children who survived events such as 9/11 bereavement or the Indian Ocean tsunami also developed the symptoms of PTSD. Yet a significant subset did not. Some research even suggests that resilience is less a rare exception than an “especially effective form of normal adaptation” – what one researcher termed “ordinary magic” (1, 2, 3). What protective factors – environmental, cognitive, and neurophysiological – serve to enhance such resilience? And what implications does such a multifactorial analysis have for resilience-promoting interventions and treatment?
What is PTSD?
Post-traumatic stress disorder (PTSD) is classified as an anxiety disorder, but unlike other anxiety disorders, does not have an element of irrationality. It occurs after a traumatic event, which the DSM-IV-TR defines as involving “actual or threatened death, serious injury or the threat to self or others” (APA, 2000) (Appendix 1). These traumas can be acute – one-off, unique and un-anticipated events such as 9/11, the Virginia Tech school shooting, or house fires. Or they can be chronic – involving continued exposure to horrific events such as chronic child abuse. In children, reactions to trauma include intense fear, helplessness, horror, agitation or disorganised behaviour; they may re-enact the traumatic event or have nightmares about it, for example.
PTSD has three symptom clusters: re-experiencing, avoidance and increased arousal (4). Children may re-experience the event by participating in repetitive play that revisits aspects of the trauma; they may have intrusive, distressing recollections of the event that are triggered by traumatic reminders – for instance, a child who survived the Indian Ocean tsunami may see a film about the sea and shriek in terror. Young children might also have nightmares as a result of the traumatic event without any recognisable trauma content.
In addition, children may avoid stimuli associated with the traumatic event, choosing not to talk about it. Avoidance may also be expressed as numbing – for example, the child who has lived through a serious car accident may feel detached from her friends and cease to enjoy playing with them. Finally, the third symptom cluster involves heightened physical and emotional arousal. The PTSD sufferer may be unable to sleep, have difficulty concentrating on his schoolwork, or be unusually angry or irritable. Thus PTSD in children must be distinguished from other anxiety or mood disorders, and clinicians should note that PTSD symptoms may manifest differently depending on a child’s age and developmental stage.
Vulnerabilities, Risks and Protective Factors in PTSD
According to the diathesis-stress model of psychopathology, individuals with certain genetic vulnerabilities are more susceptible to developing psychopathology when they are exposed to environmental stresses. Some biological vulnerabilities, such as an overactive hypothalamic-pituitary-adrenal (HPA) axis, translate into cognitive or behavioural vulnerabilities like hypervigilance or a tendency to dissociate – to ‘split off’ emotionally – when faced with trauma. However, no single factor, whether biological, psychological or environmental, is necessary and sufficient for an individual to develop PTSD (2, 5, 6).
In addition, it may be worthwhile to include protective factors (that increase resilience) in a model of psychopathology. Hoge et al. (5) believe that resilience-enhancing factors are more than the inverse of vulnerabilities – for example, a small hippocampus may be a vulnerability to PTSD, but it does not logically follow that having a normal-sized hippocampus is protection from the disorder. Rather, resilience-enhancing factors are processes and mechanisms that offer protection (5). The effects of such protective factors are often tangible only when they interact with other stresses – for instance, an inner-city child of divorced parents who has an adaptive coping strategy may excel in school and stand out amongst her peers. This section of the paper will examine vulnerabilities, risks and protective factors from three standpoints: biological, psychological and environmental.
One symptom of PTSD is the tendency to re-experience the trauma in flashbacks or nightmares. In order for re-experiencing to occur, the trauma must be coded into an individual’s emotional memory. Researchers thus suggested that people with higher levels of chemicals such as cortisol that modulated memory formation would be more prone to PTSD (5). Conversely, those with higher levels of DHEAS (dehydroepiandrosterone), which has an antagonistic relationship with cortisol, are less susceptible to stress (5).
Besides such biochemical vulnerabilities and protective factors, genetics also plays a part in susceptibility to PTSD. In one study, maltreated boys with a long version of the gene encoding monoamine oxidase A (MAOA) were less likely to commit violent crimes and score high on tests of aggression, while those with a short version of the gene were much more likely to do so (7). And in twin studies, monozygotic twins of subjects with anxiety disorders were more likely to have symptoms of anxiety (8). Such findings about the biochemical and genetic factors in PTSD have important implications about the type and timing of drug therapy for the disorder.
Finally, neurophysiology can increase or decrease susceptibility to PTSD. Brain areas such as the anterior cingulate, which is concerned with emotion processing and working memory, and the dorsolateral prefrontal area, which modulates cognitive control and helps inhibit emotional arousal, can influence the cognitive and behavioural components of a child’s response to stress (6). Similarly, a smaller-than-average hippocampus and an overactivated HPA axis may be vulnerabilities to PTSD (9) as the hippocampus is involved in the formation of conditioned fears, and a smaller hippocampus may lead to poorer regulation of the HPA axis (10).
However, this research faces some limitations. Something that looks like a vulnerability may in fact be a consequence of PTSD or vice versa, depending on the perspective from which the study is conducted. For example, a smaller-than-average hippocampus has been implicated as a potential vulnerability to PTSD and other anxiety disorders (4, 10), but also as a consequence of trauma (11). Ultimately, research on the relationship between PTSD and hippocampal size was inconclusive (12, 13). Likewise with the child’s intelligence quotient (IQ) – it is commonly believed that low IQ is another potential vulnerability to PTSD, but at the same time, the expression of PTSD symptoms may have an adverse effect on IQ test scores. (In any case, IQ is only a reflection of a child’s cognitive potential in areas such as executive function.) In sum, there is a chicken-and-egg problem – causality is difficult to determine for many biological and psychological aspects of PTSD.
Young children with PTSD may be susceptible to cognitive distortions that heighten their distress, such as believing they could have prevented the trauma. Similarly, a lower IQ may be a cognitive vulnerability, as children with a lower IQ may be more prone to such cognitive distortions and misattributions. (However, Wenar and Kerig (4) also indicate that “in order for an event to be traumatic, it must be perceived as such”; one might expect greater cognitive ability – the capacity to grasp the enormity of trauma – to be maladaptive in this case.) Likewise, poorer emotional adjustment – children who are unable to self-soothe and tend to blame themselves are more likely to have severe post-traumatic reactions (4). In addition, dissociation during trauma may also predict later PTSD symptoms (Berg et al., 2005, cited in 5).
More research has been done on the psychosocial aspects of resilience than the biological ones. Some psychological resiliency factors are associated with temperament – that is, children with a sunny disposition and secure attachment to their caregivers may be less likely to develop PTSD to begin with. (Securely-attached toddlers are willing to explore and engage with strangers in the presence of their caregivers, become distressed when caregivers leave and are soothed when caregivers return.) Alternatively, children with these characteristics can attract and take better advantage of social support networks, drawing empathy from family and community members.
Perhaps the protective psychological factors most relevant to PTSD intervention are the affective, cognitive and behavioural ones. A high level of executive function is important for inhibiting emotional arousal and regulating behaviour, which may mitigate the child’s response to trauma (6). During or after trauma, a child with a sense of hopefulness (the notion that “things will get better”) and a tendency for positive self-talk is likely to function better than a child without such characteristics (14, 15), as these cognitions may mitigate the perceived severity of trauma. Finally, a child who has a locus of self-control (the belief that one can shape one’s life) and who is competent in various tasks (arts, sports etc.) is less likely to succumb to “learned helplessness” and is more able to cope with stress (5). All these protective factors have implications for cognitive-behavioural therapy.
Arguably, environmental risk factors are the most significant predictors of PTSD. In one longitudinal study, children in high-risk environments had much higher rates of psychopathology than children in low-risk environments, even when individual resilience factors such as social-emotional competence and intelligence were taken into account – that is, low-resilience children in low-risk environments did better later in life than high-resilience children in high-risk environments (16). Consequently, even though social support networks can be enhanced or mitigated by individual characteristics (5), parental and social support is the most significant risk factor and perhaps the most important in PTSD interventions. Environmental risk factors besides parental support include a high incidence of traumatic events, chronic rather than acute trauma, and trauma that could conceivably be repeated, rather than a fluke event such as a car crash (9).
Conversely, while it is clear that environmental factors such as family cohesion, socioeconomic status and lower levels of life stress can be protective, some researchers believe it is “individuals’ contribution to these factors that confers their status as characteristics of resilience” (5). Still, the presence of positive environmental factors like family cohesion and support networks can help moderate PTSD in survivors. For instance, Hyman et al. (17) found that different levels (and perceptions) of social support had different effects on PTSD outcomes in survivors of childhood sexual abuse. Four types of social support were examined: appraisal support (advice in coping with problems), self-esteem support (increasing the individual’s self-percept), tangible support (availability of material resources) and belonging support (being part of a social group). Self-esteem support and appraisal support were ultimately most effective in reducing PTSD symptoms.
Implications for intervention
Given what we know about resilience factors in PTSD, how can we use this understanding to treat children with the disorder or to develop preventive interventions? Biochemical vulnerabilities and protective factors are useful for pharmaceutical research on drugs to treat PTSD, or to be administered as soon as possible after trauma and before the onset of PTSD. For instance, glucocorticoids administered after trauma may interfere with the retrieval of traumatic memories, while emotional arousal can be blocked with a beta-blocking (beta-adrenergic receptor antagonist) drug known as propanolol (Roozendaal, 2003 and Cahill et al., 1994, cited in 5). In addition, there may be critical sensitive periods during which drugs can affect processes of neural plasticity (such as the formation of traumatic memories), and more research should be done on this.
Cognitive-behavioural therapy is perhaps one of the most commonly used forms of treatment for PTSD, and such therapy should be tailored to a child’s developmental stage. Also, some types of therapy may be indicated for different symptoms of PTSD – Mancini & Bonanno (15) suggest that adult grief therapy focusing on insight, for example, may be most recommended for problems of internalisation such as self-blame, hopelessness and sadness, and skill-focused interventions are more suitable for externalising problems. This may extrapolate well to child PTSD, but again, more research needs to be done.
Stallard (18) did a review of CBT interventions in children with sexual-abuse-related PTSD. These interventions focused on various aspects of PTSD: decreasing sexualised (re-enacting) behaviour, helping children communicate about their abuse (decreasing avoidance), and revising abuse-related cognitions like self-blame, stigmatisation and powerlessness. While each intervention was itself effective, the relative effectiveness of each type of CBT intervention still needs to be assessed.
Post-trauma therapies seem successful in treating children, but pre-emptive interventions can help improve the resilience of children at risk for PTSD. One form of resilience-enhancing intervention involves developing competencies and empowering children. Researchers conducted a study of structured activities in Palestinian children living in war-torn areas of Gaza and the West Bank. These included activities like sports and arts, and were aimed at developing skills and competencies to help children feel successful. It was found that the intervention improved children’s internalising and externalising problem scores, but did not increase children’s hopefulness (though hopefulness scores did not decline – still a positive sign in an environment where war was ongoing) (14).
Another type of resilience-promoting intervention focuses on improving executive function (EF) in school-aged children (6), based on the premise that executive function is important for appraising a traumatic event and its emotional meaning, regulating emotions to solve problems and gather more information, and responding behaviourally to a traumatic event. The intervention improved children’s inhibitory control and verbal fluency in comparison to a control group and decreased children’s internalising and externalising problems. However, the impact of improved EF on PTSD may be difficult to measure without a corresponding traumatic event or a high-risk environment. One might expect such resilience-enhancing pre-emptive interventions to also be of use in treating childhood PTSD. Finally, given that environment and social support networks may be the most important factors in preventing or alleviating PTSD, one should consider family therapy in the treatment of PTSD, establishing therapeutic alliances where possible. Forms of social and family support should focus on improving individuals’ self-percepts, helping people ‘belong’ within the family or community, and offering guidance in coping with problems.
An ounce of prevention is worth a pound of cure; naturally, it is preferable to conduct pre-emptive interventions to increase the resilience of children in high-risk populations. These interventions can be informed by our increasing knowledge about the physiological and psychological factors that improve resilience in children. At the same time, it should be kept in mind that resilience does not equal invulnerability to trauma – that no matter how resilient a child is, environmental risks still play a significant part in his or her development. However, our knowledge of resilience, coupled with an understanding of developmental psychology, can and should also inform the treatment of children with PTSD – such as child survivors caught in the Indian Ocean tsunami in 2004, which was a severe and horrifying fluke event with no known risk factors to predict it.
Appendix 1: DSM-IV-TR diagnostic criteria for 309.81 Posttraumatic Stress Disorder
A. The person has been exposed to a traumatic event in which both of the following were present:
(1) the person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others
(2) the person’s response involved intense fear, helplessness, or horror. Note: In children, this may be expressed instead by disorganized or agitated behavior
B. The traumatic event is persistently reexperienced in one (or more) of the following ways:
(1) recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions. Note: In young children, repetitive play may occur in which themes or aspects of the trauma are expressed.
(2) recurrent distressing dreams of the event. Note: In children, there may be frightening dreams without recognizable content.
(3) acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and dissociative flashback episodes, including those that occur on awakening or when intoxicated). Note: In young children, trauma-specific reenactment may occur.
(4) intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event
(5) physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event
C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by three (or more) of the following:
(1) efforts to avoid thoughts, feelings, or conversations associated with the trauma
(2) efforts to avoid activities, places, or people that arouse recollections of the trauma
(3) inability to recall an important aspect of the trauma
(4) markedly diminished interest or participation in significant activities
(5) feeling of detachment or estrangement from others
(6) restricted range of affect (e.g., unable to have loving feelings)
(7) sense of a foreshortened future (e.g., does not expect to have a career, marriage, children, or a normal life span)
D. Persistent symptoms of increased arousal (not present before the trauma), as indicated by two (or more) of the following:
(1) difficulty falling or staying asleep
(2) irritability or outbursts of anger
(3) difficulty concentrating
(5) exaggerated startle response
E. Duration of the disturbance (symptoms in Criteria B, C, and D) is more than 1 month.
F. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
Acute: if duration of symptoms is less than 3 months
Chronic: if duration of symptoms is 3 months or more
With Delayed Onset: if onset of symptoms is at least 6 months after the stressor
(DSM-IV-TR, American Psychiatric Association 2000)
1. A.S. Masten, Am. Psychol. 56: 227 (2001).
2. “Resilience.” Harvard Mental Health Letter [Cambridge, MA]. (December 2006).
3. W.E. Copeland, G. Keeler, A. Angold, and E.J. Costello, Arch Gen Psychiatry 64, 577 (2007).
4. C. Wenar and P. Kerig, Developmental Psychopathology (5th Edition), McGraw-Hill: Boston, 2006.
5. E.A. Hoge, E.D. Austin, and M.H. Pollack, Depression and Anxiety 24, 139 (2006).
6. M.T. Greenberg, Ann. N.Y Acad. Sci. 1094, 139 (2006).
7. D. Cicchetti and J.A. Blender, Ann. N.Y. Acad. Sci. 1094, 248 (2006).
8. S. Taylor, D.S. Thordarson, K.L. Jang, and G.J.G Asmundson, World Psychiatry 5(1), 47 (2006).
9. J. Scheiner, in-class lecture: Psychology 52.2, Dartmouth College, May 9 2007
10. M.W. Gilbertson, M.E. Shenton, A. Ciszewski, K. Kasai, N.B. Lasko, S.P. Orr, and R.K. Pitman, Nature Neuroscience 5, 1242 (2002).
11. L.M Shin, S.L. Rauch, and R.K. Pitman, Annals of the New York Academy of Sciences 1071, 67 (2006).
12. C.L Pederson, S.H. Maurer, P.L. Kaminski, K.A. Zander, C.M Peters, L.A. Stokes-Crowe, and R.E. Osborn, Journal of Traumatic Stress 17(1), 37 (2004).
13. L.A. Tupler and M.D. De Bellis, Biological Psychiatry 59(5), 523 (2005).
14. M. Loughry, A. Ager, E. Flouri, V. Khamis, A.H. Afana, and S. Qouta, Journal of Child Psychology and Psychiatry 47(12), 1211 (2006).
15. A.D. Mancini and G.A. Bonanno, Journal of Clinical Psychology 62(8), 971 (2006).
16. A.J. Sameroff and K.L. Rosenblum, Annals of the New York Academy of Sciences 1094(1), 116 (2006).
17. S.M. Hyman, S.N. Gold, and M.A. Cott, Journal of Family Violence 18(5), 295 (2003).
18. P. Stallard, Clinical Psychology Review, 26(7), 895 (2006).
Diagrams for this article were created in-house by Tim Shen ’08. |
<urn:uuid:7d96e476-34cc-4c54-8de0-2cb746aec805> | seed | Toggle: English / Spanish
Neurosyphilis is an infection of the brain or spinal cord. It usually occurs in persons who have had untreated syphilis for many years.
Causes, incidence, and risk factors
Neurosyphilis is caused by Treponema pallidum, the bacteria that cause syphilis. It usually occurs about 10 - 20 years after a person is first infected with syphilis. Not everyone who has syphilis will develop this complication.
There are four different forms of neurosyphilis:
Asymptomatic neurosyphilis occurs before symptomatic syphilis.
Note: There may be no symptoms.
Signs and tests
Blood tests can be done to detect substances produced by the bacteria that cause syphilis. The oldest test is the VDRL test.
Other tests include:
In neurosyphilis, it is important to test the spinal fluid for signs of syphilis.
Tests to look for problems with the nervous system may include:
Penicillin is used to treat neurosyphilis. The medicine may be given in various ways.
It may be injected into a vein several times a day for 10 - 14 days.
You may take probenecid by mouth 4 times a day, combined with daily muscle injections -- both for 10 - 14 days.
You must have follow-up blood tests at 3, 6, 12, 24, and 36 months to make sure the infection is gone. You will need follow-up lumbar punctures for CSF fluid analysis every 6 months. If you have HIV or another medical condition, your follow-up schedule may be different.
For information on treating syphilis, see: Syphilis.
This is considered a life-threatening complication of syphilis. How well you do depends on how severe the neurosyphilis is before treatment.
The symptoms can get slowly worse.
Calling your health care provider
Call for an appointment with your health care provider if you have had syphilis in the past and now have signs of neurological problems.
Prompt diagnosis and treatment of the original syphilis infection can prevent neurosyphilis.
Hook EW III. Syphilis. In: Goldman L, Schafer AI, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011: chap 327.
Tramont EC. Treponema pallidum (syphilis). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2009:chap 238.
- Last reviewed on 10/6/2012
- David C. Dugdale, III, MD, Professor of Medicine, Division of General Medicine, Department of Medicine, University of Washington School of Medicine. Jatin M. Vyas, MD, PhD, Assistant Professor in Medicine, Harvard Medical School; Assistant in Medicine, Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M. Health Solutions, Ebix, Inc.
The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997- 2013 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.
This page was last updated: May 20, 2014 |
<urn:uuid:c99399b0-9e31-42a5-8ddd-0a0302cf6766> | seed | Undertake multivariate modeling to refine the understanding of what drives the large variance of the economic burden, even by gestational age at birth;
Be ongoing to provide the basis for ongoing assessments; and
Establish the basis for refined economic assessment of policies and interventions that would reduce the economic burden.
1. Improve the Methods of Identifying and Treating Women at Risk for Preterm Labor
In the past 30 years, important strides in obstetric and neonatal tertiary care have been made to reduce the rates of infant morbidity and mortality as a result of preterm birth. However, the primary and secondary interventions implemented to date have not reduced the rate of preterm birth. Current prenatal care is focused on risks other than preterm birth. Birth defects, adequate fetal growth, preeclampsia, gestational diabetes, selected infections, and the complications of postdate pregnancy are emphasized in the prenatal record (see Chapter 9). Preterm birth has historically not been emphasized in prenatal care, in the belief that the majority of preterm births are due to social rather than medical or obstetrical causes (Main et al., 1985; Taylor, 1985) or are the appropriate result of pathological processes that would benefit the mother or infant.
African-American women deliver their infants before 37 weeks of gestation twice as often as women of other races and deliver their infants before 32 weeks of gestation three times as often as white women. The strongest risk factors in all ethnic groups are multiple gestations, a history of preterm birth, and vaginal bleeding.
The prevention of preterm birth by the use of interventions targeting a variety of risk factors has been attempted, but these interventions have largely been without success. The diagnosis and treatment of preterm labor are currently based on an inadequate literature and are compromised by an incomplete understanding of the sequence and timing of events that precede clinical evidence of preterm labor. The accurate diagnosis of early preterm labor is difficult because the symptoms (Iams et al., 1994) and signs (Moore et al., 1994) of preterm labor occur commonly in normal women who do not deliver preterm and because manual examination of the cervix in early labor is not highly reproducible (Berghella et al., 1997; Jackson et al., 1992). Treatment efforts are primarily focused on inhibiting contractions in women with preterm labor. This approach has not decreased the incidence of preterm birth but can delay delivery long enough to allow administration of antenatal steroids and to transfer the mother and fetus to the appropriate |
<urn:uuid:a2c56d89-e469-473f-b367-4c17b909cd92> | seed | There are principally two types of acute wound; traumatic wounds and surgical wounds1.
A traumatic wound such as a minor cut, abrasion through to extensive tissue injuries are caused when a force exceeds the strength of the skin or the underlying supporting tissues. A traumatic wound is classified by whether or not it is tidy or untidy.
A surgical wound is either incised and suture or laid open to heal by a surgeon. The wound breaks the integrity of the skin including the epidermis and dermis. Surgical wounds are classified in relation to the potential for infection in the wound: they are considered to be either clean, clean contaminated, contaminated or dirty. Surgical wounds which are contaminated / dirty or infected are sometimes left open post surgery whilst the infection resolves and then they are sutured closed. This is known as ‘delayed primary closure’. Premature primary closure in these instances can be detrimental to a successful outcome.
Management of a severe traumatic wound initially involves emergency procedures; resuscitation and restoration of the circulation to the affected limb / area. Associated injuries should be considered. The blood supply must be optimised, any necrotic tissue debrided away as this can act as a focal point for bacteria, and the wound irrigated. Antibiotics and tetanus are usually given prophylactically.
The correct intervention can greatly affect the outcome for the patient: the scar, time to heal and quality of life. With any acute wound the post-operative function of the wounded area and adequate pain control is essential. If pain is not controlled adequately it can decrease oxygen uptake, increase mortality and morbidity, delay mobility and increase hospital length of stay.
For these wound types, dressing selection should be based upon absorbing wound exudate, supporting haemostasis and protecting the wound from infection. It is also critical to manage the peri-wound area. Exudate levels can be high during the inflammatory phase and leakage of corrosive exudate onto the surrounding skin under the dressing can lead to ‘blistering’. Protection of the peri-wound area with a ‘no sting’ barrier film preparation such as LBF may be appropriate2.
Other sections available:-
1 Leaper DJ and Harding KG. (1998) Wounds: Biology and Management. Oxford University Press.
2 LBF Product Information
Caveat: The information given is a guide only and should not replace clinical judgement. |
<urn:uuid:3044ad68-7296-4e13-9ec1-5432c9739d6c> | seed | What is Haemophilus influenzae?
Haemophilus influenzae is a bacteria that is commonly found in the nose and throat of children and adults. A particular type, Haemophilus influenzae serotype B (Hib), can invade and cause infections. H. influenzae may cause a variety of diseases, including meningitis (inflammation of the coverings of the spinal column and brain), blood stream infections, pneumonia, arthritis, and epiglottitis. Although it was once the most common cause of bacterial infections in children, due to widespread use of Hib vaccine few cases are reported each year. Despite its name, this bacterium has nothing to do with the influenza viruses.
Who gets H. influenzae infection?
Unvaccinated household and daycare contacts of people with known H. influenzae infection are at greatest risk. Hib infection is most common in children three months to three years of age. It is unusual in persons over the age of five. The elderly and adults with underlying disease are at greatest risk of non-serotype B disease.
How is H. influenzae spread?
H. influenzae may be spread through contact with mucus or droplets from the nose and throat of an infected person
What are the symptoms of H. influenzae infection?
Symptoms of meningitis may include fever, vomiting, listlessness, and a stiff neck or back. Other symptoms depend upon the part of the body affected.
How soon after exposure do symptoms appear?
Symptoms generally appear in less than 10 days after exposure, commonly within 2 to 4 days.
When and for how long is a person able to spread H.
The contagious period varies and, unless treated, may last for as long as the organism is in the nose and throat, even after symptoms have disappeared. A person can no longer spread H. influenzae after taking the proper antibiotics for 1 to 2 days.
Does past infection with H. influenzae make a person
No. Children who have had H. influenzae infection can get it again.
What is the treatment for H. influenzae infection?
Specific antibiotics are generally used to treat serious infections.
Should people who have been in contact with someone diagnosed
with H. influenzae infection be treated?
Preventive treatment is only recommended in specific situations. For example, treatment with an antibiotic is recommended for household members when there is at least one unvaccinated child under four years of age in the home. In certain situations, preventive treatment will be recommended in childcare centers. Casual contact such as occurs in classrooms or office settings is not usually significant enough for preventive treatment to be needed.
What can be done to prevent the spread of H. influenzae?
Hib vaccines are available. All children should be vaccinated against Hib beginning at approximately two months of age. Contact your physician or local health department for further information about vaccination. |
<urn:uuid:0d981058-2f89-4422-9761-3c5938e860b7> | seed | Find over 200 print-friendly fact sheets about heart disease and related health topics.
Thoracentesis is a procedure to remove fluid
from the space between the lungs and the chest wall called the pleural space.
It is done with a
needle (and sometimes a plastic catheter) inserted
through the chest wall. Ultrasound pictures are often used to guide the placement of the needle. This pleural fluid may be sent to a lab to determine
what may be causing the fluid to build up in the pleural space.
Normally only a small amount of pleural fluid is present in the pleural
space. A buildup of excess pleural fluid (pleural effusion) may be caused by many
conditions, such as infection, inflammation,
heart failure, or cancer. If a large amount of fluid
is present, it may be hard to breathe. Fluid inside the pleural space may
be found during a physical examination and is usually confirmed by a chest
Thoracentesis may be done to:
You will be asked to sign a consent
form before a thoracentesis. Talk to your doctor about any concerns you have
regarding the need for the test, its risks, how it will be done, or what the
results will mean. To help you understand the importance of this procedure,
fill out the
medical test information form(What is a PDF document?).
Tell your doctor if you:
Also, certain conditions may increase the difficulty of
thoracentesis. Let your doctor know if you have:
A chest X-ray is usually done before the procedure. Your
doctor may order certain blood tests, such as a
complete blood count (CBC) and clotting factors,
before your procedure.
This procedure may be done in your
doctor's office, in the X-ray department of a hospital, in an emergency room,
or at your bedside in the hospital. Your doctor may have a nurse assist with
You will need to take off all or most of your
clothes (you may be allowed to keep on your underwear if it does not interfere
with the procedure). You will be given a cloth or paper covering to use during
the procedure. During the procedure, you will be seated but leaning forward on
a padded bedside table. If your test is done in the X-ray department, X-rays or
ultrasound may be used to confirm the location of
fluid in your chest.
The needle site between your ribs will be
cleaned with an antiseptic solution. Your doctor will give you a
local anesthetic in your chest wall so you won't feel
any pain when the longer needle that withdraws the fluid is inserted. Once the
area is numb, your doctor will insert the needle to where the fluid has
collected (pleural space). You may feel some mild pain or pressure as the
needle enters the pleural space.
A syringe or a small tube
attached to a vacuum bottle is used to remove the pleural fluid. Your doctor
will collect fluid to send to the lab. Once the fluid
is removed, the needle or small tube is removed and a bandage is put on the
An X-ray may be taken right after the procedure to make
sure that no complications have occurred. If more pleural fluid collects and
needs to be removed, another thoracentesis may be done later.
procedure takes about 10 to 15 minutes.
When you are given the shot to numb your
skin at the needle site, you will feel a sharp stinging or burning sensation
that lasts a few seconds. When the needle is inserted into the chest wall, you
may again feel a sharp pain for a few seconds.
When the pleural
fluid is removed, you may feel a sense of "pulling" or pressure in your chest.
Tell your doctor or nurse if you feel faint or if you have any shortness of
breath, chest pain, or uncontrollable cough.
If a large amount of
pleural fluid was removed during the procedure, you will probably be able to
breathe more easily.
Thoracentesis is generally a safe procedure. A
chest X-ray may be done right after the procedure to make sure that no
complications have occurred. Complications may include:
Thoracentesis is a procedure to remove
fluid from the space between the lungs and the chest wall called the pleural
space. Results from a lab are usually available in 1 to 2 working days. If the
fluid is being tested for an infection, such as
tuberculosis, results may not be available for several
A small amount of clear,
colorless, or pale yellow pleural fluid, usually less than
20 mL (0.7 fl oz), is normally
present. No infection, inflammation, or cancer is found.
A large amount of pleural
fluid is present.
Fluid may be labeled as either
a transudate or an exudate. The difference between these two types of fluid has
to do with the amount of protein and other substances found in the
Reasons you may not be able to
have the test or why the results may not be helpful include:
Other Works ConsultedChernecky CC, Berger BJ (2008). Laboratory Tests and Diagnostic Procedures, 5th ed. St. Louis:
Saunders.Fischbach FT, Dunning MB III, eds. (2009).
Manual of Laboratory and Diagnostic Tests, 8th ed.
Philadelphia: Lippincott Williams and Wilkins.Pagana KD, Pagana TJ (2010). Mosby’s Manual of Diagnostic and Laboratory Tests, 4th ed. St. Louis: Mosby.
November 1, 2012
Adam Husney, MD - Family Medicine & Robert L. Cowie, MB, FCP(SA), MD, MSc, MFOM - Pulmonology
To learn more visit Healthwise.org
© 1995-2012 Healthwise, Incorporated. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated. |
<urn:uuid:cd40c6e1-c89b-436b-ac51-19a24f929e16> | seed | Alzheimer’s Project Focuses on Role of Brain Inflammation
August 20, 2007
Scientists at the University of Rochester Medical Center have received $1.37 million to continue their work looking at some of the earliest events that occur at the start of Alzheimer’s disease – a condition that now generally goes undetected until the death of key brain cells has been underway for decades.
The team led by William Bowers, Ph.D., assistant professor of Neurology and a scientist in the Center for Aging and Development Biology, is focusing on the role of inflammation in the evolution of the disease. Just as rheumatoid arthritis can ravage the body’s joints because of the inflammation it causes, scientists are realizing that the same thing happens to the brain in patients with Alzheimer’s disease. The brain can be under assault for decades as the body attempts to fend off some perceived threat.
“The inflammatory response in the brain of a person with Alzheimer’s appears to happen very slowly,” said Bowers. “It may be that initially, the body is responding to some type of insult or problem. But as the body tries to correct that problem with recurring cycles of inflammation, the process snowballs and goes beyond the point of no return – inflammation begins damaging the brain, and the death of brain cells is the eventual outcome.”
Exactly why the inflammatory process begins remains a major question for researchers. Some people may be genetically susceptible to such a process. Other possibilities include a viral infection, a head injury, or the gradual buildup of a toxic protein known as amyloid-beta.
Bowers’ group is focusing on the role of a chemical messenger known as TNF (tumor necrosis factor) that some brain cells emit. TNF is a major player in inflammation, and scientists know that its level is higher in certain brain regions in people with the disease. Bowers’ team has shown that the same is true in mice especially prone to developing signs of Alzheimer’s disease, including accumulations of amyloid-beta in the brain and distinctive tangles within neurons. But exactly how TNF may be contributing to the disease is unknown.
Drugs that target TNF are now used in people to treat diseases like rheumatoid arthritis, and scientists are beginning to explore the use of such medications in patients with Alzheimer’s disease. Bowers’ studies are crucial to understanding how such medications might work, and to perhaps creating new drugs to reduce the inflammation.
The new funding, from the National Institute on Aging, enables Bowers and his team to continue the research for five more years. Bowers also has funding from NIA to try to create a vaccine that would customize the body’s immune response to amyloid-beta, a key contributor to Alzheimer’s. |
<urn:uuid:e0c41eec-e987-4554-a617-3e02fac5d093> | seed | World J Gastroenterol. 2007 September 21; 13(35): 4707-4715.
Published online 2007 September 21. doi: 10.3748/wjg.v13.i35.4707.
©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
Iron overload and immunity
Graça Porto, Maria De Sousa, ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, IBMC, Institute of Molecular and Cellular Biology, Porto, Portugal
Graça Porto, HGSA, Santo António General Hospital, Porto 823 4150, Portugal
Received March 30, 2007; Revised April 23, 2007; Accepted April 25, 2007;
Progress in the characterization of genes involved in the control of iron homeostasis in humans and in mice has improved the definition of iron overload and of the cells affected by it. The cell involved in iron overload with the greatest effect on immunity is the macrophage. Intriguing evidence has emerged, however, in the last 12 years indicating that parenchymal iron overload is linked to genes classically associated with the immune system. This review offers an update of the genes and proteins relevant to iron metabolism expressed in cells of the innate immune system, and addresses the question of how this system is affected in clinical situations of iron overload. The relationship between iron and the major cells of adaptive immunity, the T lymphocytes, will also be reviewed. Most studies addressing this last question in humans were performed in the clinical model of Hereditary Hemochromatosis. Data will also be reviewed demonstrating how the disruption of molecules essentially involved in adaptive immune responses result in the spontaneous development of iron overload and how they act as modifiers of iron overload.
Keywords: Iron, Iron overload, Innate immunity, Adaptive immunity
THE TWO IMMUNITIES
The last decade has seen a growing understanding of the numerous functions of the immune system beyond the two classical attributes of adaptive immunity: antigen specificity and memory. The key effector cell of adaptive immunity is the lymphocyte, a cell no longer known from its two principal origins in mammals, the thymus (T) and bone marrow (B), but with several subtypes characterized by different function and cytokine production profiles[1
]. “Behind” adaptive immunity lays a complex world of cells and molecules involved in less antigen-specific tasks collectively dedicated to the function of innate immunity. Two competing models have sought to explain innate immunity. One where evolutionary conserved features of pathogens are recognized by pattern recognizing receptors[2
] known generally as toll-like-receptors (TLRs). A second model, known as the danger model, is based on the assumption that products from damaged or stressed cells provide a danger signal to the host, thus evoking an innate immunity response[3
]. The effector cells of innate immunity are mostly myeloid cells and lymphocytes whose interaction with target cells does not depend on the recognition of the Major Histocompatibility Complex (MHC). A third cell, the dendritic cell (DC), was first described by Steinman and Cohn in 1973[4
]. DCs have been described most elegantly as “the nexus for translating signals from innate recognition into cells guiding adaptive immune function”[5
One hallmark of immune system cells, whether involved in innate or adaptive immunity, is their capacity to circulate and migrate from the blood compartment into lymphoid and non-lymphoid tissues (innate immunity cells) from non-lymphoid into lymphoid tissues (DCs) and from the blood into the lymph through the peripheral lymphoid organs (lymphocytes). The other is their role in protection from pathogen infections. Since early descriptions of immune cell functions in iron overload[6
] knowledge of the reciprocal interactions between immune cell responses, intracellular iron load and response to micro-environmental changes in iron levels has increased considerably. A decisive contribution to this understanding was the clarification of the genes involved in iron homeostasis. Reviews of the functions of such genes and their link to the reticuloendothelial system and immunity have been published recently[7,8
]. The present review will focus on the evidence that the cells of the immune system are equipped to modulate iron homeostasis through the expression of several iron related genes and proteins, and how do innate and adaptive immune cells respond in conditions of iron overload. In addition, the reader will be reminded of the evidence indicating that defective immune system models, particularly experimental models, are associated with the spontaneous development of iron overload[9
]. The mechanisms underlying what could be called the “reverse” side of this same coin, i.e. immunity and iron overload are less well understood. However, taking into account that practically all cells of the immune system express iron related genes their contribution to systemic iron homeostasis should no longer be ignored.
IRON AND INNATE IMMUNITY
As a critical element of cellular activity, iron plays a pivotal role in the fight for survival between mammalian hosts and their pathogens, each displaying a wide range of mechanisms for controlling iron acquisition and utilization. Micro-organisms have developed a large number of strategies to acquire iron from the environment and to transport the element to sites of incorporation into biologically important molecules[10,11
]. On the other side, the host has developed the capacity to modulate cellular iron metabolism, not only for its optimal utilization as a catalyst for the generation of reactive oxygen species acting as strong antimicrobial molecules, but also in order to make iron less available for the micro-organisms[11,12
]. A number of genes and proteins primary involved in iron homeostasis, namely in iron binding, transport and storage are now recognised to display related immunological functions. These are summarized in Table [13-24
]. In addition, it is becoming clear that the cells of the innate immune system, as part of a non-specific defense against infection, are equipped to express genes and proteins that can modulate iron homeostasis both at the cellular and the systemic levels (see also Table )[25-42
]. One central player in this modulation is hepcidin, first described as a liver derived antimicrobial peptide[28
], and now well recognised as a key regulator of iron homeostasis and the anaemia of inflammation, at the interface of innate immunity and iron metabolism[43
]. Liver-derived hepcidin is strongly induced during infection and inflammation, causing intracellular iron sequestration and decreased plasma iron levels, a process mediated by the inflammatory cytokine cascade, namely macrophage derived IL-6 and IL-1[32,33
]. The mechanism underlying intracellular iron sequestration is mediated by the hepcidin-induced internalization and degradation of ferroportin, the only known iron exporter[44
]. The reduction in extracellular iron concentrations is believed to limit iron availability to invading microorganisms, thus contributing to host defense. Recently, hepcidin has been shown to be endogenously expressed by innate immune cells, i.e. macrophages and neutrophils, capable of migrating from the blood to a site of infection, constituting a newly recognised component of the local innate immune response to bacterial pathogens[23
]. Myeloid endogenous hepcidin mRNA expression in response to bacterial pathogens was shown to be dependent on the specific activation by the toll-like receptor 4 (TLR-4), the key pattern recognition receptor for LPS[45
]. This activation also produces down-regulation of the iron exporter ferroportin. Endogenous myeloid hepcidin production is not stimulated by iron, pointing to different pathways of hepcidin activation in response to infection or iron overload[23
]. The mechanisms underlying the differential stimulatory effects of infection and iron overload on hepcidin are still not understood. Interestingly, it was recently shown that hepcidin levels in fish also respond both to iron overload and infection, demonstrating the evolutionary conservation of hepcidin’s dual function[46
Relevant genes/proteins involved in iron homeostasis and iron overload, and their related immunological functions
In addition to the demonstrated role of neutrophils and macrophages on hepcidin gene activation and ferroportin down-modulation, other iron genes and proteins involved in iron transport from the human phagosome into the cytosol also play critical roles in TLR-4 mediated innate immunity. The natural resistance-associated macrophage protein 1 (Nramp1) is expressed in circulating phagocytes, and is recruited from the lysosomal compartment to the phagosome membrane where it functions as an efficient antimicrobial through a mechanism of iron deprivation[22
]. Nramp1 mutations in mice are shown to cause susceptibility to infection with various intracellular pathogens including Salmonella, Mycobacterium and Leishmania[21
]. Mutations in the human homologue of the gene, NRAMP1, were also shown to strongly affect the susceptibility to tuberculosis[47
]. Nramp2, also known as the divalent metal transporter 1 (DMT1) is another important iron transporter in mammalians[48,49
] and, as Nramp1, it is also induced by infection with intracellular pathogens, namely Mycobacterium[50
]. In addition, it is suggested to play an important role in recycling iron from RBC-containing phagosomes to the cytoplasm[51
]. The amount of available iron in the phagosome is also decreased by the entry in macrophages of neutrophil derived lactoferrin (Lf), another well known potent iron chelator found recently to have also a bridging role between innate and adaptive immunity. Both in vitro
and in vivo
studies showed that Lf is able to stimulate the proliferation and differentiation of T lymphocytes from their immature precursors into the Th1 or the Th2 phenotypes thus having an immunoregulatory effect on Th1/Th2 activities[15
Finally, lipocalin 2 has been recently described as a pivotal component of the innate immune system and the acute phase response[52
]. Upon infection the toll-like receptors on immune cells stimulate the transcription, translation and secretion of lipocalin 2 which then limits bacterial growth by sequestering the iron-loaded siderophore[24
INNATE IMMUNITY AND IRON OVERLOAD
If one or all of the above described iron related immune response genes either fail or the cells are overwhelmed by continuous iron overloading such as seen in transfusional iron overload, one consequence is the development of infection. Infections including rare microorganisms[53
] are among the major complications in patients with thalassemia, a group of common genetic disorders of hemoglobin synthesis clinically characterized by severe anemia and blood transfusion-dependent iron overload. Besides the well-known risks of blood borne viral infections associated with multiple transfusions, the increased susceptibility of these patients to infection is known to be associated with a wide spectrum of immune abnormalities which are, at least in part, due to the effect of iron overload, including defective chemotaxis and phagocytosis by neutrophils and macrophages and decreased natural killer cell activity[54
In contrast with the findings in transfusional iron loading, patients with severe iron overload due to Hereditary Hemochromatosis (HH) do not show evidence of increased susceptibility to infections or iron loading of macrophages. HH is a common genetic disorder of iron overload, the majority of HH patients being homozygous for the C282Y mutation in HFE
, a gene encoding a protein of the Major Histocompatibility Complex classI (MHC classI). The C282Y mutation disrupts the correct folding of the α3 domain of the protein, interfering with its interaction with β2-microglobulin (β2m) and consequently abolishing the cell surface expression of the molecule[35
]. The surface expression of HFE was shown to have a prominent role in the regulation of iron export from macrophages[55,56
Monocyte/macrophage abnormalities in HH
Anomalies in monocyte/macrophage cells have been consistently described in HH patients, including low TNF-α production by peripheral blood macrophages upon stimulation with lipopolysaccharide[57
] and a significant increase in iron regulatory protein (IRP) activity in monocytes[58
], an anomaly that was corrected after phlebotomy treatment. Interestingly, subjects with a tissue iron burden similar to HH patients, but due to secondary iron overload have an IRP activity significantly decreased suggesting that the increased IRP activity in iron overload is specific to the HFE related hereditary form of hemochromatosis[58
]. In addition, a study that investigated the release of erythrocyte-derived iron from purified human monocytes obtained from controls and HH patients showed that although HH monocytes phagocytosed less than half the number of erythrocytes taken up by control monocytes, they released twice as much iron in the form of LMW-Fe complex than controls[59
]. More recently, increased iron content was described in macrophages from HH patients transfected with wt HFE when compared with HH macrophages transfected with an empty vector[56
]. These observations are consistent with previously reported observations in macrophage cell lines derived from C282Y mutated HH patients, where HFE
was shown to loose its ability to inhibit iron release leading to a relative macrophage iron deficiency[55
]. Interestingly, Mycobacterium tuberculosis (M.tb) residing within phagosomes of macrophages from HH patients exhibit a profound defect in their ability to acquire iron from exogenous transferrin and lactoferrin relative to M.tb-infected macrophages from normal controls[60
]. Moreover, macrophages from HH patients failed to induce Nef-mediated iron and ferritin accumulation upon HIV-1 infection in contrast to macrophages expressing wild-type HFE
], thus suggesting that HFE
mutated macrophages may be better equipped to protect from HIV-1 infection, compatible with the description of a long survival in a patient with AIDS and hereditary hemochromatosis[62
]. One must therefore wonder whether the failure of macrophages from C282Y HFE
HH patients to hold on to the iron is the expression of a putative selective advantage protecting from infection brought by the appearance and the establishment of such a mutation.
Iron and the dendritic cells
Very little work has addressed the interaction between iron loading and dendritic cell (DC) function. There is, however, recent evidence indicating that, upon endotoxin induced maturation, DCs increase significantly the expression of TfR1 and down regulate expression of the export molecule ferroportin[63
], an observation compatible with an earlier finding of Kramer et al[64
] who reported that DCs generated under iron deprivation conditions were phenotypically undifferentiated and could not stimulate T cells.
IRON OVERLOAD AND ADAPTIVE IMMUNITY
The postulate that the immunological system could have a role in monitoring tissue iron toxicity, as part of its surveillance function, was first advanced in 1978, based on studies on lymphocyte traffic and positioning[65-67
]. It was implicit in that postulate that the lymphomyeloid system, and its circulating components participate in the recognition and binding of metals as a protective device against metal toxicity, and the preferential use of indispensable metals, such as iron, by bacteria or transformed cells. While a vast number of studies have clarified the reciprocal interactions between myeloid innate immunity cells and iron metabolism, fewer studies addressed this question in lymphocyte populations. Lymphocyte activation and expansion depend on the expression of transferrin receptors, required for DNA synthesis and cell division[18
] and both activated and non-activated T lymphocytes synthesize ferritin[19,20
]. Lymphocytes could, therefore, act as a “mobile” and easily “mobilizable” iron-storage compartment protecting from iron-mediated toxicity[65
]. This hypothesis motivated the study of lymphocyte function in iron overload[68
]. The influence of iron on the expansion of different T-cell subsets was demonstrated both in vitro
] and in vivo
, namely in patients with thalassemia[70
]. Results in this clinical model, however, are difficult to interpret due to the inseparable effects of blood transfusion, splenectomy, iron chelation therapy and infection. Imbalances of the relative proportions of CD4+ and CD8+ T lymphocytes, with abnormally high CD4/CD8 ratios were later reported in HH patients[71,72
], a clinical model where iron overload is not complicated by the effects of transfusion, splenectomy or desferrioxamine. Curiously, in one experimental model of iron overload seen in mice generated with targeted Hmox1 mutations, high CD4:CD8 ratios have been seen in the splenic cell populations of older mice aged 50 wk[34
]. These mice also exhibited numerous activated CD4+ cells. Hepatic inflammatory cell infiltrates were seen in the mice, a finding similar to that reported by Rodrigues et al[73
] in aging Hfe
T lymphocyte abnormalities in HH
Abnormalities in the relative proportions of the two major T lymphocyte subpopulations have been consistently described in HH patients. Reimão and co-workers first described that patients with abnormally high CD4/CD8 ratios displayed a faster re-entry of iron into the serum transferrin pool after intensive phlebotomy treatment than patients without those abnormalities[71
]. It was shown later that the amount of iron mobilized by phlebotomy correlated significantly with the number of CD8+ T cells, but not with CD4+ T cells[72,74
]. An independent study examining patients homozygous for the C282Y mutation showed that the low percentages of CD8+ T cells seen in the peripheral blood of HH patients were associated with low numbers of the same cells in the liver and with higher levels of hepatic tissue iron[75
]. HH patients had been shown earlier to have reduced percentages of CD8+ CD28+ T cells in peripheral blood[76
]. No anomalies of CD28 expression were found in the CD4+ subset. The apparent failure of the CD8+ CD28+ T cell population to expand coincided with an expansion of CD8+ CD28- T cells in peripheral blood of HLA-A3+ but not HLA-A3- HH patients[76
]. Although the described abnormalities in lymphocyte populations were systematically found in the sub-population of CD8+ T lymphocytes, the association with total body iron stores is also reflected in the total lymphocyte counts. Low total lymphocyte counts were found associated significantly with a higher degree of iron overload in HFE
-linked HH, but not in African iron overload[77
]. More recently, Barton et al[78
] also described a significant inverse relationship of total blood lymphocyte counts and severity of iron overload in hemochromatosis probands with HFE
C282Y homozygosity. Fabio et al[79
] confirmed that the presence of low numbers of total lymphocyte counts and CD8+CD28+ T cells in C282Y homozygous patients was inversely related to the transferrin saturation. In addition, they found low numbers of CD4+ T and NK cells, and a major increase in IL-4 and IL-10 production in the CD3+ CD8+ T cell subset[79
]. A study of the Vα/β T cell receptor (TcR) repertoire in a population of C282Y homozygous HH patients showed that the frequency of Vα/β TcR expansions within the CD8+ pool in the group of HH patients was significantly higher in those with iron overload related pathology (9/16) than in patients (1/16) without pathology[80
]. In the same study it was found that control subjects heterozygous for the C282Y mutation had an absence of expansions of the Vβ5.2 and Vβ12 chains in the CD8+ pool, suggesting that HFE
could have an effect in the shaping of T cell receptor repertoire.
Functional abnormalities in CD8+ T lymphocytes were also described in HH patients. The level of autophosphorylation of the CD8-associated p56lck as well as its phosphotransferase activity, as determined by phosphorylation of an exogenous substrate, was significantly reduced by two- to three-fold in HH patients relative to a control population of healthy donors[81
]. By contrast, the level of CD4-p56lck activity did not show an overall decrease relative to controls. The decreased CD8-p56lck activity seen in patients was not corrected by iron depletion. A significantly higher percentage of HLA-DR+, but not CD45RO+ cells was also found within the peripheral CD8+ T cell subset in HH patients relative to controls[76
]. Moreover, functional studies showed that CD8+ cytotoxic T lymphocytes (CTL) from HH patients exhibited a diminished cytotoxic activity when compared with CD8+ CTL from healthy controls[76
The finding of a significant association of abnormally low CD8+ T lymphocytes with a more severe clinical expression of hemochromatosis in HH patients[72,82
] raises the obvious question: are if these anomalies the follow or precede the development of iron overload. The fact that those abnormalities are remarkably stable in each individual patient, that they are not corrected by phlebotomy treatment, and that they are observed in asymptomatic patients at young ages, favors the hypothesis that they are intrinsic to the genetic defect and not a consequence of the progressive iron overload. More recently it was shown that the numbers of CD8+ T lymphocytes are genetically determined, in association with other genetic determinants at the MHC classIregion close to HLA and HFE
]. It is, therefore, conceivable that the inherited abnormalities in CD8+ T lymphocytes in HH are modifiers of the clinical expression of the disease as proposed by Cruz et al[82
] or genetically located close to a yet unidentified modifier gene of iron metabolism.
THE REVERSE TOPIC: ADAPTIVE IMMUNITY AND IRON OVERLOAD
Genetically manipulated animal models have, therefore, become wonderful and decisive tools to address the questions of the effect on iron overload of a specific gene or protein at the systemic level. Several animal models of spontaneous iron overload were described that illustrate the influence of proteins of the adaptive immunological system on iron homeostasis, all pointing to the putative importance of the MHC classIregion.
The β2-microglobulin deficient ( β2m-/-
) mice constitute the first described model of spontaneous iron overload[38,85,86
]. These mice develop a hepatic iron overload with a distribution similar to that seen in HH liver pathology, i.e., mainly in the liver parenchyma with no evidence of iron loading in the Kupffer cells[38,86
]. These mice present severe decreased cell surface expression of the MHC-classImolecules and consequently almost no CD8+ T lymphocytes[87,88
]. Intestinal uptake of ferric iron and the subsequent transfer into the plasma is inappropriately increased in β2m-/-
]. Upon treatment with hematopoietic cells derived from normal mice fetal liver iron overload is attenuated and shifted from the parenchymal to the Kupffer cells[86,89
]. However, TfSat and intestinal iron absorption remain high, suggesting that the primary defect of iron overload is not corrected. With the discovery of the HFE
gene and the demonstration that the C282Y mutated form failed to bind to β2m[35
] it was assumed that the earlier findings in β2m-/-
were due to an impaired HFE
function. However, several subsequent studies showed that this was not sufficient to explain the pathology of β2m deficient mice. In contrast to Hfe-/-
, the β2m-/-
mice display increased expression of the duodenal iron transporters DMT1 and ferroportin1, implicating a broader role of β2m in mammalian iron overload[90
]. More recently, Rodrigues et al[73
] described results of a comparative study of these two models in older mice. The results confirmed that the β2m-/-
old mice present a more severe hepatic iron overload than the Hfe-/-
old mice which also showed liver steatosis, probably as a reflection of the higher hepatic iron content causing lipid peroxidation. Earlier Levy et al[91
] had reported the finding that in mice lacking both the Hfe
and the β2m molecules, liver iron deposition is observed in greater levels than in mice lacking Hfe
double knock out mice lack mature T and B lymphocytes as well as MHC-class I and Hfe expression. Rag1 is required for normal T and B lymphocyte development. β2m is required for correct folding and cell surface expression of MHC-classIlike proteins. These mice present a more severe body iron overload than each of the single knock out models[39
]. Besides liver iron deposition in the parenchymal cells, the β2m-/-Rag1-/-
also showed iron deposition in pancreas and heart. Older mice under an iron-enriched diet develop heart fibrosis, which could be prevented by treatment with normal fetal liver hematopoietic cells. To determine whether the effect of the β2m deficiency in the β2m-/-Rag1-/-
double knock out mouse was only due to lack of Hfe expression, double knock out mice for Hfe
double knock out mice showed increased liver iron overload compared to each of the single knock out, or the β2m-/-Rag1-/-
. The distribution of the iron loading in Hfe-/-Rag1-/-
mice did not recapitulate the iron loading of the β2m-/-Rag1-/-
, since they did not present heart or pancreas iron loading.
The δ TCR-/-
mice lack the γδ intraepithelial lymphocytes. Following the administration of an iron supplemented diet, these mice showed an increased liver iron accumulation in relation to control mice[93
]. In addition, δ TCR-/-
mice had a marked reduction of tumor necrosis factor alpha (TNF-α) production by intraepithelial lymphocytes when compared with controls suggesting a role for this cytokine in intestinal iron regulation.
Finally, mice deficient in the MHC classImolecules H2Kb
have a strong reduction in CD8+ T-lymphocyte numbers[94
]. These mice present a spontaneous increase of iron content in the liver preferentially in hepatocytes with occasionally Kupffer cells iron staining[41
]. The liver iron content in this model was shown to correlate directly with the number of residual CD8+ T lymphocytes (Cardoso E and M de Sousa, unpublished observations).
The above described double knockout mouse models provide a good illustration of the modifier effect of the components of the adaptive immune system, namely a MHC classIdependent effect, on the iron overload phenotype, a conclusion also reached separately by Muckhentaler et al[90
] in a study of differential gene expression in β2m deficient mice. Altogether the results described in animal models of hemochromatosis may help to explain why immunological anomalies modify the severity of iron overload in Hereditary Hemochromatosis[82,95
The growing knowledge and availability of genetic techniques dissecting the fine components of the host response to the challenge of infection have strengthened the opportunity of revising the topic “iron and immunity”. When the main concern for this topic resided in the effects of iron deficiency on the immune response, Weinberg pioneered the opposite concern for iron overload and infection[12
]. Today it is evident that in response to infection numerous innate immunity components display metal chelating properties, including synthesis and release of lactoferrin, lipocalin and hepcidin, as discussed above. The cells involved in that response are neutrophils and macrophages. But, during evolution the macrophage, particularly the splenic macrophage, assumed the key physiological role of recognizing senescent red blood cells and recycling the iron in hemoglobin[96
]. Exhaustion of that pool in vivo
leads to “phagocytic” iron overload, such as seen in transfusional iron overload, with the expected consequences in the development of infection. If on the other hand the macrophage fails, it is to be expected that “parenchymal” iron overload will develop. This is the case in HFE
-Hereditary Hemochromatosis. Therefore, iron overload must not be seen as one entity, but two separate entities with different relationships to immunity (Figure ). Evidence was provided in this review that innate immunity is affected and affects “phagocytic” iron overload. On the reverse side, defective immune system models, namely natural and experimental defects in MHC-classIrelated genes (HFE
, β2-microglobulin and HLA) are associated with the spontaneous development of “non-phagocytic” or parenchymal iron overload.
Figure 1 A model illustration of the two topics addressed in this review: how innate immunity is affected and affects “phagocytic” iron overload (Box A) and the evidence that defective immune system models, namely natural and experimental defects in MHC-classIrelated genes (HFE, β2-microglobulin and HLA) are associated with the spontaneous development of “non-phagocytic” or parenchymal iron overload (Box B). A: Macrophages “overwhelmed” by continuous iron overloading as seen in conditions of chronic transfusion and increased erythrophagocytosis are compromised in their function of surveillance of bacterial growth resulting in increased host susceptibility to infection. As part of the natural response to bacterial infection macrophages modulate the expression of a number of genes involved in the regulation of cellular iron metabolism. By activating the cytokine cascade they induce up-regulation of liver hepcidin synthesis with further increase in macrophage iron retention and perpetuation of this cycle; B: A “non-phagocytic” or parenchymal iron overload is observed in hepatocytes of several defective immune system models associated with a relative iron deficiency in macrophages, recapitulating the findings observed in the human model of Hereditary Hemochromatosis. The mechanisms underlying the spontaneous development of iron overload in these models are not yet understood. Three possible (not mutually exclusive) mechanisms are represented in this figure: (1) the fact that both Hfe and β2m knockout mouse models lack the liver hepcidin response to iron overload[90,97,98] may support the notion of a liver-derived, systemically induced iron overload. The involvement of liver hepcidin in the development of iron overload in mice deficient in the MHC-classImolecules H2Kb and Db (HLA) was never tested; (2) the iron overload seen in the β2m-/-Rag1-/- and Hfe-/-Rag1-/- mouse models support the involvement of lymphocytes themselves as modifiers of the severe parenchymal iron overload phenotype seen in those mice; (3) finally, the recent demonstration of a strong link between the MHC-classIregion and the genetic transmission of low CD8+ T lymphocyte numbers in humans and the association of total lymphocyte numbers with a more severe iron overload phenotype in patients with Hereditary Hemochromatosis[78,82,83] opens a new possibility that another, still unidentified MHC-classIassociated gene(s) may simultaneously regulate CD8+ T lymphocyte numbers and influence the development of parenchymal iron overload.
The large new question looming in the horizon of this topic with which we wish to close this brief review is: does the MHC classIregion harbor, in addition to HFE, other gene or genes that besides regulating lymphocyte numbers also influence the development of “non-phagocytic” or parenchymal iron overload? The search for the answer to this question will probably guide many research interests for years to come.
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<urn:uuid:37dc106f-30a8-4655-b2cc-70a76b8514d5> | seed | 1. Why do personal music players raise health concerns?
- 1.1 When are we exposed to noise and sound?
- 1.2 What are noise and sound?
1.1 When are we exposed to noise and sound?
The SCENIHR opinion states:
3. SCIENTIFIC RATIONALE
In a recent report WHO states (WHO 2002, Nelson 2005) “Worldwide, 16% of the disabling hearing loss in adults is attributed to occupational noise, ranging from 7% to 21% in the various subregions”. For almost two decades, the level of 85 dB(A) was regarded as the critical intensity for the workplace; at exposures below 85 dB(A) the probability of hearing losses occurring with long-term exposure was then considered sufficiently limited (Welleschik 1979). Therefore, international standards recommended the equivalent sound pressure level (Lequ, 8h) of 85 dB(A) (A filter-weighted, 8-hour working day-weighted average) as the exposure limit for occupational noise (ISO 1999:1990; NIOSH revised criteria 1974). However, more recent studies showed that this standard did not guarantee the safety for the human auditory system. Therefore, the new EC Directive Noise at Work Regulations on the minimum health and safety requirements regarding exposure of workers to the risks arising from physical agents (noise) introduces lower exposure action value at Lequ, 8h = 80 dB(A) (Directive 2003/10/EC).
Although early reviews (eg MRC 1986) concluded that leisure noise was unlikely to be a significant threat to hearing compared to occupational noise, they noted a need for more good data and research. Since then there have been huge changes in patterns of noise exposure. Smith et al. (2000) found that the numbers of young people with social noise exposure had tripled (to around 19%) since the early 1980s, whilst occupational noise had decreased.
There is a number of studies which documented that noise from environmental sources like traffic, aircraft, construction or neighbourhood, although sometimes very annoying, do not reach the equivalent levels that can be harmful to hearing. On the other hand, they can cause non-auditory effects. In the last years a pattern of environmental noise exposures has changed substantially; the leisure noise sources became of a main public concern as it was found that they can generate sounds across a broad frequency range and from high to low sound pressure levels. The equivalent sound levels in discos may range between 104.3 and 112.4 dB(A), and between 75 and 105 dB(A) from personal music players (Serra et al. 2005). The noise dose measures over 4 hours showed an Laeq of 104.3 dB. The nightclubs' average sound level ranged between 93.2 to 109.7 dB(A). Therefore it may be concluded that sounds such as music can, at high acoustic levels, be as dangerous for hearing as industrial noise.
In the last decade, PMPs with improved qualities and suitable for playback at high sound levels became available and have been used by an increasing proportion of the population. Data shows that for the MP3 players and equivalent devices the unit sales in Europe, between 2004-2007, were estimated as about 124 million but could be as large as 165 million and for all portable audio could be in the range 184-246 million. On top of this there were about 161 million handset mobile phones sold in EU countries in 2007 only. It is estimated that today about 10-20% of these phones include a MP3 playback function. This results in an estimated additional number of 16 to 32 million PMP devices. It is expected that the fraction of mobile phones containing the PMP function will rapidly increase such that up to 75% of all phones sold by 2011 may provide this function. Notably, data are not very precise at present and it is not clear whether people who have access to PMP function actually use them on a regular basis.
The personal music players (PMPs) which now play not only music, but provide podcasts of various broadcasts or lecture material, which is delivered largely through ear-bud type insert ear phones producing a range of maximum levels around 88-113 dB(A) across different devices. In the worst case scenario, it is possible to obtain level of about 120 dB(A).
Taking into consideration the above mentioned data, the Commission requested the Scientific Committee on Emerging and Newly Identified Health Risks to assess whether the health of citizens is appropriately protected by current requirements of Community directives and European standards by formulating terms of reference.
The Working Group has considered evidence derived from a wide variety of sources, including peer-reviewed scientific literature and published reports of institutional, professional, governmental and non-governmental organisations. In common with the usual practice of SCENIHR Working Groups, no reliance has been made on unpublished work or publicly available opinions that are not science based.
During the course of the deliberations of the Working Group, a Call for Information was issued by the Commission and the replies have all been considered.
As a general rule, scientific reports that are published in English language peer-reviewed scientific journals are considered primarily. This does not imply that all published articles are considered to be equally valid and relevant for health risk assessment. On the contrary, a main task is to evaluate and assess the articles and the scientific weight that is to be given to each of them. Only studies that are considered relevant for the task are commented upon in the opinion. Many more reports were considered than are cited in the reference list. However, only articles that contribute significantly to the update of the opinion are explicitly discussed, commented and cited. In some areas where the literature is particularly scarce, namely on market trends in sales of PMPs and mobile phones with MP3 function, data obtained from professional databases were obtained and analyzed for relevance and importance by experts.
Relevant research on the assessment of health risks related to listening to PMPs’ can be divided into broad sectors such as epidemiologic studies and experimental studies in humans. Other studies, used frequently in other risk assessment procedures, such as experimental studies in animals and cell culture studies were considered occasionally, only when necessary to understand the mechanisms of potential noise induced hearing loss.
A health risk assessment evaluates the evidence within each of these sectors and then weighs together the evidence across the sectors to a combined assessment. This combined assessment should address the question of whether or not a hazard exists i.e., if there exists a causal relationship between exposure and some adverse health effect. The answer to this question is not necessarily a definitive yes or no, but may express the weight of the evidence for the existence of a hazard. If such a hazard is judged to be present, the risk assessment also estimates the magnitude of the effect and the shape of the dose-response function, used for characterizing the magnitude of the risk for various exposure levels and exposure patterns. A full risk assessment also includes exposure assessment in the population and estimates of the impact of exposure on burden of disease. Epidemiological and experimental studies are subject to similar treatment in the evaluation process. It is of equal importance to evaluate positive and negative studies, i.e., studies indicating that the exposure to noise from devices like PMPs’ and mobile phones with this function have an effect and studies not indicating the existence of such an effect. In the case of positive studies the evaluation focuses on alternatives to causation as explanation of the positive result: with what is the degree of certainty for ruling out the possibility that the observed positive result is produced by bias, e.g. confounding or selection bias, or chance. In the case of negative studies one assesses the certainty with which it can be ruled out that the lack of an observed effect is the result of (masking) bias, e.g. because of too small exposure contrasts or too crude exposure measurements; one also has to evaluate the possibility that the lack of an observed effect is the result of chance, a possibility that is a particular problem in small studies with low statistical power.
Obviously, statistical significance is only one factor in this evaluation. Other characteristics of the study are also taken into account, such as the size of the database, the assessment of the participation rate, the level of exposure, and the quality of exposure assessment. The observed strength of association and the internal consistency of the results, including aspects such as dose-response relation are particularly important. Regarding experimental studies, additional important characteristics are the types of controls that have been used and the extent to which replication studies have been performed. It is worth noting that this process does not assess whether a specific study is unequivocally negative or positive or whether it is accepted or rejected. Rather, the assessment will result in a weight that is given to the findings of a study. In the final overall evaluation phase, the available evidence is integrated over various sectors of research.
Source & ©: SCENIHR,
Note: The European Directive 2003/10/EC on the minimum health and safety requirements regarding the exposure of workers to the risks arising from physical agents (noise) is available at:
The criteria issued by the U.S. National Institute for Occupational Safety and Health (NIOSH) are available at: www.cdc.gov/niosh/topics/noise/
1.2 What are noise and sound?
The SCENIHR opinion states:
3.3. Sound: Definitions and measurements
In view of the clarity required for this document and as an aid to communications between disciplines and across national borders it is important to agree on definitions for scientific and technical purposes. It is also noted that the use of some words like e.g. ‘noise’ is not consistent between disciplines and therefore needs a definition.
Note that in the language of the electronic devices, noise is used for that part of the signal of statistical nature which is not carrying the intended information, as it is reflected for example in signal to noise ratios. Next to statistical noise there is non-statistical ‘hum’ on many signals to be tabulated. The signal on one line may actually contribute to the hum or noise on the other line specifying the ‘cross talk’.
In the world of sound, however, noise has also a slightly different meaning in that it is any sound which is not desired by a certain observer. Therefore, in the context of the current mandate, the use of the word noise has to be carefully explained: While, on the basis of the above definitions, the use of the word ‘noise’ is reserved for those cases where the potentially affected person is not intentionally listening, this is not conclusive for the users of personal music players and the like. Because the sound pressure levels of earphone devices to an outside observer remain far below the limits of physiological effects, it is the sound of personal music players which is of concern to this mandate. This outside observer may nevertheless be distracted and annoyed and may rightfully, in the lexicographic meaning of the word call noise what is sound in his neighbours ears.
For the historic importance of noise protection in work environments like factories or the transportation industry the word ‘noise protection’ and ‘noise-induced hearing loss and impairment’ have been coined while a number of such terms e.g. in the context of professional musicians and their job do not really qualify the use of the word ‘noise’. Therefore, and for the scope of comparability between the scientific literature in both cases, that of noise exposure and of sound exposure (which leads to very similar physiological effects at comparable levels) it has been decided for the purpose of this mandate to keep up with the established wording and to use the word ‘noise’ irrespective of whether the ‘noise’ exposure is wanted (e.g. when playing a personal music player) or not (e.g. in the typical workplace setting). Thus, ‘noise’ is used consistently in the context of all disease and malfunction patterns, while the word ‘sound’ is used consequently throughout this opinion to clarify that the concern is the voluntary listener of personal music players and not the observer of the listening situation.
3.3.2.Sound: Physical and technical background
Sound or Sound waves comprise a wave phenomenon. Sound waves are ‘longitudinal’ waves because sound waves consist of areas of higher and lower local pressure. The propagation of sound waves occurs in all media, i.e. in gases, liquids and solids as well as in more complex fluids like e.g. organisms and tissues.
Fundamentally, sound waves are characterized by their spectrum. A spectrum is the summation of individual frequencies (f) and amplitudes a certain signal has in the surrounding medium. In daily acoustic settings sound is a complex summation of many different sounds from different sources. Sound will not propagate through vacuum and its propagation is influenced by material properties like density and compression / shear strengths. Characteristic parameters of sound waves in a given situation derive from the fundamental wave equation which may be to challenging to evaluate for a given complex scenario.
The exposure to sound in a typical setting is determined by many factors which are not always easy to assess. For sound propagation, the geometry of the room, the surface materials and furnishings as well as its occupation, the materials and media surrounding the source and the listener play a determining role. Like for any other wave, the sound wave at a specific location depends on interference from different sources which depends on the relative phase reaching the location from different sources or after travelling different pathways. Thus, the distribution of energy and the energy absorption in sound exposure scenarios is not necessarily straightforward which leads to the many flavours of acoustics as subfields of physics and engineering, medicine and architecture. Well-known examples are the different acoustical characteristics of a furnished and unfurnished room, the sound-design of commercial products like cars and the engineering of anti-sound-reflection surfaces to be used in the prevention of sound propagation next to highways, railway lines, but also within sound-studios and in other architectural settings. Notably also details of the anatomy of the ear, the hair dress and clothing specific to one listener may affect the sound distribution before the sound reaches the sound sensitive cells in the inner ear of a specific observer.
To assess the exposure from different sources in a specific point, it is common use to analyse the different contributions by their frequency and to provide certain measurements related to sound (like power, amplitude etc) by their densities in the frequency spectrum. Depending on whether sound waves are harmonic (‘tones’, ‘hum’) or relate to uncorrelated events. Sound with an equal energy distribution across frequencies is called ‘white noise’, while most sources of sound exhibit dominating frequency bands originating from resonance phenomena. Typically, the above described complex interaction of sound waves with the particular environment and media (absorption, refraction, reflection and interference) leads to a changing spectrum of sound waves with progressing propagation or the modified position of an observer.
Source & ©: SCENIHR, |
<urn:uuid:b83421cc-5044-487f-9e95-8741a9a5f210> | seed | Genetics and racial, ethnic, and gender characteristics of COPD
Chronic obstructive pulmonary disease (COPD) may be influenced by race, ethnicity, gender, and genetic factors. Limited data exist that compare COPD in different racial/ethnic groups; however, the available data suggest that differences in COPD may exist. Potential differences in COPD between racial/ ethnic groups include genetic and biological differences; disparities in diagnosis and treatment; increasing exposure to cigarette in nonwhite populations world wide; and a lack of enrollment of minorities in epidemiological and clinical trials. Gender appears to also influence COPD. Historically, men have had higher prevalence rates of COPD than women, but recent data suggests that women may actually be more susceptible to COPD. COPD in omen may have different characteristics than in men, and it may be more severe. Importantly, in the United States, more women now die of COPD than men.
The marked variability in lung function and risk for COPD in people with similar cigarette smoking histories, together with studies of familial aggregation, support an important role for genetic risk factors in COPD. A small but important fraction of COPD cases harbor a major genetic determinant, α1-antitrypsin deficiency (AATD). This condition is most common in populations of Northern European ancestry, although affected individuals in other populations can be found. Despite significant advances in diagnosis and treatment, AATD remains highly under diagnosed. Manifestations other than classic lower-lobe predominant emphysema can include bronchiectasis, liver disease, panniculitis, and vasculitis. Intravenous augmentation with ATT protein is a commonly used treatment for severe AATD; it may result in improved pulmonary outcomes, although randomized clinical trials that support the efficacy of this treatment are not available.
Other genetic determinants of COPD have been more difficult to establish, as has been the case with many other common complex diseases. A number of genetic methods have been used. The most common studies to date have been association analysis of pathophysiological candidate genes. These studies have had mixed results; the vast majority have not been well replicated, though a few genes, such as mircosomal epoxide hydrolase, glutathione S-transferase PI, and transforming growth factor-β1, have had more consistently positive results. Studies of specific COPD-related phenotypes using these candidate genes have also been performed, with varying success. Animal models have been instrumental in analyzing COPD-related molecular pathways and they may also provide another source of candidate genes for association analysis. Several human monogenic diseases include emphysema or emphysema-like characteristics; while accounting for an extremely small percentage of obstructive lung disease or emphysema in the general population, these conditions may provide insights into mechanisms that are relevant for more common types of COPD.
Finally, genome-wide approaches represent an unbiased approach to identify novel COPD susceptibility genes. One method is to identify quantitative trait loci in animals. Traditional linkage studies in humans, of which one has been performed in COPD, have led to the discovery of several genomic regions of interest and a novel COPD-associated gene, SERPINE2. Genome-wide association studies have greater power to identify smaller effects; while they have yet to be published in COPD, they have led to successes in other complex diseases.
Racial/ ethnic differences in COPD. Overall, limited data exist on the racial/ ethnic differences in COPD susceptibility. Smoking prevalence does vary by ethnic group; some evidence suggests that susceptibility to the impact of cigarette smoking may differ as well, which may be due to genetic or other environmental factors. Available data on treatment and outcomes suggest that disparities exist between racial/ ethnic groups, but such data is sparse.
Gender differences in COPD. Though the prevalence of smoking among women has historically been less than in men, female smoking rates have been on the rise, especially in developing counties. In developing countries, exposure to biomass can be an important risk factor for COPD, especially in women. Women dying of COPD in the United States now outnumber men. Data suggest that there are differences between men and women in susceptibility to cigarette smoke. Gender may affect clinical presentation and management, although further studies are needed. GOLD -Global Initiative on Obstructive Lung Disease; BOLD - Burden of Obstructive Lung Disease; ED- emergency department; FEV1 - Forced Expiratory Volume in 1 second.
Cigarette smoking prevalence by race and gender in the United States, 1992-2004. Among black men, white men, black women, and white women, smoking rates have historically been highest in black men and lowest in black women, although rates of smoking are declining among all four groups.
Self-reported United States chronic obstructive pulmonary disease (COPD) prevalence by race and gender, 1980-2000. Data are age adjusted to the 2000 United States population. The prevalence of COPD based on self-reports of emphysema or chronic bronchitis has generally been higher among whites and women.
United States COPD death rates by gender, 1960-2000. COPD is the leading cause of death in the United States for which the absolute death rate is rising. The age-adjusted death rate between 1980 and 2000 increased by 67% overall; during this period, the increase in the COPD death rate was higher among blacks (87%) than whites and tripled among women. By 2000, the absolute number of women dying from COPD was higher than for men. Increases observed in 1999 may be the result of a different International Classification of Disease system.
Worldwide prevalence of COPD. The Prevalence of COPD in 2007 in different geographic regions based on the Burden of Obstructive Lung Disease data is presented based on results for specific cities within the countries listed. The reason for these regional differences are not entirely clear and may be due to different environmental exposures (smoking, biomass, occupation), as well as possible genetic factors.
Mechanism of protease inhibition and polymerization by α1- antitrypsin (ATT). A. The mechanism of protease inhibition by ATT, which is encoded by the SERPINA1 gene, resembles a mouse trap; the protease Typically neutrophil elastase) docks to the center loop at ATT, which swings to a more stable conformation, resulting in distortion of the structure of the protease and destruction of both molecules. B. In the Z variant (Glu342Lys) of ATT, a gap in the β-sheet A can either accept its own loop to form a latent conformation of process to irreversible polyimerization in the liver. Polymerization of the Z ATT within the liver leads to reduced circulating ATT levels; individuals with the genotype ZZ have approximately 15% of the normal plasma ATT levels.
Contributors to reduced alpha1-antitrypsin (AAT) activity among PI ZZ individuals. The most important determinant of reduced AAT activity in PI ZZ subjects is the reduced circulating level of AAT within the blood stream. However, other mechanisms have also been proposed, including reduced activity of each Z AAT molecule, inactivation of circulating AAT, and polymerization of circulating AAT.
Barriers to the diagnosis of alpha1-antitrypsin (AAT) deficiency (AATD). Despite the potentially devastating consequences, the majority of AATD subjects have not been identified; in one study, only 4% of the estimated PI ZZ individuals could be identified through local physicians. The major problem is underrecognition, though it is likely that the variable expression of disease phenotypes also plays a significant role. The role of deferral of genetic testing in AATD has not been accurately quantified.
Selection alpha1-antitrypsin alleles. The allele names are based historically on migration through an electrophoretic gel; for example, M (medium), S (small), Z (very low), and F (fast). The null alleles result in undetectable alpha1-antitrypsin and, therefore cannot be detected using serum electrophorisis. The most common alleles are the M alleles; phylogenic analysis indicate that M1A is the common ancestral form. S alleles result in a mild deficiency, while Z alleles result in both deficiency and dysfunction, with intracellular accumulation, increasing the risk for liver disease. The null alleles and other alleles (of which there are many) are quire rare.
Selected alpha1-antitrypsin (ATT) phenotype-genotype correlations. The combination of alleles that an individual inherits determines their ATT phenotype. The inheritance pattern for lung and liver disease manifestations is autosomal recessive, though the mode of inheritance for AAT levels is codominant. Levels exceeding 11uM (or 80 mg/dL) are generally felt to be protective against the development of chronic obstructive pulmonary disease (COPD), although epidemiologic studies indicate a possible increased risk of COPD in individuals with the PI MZ type.
Heterogeneity among PI ZZ subjects in the development of airflow obstruction. Despite inheriting identical variants in SERPINA1, PI ZZ subjects demonstrate significant variability in the development of COPD. In a study of 378 individuals, all with confirmed ZZ genotypes, forced expiratory volume I none second (FEV1) percentage predicted stratified by smoking status shows a wide variability, with some nonsmokers having low lung function and some smokers having preserved lung function. Other factors likely influence the development of COPD among PI ZZ subjects, which may include other diseases such as asthma or pneumonia, environmental factors, and genetic modifiers, such as interleukin-10.
Clinical presentation of alpha1-antitrypsin deficient (AATD) subjects. While early-onset of severe, lower-lobe predominant emphysema along with family history of COPD may be relatively easy to diagnose, underrecognitions of the disease still is a significant problem. Patients may present without classic pulmonary findings such as asthma or bronchiectasis, or with extrapulmonary manifestations such as liver disease, skin disease (panniculitis), or vasculitis. C-ANCA-cytoplasmic antineutrophilic cytoplasmic antibody.
Efficacy of alpha1-antitrypsin (AAT) augmentation therapy. Several investigations have assessed the efficacy of this therapy. Although there is no randomized controlled clinical trial that confirms efficacy, several observational studies provide supportive evidence. FEV1- Forced expiratory volume in 1 second.
Genetic Determinants of COPD Other Than alpha1-Antitrypsin Deficiency
A general theoretical model of the growth and decline of lung function with time. This diagram may also serve as a model of how different genetic and environmental factors could affect the development of COPD. The onset of symptoms increases with decreasing lung function but varies between individuals. Peak lung function is reached at approximately 20 years, which is typically followed by a plateau phase. Genetic variants or environmental factors (eg childhood respiratory infections) may result in reduced lung growth; with a similar rate of decline, this could result in an early onset of COPD. Genetic or environmental factors may also cat later in life, resulting in an early or more rapid decline in lung function. These mechanisms may also act in combination.
Steps to identify genetic determinants for a complex disease are as follows. 1) the phenotype(S) studied should be well defined; consider quantitative, objective, intermediate phenotypes (eg, serum markers, lung function). 2) A genetic component should be demonstrated. Studies of familial aggregation can asses the risk to relatives of affected individuals compared to unaffected individuals. Similarly, twin studies that demonstrate a higher correlation between monozygotic (identical) twins and dizygotic (fraternal) twins support a genetic etiology. The relative genetic component of the disease can be estimated by its heritability, which can be calculated by twin studies (potentially resulting in an overestimate) or family based studies. 3) Linkage analysis followed by gene localization (positional cloning) has been the standard approach for mendelian disorders and has been used with some success in complex trait genetics. Genome-wide association analyses are a more powerful method to search for novel susceptibility loci. Alternatively, candidate genes can b chosen for biological plausibility from human and animal models, gene expression, monogenic syndromes, etc. 4) Once an association is demonstrate, it is important to replicate findings in other populations. 5) an association with a genetic variant such as a single-nucleotide polymorphism is usually due to linkage disequilibrium; in other words, the variant is not in its self causative, but co-segregates in the genome with the true variant(s). Thus, further studies are usually needed to identify the functional variant(s). Gene-gene and gene-environment interactions can be studied. Functional work is important in determining pathophysiology. 6) Once the key functional variant(s) are found, the impact of the variant on the overall disease burden in the population can be determined, estimation of risk and prognosis can be provided, and, ultimately, improved understanding of the pathophysiology can new treatments can result.
Methods to identify the genetic determinants of COPD. Linkage analysis has been successful in mendelian traits, though there has been only modest success in finding novel genes associated with complex traits. The vast majority of studies have employed candidate gene-association analysis. Results of these association studies have been mixed, with lack of consistent replication a significant problem. Genome-wide association analyses have been promising in many other complex diseases. SNP - single nucleotide polymorphism; GWAS - genome-wide association studies; QTL - quantitative trait locus; CNV - copy number variation.
Population-based, case-control, and family-based genetic- association analysis. In all three types of studies, there is an association of disease status (bold outline) with the risk allele (purple). In case-control or population-based study designs, a higher frequency of AB and BB genotypes is seem among cases, which can be tested using chi-square, Armitage trend, or other tests, depending on the genetic model. In family-based analysis, parent-child trios or larger pedigrees are collected. Based on random assortment, each offspring has a 50% change of inheriting either A or B from a heterozygous AB parent. In this example, the cases are much more likely to have received the B allele, indicating deviation from random assortment. The statistical significance of the associations can be tested using the transmission disequilibrium test or its variations.
Evidence for genetic susceptibility to COPD and COPD-related lung-functions phenotypes. Familial aggregation may be demonstrated in several ways. In twin studies, higher concordance among (or smaller differences between) monozygotic versus dizigotic twins is suggestive of genetic influences. Studies of lung function have ranged from showing the same correlation in monozygotic and dizygotic twins to show that monozygotic twins have twice as much correlation; however, evidence for greater monozsygotic concordance has been demonstrated in most studies. In many family studies, a higher correlation has been demonstrated among more closely related family members (eg, siblings versus spouses), which also suggests a genetic influence. Heritability is an estimate of the proportion of genetic, as opposed to environmental, contributions to phenotypic variation. Several factors need to be considered, such as: 1) twin studies, 2) inclusion of covariates such as height and smoking can significantly affect heritability estimates, 3) different models and different populations (eg, general population versus COPD families) make direct comparisons difficult. Nevertheless, most heritability estimates suggest a significant impact of genes on lung-function levels. Finally, several studies in COPS using various phenotypes of airflow obstruction, chronic bronchitis, or a combination, have demonstrated a relative risk greater than 1 to siblings, indicate the involvement of familial/genetic components in COPD. FEF -forced expiratory flow; FEV1 - forced expiratory volume in 1 second; FVC - forced vital capacity.
Linkage analysis of lung function in the general population and in COPD families. Linkage analysis uses relatively widely spaced genetic markers throughout the genome and relies on larger regions of chromosomal sharing within families to find markers that co-segregate with disease loci. While highly successful for mendelian diseases, linkage analyses have been more challenging for complex diseases. Several studies have performed linkage analysis of lung function in families that were not selected for lung disease. To date, only one linkage analysis in COPD families has been reported, in the Boston Early-Onset COPD Study. Few regions of interest have been replicated between the general population studies and the COPD study; reasons for this include phenotypic and genetic heterogeneity and small sample sizes. One candidate gene foe lung function (SMOC2) and two candidate genes for COPD (TGFbeta1, SERPINE2) were identified within these linkage regions. Genomic regions with suggestive evidence of linkage in extended pedigrees (logarithm of the odds [LOD] greater than or equal to 1.9) were included; regions linked to more than one phenotype or in more than one study are shown in bold. FEF - forced expiratory flow; FEV1 - forced expiratory volume in 1 second; FVC - forced vital capacity.
Summary of the genetic-association studies of COPD and COPD related lung-function phenotypes (eg, forced expiratory volume in 1 second, lung-function decline). Candidate genes with significant associations in at least two studies are reported, excluding studies of asthma and SERPINA1. Studies were considered positive or negative based on the author's report and primary analysis (suggestive findings from gene-gene interactions and subgroup analyses were generally not included). Most candidate genes have had both positive and negative studies.
Reasons for a lack of replication in COPD genetic association studies. Of the numerous COPD genetic association studies published, few have been consistently replicated. Some have replicated an association, but in the opposite direction. Small sample size, genetic heterogeneity in different study populations, failure to adjust for multiple statistical testing, lack of assessment/ adjustment for population stratification, and genotyping error all are potential contributors to these inconsistent results. With the rapidly decreasing cost of single-nucleotide polymorphism genotyping and the availability of the HapMap, a lack of appropriate coverage of a gene or the genome) via genome-wide association studies) may become less of a problem, except for rare variants. TDT-transmission-disequilibrium test; FBAT- family-based association test; SNP- single-nucleotide polymorphism.
Selected replication genetic associations in COPD. Several genes have been associated in at least two studies for COPD or lung function phenotypes such as forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), and FEV1 decline. These genes have generally come from three groups: protease-antiprotease, oxidant/antioxidant and xenobiotic metabolizing enzymes, and immune/inflammatory mediators. However, these pathways have been the most heavily studied source for candidate genes, so they may not be the most biologically important pathways. SNP- single-nucleotide polymorphism.
Selected Genetic Association Studies for COPD-Related Phenotypes. One of the problems in the genetics of COPD (and in fact, for most complex diseases) is the inherent heterogeneity of COPD cases. COPD-related subtypes, such as emphysema- versus airway-predominant disease may have different genetic determinants. In addition, COPD-related phenotypes, such as pulmonary hypertension may share genetic determinants with non-COPD related pulmonary hypertension, or have determinants unique to COPD.
Other Rare / Genetic Diseases Associated with COPD and/or Emphysema-like Phenotypes. While alpha 1-antitrypsin deficiency is the most widely studied single gene disorder leading to COPD, other genetic disorders also have COPD or emphysema-like conditions as part of their syndrome constellations. While these disorders can account for only a small proportion of COPD or COPD-like conditions, they may be helpful in finding the genetic determinants of more common varieties of COPD, and (in some cases) should also be considered in cases that appear to be typical COPD but have other unusual features. These disorders can be: 1) single gene disorders with the causal gene identified, such as Marfan syndrome, 2) disorders where the specific causal gene responsible for COPD has not been found (e.g. Down syndrome), or 3) the genetic mechanisms are unclear (Hypocomplementemic urticarial vasculitis). In addition, the strength of the association with COPD or emphysema varies from clear disease association (cutis laxa, Marfan syndrome) to case reports of an association (Sialuria, Niemann-Pick disease).
Mouse Models of COPD
Gene Knockout / Loss of Function and Transgenic Animal Models of COPD and/or Emphysema. Animal models have played a key role in our understanding of COPD, beginning in the 1960's with providing key support for the protease-antiprotease hypothesis. Mouse strains with differential susceptibilities to emphysema and COPD have been described. In some cases, the genetic determinants have been found; in others, quantitative trait locus (QTL) mapping to determine the loci responsible for these findings holds great promise. The advent of mouse knockouts and transgenic mice that overexpress a protein of interest (often limited to a specific tissue) has led to significant improvement in our understanding of disease pathways, especially in models involving cigarette smoke exposure. The applicability of these models to human disease is not always clear; however, as 1) fundamental differences exist between human and animal lung structure and function, 2) human disease genetic variants generally do not lead to complete loss of protein function; 3) loss of protein function at a blastocyst stage may lead to compensation, and overexpression may interfere with expression of other genes; 4) the lung may be involved nonspecifically in systemic disease, and 5) models may be incomplete or have poor overlap with human disease.
Mouse Strains Associated with COPD and/or Emphysema. In addition to genetically engineered knock-out or transgenic mouse models of emphysema, there are a variety of naturally occurring murine strains that have increased susceptibility to emphysema. Adapted from Mahadeva. |
<urn:uuid:f725e3b9-9c2b-4502-8558-fb143a7a1c1a> | seed | Gastroinestinal disorders occur when the digestive tract (gastrointestinal) does not function properly. As a result, patients may have difficulty digesting food, absorbing nutrients, or having normal bowel movements.
Several body parts, including the mouth, esophagus, stomach, small intestine, large intestine, and anus, make up the digestive (gastrointestinal) tract. The digestive process begins when food enters the mouth.
When a person begins chewing food, digestive enzymes in the saliva break down the food before it is swallowed.
The esophagus is a muscular tube that carries food and liquids from the mouth to the stomach. The stomach contains harsh enzymes that break down food so it can be absorbed by the body.
Food then enters the small intestine, which contains three parts:
the duodenum, jejunum, and ileum. Most of digestion occurs in the small intestine because it is responsible for absorbing nutrients from food.
The remaining food then enters the colon, which also has three parts:
the cecum, colon, and rectum. The large intestine absorbs any remaining water from indigestible food matter and eliminates the unusable food matter, or waste, from the body. The anus is the external opening of the rectum. It allows waste (feces) to be excreted from the body.
There are many different types of gastrointestinal disorders. Some gastrointestinal disorders affect multiple parts of the digestive tract, while others only affect the esophagus, abdomen/stomach, intestines, or anus/rectum. The severity of gastrointestinal disorders varies significantly, depending on the specific type of the disease. Some disorders, such as indigestion, are mild while others, such as Crohn's disease, are life-long.
Abdominal pain, abdominal wall inflammation, achalasia, acid reflux, anal fistula, appendicitis, bleeding stomach ulcers, bloating, Chinese restaurant syndrome, colic, colonic spasm, colonoscopy, digestive enzyme, digestive enzyme insufficiency, digestive tonic, digestion, difficulty swallowing, diverticular disease, diverticulosis, duodenal ulcer, dyspepsia, dysphagia, esophageal spasm, fat excretion in stool, fatty liver, fistula, flatulence, gas, gastric spasm, gastric ulcer, gastritis, gastroenteritis, gastroesophageal, gastroesophageal reflux disease,
gastrointestinal, gastrointestinal concerns, gastrointestinal conditions, gastrointestinal disorders, gastrointestinal tract, H. pylori, H. pylori gastric infection, H. pylori infection, heartburn, Helicobacter pylori bacteria,
hiccough, hiccup, hypochlorhydria, ileus, indigestion, infantile colic, intestinal disorders, intestinal malabsorption, low stomach acid, Menkes' kinky-hair disease, necrotizing enterocolitis, non-tropical sprue, non-ulcer dyspepsia, pancreatic enzyme insufficiency, peritonitis, poor appetite, poor digestion, post-operative ileus, proctitis, pyloric stenosis, rectal inflammation, rectal prolapsed, reflux, regional enteritis, spleen disorders, splenomegaly, sprue, steatorrhea, stomach inflammation, stomachache, stomach upset, swallowing, upset stomach, zinc malabsorption.
disorders that affect multiple parts of the gastrointestinal tract
Diarrhea: Diarrhea occurs when an individual has loose stools or watery stools. Diarrhea is a symptom of an underlying health problem, such as an infection, that prevents the intestines from properly absorbing nutrients from food. Acute diarrhea lasts a few days and affects nearly everyone at some point in their lives. Chronic diarrhea generally lasts longer than four weeks and may be a sign of a serious condition such as inflammatory bowel disease (IBD) or gastroenteritis.
Diarrhea is usually caused by a viral, bacterial, or parasitic infection. Diarrhea that is caused by an infection (often called infectious diarrhea) may be passed from person to person. Viruses, such as the Norwalk virus, cytomegalovirus, viral hepatitis herpes simplex virus, and rotavirus are the most likely to cause diarrhea. Infants and young children are most likely to develop diarrhea as a result of a rotavirus infection. If an individual consumes food or water that is contaminated with certain bacteria or parasites, he/she may develop diarrhea. This type of diarrhea is often called traveler's diarrhea because it frequently occurs in people who are traveling to developing countries. Common bacterial causes of diarrhea include campylobacter, salmonella, Escherichia coli (E. coli), Shigelladysenteriae, and Clostridium difficile. Common parasites that are known to cause diarrhea include Giardia lamblia and cryptosporidium.
Diarrhea may be caused by a number of other factors, including lactose intolerance, certain medications (especially antibiotics and anti-HIV medications called antiretrovirals), artificial sweeteners called sorbitol and mannitol (commonly found in sugar-free products and many types of chewing gum), surgery, or other gastrointestinal disorders (such as irritable bowel syndrome or IBS).
Symptoms of diarrhea often include frequent and loose stools, abdominal pain or cramping, bloating, fever, excessive thirst, and dehydration. Diarrhea causes dehydration because the body loses water and salts. Infants and young children are at risk of developing severe dehydration as a result of diarrhea. Patient with severe diarrhea may be unable to control the passage of stool, a condition known as fecal incontinence. When a patient experiences frequent, severe, and bloody diarrhea, the condition is often called dysentery.
Diarrhea usually requires little to no medical treatment. Individuals with diarrhea should drink plenty of water. Patients may also benefit from drinks that contain electrolytes, including Pediatric Electrolyte®, Pedialyte®, or Enfalyte®. Individuals should avoid diuretics, such as caffeine, because they worsen symptoms of dehydration. Certain foods, including rice, dry toast, and bananas may help reduce symptoms of diarrhea. In addition, anti-diarrheal medications, such as bismuth subsalicylate (Pepto-bismol®, Bismatrol®, or Kaopectate®), diphenoxylate atropine (Lomotil®, Lofene®, or Lonox®), or loperamide hydrochloride (Imodium®), may also be taken to reduce diarrhea in patients older than three years of age.
If diarrhea continues for longer than four days or blood is present in the stool, patients should visit their healthcare providers to determine the underlying cause. If an infection is causing symptoms, an antimicrobial medication may be prescribed. The specific type, dose, and duration of treatment depend on the severity and type of infection.
Irritable bowel syndrome (IBS): Irritable bowel syndrome (IBS), also called spastic colon, mucous colitis, spastic colitis, nervous stomach, or irritable colon, is a long-term condition that is characterized by abdominal pain, cramping, diarrhea, and constipation. IBS is a functional bowel disorder because the bowel appears normal but does not function properly.
Although the exact cause of irritable bowel syndrome (IBS) is unknown, researchers believe that poor diet, neurotransmitter imbalances, and infections may contribute to the development of the disorder.
The colon contracts (colon motility) to move the contents inside the colon toward the rectum. During this passage, water and nutrients are absorbed into the body and waste is excreted as stool. A few times each day, contractions push the stool down the colon resulting in a bowel movement.
In IBS patients, the muscles of the colon, sphincters, and pelvis do not contract properly. As a result, patients experience constipation or diarrhea. This causes symptoms of abdominal pain, cramping, bloating, and a sense of incomplete stool movement. Symptoms may improve after the patient has a bowel movement.
Health complications arising from IBS include hemorrhoids (aggravated by diarrhea and/or constipation), depression, weight loss, vitamin and mineral deficiencies, and psychosocial problems.
Most people can control symptoms of IBS with diet, stress management, lifestyle modification, and prescribed medications. A medication called loperamide (Imodium®) is commonly used to treat IBS patients with diarrhea. Laxatives, such as polyethylene glycol (Miralax®), sorbitol, and lactulose (Cephulac®), may be used. Phosphate enemas (Fleet Phospho-soda®) and emollient enemas (Colace Microenema®) have also been used. Suppositories, such as bisacodyl (Dulcolax®), may also be taken. The most widely studied drugs for the treatment of abdominal pain are a group of drugs called antispasmodics, which cause muscle relaxation. Commonly used antispasmodics include hyoscyamine (Levsin® or Levsinex®), dicyclomine (Bentyl®), and methscopolamine (Pamine®).
For some patients, however, IBS may be disabling. They may be unable to work, attend social events, or even travel short distances due to urgency to defecate (pass stool) and/or pain in the colon.
Inflammatory bowel disease (IBD): Inflammatory bowel disease (IBD) refers to two chronic diseases that cause inflammation of the intestines: ulcerative colitis
The cause of IBD remains unknown. However, current research indicates that IBD most likely involves a complex interaction of factors, including heredity, the immune system, and antigens in the environment.
The symptoms of these two illnesses are very similar, which often makes it difficult to distinguish between the two. In fact, about 10% of colitis (inflamed colon) cases cannot be diagnosed as either ulcerative colitis or Crohn's disease. When physicians cannot diagnose the specific IBD, the condition is called indeterminate colitis.
IBD causes chronic inflammation in the gastrointestinal tract and may lead to complications, such as colon cancer. The most common symptoms of both ulcerative colitis and Crohn's disease are diarrhea (ranging from mild to severe), abdominal pain, decreased appetite, and weight loss. If the diarrhea is extreme, it may lead to dehydration, increased heartbeat, and decreased blood pressure. As food moves through inflamed areas of the gastrointestinal tract, it may cause bleeding. Continued loss of blood in the stool may result in low levels of iron in the blood, a condition called anemia.
In addition, Crohn's disease may also cause intestinal ulcers, fever, fatigue, arthritis, eye inflammation, skin disorders, and inflammation of the liver or bile ducts.
Ulcers may extend through the intestinal wall creating a fistula (an abnormal opening). If an internal fistula develops, food may not reach the area of the intestine involved in absorption. External fistulas in the anus may result in continuous bowel drainage onto the skin. Fistulas may also become infected, a condition that can be life threatening if left untreated. Symptoms of a fistula may include pain, fever, tenderness, itching, and general feeling of discomfort.
Toxic megacolon is a rare, but potentially life-threatening complication of severe IBD. Toxic megacolon is characterized by a dilated colon (megacolon), abdominal distension (bloating), and occasionally fever, abdominal pain, or shock. In severe cases, the condition may cause the colon to become paralyzed. Toxic megacolon prevents the individual from having bowel movements. If the condition is not treated, the colon may rupture, resulting in peritonitis, a life-threatening condition that requires emergency surgery.
Other complications may include dehydration, malnutrition, obstruction, ulcers, and anal fissures.
Many medications are used to treat IBD. Anti-inflammatories, such as sulfasalazine (Azulfidine®), mesalamine (e.g. Asacol® or Rowasa®), olsalazine (Dipentum®), and balsalazide (Colazal®), help reduce inflammation. Corticosteroids, such as prednisone (Deltasone®), have been shown to effectively reduce inflammation of the gastrointestinal tract in IBD patients. Medications, called immunosuppressants, have been used to treat IBD. Examples include azathioprine (Imuran®), mercaptopurine (Purinethol®), cyclosporine (e.g. Neoral® or Sandimmune®), and infliximab (Remicade®). A fiber supplement, such as psyllium powder (Metamucil®) or methylcellulose (Citrucel®), may help relieve symptoms of mild to moderate diarrhea. Inflammation may cause the intestines to narrow, resulting in constipation. Laxatives may be taken to relieve symptoms of constipation. Oral laxatives such as Correctol® have been used. A qualified healthcare provider may recommend acetaminophen (Tylenol®) to relieve mild pain. Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Advil® or Motrin®) or naproxen (Aleve®), as researchers have found a strong relationship between NSAIDs and IBD flare-ups. Therefore, NSAIDs should not be taken.
If all other treatments fail to relieve symptoms, a qualified healthcare provider may recommend surgery. Surgery is more commonly performed in ulcerative colitis patients because inflammation is limited to the colon. During the procedure, the entire colon and rectum is removed (proctocolectomy).
A new procedure, known as ileoanal anastomosis, eliminates the need for recovered patients to wear a bag to collect stool. This new procedure involves attaching a pouch directly to the anus, allowing the patient to expel waste normally. However, the patient may have as many as five to seven watery bowel movements a day because there is no longer a colon to absorb water. Between 25 and 40% of patients with ulcerative colitis eventually need surgery.
Indigestion (non-ulcer dyspepsia): Indigestion, also called non-ulcer dyspepsia (upset stomach), is a general term that describes discomfort in the upper abdomen. Patients who have indigestion typically suffer from several symptoms, including heartburn, bloating, belching, and nausea.
Indigestion affects nearly everyone from time to time, and it is not considered a serious health condition.
Indigestion may occur if a patient eats too much of a particular food (especially fatty or spicy foods) or eats too quickly. Alcohol, stress, and anxiety may also contribute to indigestion.
Because indigestion is such a common condition, it generally does not require a diagnosis. However, patients who frequently experience indigestion should visit their healthcare providers because it may be a symptom of an underlying medical condition, such as acid reflux disease.
Antacids, such as calcium carbonate (e.g. Tums®, Alka-Mints®, and Rolaids Calcium Rich®), may be taken by mouth to treat symptoms of heartburn and upset stomach. Anti-flatulant medications, such as alpha-galactosidase enzyme (Beano®), simethicone (Gas-X®, Genasyme®, or Mylanta® Gas Relief), may be taken by mouth to prevent and/or treat symptoms of bloating and flatulence (gas).
glutamate symptom complex (Chinese restaurant syndrome): Monosodium glutamate symptom complex, also called Chinese restaurant syndrome, is a group of symptoms that some patients develop after eating Chinese foods. Symptoms typically include flushing, headache, sweating, facial pain or swelling, numbness or burning around the mouth, and chest pain.
Although it has been suggested that a food additive in Chinese food, called monosodium glutamate (MSG), may cause the reaction, it has not been proven. Since there is limited scientific data about the condition, it remains unknown if the frequency and amount of MSG exposure increases or decreases an individual's risk of experiencing symptoms.
Patients generally do not require treatment for monosodium glutamate symptom complex because symptoms are mild and resolve on their own. However, if patients experience chest pain or difficulty breathing, they should seek immediate medical treatment because this may be a sign of a serious allergic reaction called anaphylaxis.
Diverticulosis and diverticulitis: Diverticulosis refers to small, bulging pouches (diverticula) in any part of the digestive tract. Diverticula are most often found in the large intestine (colon). However, they may also develop in the esophagus, stomach, or small intestine.
Diverticulosis is a common condition that affects more than half of Americans who are older than 60 years of age. Most patients do not know they have diverticulosis because they do not experience any signs or symptoms of the condition.
However, if the diverticula become infected or inflamed, the condition is called diverticulitis. Patients with diverticulitis typically experience intense abdominal pain, nausea, bloating, bleeding from the rectum, tenderness in the abdomen, difficulty or pain during urination, fever, and changes in bowel movements.
Diverticulitis is usually diagnosed after a computerized tomography (CT) scan is performed. A machine produces images of the internal organs in the abdomen. Inflamed diverticula will be apparent if the patient has diverticulitis.
Mild cases of diverticulitis can be treated with rest, changes in the diet, and antibiotics. Patients should not eat any fiber, including whole grains, fruits and vegetables, for several days. This restricted diet gives the colon time to heal. Antibiotics, such as metronidazole (Flagyl®), moxifloxacin (Avelox®), ciprofloxacin (Cipro®),
amoxicillin/clavulanate (Augmentin®), and Imipenem (Primaxin®) are commonly prescribed to kill the bacteria that are infecting the diverticula.
Serious cases of diverticulitis may eventually require surgery to remove the infected part of the colon.
Peptic ulcers: An ulcer is an open sore or break in a body tissue. Peptic ulcers develop on the inside lining of the stomach (gastric peptic ulcer), upper small intestine (duodenal peptic ulcer), or esophagus (esophageal peptic ulcer).
Researchers have found that a bacterial infection with Helicobacter pylori is the most common cause of gastric and duodenal ulcers. Some medications, including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen (Motrin® or Advil®), may also cause gastric and duodenal ulcers. In addition, smoking tobacco increases a patient's risk of developing ulcers. It remains unclear whether or not excessive alcohol consumption leads to an increased risk of ulcers.
Esophageal peptic ulcers are usually associated with acid reflux disease.
Contrary to popular beliefs, diet and stress do not cause peptic ulcers. However, high levels of stress and acid foods and beverages, such as coffee, may aggravate symptoms of peptic ulcers.
Peptic ulcers generally cause pain that may be felt anywhere from the chest to the stomach. Pain may last a few minutes to several hours. Symptoms are often the worst when the stomach is empty or at night. They may also come and go for a few days to weeks. Less common symptoms include vomiting blood, dark blood in the stools, nausea, vomiting, and unexplained weight loss.
Most ulcers are diagnosed after an X-ray is taken of the upper gastrointestinal tract. An endoscopy may also be performed. During the procedure, a thin tube with a camera (endoscope) is inserted into the mouth and into the digestive tract. This allows the healthcare provider to see if ulcers are present.
Patients take antibiotics, such as amoxicillin (Amoxil®), clarithromycin (Biaxin®), or metronidazole (Flagyl®), if an H. pylori infection is causing peptic ulcers. Patients also take medications called acid-blockers, which reduce the amount of acid in the stomach. As a result, the patient experiences less pain, and the gastrointestinal tract is able to heal. Examples of acid blockers include ranitidine (Zantac®), famotidine (Pepcid®), cimetidine (Tagamet®), and nizatidine (Axid®).
Patients should take their medications exactly as prescribed. If medication is not taken regularly or stopped too early, the ulcer may not heal properly. Also, during treatment, patients should not smoke, consume alcohol, or take nonsteroidal anti-inflammatory drugs (NSAIDs) because they may worsen symptoms.
Pyloric stenosis: Pyloric stenosis is a rare condition that occurs when babies are born with abnormally large muscles at the opening at the bottom of the stomach (pylorus). The pylorus connects the stomach to the small intestine.
Babies with pyloric stenosis are unable to transport food into the small intestine. This may lead to: extremely forceful vomiting (also called projectile vomiting) that may contain blood, weight loss, dehydration, and electrolyte imbalances. Babies are usually hungry after vomiting. They may cry without tears because they are dehydrated.
The exact cause of pyloric stenosis remains unknown. However, researchers believe that genetics plays a role.
Most patients are diagnosed and treated when they are three to 12 weeks old. Babies with pyloric stenosis need to have surgery as soon as possible to correct the pylorus. The surgical procedure, called pyloromyotomy, involves reducing the size of the pylorus muscles. Patients typically experience an improvement in symptoms about 24 hours after surgery.
Colic (infancy): Colic is usually defined as crying for more than three hours a day, three days per week, for longer than three weeks in an otherwise healthy baby.
It remains unknown what causes colic. However, researchers have suggested that it may be caused by gastrointestinal problems, such as lactose intolerance or an immature digestive system. This is because sometimes a colic episode stops after a baby passes gas or has a bowel movement. Other possible causes include maternal anxiety, differences in the way a baby is fed or comforted, and/or allergies.
There is currently no treatment that has been proven to be effective for the treatment of colic in babies. Colic typically goes away once the baby reaches three months of age.
Biliary colic: Biliary colic, also called a gallbladder attack, describes pain and nausea that accompanies many disorders that affect the gallbladder. The gallbladder is an organ that stores digestive fluids that are needed to break down fats in foods.
Biliary colic may occur when a gallstone moves through the biliary tract towards the small intestine. An attack may also be the result of cholestasis, which occurs when the flow of bile is blocked. Gallbladder attacks may also occur if the gallbladder becomes inflamed.
Gallbladder attacks generally last one to four hours. Common symptoms include pain on the right side of the abdomen, nausea, vomiting, and bloating. The gallbladder, which is located in the lower right side of the abdomen, is usually tender to the touch. The pain may be dull, sharp, or excruciating. It is common for the pain to radiate to the right shoulder blade.
A healthcare provider will be able to tell if a patient is having gallbladder attacks after a detailed medical history and physical examination is performed. The next step is to determine the underlying cause of the symptoms.
Blood tests and liver function tests may be performed to determine if the patient has cholestasis. If the patient's alkaline phosphatase levels are three times higher than normal, cholestasis is indicated.
A computerized tomography (CT) scan, magnetic resonance imaging (MRI) scan, or ultrasound may also be performed. These tests produce images of the internal organs and may help the healthcare provider detect abnormalities, such as gallstones, that may be causing the condition.
An endoscopic retrograde cholangiopancreatography (ERCP) may be performed at the hospital to check for problems in the liver, gallbladder, bile ducts, and pancreas. During the procedure, a thin, flexible tube with a camera is inserted through the mouth into the small intestine. The tube then hooks into the bile duct, allowing the healthcare provider to see the biliary tract.
Treatment of gallbladder attacks depends on the underlying cause. For instance, a gallstone may need to be surgically removed if it is causing symptoms. Antibiotics may be prescribed if an infection is the cause. If a medication is the suspected cause, a healthcare provider may recommend an alternative medication.
Gastroenteritis: Gastroenteritis describes inflammation of the stomach and intestine that causes diarrhea, vomiting, and cramps.
Gastroenteritis is often mistaken for the stomach flu or food poisoning because it causes similar symptoms. Although some doctors may call gastroenteritis the flu, gastroenteritis is not caused by any of the influenza viruses.
An infection in the digestive tract may cause gastroenteritis. This may happen if patients consume foods or beverages that contain disease-causing bacteria, viruses, or parasites. In some cases, the food itself may irritate the patient's digestive tract. For instance, if a lactose intolerant patient consumes a dairy product, the stomach and intestines become irritated, which may lead to gastroenteritis. In addition, some mediations, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), some antibiotics, caffeine, laxatives, and steroids, may cause gastroenteritis.
Most patients recover quickly from gastroenteritis. However, babies and the elderly have a greatest risk of developing life-threatening complications, such as dehydration and poor nutrition.
If an infection is causing gastroenteritis, patients take medications called antimicrobials to kill the disease-causing organisms. Commonly prescribed antimicrobials include ciprofloxacin (Cipro®), trimethoprim/sulfamethoxazole (Bactrim®), and rifaximin (Xifaxan®, RedActiv®, or Flonorm®). Adults may also take medications, called antiemetics, which reduce vomiting. Commonly prescribed antiemetics include promethazine (Phenergan® or Anergan®), prochlorperazine (Compazine®), or ondansetron (Zofran®). Anti-diarrheals, such as diphenoxylate atropine (Lomotil®, Lofene®, or Lonox®) or loperamide hydrochloride (Imodium®), may also be taken to reduce diarrhea in patients older than three years old.
Gaucher's disease: Gaucher's disease is a rare, inherited disorder that occurs when a fatty substance called glucocerebroside accumulates in the spleen, liver, lungs, and bone marrow. In some cases, it also affects the functioning of the brain.
Patients with Gaucher's disease are born with low levels of a digestive enzyme called glucocerebrosidase, which breaks down glucocerebroside. This deficiency causes glucocerebroside to build up in the body.
There are three types of Gaucher's disease: Type I, Type II, and Type III. Type I is the most common form. It causes enlargement of the liver (hepatomegaly) and spleen (splenomegaly) and it may also affect the lungs and kidneys. When fat develops in the liver, it is often called hepatic steatosis. Type I may develop at any age. Type II is a fatal condition that develops during infancy and causes severe brain damage. Most children with Type II Gaucher's disease die by the age of two years old. Type III causes the liver and spleen to enlarge and brain damage gradually occurs over time. Type III usually occurs in children and adolescents.
Gaucher's disease is diagnosed after a blood test. Patients with the disorder will have low levels of glucocerebrosidase in their blood.
There is currently no cure for Gaucher's disease. Patients with Type I and Type III Gaucher's disease take enzyme replacement therapy, which has been proven to effectively manage symptoms. However, there is no effective treatment to manage the symptoms of Type II.
Gastroesophageal reflux disease (GERD): Gastroesophageal reflux disease (GERD), also called acid reflux disease, occurs when liquid from the stomach backs up (regurgitates) into the esophagus. This liquid may contain stomach acids and bile. In some cases, the regurgitated stomach liquid can cause inflammation (esophagitis), irritation, and damage to the esophagus.
It remains unknown exactly what causes GERD. Several factors, including hiatal hernias (when the stomach pushes up through a hole in the diaphragm muscle), abnormally weak contractions of the lower esophageal sphincter, and abnormal emptying of the stomach after a meal, have been associated with GERD.
Common symptoms of GERD include a burning sensation in the chest that may spread to the throat (heartburn), chest pain (especially when lying down), difficulty swallowing (dysphagia), regurgitating food or sour liquid, coughing, hoarseness, sore throat, and wheezing.
Several factors may worsen symptoms of the condition. For instance, spicy foods, fatty foods, chocolate, caffeine, tomato sauce, carbonated beverages, mint, alcoholic beverages, large meals, lying down after eating, some medications (e.g. sedatives, tranquilizers, or blood pressure drugs), and cigarette smoking may worsen symptoms of GERD.
Most cases of GERD can be diagnosed based on the patient's symptoms.
GERD is usually a lifelong condition because there is no cure for the disorder. Patients must take medications for the rest of their lives to manage symptoms. In addition, patients should not smoke because it may increase the amount of stomach acid and worsen symptoms.
Patients with mild cases of GERD may be able to manage their symptoms with over-the-counter medications and changes in the diet. Patients may experience improvements in symptoms if they eat smaller meals and eliminate foods that are known to cause heartburn.
Antacids, such as Gelusil®, Rolaids®, Mylanta®, Maalox®, or Tums®, may neutralize stomach acid and provide quick relief of GERD symptoms. However, they will not help the esophagus heal. Patients who take antacids frequently may experience diarrhea or constipation.
Some over-the-counter H-2 receptor blockers, such as cimetidine (Tagamet HB®), famotidine (Pepcid AC®), nizatidine (Axid AR®), and ranitidine (Zantac 75®), may also help provide quick relief of symptoms. These medications reduce the amount of stomach acid that is produced. Side effects of H-2 receptor blockers, which are uncommon, may include changes in bowel movements, dry mouth, dizziness, or drowsiness. Proton pump inhibitors, such as omeprazole (Prilosec®), may also be taken short-term to help the esophagus heal. Patients should not take these medications long term unless they talk with their healthcare providers first.
Patients with persistent GERD may require prescription-strength medications to manage symptoms and prevent esophageal damage. H-2 blockers, such as Axid®, Pepcid®, Tagamet®, and Zantac®, are commonly prescribed. Examples of prescription-strength proton pump inhibitors include esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®), pantoprazole (Protonix®), and rabeprazole (Aciphex®).
Achalasia: Achalasia is a rare disease that occurs when the muscles of the esophagus are unable to relax. The esophageal sphincter, which is the muscle between the lower esophagus and stomach, is unable to relax enough to allow food to pass into the stomach. Also, the lower half of the esophagus does not contract and relax properly. As a result, the food is not properly pushed down into the stomach, and patients have difficulty swallowing food (dysphagia).
The exact cause of achalasia remains unknown. Researchers believe that several factors, including infections, genetics, and abnormalities in the immune system, may contribute to the development of the condition.
The most common symptom of achalasia is difficulty swallowing solid foods and liquids. Some patients experience heavy sensations in the chests after eating that feels like chest pain. If food collects in the esophagus, it may cause irritation and lead to esophagitis (inflamed esophagus). Some patients may regurgitate their food if it is trapped in the esophagus. If regurgitated food enters the windpipe (trachea), it may cause infections such as pneumonia.
Since patients have difficulty swallowing and consuming foods and beverages, they typically experience weight loss. Other complications may include malnutrition and dehydration.
Achalasia is usually diagnosed after a video-esophagram is performed. During the procedure, the patient drinks a barium solution and video X-rays are taken of the esophagus. The healthcare provider is able to see if the barium enters the stomach properly. If the patient has achalasia, the barium will stay in the esophagus longer than normal. In addition, the lower end of the esophagus will be very narrow.
Some patients may experience an improvement in symptoms if they eat slowly, take small bites, and chew their food thoroughly.
In addition, patients with achalasia usually take nitrates, such as isosorbide dinitrate (Isordil®), and calcium-channel blockers, such as nifedipine (Procardia®) or verapamil (Calan®), to relax the muscles of the esophagus. These medications provide short-term relief of symptoms.
A procedure called forceful dilation, or stretching of the lower esophageal sphincter, is often needed to open the esophagus and allow food to enter the stomach. During the procedure, a tube with a balloon at the end is inserted into the patient's esophagus. The balloon is placed across the sphincter and inflated. As a result, the sphincter stretches out. Forceful dilation successfully treats 65-90% of patients with achalasia. The most serious complication of forceful dilation is rupture of the esophagus, which occurs in about five percent of patients. If a rupture occurs, antibiotics and/or surgery may be required. Forceful dilation is generally quicker and less expensive than surgery.
If forceful dilation is unsuccessful, a surgical procedure, called esophagomyotomy, may be performed. During the procedure, the sphincter is cut, which expands the esophagus and makes it easier for the patient to swallow. The procedure is more effective than forceful dilation. An estimated 80-90% of patients are treated successfully with esophagomyotomy. However, in some cases, dysphagia may return. The most common side effect of esophagomyotomy is GERD. In order to prevent GERD, the esophagomyotomy may be modified so that it does not completely cut the sphincter or the esophagomyotomy may be combined with anti-reflux surgery. Regardless of which surgery is performed, some healthcare providers recommend lifelong treatment with GERD medications, such as Axid®, Pepcid®, Tagamet®, or Zantac®. Other doctors only recommend lifelong treatment if GERD is diagnosed 24 hours after surgery.
Botox injections in the lower sphincter are the newest treatment for achalasia. The botulinum toxin is injected to weaken the sphincter. The effects of treatment usually last for several months. Patients may require additional injections. Patients who are elderly or unable to undergo surgery typically receive this treatment. It may also be performed to help patients gain weight and improve their nutritional status before surgery.
Esophageal spasms: Patients may experience spasms in the esophagus. Esophageal spasms may cause difficulty swallowing, painful swallowing, sensation that something is stuck in the throat, heartburn, and chest pain.
The exact cause of spasms remains unknown. However, eating hot or cold foods may contribute to the condition. Also, gastroesophageal reflux disease (GERD) or heartburn may also play a role in the development of esophageal spasms.
Patients typically take nitrates, such as isosorbide dinitrate (Isordil®), or calcium-channel blockers, such as nifedipine (Procardia®) or verapamil (Calan®), to relax the muscles.
acute abdomen and stomach disorders
Appendicitis: Appendicitis occurs when an organ in the lower right-side of the abdomen, called the appendix, becomes inflamed and filled with pus.
The cause of appendicitis is not always clear. In some cases, appendicitis may occur if food waste or a solid piece of stool becomes trapped in an opening near the appendix. It may also occur after an infection.
The most common symptom of appendicitis is severe pain in the lower right-hand side of the abdomen. Additional symptoms may include nausea, vomiting, loss of appetite, low-grade fever, constipation, bloating or inability to pass gas, diarrhea, and abdominal swelling.
Patients with appendicitis will have high levels of white blood cells in their blood. Imaging studies are also performed to determine if the appendix is enlarged.
Patients with appendicitis must have their appendix surgically removed as quickly as possible. Since the appendix has no known purpose, the patient's life is unaffected after the appendix is removed.
If the appendix is not removed quickly, it may break open or rupture. If the appendix ruptures, it may lead to an infection in the lining of the abdominal cavity. Infections may cause a condition called peritonitis, which occurs when the abdominal lining becomes inflamed. If the appendix ruptures, the patient may start to feel better. However, soon after, the abdomen may swell because it becomes full of gas and fluid. At this point, the abdomen usually feels hard, tight, and tender to the touch. Severe pain also develops throughout the entire abdomen. Patients may be unable to pass gas or have a bowel movement. Additional symptoms of peritonitis include fever, thirst, and decreased urination.
Patients who have symptoms of peritonitis should seek immediate medical treatment. Even if the condition is treated quickly, it may be fatal. Patients will receive aggressive treatment with intravenous antibiotics. Surgery is necessary to remove the burst appendix. Patients will also receive all fluids and nutrition through injections until their condition is improved.
Stomach inflammation (gastritis): Stomach inflammation, also called gastritis, may develop suddenly (acute) or gradually over a longer period of time (chronic).
Most cases of gastritis are caused by an infection with the same bacterium (Helicobacter pylori) that causes stomach ulcers. Gastritis may also be caused by traumatic injury or surgery, excessive alcohol consumption, and regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Motrin® or Advil®) or naproxen (Aleve®).
A condition called bile reflux disease may also cause, or occur simultaneously with, gastritis. Bile reflux occurs when bile, a fluid that helps digest fats, flows upward from the small intestine into the stomach and esophagus. Bile reflux has also been found to be common after gallbladder removal, or as a result of complications from gastric surgery which may damage the pyloric valve (a ring of muscle that separates the stomach from the duodenum) such as gastrectomy, or gastric bypass. Further inflammation and damage to the lining of the stomach and esophagus may occur as a result.
In rare cases, gastritis may occur when the body's own immune cells attack the stomach. It remains unknown what triggers this autoimmune reaction. The acid in the stomach may worsen symptoms of gastritis.
Symptoms of gastritis generally include a burning pain or aching in the upper abdomen that may worsen when food is eaten, nausea, vomiting, loss of appetite, bloating, feeling of fullness in the upper abdomen after eating, and weight loss. In some cases, gastritis may cause stomach bleeding. Symptoms of stomach bleeding include blood in the vomit and black or dark-colored stools.
In some cases, gastritis may lead to ulcers and an increased risk of stomach cancer.
In most cases, patients fully recover quickly once treatment is started. Patients typically take antacids, such as Tums®, Mylanta®, or Rolaids®, to help neutralize the stomach acid. This helps reduce symptoms of gastritis quickly. Acid blockers, such as cimetidine (Tagamet®), ranitidine (Zantac®), nizatidine (Axid®), or famotidine (Pepcid®), may be taken to reduce the amount of stomach acid that is produced. Proton pump inhibitors, such as omeprazole (Prilosec®), lansoprazole (Prevacid®), rabeprazole (Aciphex®), and esomeprazole (Nexium®), may also be taken to reduce the amount of stomach acid produced.
If an infection with H. pylori is causing gastritis, patients generally receive a combination of antibiotics and proton pump inhibitors. Commonly prescribed antibiotics include amoxicillin (Amoxil®), clarithromycin (Biaxin®), and metronidazole (Flagyl®).
Hypochlorhydria (low stomach acid): Hypochlorhydria occurs when patients have low levels of stomach acid, also called hydrochloric acid. The body needs stomach acid in order to break down foods so that they can be absorbed in the intestines.
Natural aging, a poor diet, chronic use of certain medications, and past infection with the Helicobacter pylori bacteria may limit a patient's ability to produce hydrochloric acid.
Hypochlorhydria may also be a symptom of an underlying medical condition such as Addison's disease, depression, asthma, eczema, gallstones, hepatitis, osteoporosis, psoriasis, thyroid disease, and autoimmune disorders.
If there is low acidity in the stomach, patients may only be able to partially digest food. This may lead to malnutrition. Symptoms of hypochlorhydria may include bloating, gas, belching, burning or dryness of the mouth, heartburn, multiple food allergies, rectal itching, redness or dilated blood vessels in the cheeks and nose, adult acne, hair loss (in women), iron deficiency, undigested foods in the stool, yeast infection, as well as diarrhea or constipation. Patients with hypochlorhydria also have an increased risk of developing infections in the gastrointestinal tract because it provides an ideal environment for disease-causing organisms, such as bacteria.
Patients with hypochlorhydria take betaine hydrochloride or glutamic acid hydrochloride with meals and snacks. These medications increase the amount of stomach acid, which helps the body properly break down and digest foods.
Ileus: Ileus occurs when the small and/or large intestine is partially or completely blocked. Ileus is a non-mechanical blockage. Unlike mechanical blockages, which occur when the bowel is physically blocked, a non-mechanical blockage occurs when the rhythmic contractions that move material through the bowel, called peristalsis, stops.
Ileus is usually associated with an infection of the peritoneum, which is the membrane that lines the abdomen. This is most common in infants and children. Intestinal surgery may lead to temporary ileus that lasts two to three days. Ileus may also be a complication of surgery on other body parts, such as the chest or joints. Other medical conditions, including kidney disease and heart disease, may cause ileus. Some chemotherapy drugs, such as vincristine (Oncovin®, Vincasar PES®, or Vincrex®) or vinblastine (velban® or Velsar®), may cause ileus.
Symptoms of ileus may include abdominal distention, abdominal cramping, nausea, vomiting, bloating or failure to pass gas, and difficulty having bowel movements.
Patients with ileus must receive nutrition and fluids intravenously to give the intestines time to heal. If an infection is causing the condition, antibiotics are prescribed. Other medications, including cisapride and vasopressin (Pitressin®), may be prescribed to stimulate the intestines to contract and relax.
Celiac disease (non-tropical sprue): Celiac disease, also called non-tropical sprue, is a digestive disorder that occurs when an individual's immune system overreacts to gluten, a protein found in wheat, rye, barley, and oats.
When a patient with the disease eats food that contains gluten, the immune cells flood to the stomach and intestine to destroy the gluten. However, among these immune cells are autoantibodies that attack the lining of the intestine by mistake. As a result, the intestinal lining becomes damaged.
It has not been determined what triggers this reaction in celiac patients. However, celiac disease is associated with autoimmune disorders, such as lupus. Autoimmune disorders occur when the patient's immune system mistakenly identifies body cells as harmful invaders, such as bacteria. As a result, the immune cells in celiac patients attack the patient's intestinal cells when gluten is consumed.
Celiac disease causes symptoms of abdominal pain and bloating after consuming gluten.
Additionally, complications, including poor absorption, may occur if the patient continues to eat gluten-containing foods. When the intestinal lining is damaged, patients have difficulty absorbing nutrients. Symptoms of poor nutrition include weight loss, diarrhea, abdominal cramps, gas, bloating, fatigue, foul-smelling or grayish stools that may be oily (steatorrhea), stunted growth in children, and osteoporosis (hollow, brittle bones).
If celiac disease is suspected, blood tests will be performed to determine whether or not the patient has autoantibodies associated with the disease. If autoantibodies are present, a positive diagnosis is made.
Although there is currently no cure for celiac disease, the condition can be managed with a gluten-free diet. Patients should avoid all foods that contain gluten. This includes any type of wheat (including farina, graham flour, semolina, and durum), barley, rye, bulgur, Kamut, kasha, matzo meal, spelt, and triticale. Therefore, foods such as bread, cereal, crackers, pasta, cookies, cake, pie, gravy, and sauce should be avoided unless they are labeled as gluten-free. In general, patients who strictly follow a gluten-free diet can expect to live normal, healthy lives. Symptoms will subside several weeks after the diet is started, and patients will be able to absorb food normally once they avoid eating gluten. A dietician or certified nutritionist may help a patient with celiac disease develop a healthy diet. Patients with celiac disease may also find gluten-free cookbooks to be a helpful resource. Many products, including rice flour and potato flour, can be used as substitutes for gluten-containing flour.
Menke's kinky hair disease: Menke's kinky hair disease, also called Menke's disease, is an inherited disorder that decreases the body's ability to absorb copper. Cells in the body need copper to function properly. The disease is characterized by sparse and coarse hair, short stature, and progressive deterioration of the nervous system.
Symptoms develop during infancy. Babies with Menke's kinky hair disease show slightly slowed development for two to three months after birth. The baby's condition will worsen after this time and he/she will lose previously developed skills. Other symptoms include silver or colorless hair, seizures, and osteoporosis (hollow and brittle bones).
There is currently no cure for Menke's kinky hair disease. Patients may receive injections of copper. However, patients typically die by the age of ten.
Acrodermatitis enteropathica: Acrodermatitis enteropathica is an inherited condition that occurs when the body is unable to absorb zinc. This trace element is necessary for the functioning of over 300 different enzymes and plays a vital role in an enormous number of biological processes.
The exact cause of acrodermatitis enteropathica remains unknown. However, researchers believe that genetics may play a role.
Symptoms of acrodermatitis enteropathica may include red and swollen patches of dry and scaly skin, crusted or pus-filled blisters on the skin, swollen skin around the nails, mouth ulcers, red and glossy tongue, impaired wound healing, as well as hair loss on the scalp, eyelashes, and eyebrows. Additional symptoms may include pinkeye, sensitivity to light, decreased appetite, diarrhea, irritability, failure to grow, and depressed mood.
A zinc deficiency can be diagnosed after a blood test.
Although there is no cure for the disorder, zinc supplements taken by mouth daily have been shown to effectively manage symptoms. Without treatment, acrodermatitis enteropathica will lead to death. Skin lesions usually heal one to two weeks after treatment is started. Other symptoms begin to improve within 24 hours.
Hemorrhoids: Hemorrhoids are inflamed veins in the anus and rectum. Hemorrhoids may develop inside or outside of the rectum, depending on the specific veins that are affected.
Hemorrhoids are common, affecting nearly half of individuals who are older than 50 years of age.
Hemorrhoids develop when there is increased pressure in the veins of the anus and rectum. This is often due to straining during constipation, sitting or standing for extended periods of time, pregnancy, childbirth, and diarrhea. Obese patients have an increased risk of developing hemorrhoids.
Internal hemorrhoids are not painful because pain nerves are not present inside the membranes of the rectum. However, internal hemorrhoids may cause bleeding when stools are passed. External hemorrhoids are usually painful. The veins outside of the rectum are swollen and may itch. Bleeding may occur, especially when straining to move the bowels.
External hemorrhoids can be diagnosed after observing the inflamed veins. If internal hemorrhoids are suspected, a healthcare provider may examine the rectum with an anoscope, proctoscope, or sigmoidoscope.
Mild cases of hemorrhoids are usually treated with over-the-counter creams or ointments, such as Preparation H®. Warm baths may also help improve symptoms.
If a blood clot forms in a hemorrhoid, a healthcare provider can make a surgical incision to remove the clot.
Rubber band litigation may be used to treat severe or persistent cases of hemorrhoids. During the procedure, small rubber bands are inserted around the base of the hemorrhoids. This cuts off the blood supply in the vein until the hemorrhoid falls off.
During a procedure called sclerotherapy, a chemical is injected near the hemorrhoid to shrink the inflamed vein.
If these therapies are ineffective, the hemorrhoids may be surgically removed in a process called hemorrhoidectomy.
Rectal prolapse: Rectal prolapse occurs when the inner lining of the rectum, called the rectal mucosa, protrudes from the anus. Rectal prolapse occurs when the tissues that normally support that rectal mucosa become loose and allow the tissue to slip down through the anus.
Without treatment, the condition may worsen and a large part of the rectum may protrude from the body through the anus. When this happens, the condition is called a complete prolapse. Most patients do not realize that they have rectal prolapse until it reaches this stage. Initially, the rectum may protrude during certain activities, such as coughing or laughing. Eventually, the prolapsed rectum may protrude more frequently or permanently.
Patients may be able to feel the tissue protruding out of the anus. Common symptoms of rectal prolapsed include pain during bowel movements, mucus or bleeding from the protruding tissue, and inability to control bowel movements.
Most patients with rectal prolapsed require surgery. The surgeon reattaches the rectum to the backside of the inner pelvis. Surgery may be performed through the abdomen or the perineum.
Stool softeners, such as calcium docusate (Surfak®) or sodium docusate (Colace®), may help reduce pain and straining during bowel movements.
Rectal inflammation (proctitis): Rectal inflammation, also called proctitis, occurs when the lining of the rectum (rectal mucosa) becomes swollen. Patients with proctitis often experience rectal bleeding, anal and rectal pain, frequent urge to have a bowel movement, passing mucus through the rectum, feeling of rectal fullness, and diarrhea.
There are many potential causes of proctitis. The most common cause is sexually transmitted diseases, which are acquired through anal or oral-anal intercourse. Other causes may include inflammatory bowel disease (IBD) and bacterial infections, such as streptococcus. Less common causes include chemicals (such as hydrogen peroxide enemas), injury to the rectum, radiation therapy that is applied near the rectum (for conditions such as prostate or cervical cancer), and medications or objects that are inserted into the rectum.
Several tests may be performed to diagnose the underlying cause of proctitis. Blood tests may be performed to detect possible infections. A colonoscopy may be performed to examine the inside of the colon for abnormalities. Healthcare providers may also use a swab to collect a sample of fluid from the rectum or urethra. The sample is then tested for STDs.
Most cases of proctitis are effectively treated and patients experience a full recovery. Treatment depends on the underlying cause of proctitis. If a bacterial infection is present, antibiotics, such as ciprofloxacin (Cipro®), levofloxacin (Levaquin®), penicillin, amoxicillin (Amoxil® or Trimox®), azithromycin (Zithromax®), clarithromycin (Biaxin®), or clindamycin (Cleocin®), may be taken. If a viral infection (e.g. herpes) causes proctitis, antivirals, such as such as acyclovir (Zovirax®), may be taken. Corticosteroids may be taken if radiation therapy is causing proctitis. If IBD is causing symptoms, anti-inflammatories, such as sulfasalazine (Azulfidine®) or anti-diarrheals, such as psyllium powder (Metamucil®), may be taken.
Laxative-induced colon damage: Laxatives are medications that are used to stimulate bowel movements. They are primarily used to treat constipation. Patients who overuse laxatives may develop colon damage. Long-term use of laxatives may cause the muscles in the colon to become weak from lack of use. The nerves in the lining of the colon may also become damaged. As a result, this may slow intestinal mobility and cause constipation.
Symptoms of laxative abuse include weight loss, hair loss, vomiting, abdominal pain, low energy, dehydration, dry eyes, headaches, mood swings, and bone pain.
Therefore, patients should not take laxatives more frequently than the packaging label suggests. If symptoms persist, patients should consult their healthcare providers to diagnose and properly treat the underlying cause. |
<urn:uuid:50bfa3d1-af7c-4130-baad-07c0d469eeb3> | seed | Remembering SARS: A Deadly Puzzle and the Efforts to Solve It
On this Page
- A CDC-Wide Response
- Identifying the Cause
- Can We Stop It?
- Solving the Mystery
- Case Definition
- Travel Advisories and Alerts
- Protecting Healthcare Workers
- Communicating with Media and Public
- Future Challenges
- Disease Detectives
- Global Response
- Health Security in Action
- 10 Compelling Facts
In the 2003 global disease outbreak, what became known as SARS-CoV started as a mystery illness—without name, origin, or cure. Public health scientists across the globe scrambled to understand and contain this health threat.
CDC began working with the World Health Organization (WHO) in late February to investigate and confirm outbreaks of an unusual pneumonia in Southeast Asia. As WHO led a global effort to understand the illness and how to prevent its spread, questions outnumbered answers. At the time, all that was known about the new disease was that people quickly become severely ill and that it could be fatal.
By the time WHO issued a global alert on March 12, cautioning that the severe respiratory illness may spread to hospital staff, CDC had confirmed this was not “bird flu,” the influenza A (H5N1) that had been reported recently in Hong Kong. The mystery illness was given a name: Severe Acute Respiratory Syndrome (SARS), although scientists still did not know which microbe was causing SARS.
On March 14, the response to this health threat became more urgent for CDC when several SARS cases were reported in Canada. That same day, CDC activated its Emergency Operations Center (EOC).
A CDC-Wide Response
For decades, when invited by the WHO or Ministries of Health, CDC has lent expertise to global disease outbreak responses. Typically, CDC’s infectious disease centers manage those responses. However, when the response effort may need more staff and supplies than usual or when the response might go on for an extended time, the CDC Director can activate the EOC. Activating the EOC means the incident commander can assemble expert staff and volunteers from across the entire agency to help.
During the 133 days of CDC’s emergency response phase of the SARS outbreak, more than 850 people from across the agency were deployed to the EOC. Within hours of activating the CDC response, 112 staff were deployed to response teams, CDC laboratories, and affected countries. Within 3 days, 200 staff were working 24/7 on the response.
Staff assignments were far reaching in scope:
- Develop a case definition so medical staff could determine who may or may not have SARS
- Offer case-by-case consultation to public and private healthcare providers
- Provide guidance on managing the care of patients
- Provide guidance on how to protect health workers on the job
- Determine in the lab what was causing SARS
- Once the microbe was identified, create diagnostic tests
- Provide guidance on isolation and quarantine to prevent spreading the disease
- Track and analyze cases to define risk and stop disease spread
- Monitor travelers’ health at points of entry to the United States
- Communicate health messages to the public, especially travelers
- Report U.S. cases to WHO
While the urgent tasks of disease outbreak response was ongoing, CDC scientists also considered the possibility that this outbreak could became a pandemic? On March 28, CDC began developing pandemic response plans (Team “P”) in case the SARS epidemic became uncontrollable. Team P was supported by the Mathematical Modeling team who calculated the expansion of the outbreak.
Most CDC staff deployed for the SARS response worked on teams at CDC’s headquarters in Atlanta. However, 235 staff went into the field; 67 were deployed to 10 international locations. Domestically, CDC sent 165 staff to 19 points of entry, including quarantine stations already staffed by CDC. Deployments ranged in length from 1 to 133 days; average 45.Top of Page
Identifying the Cause
On March 24, CDC reported that its lab scientists, along with scientists from collaborating international labs, believed SARS may be caused by a new virus from the coronavirus family.
By April 14, CDC had identified the complete genetic sequence of the new virus—adding a critically important 15 additional nucleotides to the beginning of the sequence determined by a Canadian laboratory two days earlier. These results came just 12 days after a team of 10 scientists began working around the clock to identify the etiologic agent from a throat culture from a patient with SARS.
With the complete gene sequence known, scientists could then start to look for drug treatments, diagnostic tests and possible vaccines to prevent or treat the new coronavirus. Lab tests to rapidly identify infected people would be an important step in reducing spread of SARS.
Can We Stop It?
While still not fully knowing how SARS spread, CDC focused on detecting cases as early as possible and applying infection-control measures in health-care settings and the community to limit SARS in the United States.
Based on outbreaks in healthcare settings outside the United States, it appeared that some healthcare workers did not know how best to use protective equipment to avoid contaminating themselves, especially when removing gloves and masks.
To protect healthcare workers, CDC advised using strict infection control actions to keep SARS from spreading from ill patients to those caring for them. Specifically, the use of N-95 respirators and surgical masks in hospitals could work. The masks could also help to stop the potential spread in communities.
However, CDC recommended training to correct the way workers used and removed protective equipment and stressed the importance of hand hygiene. The N-95 respirator is typically worn by healthcare workers to prevent exposure to airborne disease like tuberculosis. However, if the mask doesn’t fit correctly, it doesn’t do a very good job of keeping them from breathing in very small germs that may hang in the air after a sick person coughs.
Healthcare workers or visitors who had direct contact with patients were advised to wear N-95 respirators and CDC recommended that patients should be cared for in special air isolation rooms.
By March, CDC scientist knew that the research, thus far, indicated that fairly prolonged contact, face-to-face, was typically how SARS spread from person to person. However, CDC’s disease detectives had begun to collect information that suggested it spread from much briefer contact between people. An entire investigative team from CDC was exploring cases of spread among people in hotels where guests came in contact with sick people only briefly. During these instances as well, CDC recommended strict infection control measures including hand washing, gloves, avoiding sharing household items, and limiting interaction between ill patients and others.
CDC also advised on quarantine and isolation methods to help prevent community spread.
Solving the Mystery of “Super Spreaders”
While we may never know with certainty where the SARS virus originated, it likely moved from animals to humans. Lab research confirmed that SARS can infect a number of animals, including palm civets that live in China where the 2003 outbreak originated. A civet is a meat-eating mammal that has a cat-like appearance, but the animal is not a cat.S ARS-CoV was also found in the blood of animal handlers.
In the 2003 outbreak, in some instances outside the United States, a single SARS patient infected large numbers of people. At the same time, other patients did not infect people who came in contact with them.
Researchers found that the virus was typically spread from person to person by large droplets (less efficient spread because it would be too big to linger in the air); however, at other times, clusters of illness suggested aerosol spread (where the virus can linger in the air longer after an ill person coughs) causing more spread of infections from a single sick person.
CDC investigated the so-called “super spreaders.” They wanted to know if there were differences in when and for how long people ill with SARS might shed the virus, making them contagious to others. In the past, super spreaders had been documented during other disease outbreaks such as rubella, tuberculosis and Ebola. A common feature of super spreaders was that hospitals served as a source for the disease to widely infect others.
By May 9, CDC had investigated five people with probable SARS they categorized as super spreaders. These patients had infected 10 or more healthcare workers, family members, and social contacts while hospitalized.
In one instance, a 22 year-old visited Hong Kong for a shopping trip and, later while staying at a hotel, developed fever and cough which led to hospitalization. The patient was directly linked to probable SARS infections in 21 people during her hospital stay; nine healthcare workers and 12 family members or visitors.
In another case, a 60-year- old was hospitalized with kidney disease and released. He was readmitted days later for gastritis. A total of 62 people with probable SARS were linked to his case; 25 healthcare workers, 20 other patients, and 17 family and social contacts.
During the investigation, CDC determined that these “super spreaders” or large clusters of cases could not be predicted based only on whether people took precautions to prevent infection. They documented that in some instances where precautions were not used, such as using gloves, face masks and hand washing, ill patients still did not infect others.
CDC also found that super spreading events were more likely when the person was severely ill, when the patient was in contact with many more people (greater potential for spread) and if the patient was older aged.
These patients became hidden reservoirs of infection on the wards or in the community. Investigators determined that people with other health problems made it more difficult for their illness with SARS to be detected. CDC recommended, during the SARS outbreak, that patients with other health conditions who also had fever should be isolated.
These clusters of illness were puzzling. They were also a reminder how important early detection and access to information on outbreaks of unexplained illness can be. “When you first see a cluster, people need to recognize that these clusters can have global implications, and this is a dramatic example of that,” Dr. Jim Hughes, who led the CDC outbreak response, said during a March 18, 2003, teleconference.
Credible information has to be monitored in a real-time fashion to detect new diseases that may emerge from nature or from deliberate acts. Information about patterns of illness in a population may come from pharmacies, hospitals, laboratories, or Internet searches.
Determining a Case Definition
In the United States, CDC defined a case of SARS in three ways: patient symptoms, possible exposure to the illness, and, later, by lab results.
During the outbreak, state and local health departments reported 1,460 unexplained respiratory illnesses to CDC. Of those, 398 appeared to be SARS based on patient symptoms and possible exposure through travel. Only 72 of the 398 had chest X-rays that looked like pneumonia moving them from possible cases to probable cases of SARS. Only eight of the 72 probable cases were confirmed by lab results to be SARS. No one died from SARS in the United States.
An outbreak investigation needs a good case definition to help public health officials know who is ill from the disease and who is not. Describing the outbreak’s intensity requires identifying accurately who is ill.
The early case definition for SARS included a cluster of symptoms like fever and respiratory illness from an unknown cause. In addition, the ill person also had to have traveled to affected areas within 10 days of symptoms beginning or been in close contact with someone who traveled in affected areas.
CDC sent its case definition to state and local health departments. At the beginning of the outbreak, CDC asked state and local health departments to report all respiratory illnesses that they thought should be evaluated for SARS, casting a wide net.
An Atlanta-based team at CDC collected the reports and when a patient met the case definition, the patient’s data was added to a “line list.” This data could be analyzed to determine who was at greatest risk and how the illness progressed. In 2003, reporting this information was paper-based and the information was then entered electronically and merged with laboratory data.
Intense laboratory work went on at CDC and across the CDC-supported laboratory response network.
During the outbreak, labs were testing for alternate causes for a patient’s illness. Early on labs were looking for multiple types of pneumonia, influenza viruses and other viral respiratory illnesses. The list was exhaustive but necessary to rule out other microbes that could be causing illness. As specimens flooded in, patients, hospitals, and communities waited to see if they had a case of SARS. During the early phase of the outbreak, anxiety was high among patients, healthcare workers, public health officials and the public because we did not have a rapid test to reliably diagnose SARS infection.
During this time the United States was also experiencing seasonal flu. So while more than 1,000 unexplained respiratory illnesses were reported to CDC, countless additional illnesses were investigated and ruled out for SARS by state and local health departments. This response also relied on astute healthcare providers to detect and report illnesses that might have been SARS.
Issuing Travel Advisories and Alerts
SARS was introduced to the United States through air travel. The United States had eight lab-confirmed cases of SARS and no deaths. SARS, for the United States, was a travel-associated illness.
During the outbreak, CDC quarantine officers handed out health alert notices to passengers arriving from 11,480 flights originating from areas with SARS. CDC officials were meeting planes, cargo ships and cruise ships coming to the United States from China.
The most visited spots on CDC’s website during the outbreak where those related to travel safety. SARS was a severe illness with a short incubation period (the time from exposure to illness). CDC, in the midst of the outbreak, determined it needed to rank levels of concern about potential risk to travelers. Up to that time, CDC had never advised against travel to any region, even during the plague epidemic in India in 1994. So CDC explained its new ranking system.
- A travel alert from CDC was a notification that an outbreak of disease is ongoing in a geographic area.
- A travel advisory recommended against travel to an area unless essential.
Once issued, downgrading an advisory to alert required good disease detection in the area combined with no evidence of ongoing spread.
Protecting Healthcare Workers
As the outbreak of SARS unfolded in Southeast Asia, hospital workers were becoming ill from contact with ill patients. In the United States the SARS virus did not spread within a community or a hospital. No healthcare worker became infected with SARS. In Singapore, Canada, and Vietnam the illness spread among healthcare workers but was stopped from spreading into the wider community. However, in China, Taiwan and Hong Kong the disease also spread widely in the community. In the United States, based on lab results, only one possible household transmission of SARS was reported and no healthcare workers acquired SARS from patients.
CDC offered guidance for healthcare workers and other occupations such as people in the hotel and travel industry about ways to avoid becoming ill with SARS.
Communicating with the Media and the Public
By the early spring of 2003, the airline and tourism industries had lost billions of dollars due to public fears about SARS. Globally, some airlines and businesses declared bankruptcy as a result. The public wanted information to help protect themselves and their loved ones from an illness without a treatment. Misinformation was high and, in some cases, people believed they could avoid illness by avoiding people who looked Asian. CDC’s communication staff worked tirelessly to answer the tough questions from the public and to manage expectations about the speed of the response and reduce stigmatizing behaviors.
The communication response included:
- 10,166 press calls triaged
- 21 telebriefings announcing latest SARS information
- 23 Health Alert Network messages sent to public health, clinicians and media subscribers
- 2,079 clinicians consulted through CDC’s Clinical Information Line and 18 updates sent through the Clinician Registry with nearly 600,000 messages distributed.
- 3 SARS satellite broadcasts with about 1.9 million participants
- About 17 million page views on CDC SARS website, peaking the week of April 20-26
By May the SARS outbreak was waning; however, people remained fearful of the outbreak and were sometimes uncertain about how to balance avoiding the risk of infection with getting on with life. In fact, CDC issued guidance to businesses and universities who were restricting the presence of people who traveled from China.
Dr. Julie Gerberding, then CDC director, said, “It’s very important that people appreciate that this is a respiratory illness caused by a virus, probably a new virus, and is not a disease that is in any way related to being Asian. So we want to ask people’s support and help in recognizing how difficult this is for people and take the high road. This is a time when all of our communities need support and empathy, not stigma or bias or shunning that has been reported in some international press.”
Addressing Future Challenges
It took many types of public health actions globally to contain SARS in six months. When the SARS virus reached Hong Kong in 2003, it had a fast track to all points in the world and it was finally stopped using the tools of disease detection (known as epidemiology):
- The path of the disease had to be tracked
- The rate of spread had to be calculated
- The clinical case needed to be defined
- Guidance for treatment had to be created
- Restrictions on travel were needed, and
- Lab scientists had to tease out the microbe’s origin
Ultimately that work was done. Without question, future mystery illnesses will emerge. The questions will be the same—what is causing the illness, where did it come from, can it be contained, who is at greater risk? The cost in lives and economic upheaval from future mystery illnesses will depend, in part, on how quickly we can detect the threat and answer the questions of life and death.
“Ten years ago a global outbreak of SARS emerged. In six months SARS killed hundreds of people and cost tens of billions of dollars,” said CDC’s current Director, Dr. Tom Frieden. “A decade after the SARS epidemic we’ve made progress but we remain at risk from global health threats.”
The basic tools of shoe leather and spreadsheets that CDC’s disease detectives relied on to answer outbreak questions on smallpox, legionnaires, e-coli and SARS can’t be replaced; but, new tools can make our disease detectives more precise and faster in solving health mysteries. Molecular tools and bioinformatics exist today and without these tools CDC runs the risk of delays in confronting deadly health threats.
The threat to our nation’s health security doesn’t start when we first spot a new killer superbug. The looming threat to our nation’s health security starts when CDC fails to keep pace with the rapidly growing field of molecular diagnostics. Without these tools, the advantage goes to the superbugs. CDC’s current capacities in these “next generation” tools do not meet the challenges of this rapidly evolving field. Genetic sequencing of infectious pathogens could revolutionize how CDC investigates and controls outbreaks.
Genomic sequencing rapidly generates massive amounts of information on a pathogen and it is bioinformatics that helps put the puzzle together quickly, accurately, and at decreased cost. By using molecular typing, CDC could more quickly find patterns that answer the “who, what, when and how” these pathogens kill.
With enhanced molecular-based science and bioinformatics CDC could rapidly and correctly diagnose infectious diseases, more quickly control outbreaks, recreate disease transmission patterns, tackle antimicrobial resistance, and target interventions, like vaccines. “We have a unique window of opportunity,” Frieden said. “The world is committed to reducing threats to health and we have new technology that can take many important disease threats off the table, if we act now.”
The 2003 SARS outbreak starkly proved the world’s collective economic vulnerability to epidemic shocks. Fragile business alliances, trade, and travel were instantly in jeopardy as people across multiple continents waited for public health scientists to solve the mystery: what was killing patients and the health workers attempting to care for them. This uncertainty resulted in tens of billions of dollars in economic loss in less than six months.
In the first decade of the 21st Century, novel influenza, bioterrorist threats with anthrax, and constantly evolving microbes tested the limits of 20th century public health models. “We face a perfect storm of vulnerability,” Frieden explained. The threats of new microbes, resistant microbes outsmarting the drugs to treat them, global risks in travel and trade, and the ease of creating deadly microbes in boutique labs push the limits of acceptable risk. The global response to health threats must change.
While detecting a new disease threat, assessing the risk to individuals and populations, identifying the microbe, guiding the treatment, and containing the spread in less than 6 months is no small feat, the timeline between detecting and responding must be shortened.
Within weeks of the WHO’s first reports of what became known as SARS, people were already ill across continents. Imagine a world that could detect early and respond rapidly to an emerging threat—where local disease detection in even remote areas replaced disease detection at national borders. Global public health is shifting the focus from control at borders to disease detection and control at the sources.
There is a brief window of opportunity to contain pressing threats if the capacity is built in all countries, even the poorest countries. Every country needs at least active surveillance systems, capacities for laboratories, disease detectives, trained rapid response teams, and drugs or vaccines to control disease. The updated WHO International Health Regulations require nations to investigate, assess threats, respond and, importantly, disclose known and suspected threats without delay.
CDC continues to lead in helping standardize lab work, train disease detectives, and introduce new mobile devices to quicken decisions with data collected in a community. CDC supports WHO’s approach to adopt the same norms, rules, and processes to link data from multiple sources to help public health and healthcare workers put information to use.
For decades CDC has been a leader in containing major global health threats. “CDC will continue to work 24/7 with our international partners to detect threats quickly, respond rapidly, and prevent new threats from emerging,” Frieden said.
While disease investigators were determining where this emerging disease had traveled and who was more likely to get sick from the disease, lab scientists wanted to find what microbe was at fault. The lab experts wanted to unlock any clues to help rapidly diagnose and then treat or cure the disease.
The clues did not come easily. For CDC, an initial challenge was simply receiving samples in good enough shape to test. Early in the outbreak, SARS was happening half way around the globe from the United States, and CDC was not receiving the samples it needed to keep pace with the outbreak.
In mid-March, CDC’s lab scientists were working around the clock on the specimens they had received—comparing any microbes they detected with reference samples kept from previous outbreaks. Nothing was matching. CDC admitted, “We are looking at bacteria. We’re looking at viruses. We’re looking at atypical bacteria. We are checking for absolutely everything.” In a March 17 teleconference, CDC reported its scientists were not suspicious that this was a common organism, or “we would have found it by now.”
CDC scientists were confident they would identify the disease, but knew it would take more than one sample to definitively name the microbe causing the illness called SARS. It would not be enough to just find it in one person. The scientists would need to find the microbe in most of the people who had been ill and, just an important, not find it in people who had not been identified as having SARS.
The challenge was the quality of the specimens. While lung tissue or blood samples were shipped to CDC from patients who had died, the key was to have samples from early in the course of the disease. CDC emphasized the need to get respiratory secretions and blood samples from people who had only recently developed symptoms. If respiratory secretions came from people after they had started to recover, it could be impossible to detect the microbe.
Nucleic acid testing was an important element to unraveling the secrets of this outbreak. Some viruses could not be grown in lab cultures or they would take a very long time to grow in numbers high enough to be detected by current lab technology. With speed a factor, CDC had to resort to the most sensitive nucleic acid technology that it had in 2003. And, sometimes, that led to false negatives from those tests.
By March 24, CDC reported its labs cultured coronavirus from two patients. In one patient, the tissue was culturing (growing) virus and the scientists could see the virus. They described it—a circular virus that looks like it has a corona or sort of crown effect, and that is basically little spikes of protein that surround the virus which gives that appearance.
Still cautious, CDC scientist, Dr. Larry Anderson admitted, “We’re finding evidence of it in actual affected tissue, including in kidney tissue from one patient.” Confidence increased when CDC’s labs found that the patient’s blood antibody test from early in his illness was negative and by the end of his illness, the antibody test had turned positive. So, in other words, the patient “seroconverted”—meaning he had a negative test and then a positive test. This change in antibodies in the blood implied the microbe caused the illness.
CDC had found the virus genetic material in lung secretions and lung tissue. In collaboration with laboratory partners in the global arena, evidence was mounting that this new coronavirus was causing SARS. “We know from sequencing pieces of the virus RNA that it is not identical to the coronaviruses we’ve seen in the past.”
On March 27, CDC’s director for infectious diseases, Dr. Jim Hughes said, “Labs in many countries now have found evidence of coronavirus infection in these patients. That’s in contrast to just a few days ago, you may recall, when metapneumovirus was clearly the leading candidate. I would say coronavirus likelihood is going up. Metapneumovirus likelihood is going down. We keep an open mind on these things. And the possibility of some co-infection, at least in some patients, has to be kept in mind.
Anderson explained, “We pursued metapneumovirus, but continued to look for other agents. A group in Hong Kong and Germany identified some particles and secretions that suggested not a paramyxovirus by size. Our electron microscope identified coronavirus-like particles in tissue culture. We then used molecular techniques to look at the genetics of this virus and confirmed that is was, in fact, a coronavirus. We then developed tools to look at additional specimens and provided the tools to other laboratories.”
Using a secure Internet site, laboratories were sharing pictures of the virus so they could understand each other’s work. The global scientific community came together to combat a global epidemic.
Hughes noted, “Ten days ago we didn’t have any antibody test to detect infection with this previously unrecognized coronavirus. As a result of a lot of hard work that’s been done here over the past 10 days, we now have two tests that look promising. They appear to perform well in suspect cases.”
To check the accuracy of the new tests, CDC looked for evidence of the coronavirus antibody in blood collected from 400 people around the United States without any suggestion of SARS, and they were all negative. The diagnostic test worked.
The scientific achievements in the first week after receiving lab specimens were “truly unprecedented.” CDC’s lab scientists developed a test to send to health departments across the nation to improve the diagnosis of SARS. A more accurate and more rapid diagnostic tool would help identify who was or was not sick form SARS so resources to contain the outbreak could be concentrated where needed.
Health Security in Action
On March 15, 2003, following the World Health Organization’s global alert three days earlier, CDC issued its first health alert in the SARS outbreak.
CDC explained, “The emergence of two clusters of this illness on the North American continent indicates the potential for travelers who have been in the affected areas of Southeast Asia to have been exposed to this serious syndrome. We do know that it may progress rapidly and can be fatal.”
During the investigation into the SARS outbreak, CDC’s quarantine staff played an important role in the following ways:
- Provided information to returning travelers arriving in the United States either directly or indirectly from Hong Kong, Guangdong Province, People’s Republic of China and Hanoi, Vietnam on airplanes, cargo ships or cruise ships
- Distributed health alert notices to those travelers advising them that they may have been exposed to people who had SARS and recommending they monitor their health for at least 7 days and to contact their physicians if they become ill with a fever accompanied by a cough or difficulty breathing;
- Boarded airplanes and ships with travelers reported to be ill to assess whether their symptoms match the case definition of SARS
- Provided timely updates to government agencies partnering in these activities as well as to travel industry organizations;
- Worked with CDC’s SARS investigation team and local and state health departments to assist in the investigation of suspected cases of SARS.
Dr. Marty Cetron, who was with CDC’s Division of Global Migration and Quarantine in 2003 and is now its director, explained how isolation and quarantine contributed to the outbreak response. The public and media were curious and concerned about these official and rarely used response tools.
During a March 21 briefing about CDC’s SARS response, Cetron said: “We meet all the direct and as many of the indirect arriving flights as we're aware of, and that's an ever-increasing number. More than 50 flights a day are being met arriving from these locations where there's transmission. Now, in the event that there is a sick passenger reported either in flight in transit or at the airport on arrival, a quarantine inspector or a designee of the quarantine station will meet that flight, get on board, isolate and take off the ill passenger, and facilitate that person's going to a healthcare facility and getting that case reported.”
Since SARs, many changes and improvements have been made in CDC’s Division of Global Migration and Quarantine that will help CDC better address future threats from large outbreaks like SARS. In 2003, CDC had eight quarantine stations around the country. Partially in response to SARS but also due to greater concerns about infectious disease spread and bioterrorism, CDC expanded the number of quarantine stations to 20 (between the years 2004-2007). The quarantine stations are located at major ports of entry and land border crossings where 85% international travelers arrive. Quarantine officers are responsible for activities as various as responding to reports of illnesses, to screening cargo and inspecting animals and animal products, to monitoring the health of and collecting any medical information of new immigrants, refugees, asylees, and parolees.
In addition, CDC has taken steps to help ensure that people who are ill with a serious disease do not fly. In collaboration with the Department of Homeland Security, CDC established the national public health “Do Not Board” list in June 2007. The list is an important tool that health officials can use when they determine that someone poses a disease threat to others and is likely to travel by air. To date, the list has been used more than 250 times to prevent travelers with tuberculosis and other serious illnesses from boarding a plane.
CDC has developed better and faster ways to communicate to airline passengers who may have been exposed to a serious illness on an airplane. During SARS, CDC and its airport partners gave out 2 million printed T-HANs (Travel Health Alert Notices) with information and recommendations for people who may have been exposed to SARS while traveling.
CDC now uses electronic messaging at airports to quickly provide health messages to international travelers. During last year’s international measles outbreak, CDC posted electronic messages in airports, reaching more than 2.7 million people per month. Electronic messaging is less expensive, environmentally friendly and a faster way to reach more people than through print methods.
Following the 2009 flu pandemic, CDC established the Community Interventions for Infection Control Unit to prevent the spread of pandemic flu and other infectious diseases within communities through research and education on non-pharmaceutical interventions (such as hand washing, school closures, social distancing measures). Research in this area will help inform recommendations for future pandemics and for other illnesses like SARS.
During the outbreak, CDC quarantine officers handed out health alert notices to passengers arriving from 11,480 flights originating from areas with SARS. CDC officials were meeting planes, cargo ships and cruise ships coming to the United States from affected areas of Southeast Asia. CDC issued a travel advisory recommending against travel to Southeast Asia, unless essential. Up to that time, CDC had never advised against travel to any region, even during the plague epidemic in India in 1994.
The CDC EOC activation for SARS ended on July 25, 2003. Worldwide there were 8,096 reported cases of SARS and 774 deaths. On October 5, 2012, the National Select Agent Registry Program declared SARS coronavirus a select agent. CDC regulates the Select Agent program of biological agents and toxins that have the potential to pose a severe threat to public health and safety.Top of Page
10 Compelling Facts about SARS
- CDC had never advised against travel to any region, even during the plague epidemic in Indian in 1994, until the SARS outbreak.
- The CDC-wide activation for SARS marked the first use of its newly created Emergency Operation Center, built as a result of lessons learned from our 2001 response to the anthrax bioterrorism event, where 1,700 CDC staff responded without a dedicated EOC.
- Deployment statistics calculated that CDC staff contributed the equivalent of 46,714 days of work devoted to the SARS response. Another 71 people volunteered but were not deployed by the end of the response.
- Of the eight lab-confirmed cases of SARS in the United States, six were identified in the first month surveillance for SARS began. Five traveled to Hong Kong, two to Toronto, and one to Singapore.
- Among people with SARS in the United States, the majority were male (53%) with a median age of 39.
- In the United States, the only possible case of secondary spread was between a married couple and both had traveled internationally.
- SARS-CoV comes from the family of viruses that also cause the common cold in humans.
- In 2000, nearly 46,000 residents from China, Hong Kong, and Vietnam traveled to the United States. During the same time, about 83 million travelers arrived in China, 13 million in Hong Kong and 2 million in Vietnam.
- Understanding respiratory illnesses is a challenge. About 40–60 percent of people with pneumonia will never know what microbe caused the illness, even after much testing.
- On April 22, 2003, even after the cause of SARS was identified as a new coronavirus and the number of cases were leveling off, CDC cautioned about the epidemic, “we have no capacity to predict where it’s going or how large its ultimately going to be . . .”
- Page last reviewed: April 26, 2013
- Page last updated: April 26, 2013
- Content source: |
<urn:uuid:2392de51-a244-4d53-9868-d0d20be2ec2e> | seed | "Craig" showed core symptoms of autism spectrum disorder, including social impairment (i.e., lack of interest in peers, nonverbal communication limits, deficits related to sharing/directing attention), an atypical communication trajectory (i.e., early language delay, stereotyped language including echolalia), and repetitive play and restricted interests (i.e., lining up toys, collecting atypical objects, distress surrounding idiosyncratic changes in his environment). These symptoms were prominent around 18 months with concerns raised in his preschool classroom at age 2. Craig was referred for an evaluation and was initially diagnosed with a speech and language delay before receiving a provisional diagnosis of an autism spectrum disorder (pervasive developmental disorder not otherwise specified) at age 3. Subsequent evaluation at age 5 resulted in a formal diagnosis of autistic disorder.
In the school setting, Craig was identified for special education in kindergarten. Testing showed cognitive abilities at the lower limits of the average range with relative weaknesses regarding complex verbal reasoning. At age 12 Craig was evaluated for symptoms of hyperactivity and inattention, tics, and ongoing difficulties with inflexibility and repetitive speech and behavior. His parents described Craig having difficulties with anxiety and observed that complaints of unhappiness also emerged around the time. He was diagnosed with Tourette's syndrome on the basis of both vocal and motor tics. A trial of risperidone helped significantly with his tics and some of his repetitive behavior. A methylphenidate trial seemed to help with his hyperactivity and inattention, and methylphenidate was therefore continued until he completed his formal schooling at 20 years old, after which point on-off-on trials revealed no continued benefit. He was also treated by a psychotherapist for anxiety and compulsivity. He had difficulty engaging in cognitive-behavioral therapy (CBT) approaches. Psychotherapy came to focus on managing anxiety through coping strategies, which consisted primarily of relaxation exercises and family support.
Beginning at age 12, Craig expressed pervasive concerns about one aspect of his identity or another. Initially, these concerns were about his diagnosis. He would complain repeatedly that he did not want to have autism and would ask repeatedly if his doctor could cure it. He later expressed desires to have other disorders, including Down's syndrome, so that he could look like the other children in his special education program. By age 13, he began demanding to be called by different names by those around him. He remarked that his various names "did not feel right" with some people or in some situations. This began with selected iterations of his own name (full name, nickname, and so on) but expanded over time to include female names as well as nonsensical names.
At age 15, Craig was preoccupied with his physical appearance and complained that he looked too old. This preoccupation appeared to coincide with the development of significant acne, which resolved after treatment but without relief of the preoccupation. He began to express a belief that he was too tall, weighed too much, or looked too old, despite being of average appearance, height, and build. At age 18, he was unable to talk about anything other than his height or weight during his medical visits, with a constant demand for reassurance that he did not look "too old." At times he became so upset when talking about his appearance or his height that he stated, "I wish I was in heaven." When immediate verbal reassurance was not satisfying, he would try to demonstrate that he was not tall. For example, when someone at church commented that he was a "nice young man," he spent the next 15 minutes jumping up to show that he could not touch the ceiling, which he said demonstrated that he was not "a man" but remained a boy. This preoccupation interfered significantly with his functioning in school and social settings. Reference to his age or height would invariably result in intense distress and dysregulation during which Craig would often express his anger and demand that those who made the comments retract them and provide significant reassurance that he was young and developmentally disabled. At age 22, his ongoing obsession with his appearance almost caused him to lose his job when he erupted in an angry tirade after a coworker called him a "nice young man."
Exposure and response-prevention therapy was initiated, along with 125 mg of D-cycloserine 1 hour before each session to augment extinction learning (1). Over the course of four sessions, he was able to progress quickly through a stimulus hierarchy, including his height being recorded repeatedly, loudly being called by the "wrong" name (his given name), being called a "nice young man" repeatedly, and so forth. He showed a marked improvement in his preoccupation with his name, height, and appearance across multiple settings and was able to increase his hours at work.
Presentation at the Case Conference
Craig's preoccupation with his age and appearance no longer caused significant impairment. He continued to complain of significant "anxiety" on a daily basis, particularly in the late afternoon and evening when he was at home with his parents. He was unable to provide a complete description of the thoughts that accompanied this anxiety, but his mother noted that he would complain of "not knowing what to do" at that time of day. At the case conference, the possibility of depression was raised, with the reflection that his inability to find a desirable activity might indicate anhedonia. A current diagnosis of a major depressive episode could not be established. Over the course of questioning about active symptoms, however, his mother noted two previous episodes that suggested major depressive disorder, including worsened complaints of not knowing what to do, decreased energy, increased sleep, worsened concentration, and occasional tearfulness, each of which had lasted a month or more during his early teenage years.
Craig continued to receive psychotherapy in monthly sessions focused on releasing obsessive worries, but with little benefit. His aripiprazole dosage was increased to 20 mg daily. His mother noted spontaneous crying, worsened complaints of boredom and anxiety, increased sleep, decreased energy, and passive suicidal ideation. He was diagnosed with major depressive disorder and, because of previous side effects with serotonin reup-take inhibitors during adolescence, he was started on lamotrigine with a gradual titration from 25 mg/day to 100 mg/day. The behavioral activation approach was also reviewed with his family in some detail, including specific plans to increase structured activities. Over the course of 2 months, Craig showed significant improvement in all depressive symptoms, with only occasional complaints of not being sure what to do. With a further titration of his lamotrigine dosage up to 200 mg/day, he showed markedly decreased sleep, increased energy, and increased time spent disassembling and reassembling antique telephones, which he collected as a hobby. When Craig's daily dosage of lamotrigine was reduced back to 100 mg, these symptoms resolved with only a minor return of complaints of anxiety. Craig has been stable on this dosage for 12 months, and focal concerns about height, weight, and age have not been prominent for 21 months.
Dr. Veenstra-VanderWeele: Body Dysmorphic Disorder in Autism?
Before Craig was referred for psychotherapy, his most impairing problem was his preoccupation with being too tall or looking "old," which was diagnostically most consistent with comorbid body dysmorphic disorder. The diagnosis of body dysmorphic disorder was initially useful in that it offered options for treatment with some evidence base (2), as opposed to continued supportive psychotherapy approaches. Furthermore, Craig's body dysmorphic disorder symptoms appeared consistent with the typical syndrome. However, comorbid body dysmorphic disorder in autistic disorder had not previously been described in the literature.
The number of children, adolescents, and adults diagnosed with autism spectrum disorders has increased in recent years (3), and the largest increase has occurred for individuals who have a higher IQ and those with pervasive developmental disorder not otherwise specified (3, 4). In the past, these individuals may have been less likely to receive an autism spectrum disorder diagnosis and may instead have received other diagnoses, including obsessive-compulsive disorder (OCD) and related disorders. As patterns of autism spectrum disorder diagnosis evolve, it is important to remain cognizant of emerging patterns of previously unrecognized potential comorbidities.
Diagnosis of an autism spectrum disorder is based on three domains of symptoms—social impairment, restricted and repetitive behavior, and communication impairment. The complex repetitive or compulsive behaviors commonly seen in autism spectrum disorders are often seen as a link to OCD and related disorders (5, 6). Despite interest in this potential link, little attention has been paid in the autism spectrum disorder population to other comorbid disorders within the OCD spectrum. Our observations in this case suggest that one of these OCD spectrum disorders, body dysmorphic disorder, can occur in the context of an autism spectrum disorder (7, 8). Given the social deficits expected in autism, clinicians might assume that patients with autism would not have self-awareness or self- consciousness about their appearance. If persons with autism are not able to conceptualize the perspective of another person, as some have argued (9), it would not seem possible for them to become overly preoccupied with others' perceptions of their appearance.
However, both autism spectrum disorders and body dysmorphic disorder include repetitive, preoccupying thoughts or behaviors as central symptoms. Neuropsychological testing in each disorder reveals a tendency to focus on individual parts of a complex figure or pattern (10, 11). This failure to see the forest for the trees is often described as a defining feature of autism spectrum disorders (12) and is also central in body dysmorphic disorder, where exaggerated focus on one or more body features becomes all-consuming. Both disorders also include impairment in the social domain. A person with body dysmorphic disorder believes that others will view his or her appearance as flawed. Social phobia is a common comorbidity in body dysmorphic disorder (13). In autism spectrum disorders, where social dysfunction is universal, symptoms of social phobia are also common (14).
Dr. Warren: Psychological Treatment of Body Dysmorphic Disorder in Autism
In the absence of a definitive functional diagnostic structure that guides intervention, body dysmorphic disorder has been addressed with a number of psychotherapeutic modalities. While the efficacy of psychoanalytic intervention is unclear, a few intervention studies (both open and randomized controlled trials) support the effectiveness of CBT in treating body dysmorphic disorder (2, 15, 16). The functional components of this intervention typically include exposure and response prevention; addressing cognitive processes related to body dissatisfaction; and psychoeducation about the nature of the disorder. Concerns about being too tall or of too mature a build, as in the case of Craig, are not described in the literature as common foci of body distress. However, addressing Craig's body dissatisfaction was central in his care.
A course of systematic exposure and response prevention was used in conjunction with a trial of D-cycloserine. Craig was hesitant about pursuing exposure and response prevention but quite eager to try D-cycloserine. Like most patients presented with the rationale and framework of exposure and response prevention, he was concerned about actively approaching distressing triggers. However, with parental support as well as reassurance that he would never be asked to approach a level of distress that was too much to tolerate, Craig agreed to participate in a 4-week course of clinic-based exposure and response-prevention strategies. Three areas of focus were selected for intervention: reference to his name (selected because it was a mild trigger and therefore a likely successful entry point), reference to his height and other physical measurements, and reference to his age and growing up. Exposure hierarchies were created for each area, and Craig was able to progress through these hierarchies in a short time in the clinic setting. Creation of the hierarchies themselves and explication of the rationale of the intervention were particularly challenging given Craig's intense distress in even discussing triggers as well as his cognitive and autism spectrum disorder profile (i.e., low average IQ, limited metacognitive skills/ insight). Treatment with D-cycloserine seemed to help Craig approach a distress hierarchy, possibly both because of the therapeutic effect of the drug itself and because of Craig's belief that it would allow him to tolerate the discussion.
Another significant point of intervention was clarification with Craig's caregivers about the nature of his distress and his attempts to seek reassurance and relief from them, which often created more distress and increased his need to seek reassurance. A response-prevention strategy was outlined with his parents, including acknowledging and supporting his distress but not directly providing reassurance. Particular emphasis was placed on creating realistic systems of response prevention. Craig was not able to tolerate complete withholding of reassurance, but the reassurance could be effectively scheduled or delayed such that his distress or anxiety was largely dispelled before the reassurance was given.
As noted earlier, Craig showed a significant benefit from this limited intervention when it came to specific references to his name, height, and appearance; however, what was also quite clear from the start was that his distress was tied to a larger theme of coherent identity. The unavoidable psychodynamic interpretation was that these triggers were tied to conflicts about becoming an adult. The focus of his discomfort with adulthood became his physical appearance, but that only seemed a marker for the pressure and loss that accompanied finishing high school and facing an uncertain future. For a majority of his childhood and adolescence, Craig was often identified as a child with autism and was in turn granted special accommodations and support. This became Craig's predominant and preferred way of classifying himself, and he often used it in defense against the psychosocial reality of the end of school, difficulties finding a rewarding job, isolation from peers, and numerous functional limitations that might realistically be part of his future. In this position, Craig faced an extra challenge because he had a partial awareness of many of these realities but lacked the cognitive ability to fully hold on to and process these challenges. Thus, in the case of Craig, it appears that his autistic disorder and related vulnerabilities contributed to a specific presentation of body dysmorphic disorder superimposed on broader identity issues.
Dr. Sanders: Recognition of Depression in Autism
Although the risk of depression in autism spectrum disorders appears to be elevated (14, 17), the diagnosis can be difficult to establish because of limited self- report of mood and other cognitive symptoms (18). Craig was clearly facing potent interpersonal and psychosocial struggles that were painfully accompanied by an increasing awareness of these struggles. Comorbid depression can be difficult to distinguish from primary symptoms of an autism spectrum disorder. Typical symptoms can include decreased interest, boredom, increased aggression or irritability, decreased self-care, sleep problems, appetite changes, negative self-image, psychomotor retardation, somatic complaints, and regression (sometimes incontinence). Children and adolescents with an autism spectrum disorder may exhibit some of these symptoms in the absence of depression. Worsening of the core autism symptoms during a depressive episode is another complicating factor. It can be helpful to view the overlapping symptoms as both core symptoms of the autism spectrum disorder and symptoms of the comorbid depression. The new symptom cluster might include, for example, an increase in previous sleep problems or aggression and the new onset of decreased interest in previously preferred activities.
Children with an autism spectrum disorder often lack the skills to express their emotions and feelings with the same degree of insight into psychological processes that typically developing peers have. They routinely have problems discussing abstract subjects, such as guilt and meta-cognitive skills. Moreover, because no scales have been designed specifically to assess depression in the population with autism spectrum disorders, we must rely on outward signs and symptoms seen during examination and conveyed in the history provided by the caregiver.
Although there are challenges to making the diagnosis of depression in patients with autism spectrum disorders, for some individuals depression may represent a primary treatment focus within a complex psychiatric and neuro-developmental profile.
Craig improved symptomatically from incessant reassurance-seeking behaviors to repetitive but redirectable discussion of the specifics of antique telephones. With the initiation of lamotrigine, he regained the good sense of humor that was evident in wordplay from his early days in the clinic. He also successfully expanded his range of adult activities, including taking on additional hours at his first job placement and taking a second job placement on the weekends to earn money to put toward his hobby. As he has directed more of his attention outward, he has appeared to struggle less with his concerns about his name and appearance. At his most recent visit, he described "biting my tongue" when the nurse remarked on how tall he was.
The authors thank Susan McGrew, M.D., and Jeri Fitzpatrick, M.D., for particularly valuable comments during the case conference and in subsequent discussions; Eric Hollander, M.D., for helpful discussions of body dysmorphic disorder in the autism spectrum disorders population; and Autism Speaks for support of the Autism Treatment Network site and the corresponding multidisciplinary clinical case conference in the Vanderbilt Treatment and Research Institute for Autism Spectrum Disorders. |
<urn:uuid:9eef4805-bbc8-4a1f-ba8e-4f74ca32d1f7> | seed | A review of trisomy X (47,XXX)
1 Department of Pediatrics, University of Colorado Denver School of Medicine, 13123 East 16th Ave, Aurora, Colorado, 80045, USA
2 Child Development Unit, The Children's Hospital, 13123 East 16th Ave B140, Aurora, Colorado, 80045, USA
3 Psychiatry and Behavioral Services, Montefiore Medical Center, 111 East 210th Street, Bronx, New York, 10467, USA
Orphanet Journal of Rare Diseases 2010, 5:8 doi:10.1186/1750-1172-5-8Published: 11 May 2010
Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment. |
<urn:uuid:68ab96ff-83b4-4e03-825c-c6956dddc0d1> | seed | Electric Shock, a condition that occurs when there is a flow of electricity through that body. It is usually caused by contact with poorly insulated wires or ungrounded electrical equipment , by using electrical equipment while in contact with water, or by being struck by lightning. The severity and effects of electric shock depend mostly on the amount of current passing through the body and the duration of contact.
A slight, harmless shock produces only a jarring or startling sensation. Severe shocks produce muscle contractions, which lead to muscular spasms, paralysis, unconsciousness, or death. A fatal electric shock is called electrocution. Burns may occur where the current enters and leaves the body.
When an electric shock is caused by contact with electrical wires or equipment, the victim should be freed from the source of current immediately—either by shutting off the source (as by pulling a circuit breaker) or by separating the victim from the point of contact. Since the human body is a good conductor of electricity, the victim should not be touched with bare hands; dry, insulated gloves or a dry, nonconductive material (such as rubber or wood) should be used to push or pull the victim away from the source of current. In addition, the rescuer should stand on something dry and nonconductive.
A survivor of electric shock is often panicky with fear and is pale, trembling, and sweating. A doctor should be called immediately. First aid includes keeping the victim warm and in a horizontal position. If the victim stops breathing, mouth-to-mouth resuscitation should be given. Professional medical treatment may include treatment for burns and the administration of drugs and oxygen.
In most cases electric shock can be prevented by taking certain precautions, especially around the home. All appliances and switches should be in locations far from water and they should not be touched while standing in water or with wet hands. All electrical equipment should be permanently grounded. Frayed cords should be discarded and unused sockets covered or sealed. Before making any electrical repairs fuses should be removed or circuit breakers turned to the "off" position. Bare wires which could possibly be carrying current should never be touched. |
<urn:uuid:bbe46be1-7153-47dd-86f5-750fa4a872db> | seed | First Published in R&D Systems 2003 Catalog
The IL-10 family's history provides insight into the use of, and need for, new topological maps and sequences for the identification of new molecule superfamilies.
As part of an effort to better understand their relationships and roles in biology, various classification schemes have been devised which create groups, classes, families and superfamilies. While the criteria that distinguish a family from a superfamily are not always clear, the underlying basis for most classifications is 3-dimensional structure, function, or gene organization. Functional designations (e.g. proinflammatory, chemotactic) often give rise to loose confederations of structurally unrelated molecules. Structural designations, by contrast, are based on motifs and topologies that transcend both function and taxonomy. The cystine knot superfamily, for example, has two disulfide bond-generated loops through which passes a third disulfide bond. In plant enzymes, the first, second, fourth and fifth cysteines create loops; in animal growth factors, the second, third, fifth and sixth cysteines generate loops.1, 2
Cytokines have generally been placed in one of seven protein fold-based superfamilies. b-trefoil
(cloverleaf) family, while the TNF superfamily demonstrates a "beta-jellyroll" type
fold. The cystine-knot superfamily includes PDGF, NGF, glycoprotein hormones
and TGF-beta related molecules (activins, GDFs, BMPs). A number of molecules
are also defined as being "alpha-helical", and within this grouping are at
least three subtypes: those with short alpha-helices [8-10 amino acids (aa), i.e. IL-2,
IL-3 and IL-4]; alpha-helices (10-20aa, i.e. Epo,
GH and gp130 cytokines); and those with multiple repeat alpha-helices (i.e. IFN-gamma
and IL-5).4 In general, a-helix cytokines contain four alpha-helices.
IFN-gamma and IL-5, however, contain eight. IL-10 contains six alpha-helices
(both long and short).5 Based
on this pattern, sophisticated bioinformatic algorithms have been developed
to facilitate EST searching for IL-10-like molecules in various databases.
In 2000, a new cytokine was a-helical profile similar to IL-10.6 Although
it had limited overall aa homology to IL-10 (21%), 80% of the 50 aa that generate
IL-10's alpha-helical structure were conserved. This molecule has subsequently
been isolated and named IL-19.6 In
2001, a second IL-10-like molecule (IL-20) was also identified through bioinformatics.7 Based
on these topologies and primary sequence, at least three other heretofore unrecognized
IL-10 family members have subsequently been identified. These include IL-22/TIL,
IL-24/mda-7 and IL-26/AK155 (plus numerous viral homologs).5, 8 Within
the context of function, these molecules share little similarity. Within the
context of discovery, these molecules are at the cutting edge of technology.
The structure common to all mature IL-10 family members is the alpha-helix.
Although no empirical evidence exists, it is suggested that all possess six
has four cysteines, only one of which is conserved among family members. Since
IL-10 demonstrates a V-shaped fold that contributes to its dimerization (Figure
1), it appears that disulfide bonds are not critical to this structure. Amino
acid identity of family members to IL-10 ranges from 20% (IL-19) to 28% (IL-20).5, 8
IL-10 (CSIF/Cytokine Synthesis Inhibitory Factor)
IL-10 was first described as a Th2 cytokine in mice that inhibited IFN-alpha
and GM-CSF cytokine production by Th1 cells.9, 10 In mice, IL-10
is a homodimeric, glycosylated polypeptide of 17-21kDa (native/monomeric).
It is 178 aa in length with an 18 aa signal sequence (ss) and a 160 aa mature
As noted, it has six alpha-helices. The first four are N-terminal and are central
to the molecule while the last two are C-terminal helices and shared with an
adjoining IL-10 molecule, forming a non-covalent homodimer.8, 13 Mouse
IL-10 is inactive on human cells.14 Mouse
IL-10 shares 85% aa identity with rat IL-10,15 85% aa identity with
cotton rat IL-10,16 and 84% aa identity with guinea pig IL-10.17
Human IL-10 is also 178 aa in length with an 18 aa ss and a 160 aa mature segment. Its molecular weight is approximately 18 kDa (monomer). Unlike mouse IL-10, human IL-10 contains no potential N-linked glycosylation site and is not glycosylated.8, 18 It also contains one fewer cysteine residue than mouse IL-10 (4 vs. 5). Both IL-10s show two intrachain disulfide bonds, and form nondisulfide-linked homodimers.19 The length of alpha-helices A -->F in human IL-10 are 21, 8, 19, 20, 12 and 23 aa, respectively.5 As noted, helices A --> D of one monomer noncovalently interact with helices E and F of a second monomer, forming a noncovalent V-shaped homodimer. Functional areas have been mapped on the IL-10 molecule. In the N-terminus, pre-helix A residues #1-9 are involved in mast cell proliferation, while in the C-terminus, helix F residues #152-160 mediate leukocyte secretion and chemotaxis.20 In contrast to mouse, human IL-10 is active on various species including mouse18 and canine cells.21 Mature human IL-10 is 72%, 74%, 76%, 77%, 76%, 71% and 96% aa identical to mouse,11 rat,15 pig,22 guinea pig,17 cotton rat,16 dog21 and monkey IL-10,23 respectively. In human, IL-10 circulates at a concentration of approximately 0.5 pg/mL.24
Rat IL-10 has been cloned and found to be highly orthologous to mouse IL-10. It has a mature length of 160 aa and possesses five cysteines plus two potential N-linked glycosylation sites.15, 25 As with human IL-10, rat IL-10 is active on mouse cells.25 Mature rat IL-10 is 85%, 85% and 84% aa identical to mouse,11 cotton rat16 and guinea pig17 IL-10, respectively.
Cells known to express IL-10 include CD8+ T cells,26, 27 microglia,28 CD14+ (but not CD16+) monocytes,29, 30 Th2 CD4+ cells (mice),31 keratinocytes,32 hepatic stellate cells,33 Th1 and Th2 CD4+ T cells (human),34 melanoma cells,35 activated macrophages,36, 37 NK cells,38 dendritic cells,39 B cells (CD5+ and CD19+)40, 41 and eosinophils.42
IL-19 was originally isolated from an Epstein-Barr virus-transformed human
B-cell library.6 It is 177 aa in length and contains an 18 aa ss
plus a 159 aa mature segment. The mature region contains six cysteines and
two potential N-linked glycosylation sites. When expressed in transfected cells,
IL-19 is approximately 35-40 kDa in size (predicted MW = 21 kDa), suggesting
extensive glycosylation. There is a potential alternate splice site that adds
38 aa to the N-terminus. The significance of this observation is unknown. If
IL-19 is aligned to optimize its alpha-helical configurations, it shares less
than 20% aa identity with IL-10. More than 80% of the 50 aa that generate IL-10's
dimeric structure are conserved in IL-19, suggesting it likely forms noncovalent
dimers. Cells known to secrete IL-19 include monocytes and B cells.6, 43
IL-20 was initially identified in a human keratinocyte library during a bioinformatics search for molecules expressing amphipathic helices. When cloned, it was found to consist of a 176 aa polypeptide that contains a 24 aa ss, a 152 aa mature segment, six cysteines, and no potential N-linked glycosylation sites.7 It is not known if this molecule forms a dimer; there are reports both for and against this configuration.7, 44 There is 26% aa identity between human IL-20 and IL-10, and 41% aa identity between IL-20 and IL-19 with conservation of all six cysteines.6, 7 The IL-20 gene maps to chromosome 1 with IL-10, IL-19 and IL-24/mda-7.7 Mouse and human IL-20 show 76% aa identity in the mature segment.7, 45 Cells known to produce IL-20 are monocytes43 and (perhaps) keratinocytes.7, 46
IL-22/TIF (T cell-derived Inducible Factor)
Human IL-22 is a 179 aa polypeptide that contains a 33 aa ss and a 146 aa
mature region.47, 48 The mature molecule contains three potential
N-linked glycosylation sites plus four cysteines, only two of which are conserved
in IL-10.5 While it is suggested to form a homodimer,44 it
can also apparently accommodate a monomeric configuration.5, 8 Thus,
its native form is unclear. There is 24% aa identity between mature human IL-22
and IL-10. Mouse IL-22 is 179 aa in length with a 33 aa ss, 146 aa mature segment
and four potential N-linked glycosylation sites.49, 50 Its native
molecular weight is approximately 25 kDa.49 While there is only
one human gene, there are two IL-22 genes (IL-22 alpha and IL-22 beta) in
select mouse strains (C57/Bl), which are the result of gene duplication.50 Each
gene is 179 aa in length, yet demonstrates differences in aa at positions #36
(Val to Ile), #103 (Val to Ile), and #112 (Gln to Arg). In C57 mice, it is
not known if the IL-22 beta gene is functional as it lacks essential promoter
elements. In the standard a-form of IL-22, there is also a polymorphism with
an Asn substituted for a Ser at position #84.50 There is 81% aa
identity in the mature regions of human IL-22 and mouse IL-22 alpha. Cells
known to express IL-22 include NK cells and CD4+ Th1 cells.43
IL-24/mda-7 (melanoma differentiation associated gene-7)
IL-24 was originally isolated from actively proliferating melanoma cells.51 It consists of a 207 aa precursor with an extended 47 aa signal sequence and a 160 aa mature segment.52 Contrary to initial reports, it is secreted and has a native molecular weight of approximately 35 kDa.53 Within the mature segment, there are three potential N-linked glycosylation sites and two cysteines. Thus, it differs markedly from all other known IL-10 family members in the potential for disulfide-bonding.51 In its mature segment, it shares 20% aa identity with IL-10. Human IL-24 is active on rat cells. IL-24 in mouse is a 27 kDa, glycosylated polypeptide also known as FISP.54 It is 220 aa in length with an extended 60 aa ss and a 160 aa mature segment. It shares 69% and 84% aa identity with human and rat IL-24, respectively, in its mature segment.52, 54 Rat IL-24 is also known as mob (mobster)-5 and c49a. It was discovered after Ha-ras-activation in cell lines.52 It is 183 aa in length and contains a 23 aa ss plus a 160 aa mature segment.52, 55 As with human IL-24, there are only two cysteines in the mature segment. It is 69% aa identical to human.55 Cells known to express IL-24 include Th2 cells (in mouse),53 melanocytes,51, 55, 56 breast epithelium,56 fibroblasts (in rat),55 monocytes,43, 54 vascular smooth muscle,57 NK cells,58 B cells58 and CD4+ CD45RA+ (naïve) T cells.43
IL-26/AK155 is a 36 kDa homodimer that was initially identified in the supernatant of cultured herpesvirus-transformed T cells.59 Its open reading frame encodes a 171 aa precursor that contains a 21 aa ss and a 150 aa mature segment. Its mature segment shares 25% aa identity with human IL-10 and retains the typical six alpha-helix pattern seen in IL-10. Remarkably, there is no mouse counterpart to IL-26.8 Cells known to express IL-26 include CD4+ CD45RO+ T cells and NK cells.43
The receptors for the IL-10 family are all members of the class II cytokine
receptor family (CRF2).53 All functional receptors are heterodimers
composed of an alpha or type 1 (R1) chain and alpha beta or type 2 (R2) chain.
At a minimum, it would appear that there are at least two alpha and two beta
chains involved in each signaling receptor complex.60 Traditional
nomenclature has often defined the alpha subunit as being the ligand-binding
molecule and the beta subunit
as being the signal transducing subunit. For at least one member of the IL-10
family, both subunits can serve as ligand-binding moieties47, 61 and
the alpha-subunit in this case generally serves as a STAT3 docking port (i.e. the
first step in signal transduction).60 Class II cytokine receptors
are characterized by the presence of two fibronectin type III (FNIII) domains
in their extracellular region. These typically are 90-100 aa globular modules
that consist of seven beta-strands that form two beta-sheets (reminiscent of
Ig domains). These domains are typically associated with cell surface adhesion
IL-10 R1: Human IL-10R1 is a 90-110 kDa, type I transmembrane
glycoprotein that is expressed on a limited number of cell types.63 The
open reading frame encodes a 578 aa protein that contains a 21 aa ss, a 215
aa extracellular region, a 25 aa transmembrane segment, and a 317 aa cytoplasmic
domain. There are two FNIII motifs within the extracellular region and a STAT3
docking site plus a JAK1 association region within the cytoplasmic domain.60, 63, 64 IL-10R1
binds human IL-10 with a Kd of 200 pM. It does not bind mouse IL-10. There
is 56% aa identity overall between human and mouse IL-10R1, with 57% aa identity
in the extracellular region.63, 65 The mature form of mouse IL-10R
is 110 kDa and 560 aa in length.65 It contains a 224 aa extracellular
region, a 24 aa transmembrane segment, and a 313 aa cytoplasmic domain.
IL-20 R1/RA: Human IL-20R1, also known as zcytor7, is a 553 aa type I transmembrane protein of which little is known structurally.66 Originally identified by Zymogenetics, Inc., it has since been identified as one member of the IL-20 signaling complex.7 Overall, it shares approximately 21% aa identity with mature IL-10R1.
IL-22 R/CRF2-9: Human IL-22R, also known as zcytor11, is a 574 aa type I transmembrane protein that contains a 574 aa extracellular region, a 23 aa transmembrane segment, and a 346 aa cytoplasmic domain.47 It shares approximately 15% aa identity overall to IL-10R1, and 17% aa identity within the extracellular region.
Soluble IL-22 R/CRF2-10: A genetically distinct soluble receptor for IL-22 has recently been identified that is 40 kDa in size and 210 aa in length.67, 68, 69, 70 As with the other IL-10R family members, it contains two FNIII motifs. Two alternate splice forms have been noted in addition to the standard 210 aa form. One splice form is truncated and only 131 aa in length.69 The second splice form is extended by 32 aa, creating a 242 aa mature molecule.67, 69, 70 This long form is only found in placenta and may regulate both IL-22 and IL-20 activity. The standard form is strictly an antagonist for IL-22 activity (STAT activation).69 Cells known to make the standard form include plasma cells, monocytes, B cells, CD4+ T cells and type II greater alveolar cells.68
IL-10R2/CRF2-4: Human IL-10R2 is a 60 kDa, 325 aa glycoprotein
that contains a 201 aa extracellular region, a 29 aa transmembrane segment,
and a 76 aa cytoplasmic domain.71 Its cytoplasmic domain is associated
with Tyk2 kinase.64 Relative to human IL-10R1, it shows 16% aa identity
overall and 21% aa identity in the extracellular domain. Its designation as
CRF2-4 follows that for CRF2-1 (IFN-alpha beta R), CRF2-2 (IFN-gamma receptor)
and CRF2-3 (tissue factor receptor). The mouse IL-10R2 molecule is 329 aa in
mature length, with a 100 aa cytoplasmic region, a 29aa transmembrane segment,
and a 200 aa extracellular domain.72,73 It is 69% aa identical to
human IL-10R2 overall, with 75% aa identity in the extracellular region.72
IL-20 R2/RB: IL-20R2 is also known as DIRS1 in the patent
literature [Parnam, C.L. (1999) WO 9946379A2]. It is 311 aa in length and contains
the typical FNIII domain. Over the entire ORF, there is 28% aa identity, human
IL-10R2 to human IL-20R2.74 In combination with IL-20R1, IL-20R2
is a functional part of the IL-20 receptor.7
To date, the five transmembrane receptors contribute various combinations to IL-10 family binding. Currently, published data8, 64, 75 suggest the following:
IL-10: Binds to IL-10R1 / IL-10R2
IL-19: Binds to IL-20R1 / IL-20R2
IL-20: Binds to IL-20R1 / IL-20R2 and IL-22R / IL-20R2
IL-22: Binds to IL-22R / IL-10R2
IL-24: Binds to IL-20R1 / IL-20R2 and IL-22R / IL-20R2
IL-26: No known receptor
It is clear that IL-10 and its family members share common receptors. Often,
however, cytokines have distinct, if not antagonistic, functions. As an example,
both IL-10 and IL-22 signal through IL-10R2 and each activate JAK1 and TYK2,
thus resulting in STAT3 activation.53, 76 IL-22, however, also induces
serine phosphorylation of STAT3 (IL-10 does not), an event that is associated
with MAP kinase pathway activation.76, 77 This notable difference
in signaling is reflected in at least one function of IL-10 and IL-22. IL-10
suppresses both IL-1 and TNF-alpha production by LPS-stimulated monocytes while
IL-22 does not.47
IL-10: The volume of information published related to IL-10 function is considerable. In brief, the following information outlines general functions on select cells.
On T cells, the initial observations of IL-10 inhibition of IFN-gamma production
is now suggested to be an indirect effect mediated by accessory cells.9, 10 Additional
effects on T cells, however, include: IL-10 induced CD8+ T cell
chemotaxis,20, 78 an inhibition of CD4+ T cell chemotaxis
towards IL-8,20 suppression of IL-2 production following activation,79, 80 an
inhibition of T cell apoptosis via Bcl-2 up-regulation,81 and an
interruption of T cell proliferation following low antigen exposure accompanied
by B7/CD28 costimulation.82
On B cells, IL-10 has a number of related, yet distinct functions. In conjunction
with TNF-beta and CD40L, IL-10 induces IgA production in naïve (IgD+)
B cells. It is believed that TGF-beta/CD40L promotes class switching while
IL-10 initiates differentiation and growth.83, 84 When TGF-beta is
not present, IL-10 cooperates with CD40L in inducing IgG1 and IgG3 (human),
and thus may be a direct switch factor for IgG subtypes.85 Interestingly,
IL-10 has divergent effects on IL-4 induced IgE secretion. If IL-10 is present
at the time of IL-4 induced class switching, it reverses the effect; if it
is present after IgE commitment, it augments IgE secretion.86 Finally,
CD27/CD70 interaction in the presence of IL-10 promotes plasma cell formation
from memory B cells.87
Mast cells and NK cells are also impacted by IL-10. On mast cells, IL-10 induces
histamine release while blocking GM-CSF and TNF-alpha release. This effect
may be autocrine as IL-10 is known to be released by mast cells in rat.88,89 As
evidence of its pleiotrophic nature, IL-10 has the opposite effects on NK cells.
Rather than blocking TNF-alpha and GM-CSF production, IL-10 actually promotes
this function on NK cells.90 In addition, it potentiates IL-2 induced
NK cell proliferation and facilitates IFN-?gamma secretion in NK cells primed
by IL-18.90, 91, 92 In concert with both IL-12 and/or IL-18, IL-10 potentiates
NK cell cytotoxicity.92
IL-10 has a pronounced anti-inflammatory impact on neutrophils. It inhibits
the secretion of the chemokines MIP-1 alpha, MIP-1 beta and IL-8,93, 94 and
blocks production of the proinflammatory mediators IL-1 beta and TNF-alpha.94 In
addition, it decreases the ability of neutrophils to produce superoxide, and
as a result interferes with PMN-mediated antibody-dependent cellular cytotoxicity.95 It
also blocks IL-8 and fMLP-induced chemotaxis, possibly via CXCR1.96
On dendritic cells (DCs), IL-10 generally exhibits immunosuppressive effects. It would appear to promote CD14+ macrophage differentiation at the expense of DCs.97 Macrophages, while phagocytic, are poor antigen-presenting cells. IL-10 seems to decrease the ability of DCs to stimulate Tcells, particularly for Th1 type cells.98, 99 How IL-10 accomplishes this is unclear, as the data within the literature is conflicting. Relative to MHC-II expression, it can be down-regulated,100, 101 unchanged,99, 102 or up-regulated.98, 101 With respect to B7-1/CD80, IL-10 will either up-regulate98, 101 or down-regulate100, 101, 103 its expression. B7-2/CD86 plays a key role in T cell activation. For this molecule, IL-10 is involved in both up-regulation98, 100 and down-regulation.100, 101, 102 Perhaps the most significant modulation, however, occurs with CD40 (IL-10 seems to reduce its expression).101, 103 At the regional level, IL-10 may block immunostimulation by inhibiting Langerhans cell migration in response to proinflammatory cytokines.104 Alternatively, IL-10 blocks an inflammation-induced DC maturation step that normally involves CCR1, CCR2 and CCR5 down-regulation and CCR7 up-regulation. This blockage, with retention of CCR1, CCR2 and CCR5, results in a failure of DCs to migrate to regional nodes. The result is an immobile DC that will not stimulate T cells but will bind (and clear) proinflammatory chemokines without responding to them.105
On monocytes, IL-10 has a number of documented effects. For example, IL-10 seems to clearly reduce cell surface MHC-II expression.20, 106, 107, 108 It also inhibits IL-12 production following stimulation.109 While it promotes a monocyte to macrophage transition in conjunction with M-CSF,110 the phenotype of the macrophage is not clear (i.e. CD16+/cytotoxic vs. CD16-).106, 111 IL-10 also reduces monocyte GM-CSF secretion112 and IL-8 production,20 while promoting IL-1ra release.20 Hyaluronectin, a connective tissue component, is now known to be secreted by monocytes in response to IL-10.113 This may have some importance in cell migration, particularly tumor cell metastases, where hyaluronectin is known to interrupt cell migration through extracellular space.
IL-19: To date, there is no known function for IL-19.8
IL-20: The only suggested function for IL-20 involves keratinocytes. Partly based on overexpression studies, it is proposed that IL-20 induces keratinocyte differentiation and proliferation.7, 46 IL-20R is expressed on keratinocytes and endothelial cells,7 and keratinocytes likely express the IL-20 cytokine.114
IL-22: The functions associated with IL-22 are limited. IL-22
induces acute phase proteins in hepatocytes (i.e. haptoglobin, alpha
1-antichymotrypsin)8, 48 and
may reduce IL-4 production by certain Th2 cells.47 In addition,
pancreatic acinar cells, which synthesize inactive precursor forms of digestive
enzymes, are now known to express PAP1 (pancreatitis-associated protein-1)
and osteopontin in response to IL-22.115 These are two molecules
that may have protective or trophic effects during inflammation.
IL-24: IL-24/mda-7 was initially believed to induce melanocyte/melanoma
cell differentiation. Melanoma cells lack IL-24 expression, while melanocytes
express IL-24. In the presence of IL-24, melanoma cell growth was inhibited
(G2/M arrest).51, 57 Thus, it appeared that mda-7/IL-24 may be a
tumor suppressor molecule.56,116 Subsequent studies have shown that
IL-24 can inhibit tumor growth in cells other than melanoma (i.e. non-small
cell lung carcinoma, breast cancer, prostate cancer),117, 118, 119 and
that apoptosis can be induced in transformed cells without negatively impacting
any normal cell types.57, 113, 119 Aside from its ability suppress
tumors, IL-24 has also been shown to induce IL-6 and TNF-alpha secretion by
monocytes, demonstrating an activity antagonistic to that of IL-10.58
IL-26: To date, almost nothing is known about IL-26 activity.
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<urn:uuid:498592dc-14e7-4ab4-805c-78fafecafc7e> | seed | Every parent expects their child to receive routine childhood vaccinations during well-baby check-ups. An equally important component of these visits is the monitoring of your child’s growth and development. Your pediatrician or family physician will measure your child’s growth parameters: height (length), weight and head circumference. She will plot them on standard growth charts to determine how your child’s growth compares to other children and, more important, whether he or she is following a consistent and healthy pattern of growth over time.
The higher your child’s percentile on the growth chart, the bigger he or she is compared to others of the same age. For example, if your 6-month–old baby is in the 60th percentile for weight and 70th percentile for height, it means that he’s heavier than 60 percent of 6-month-old babies and lighter than 40 percent, and taller than 70 percent of babies his age and shorter than 30 percent. A higher percentile ranking doesn’t indicate better health nor does a lower one indicate poor health. It just shows where your child is, compared to the growth of others his or her age.
Many factors affect the growth of your child including diet and activity, family history of growth (especially height of the parents) and overall health. Two of my five exceptionally charming grandchildren are likely to be taller than average (as children and adults) as their parents are both taller than average.
Growth normally can be erratic, and children sometimes go through spurts of rapid growth alternated with periods of slower growth. When should you worry about your child’s growth? It’s concerning if a pattern of growth changes significantly. For example, if your child has been in the 60th percentile for three years and then slows to the fifth to 10th percentile, you and your doctor will want to determine why the pattern has changed. Remember that patterns and trends of growth are more important than any individual plot on a growth chart.
Why measure head circumference? If your baby’s head growth is less than average, your doctor will make sure his other development—speech, motor, social, fine motor—is normal. If it’s faster and larger than average, there are other very rare problems to look for.
Do birth weight and length matter? Probably less than you think. Birth weight can be affected by many factors, including blood flow across the placenta and gestational age. A baby born at 34 weeks of gestation will be smaller than if he waited in the uterus another four to six weeks, but he’ll catch up. The stature of parents is the best indicator of eventual adult height.
Dr. Joseph Kahn is president of Mercy Kids (mercykids.org), an expansive network of pediatric care dedicated to meeting the needs of every child, every day. |
<urn:uuid:e1289bcd-531b-4cec-ada1-ffb929cd4edf> | seed | Though prevention of adolescent tobacco use is a major public health goal, there is little information on the ability of pediatricians to identify adolescents experimenting with tobacco and regular tobacco users.
To pilot use of a short questionnaire and analysis of urinary cotinine level to identify adolescent smokers in a pediatric practice, and to determine characteristics of tobacco users.
Suburban pediatric practice.
Consecutive high school students completed a short questionnaire and urine cotinine assessment. Three groups were defined: smokers (urine cotinine level >100 ng/mL), experimenters (smoked within the last year; urine continine level ≤100 ng/mL), and nonsmokers. Logistic regression was used to examine characteristics of experimenters.
One hundred twenty-four adolescents were enrolled throughout 3 months: 83 nonsmokers (67%), 28 experimenters (23%), and 13 smokers (10%). The questionnaire alone identified 92% of regular smokers. Smoking frequency increased by grade level. Smoking initiation occurred with peers. Compared with nonsmokers, smokers and experimenters were more likely to be older and have a majority of friends who smoked. Smokers were more likely to have a family member who smoked. A majority of smokers and experimenters had tried to quit and understood the adverse health effects of tobacco use.
Adolescent smokers and experimenters were identified using a brief questionnaire. This method will allow pediatricians the opportunity to identify at-risk adolescents before they become regular smokers. Further studies at primary care offices are needed to examine identification of adolescents at highest risk and examine methods to initiate smoking cessation before addiction is established. |
<urn:uuid:d21ba756-1b0d-4b13-a323-d4d46f42c935> | seed | Which Form to Use
Decide which form to use based on the level of potential risk to the research subjects.
Greater than minimal risk
Full IRB review
If your research project involves greater than minimal risk, it must be go through full IRB review for approval.
Examples of full IRB review research:
- Research with children and other vulnerable populations
- Research that involves experimental drugs or devices, invasive procedures
- Research involving deception
- Survey research that involves sensitive questions or information about sexual practice or illegal behavior
- Any survey or interview that is likely to be stressful for the subject
To qualify for expedited review, an activity must:
- Involve no more than minimal risk, and
- Be found on the list of Expedited Review Categories of Research
Minimal risk: the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or test.
Examples of minimal risk research:
- Non-invasive recording of data from subjects
- Minimal blood draw amounts
- Voice recordings
- Non-stressful research on individual or group behavior
- Moderate exercise by healthy volunteers
When making a decision about minimal risk of research, consider both magnitude and likelihood of risk. A more serious risk may be permissible if its probability is extremely low. For example, airplane flight carries a risk of death, but it occurs only once in some millions of passenger miles.
Risks of ordinary, non-invasive diagnostic tests such as routine blood draws in adults, general physical exams, pen-and-paper tests, and ultrasound exams (at accepted levels) are okay; however, minimal risk may be age- or context-dependent: blood draws may be minimal risk for someone old enough to give consent, but not for a needle-shy child. And the context-dependent "ordinary" risk of a sick patient experiencing numerous invasive procedures differs from that of a healthy individual.
Remember that risks need not be "physical" to be "greater than minimal." For example: a privacy/confidentiality risk, informational risk, or risk of embarrassment may qualify the research as "greater than minimal risk," requiring full IRB review.
Screening for IRB review exemption
DHHS Guidelines (45 CFR Part 46.101(b) and (c)) define research as exempt from further IRB review when the research involves no risk to the subject. Research that is considered exempt from full IRB review must still be submitted to the IRB and screened for exempt status. The final determination of level of review will be made by the IRB upon receipt of the application form.
Examples of exempt research: survey interview research with adult subjects; the use of nonidentifiable laboratory specimens; review of nonidentified existing records; observation of the public behavior of subjects where there is no manipulation of the subject; and some educational testing and classroom activity.
Use the Exempt Review Categories of Research to decide which exemption category might apply to your research and which form to then use. If you don't see a category for your research, expedited or full IRB review is probably required.
Exempt review categories of research
Category 1. Research conducted in educational settings, involving normal educational practices.
Instructional Research in Educational Settings
Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as:
- Research on regular and special education instructional strategies, or
- Research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.
This category may be applied to research involving children.
Examples of Research in Category 1:
- Evaluating the use of accepted or revised standardized tests
- Testing or comparing a curriculum or lesson
- A program evaluation of pharmacy continuing education
Category 1 Form:
Category 2. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior.
Surveys/Interviews; Standardized Education Tests; Observation of Public Behavior
Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior unless:
- Information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and
- Any disclosure of the human subjects' responses outside the research could reasonably place employability, or reputation.
Surveys on sensitive or personal topics that may cause stress to study participants are not exempt from IRB review.
This section pertaining to standardized educational tests may be applied to research involving children. This category may also apply to research with children when the investigator observes public behavior but does not participate in that behavior or activity. This section is not applicable to survey or interview research involving children.
Examples of Research in Category 2:
- Surveying teachers, nurses, or doctors about a technique or an outcome
- Interviewing managers about a management style or best practice
- Conducting a focus group about an experience or an opinion of a community program
Category 2 Form:
Category 3. Research involving the activities in category 2 and the human subjects are elected or appointed public officials or candidates for public office.
Public Officials; Surveys/Interviews; Educational Tests; Observation of Public Behavior
Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior not exempt under category 2 if:
- The human subjects are elected or appointed public officials or candidates for public office, or
- Federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.
Examples of Research in Category 3:
- Interviewing public officials about a local or global issue
Category 3 Form:
Category 4. Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens.
Existing Data; Records Review; Pathological Specimens
Research, involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.
To qualify for this exemption ALL of the data, documents, records, or specimens must be in existence before the project begins.
Records considered private based on federal and state statute, including medical records and education records, require written release by the study subject or by the custodian of the record. Researchers are cautioned that review of private records involving access to and/or recording of identifiable information is not exempt from IRB Review and requires written consent of the study subject. Review of existing public records do not require prior consent of subjects.
Pathological or diagnostic specimens that are considered waste and are destined to be destroyed can be used in research and are considered exempt from IRB review if there are no patient identifiers linked to the specimen and if the data is not intended to be used in the diagnosis or treatment of a patient. (If either of these conditions apply, consent of the research subject and IRB review is required.) Specimens retrieved as extra during a clinical procedure require IRB review and written consent from the subject.
Inclusion of fetal tissue in the pathological specimens category of exempt research is prohibited by regulation.
Examples of Research in Category 4:
- Analyzing de-identified tissue samples or data set
- Analyzing de-identified national test scores
- Analyzing census data about aging or housing
Category 4 Form:
Category 5. Reserved for Federal Government Research. Not available for local IRB exemptions.
Public Service Programs; Demonstration Projects
Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine:
- Public benefit or service programs
- Procedures of obtaining benefits or services under those programs
- Possible changes in or alternatives to those programs or procedures; or
- Possible changes in methods or levels of payment for benefits or services under those programs
Category 6. Taste and food quality evaluation and consumer acceptance studies.
Taste Testing and Food Quality Evaluation
Taste and food quality evaluation and consumer acceptance studies:
- If wholesome foods without additives are consumed, or
- If a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.
This category may be applied to children; however, university policy requires written parental consent to include children in taste testing studies.
Examples of Research in Category 6:
- Taste testing whole grain food products
- Comparing taste or smell of molasses, cheese or milk
- Sampling texture of ice cream
Category 6 Form:
What if more than one category applies to the research?
Complete the exempt application form where the majority of the research clearly matches. Include description of the additional exempt category research in this application as well. |
<urn:uuid:72cf3e4d-f122-4195-9ea9-b89f1668f234> | seed | When A Patient Presents With A Painful Red Toe
- Volume 22 - Issue 10 - October 2009
- 112503 reads
- 0 comments
Deep frostbite. In deep frostbite, the skin is numb and feels hard like wood. It looks pale or white. At this point, muscle and bone may be frozen. In more severe cases of frostbite, the skin can turn blue, gray or even black because of tissue injury. These changes sometimes do not happen until after the area warms up. Deep frostbite needs immediate medical attention. In severe cases, deep frostbite can lead to permanent injury, amputation and even death.
Risk factors for frostbite include the following:
• inadequate shelter
• inadequate or constrictive clothing
• wind chill factor
• high altitude
• prolonged exposure to cold
• prolonged exposure to moisture
• malnutrition and exhaustion
• previous cold injury (previous injury increases risk twofold)
• peripheral vascular disease, diabetes mellitus or thyroid disease
• improper behavioral response to cold ambient temperature
• blocked arteries, atherosclerosis or other problems that affect blood circulation
• exposure to drugs with vasoconstrictive effects such as beta-blockers, which decrease the blood flow to the skin
• a low percentage of body fat
• drinking alcohol, which increases the loss of body heat
• drinking caffeine, which increases dehydration
• using nicotine, which decreases blood flow to limbs
A Guide To The Differential Diagnosis
Erysipelas. This is an acute infection of skin and subcutaneous tissue caused by beta-hemolytic Streptococcus with spreading inflammation and swelling. The area is warm and the patient may have a temperature.
Raynaud’s disease. This is a vasospastic disorder of the small peripheral arteries. The most common form is idiopathic primary Raynaud’s disease and is found in young women. Secondary Raynaud’s disease may be due to other connective or soft tissue disorders such as rheumatoid arthritis, systemic lupus or scleroderma. Occasionally, secondary Raynaud’s disease may be due to peripheral vascular occlusive disease, neurogenic lesions or drug intoxications.
Contributing factors include cold exposure and nicotine. Raynaud’s disease is often seasonal and most active in the cold weather months.
Paronychia. This infection develops along the edge of the toenail.
Thrombosis obliterans. This is inflammatory thrombosis of small and medium-sized arteries and some superficial veins, causing arterial ischemia in distal extremities and superficial thrombophlebitis. Tobacco use is the primary risk factor.
Dry gangrene. Dry gangrene is the term used to describe the death of tissue caused by a lack of blood supply. It is most common in people with advanced blockages of the arteries (arteriosclerosis) resulting from diabetes.
Acute irritant contact dermatitis. This occurs when the skin comes in contact with a strong toxic chemical and causes a rash (sharp borders with vesicles or bullae). The rash occurs within minutes to hours after exposure and, in most cases, healing occurs soon after exposure ceases.
Bullous diabeticorum. This is a distinct, spontaneous, noninflammatory, blistering condition of acral skin unique to patients with diabetes. Blisters occur spontaneously and abruptly, often overnight and usually without known antecedent trauma. Lesions tend to be asymptomatic although patients have described mild discomfort or burning. Blisters heal spontaneously within two to six weeks of onset.
Pertinent Insights On Pathophysiology
With frostbite type injuries, two main reactions take place when tissues come into contact with very cold temperatures. |
<urn:uuid:26f6f973-83f5-4b9b-8240-071e63202158> | seed | WINSTON-SALEM, N.C. – Predictors of atrial fibrillation (AF or afib) might offer physicians a better way to prevent stroke in blacks, according to a new study done by researchers at Wake Forest University School of Medicine.
AF is an irregular and often rapid heart rate that commonly causes poor blood flow to the body, as well as symptoms of heart palpitations, shortness of breath and weakness. Despite low reported prevalence of AF – one of the major risk factors for stroke – in black patients, they suffer strokes five times more often than white patients and die from them two times more often.
That paradox might result from limitations in the methods (electrocardiograms (ECG) or self-report) used to detect AF, said Elsayed Z. Soliman, M.D., M.Sc. M.S., associate director of the Epidemiological Cardiology Research Center (EPICARE) at the School of Medicine and lead author of the study.
“The limitations stem from the fact that AF is intermittent in at least 30 percent of patients, and most patients are not aware if they have AF or not,” Soliman said. “Trying to detect AF using an ECG, or simply counting on patients to know if they have it, leads to under-diagnosis of the condition most of the time. Our research suggests that being proactive in predicting it may be a better approach.”
The study appears in the current issue of Stroke, the peer-reviewed journal of the American Heart Association and American Stroke Association.
An electrocardiogram is a diagnostic tool that measures and records the electrical activity of the heart. Interpretation of an ECG report allows diagnosis of a wide range of heart conditions from minor to life threatening.
Doctors use ECGs to diagnose AF, and therefore assess the risk of stroke in different patients. However, ECG reports of AF have not been as useful for identifying black patients at high risk. While black patients suffer more ischemic strokes than white patients, their ECG results do not indicate AF as often.
For the study, researchers reviewed ECG data from the Atherosclerosis Risk in Communities (ARIC) study supported by the National Heart, Lung and Blood Institute. More than 15,000 people in North Carolina, Mississippi, Minnesota and Maryland participated in the study during the 1980s and 90s.
Researchers found that, while ECG reports of AF were significantly less in black participants than in whites, black participants ultimately suffered more ischemic strokes. However, the analysis uncovered that ECGs on black participants revealed a higher rate of predictors of future AF than did the ECGs of the white participants. These ECG predictors of AF (P-wave terminal force, P-wave duration, P-wave area and PR duration) represent electrical activity within the upper two chambers of heart, or atria, which are the sources of blood clots that cause stroke if AF occurs. These ECG predictors of AF were strongly predictive of strokes and AF in blacks and whites, so researchers believe their existence could be considered as presence – or future presence – of AF.
“With the blacks having more abnormal ECG predictors of AF, as the results showed, there is a possibility that blacks might actually have a higher prevalence of AF than previous studies have picked up on,” Soliman said. “Blacks may have more “intermittent” AF, the difficult type of AF to detect, which could be the reason why previous studies underestimated AF diagnosis more in blacks.”
Soliman added that physicians, knowing this, should use the ECG to evaluate black patients’ risk of stroke by determining if the patient has certain predictors of AF, instead of the condition itself. If so, the patients may be able to be treated with blood thinners as if they have AF. It is a treatment adjustment that could help prevent stroke, however further investigation into the subject is needed, he said.
“P-wave terminal force in the ECG may provide a strong independent predictor for incidence stroke and AF in clinical practice,” Soliman said.
“For the physician evaluating black patients for the risk of stroke, these results show that you cannot think AF is less common in this population,” Soliman said.
Soliman said that the next step in research on this subject is to do a long-term ECG study to confirm the hypothesis that AF, especially intermittent AF, has been under-diagnosed in blacks.
“We need further studies using long-term ECG recording – 48 hours to 72 hours – or event monitors to detect AF” he said. “The cost of these tests on population studies has always been an obstacle. However, with the results of this study, it may be worth it.”
Co-authors on the study are Ronald J. Prineas, M.D., Ph.D., L. Douglas Case, Ph.D., Zhu-ming Zhang, M.D. and David C. Goff Jr., M.D., Ph.D., all of the Division of Public Health Sciences at the Wake Forest University School of Medicine. |
<urn:uuid:78e7cb3c-e107-40f6-85b2-b53a3359d087> | seed | Why are some successful, some not?
In a study published in the December 2009 issue of the Journal of the American Dietetic Association, researchers from UC San Diego School of Medicine identified overweight adolescents who successfully lost weight, and overweight adolescents who did not, and compared the two groups on weight control behaviors, dietary intake and physical activity to determine which strategies are effective.
“Our findings provide a glimpse of optimism that adolescents can lose a significant amount of weight and maintain this weight loss,” said Kerri Boutelle, PhD, associate professor in UCSD’s Departments of Pediatrics and Psychiatry and at Rady Children’s Hospital-San Diego. “Second, our findings suggest that there are no magical solutions, but that behaviors such as eating more fruits and vegetables, eating less fat and decreasing sedentary time seem to offer the most promise for success.”
Adolescent obesity is a major public health problem that impacts one out of every three youth, resulting in four to five million overweight youth in the United States. Research shows that one of the strongest predictors of adult obesity is adolescent obesity, with 70 percent of obese adolescents becoming obese adults. Findings from this study have the potential to guide both future research studies and clinical interventions for obesity in adolescents.
Boutelle and co-authors surveyed 130 adolescents, 62 of whom had been successful in losing weight and 68 who had not. Questioning adolescents and their parents, the authors evaluated weight control strategies, sedentary behaviors, dietary intake, physical activity, weighing frequency and current weight status.
The successful adolescents reported increased exercise levels, drinking less soda, walking more, climbing stairs and self-weighing. Overall, a higher percentage of adolescents who lost weight reported using six or more healthy weight control behaviors compared to those who did not lose weight. Fewer of the adolescents who lost weight reported using any of the structured behavior strategies that were assessed.
“Self-weighing may be a helpful monitoring tool for overweight adolescents,” explained Boutelle. “In the current study, the largest percentage of adolescents who lost weight reported weighing themselves on a weekly basis, while the largest percentage of adolescents who did not lose weight reported weighing themselves less than monthly. Last, the group that lost weight did not report using unhealthy weight control behaviors. Adolescents would benefit from hearing this information from dietitians and other health care providers to prevent development of unhealthy weight control behaviors in overweight teens.”
# # #
Full text of the article – “Weight control strategies of overweight adolescents who successfully lost weight” – is available upon request Contact Lynelle Korte at 314-447-9227 or [email protected]
UC San Diego School of Medicine
The School of Medicine was founded just over 40 years ago and in that short time has become a world-class institution, recognized as having global leaders in research, technology, translational medicine, education and clinical excellence. The region’s only medical school, it is dedicated to cultivating and supporting future practitioners and has 521 medical and 289 graduate students, 74 MD/PhD students and more than 600 interns and residents. With a faculty of more than 1,000, the School of Medicine consistently ranks in the top two nationally in research funding per faculty member and ranked 12th in the nation in NIH research funding in fiscal year 2008.
Media Contact: Kim Edwards, 619-543-6163, [email protected] |
<urn:uuid:f891cced-d94c-4180-9ba6-7f01fa361cd2> | seed | |Home | About | Journals | Submit | Contact Us | Français|
Pediatric gliomas are rare and heterogeneous tumors. The Surveillance, Epidemiology, and End Results (SEER) database allows a large-scale analysis of the clinical characteristics and prognostic features of these tumors.
We analyzed available SEER data on 6212 patients less than 20 years old at diagnosis of glioma (1973–2005), according to 4 age categories: age < 1 year, 1–3 years, 3–5 years, and 5–20 years.
The overall 5- and 10-year survival estimates were 71%±0.62% (SE) and 68%±0.67%, respectively. More than two fifths (41%) of gliomas were cerebral; the frequency of cerebellar tumors (22%–32% of gliomas) increased sharply after the first year of life. Of the tumors for which grade was available, 77% were low-grade (grade I or II). Tumor grade emerged as the most significant independent prognostic factor in all age groups except the youngest age group, in which extent of resection was most significant. Surgery other than gross total resection was an adverse prognostic factor (hazard ratio, 2.18; 95% CI, 1.78–2.67). Age <3 years predicted a greater likelihood of survival in patients with high-grade gliomas and brainstem tumors. On the other hand, Age < 3 years predicted a lower likelihood of survival in patients with low-grade gliomas. Children <1 year old received less radiotherapy than older patients (P< 0.0001) and were less likely to undergo gross total resection (p < 0.0001)
The survival of children with gliomas is influenced by histologic subtype, age, and extent of resection. Despite its limitations, the SEER database provides a useful tool for studies of rare tumors such as pediatric gliomas.
Gliomas comprise a broad, heterogeneous spectrum of central nervous system (CNS) tumors that account for 56% to 70% of all pediatric CNS tumors, depending on the registry and the histologic criteria used.1, 2 In pediatric patients, these tumors are classified as low-grade gliomas (LGGs) and high-grade gliomas (HGGs). The former group includes tumors such as pilocytic astrocytoma (PA, WHO grade I),3 and fibrillary astrocytoma (FA, WHO grade II), while the latter group includes mainly anaplastic astrocytoma (AA, WHO grade III) and glioblastoma multiforme (GBM, WHO grade IV).
Historically, clinical trials and retrospective studies have been small. Therefore, LGG4–8 studies have historically included patients with different tumor histologies, as have studies of HGGs.9, 10 Whereas some studies have found the specific tumor grade (i.e., grade I vs. II in LGG and grade III vs. IV in HGG) to be a predictor of survival,4, 9, 10 others have not.5, 8, 11 Age was shown to influence survival in both HGG and LGG.12–15 Hence it is imperative to determine prognostic factors in a large cohort of pediatric glioma patients.
The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database is the gold standard for cancer registries 16 and provides an opportunity for large-scale analysis of rare tumors such as pediatric glioma. We used the SEER database to analyze possible prognostic factors in pediatric patients with glioma.
Data on pediatric patients (<20 years old) who had a reported diagnosis of glioma during the period January 1973 through December 2005 were obtained from the SEER 17 database (http://seer.cancer.gov/data/) which was accessed in November 2008 for the purpose of this study. We used a case listing session of the SEER*Stat 6.4.4 program to generate a matrix of cases that fit our study criteria. The selection query, based on the International Classification of Childhood Cancer, third edition (ICCC-3), 17 was as follows: astrocytomas, oligodendrogliomas, mixed and unspecified gliomas, and neuroepithelial glial tumors of uncertain origin. Patients who were registered only on the basis of autopsy or death certificate were excluded. The number of all pediatric patients with CNS tumors was retrieved for comparison.
Primary tumor sites were grouped in the following categories: cerebrum, cerebellum, brainstem, spine, ventricles, and other, including not otherwise specified (NOS). (The term NOS is entered in the SEER database when tumor site, surgery, or pathology data are not available). Tumors were assigned to grades according to the current (2007) WHO classification.3 When grade assignment was not possible, e.g. for glioma NOS, the grade provided in the SEER database was used if available. Patients were grouped as follows by age at the time of diagnosis: age <1 year, 1–3 years, 3–5 years, and 5–20 years; the age groups were arbitrarily defined.
We used MedCalc for Windows version 18.104.22.168 (MedCalc Software, Mariakerke, Belgium) for statistical calculations and survival estimates. Death from any cause was used to calculate survival, as death from causes other than the malignancy is rare in the studied population. Survival estimates were calculated by the Kaplan-Meier method and compared by using the log-rank test. The chi-square test was used to compare demographic and clinical data. When appropriate, the log-rank test for trend and the chi-square test for trend were used to compare variables across the age groups. In these models, successive age groups were labeled with numbers (1 to 4) and the presence of each variable was tested in a 2×4 table (present/absent in the 4 age groups). Cox proportional-hazards regression was used to conduct multivariate analysis.
The SEER database included 9951 pediatric patients with CNS tumors, 6250 of whom met our search criteria. Thirty-eight patients characterized on the basis of autopsy/death certificate were excluded, leaving 6212 patients for this analysis. The median age at diagnosis was 9 years; male sex (53%) and white race (83%) were predominant. Approximately half of all pediatric CNS tumors diagnosed during the first 4 years of life were gliomas; the proportion of gliomas then increased with age as the frequency of other CNS tumors declined (Fig. 1A).
While the International Classification of Diseases for Oncology, version 3 (ICD-O-3) codes were available for all 6212 tumors, histologic grade was available for only 41% (n=2547). We used the WHO 2007 classification for CNS tumors 3 to grade 3247 (52%) of the 6212 tumors according to their histologic subtype (i.e., pilocytic astrocytoma = grade I). We were unable to grade 2965 (48%) of the tumors on this basis; we used the original SEER-assigned grade for 1209 of these tumors, leaving 1756 (28.3%) ungraded (Table 1). When tumors were categorized as LGG (grades I and II) and HGG (grades III and IV), we found only 4% discordance between the grades we assigned and the original SEER-assigned grades. Twenty-three percent of the tumors that could be assigned to a grade were HGG (n=1037; 17%; Table 1), although this proportion varied according to age and primary site (Fig. 1B).
Most tumors were histologically confirmed (n=5177, 84%), while a minority (n=1012, 16%) were diagnosed on the basis of radiologic or clinical information. More than half of the latter group of tumors (57%) were located in the brainstem, 28% were located in NOS sites, and 10% were in the cerebrum.
The SEER database offered limited information about treatment. Radiation was used to treat 37% of the tumors overall; among graded tumors, more than half of those irradiated (52%) were LGG. Most irradiated tumors were located in the brainstem (34%) or cerebrum (32%).
Information about primary site–directed surgery was available for 4168 patients. One third of these (n=1431) underwent gross total resection (GTR). GTR was performed for 44% of cerebellar tumors, 25% of cerebral tumors, 22% of ventricular tumors, 21% of spinal tumors, and 6% of brainstem tumors.
In the 4 age categories, there were 242 patients (3.9%) less than 1 year old, 640 patients (10%) 1–3 years old, 745 patients (12%) 3–5 years old, and 4585 patients (74%) 5–20 years old. Table 2 lists patient characteristics according to age group.
Astrocytoma was the most common histologic subtype (75%) (Fig. 2A). Only 5.1% of the tumors overall were oligodendrogliomas. The proportion of oligodendroglioma varied across the age groups and was less than 2% in the youngest group. Among tumors diagnosed during the first year of life, approximately one third (36%) were grade I, one third (31%) were grade II, and the remainder were grade III (14%) or IV (19%) (Fig. 2B). More than half of tumors were grade I in the 1–3 and 3–5–year age groups, but the proportion was slightly lower in patients older than 5 years. The tumor sites differed substantially across the age groups. During the first year of life, cerebral and brainstem sites were most common (Fig. 2C). After the first year of life the cerebellum became a more prominent site (22% to 32% of known tumor sites).
Only 12% of tumors (n=30) diagnosed during the first year of life were irradiated. Most of these (n=19) were not graded. The chi-square test for trend showed significantly more use of radiotherapy in patients older than 1 year than in younger patients (P<0.0001); in children older than 5 years, 42% of tumors were irradiated.
Twelve percent (n=30) of patients diagnosed during the first year of life had GTR (Fig. 2D), and 19% of cerebral tumors in this group were grossly resected. Among patients older than 1 year, 22%–24% had GTR (chi-square test for trend comparing GTR vs. other surgeries in this age group, P=0.0001) and 26% of cerebral tumors were grossly resected. Only 14% of cerebellar tumors in children <1 year old received GTR, vs. 45% of cerebellar tumors in older children. A similar percentage of tumors (19%–27%) were partially resected in all age groups.
The 5-, 10-, and 15-year survival estimates (±SE) for all studied patients were 71% ± 0.62%, 68% ± 0.67% and 65% ± 0.73%. In a univariate analysis using the log-rank test, the following factors were significant (P<0.05) adverse prognostic factors: higher tumor grade (Fig. 3A), age < 1 year at diagnosis (Fig. 3B), brainstem primary tumor site (Fig. 3C), surgical biopsy only or no surgery ( Fig. 3D), and mixed or unspecified histologic subtype. This later group of tumors as defined by the ICCC-3 encompasses both mixed gliomas (ICD-O-3, 9382/3; n=171) and unspecified gliomas (ICD-O-3, 9380/3; n=1051). The outcome of patients with the former histology is significantly better than unspecified gliomas within this group (5-year survival, 73% ± 3.6% and 40% ±1.6%, respectively; P<0.001).
Non-white race, absence of histologic confirmation, and use of radiation therapy were also significant adverse prognostic factors in univariate analysis (data not shown).
Of all prognostic factors identified in univariate analysis, tumor grade was the best predictor of survival; when viewed as an “internal control,” this finding showed that tumor grading as applied in this study worked well to stratify the studied tumors, minimizing the impact of lack of central pathology review. Further, the specific tumor grades within the LGG and HGG categories were predictive of survival (grade I vs. grade II; P<0.0001 and grade III vs. grade IV; P<0.0001). Similar results were found when analysis was applied on original grading as provided by the SEER (data not shown).
The 10-year survival estimates were lower for patients < 1 year old (59% ± 3.6%) than for older patients: 81% ±1.8% for those 1–3 years old, 69% ±1.9% for those 3 –5 years old, and 66% ±0.8% for those > 5 years old. Figure 4A–D shows the 10-year survival estimates for the age groups according to histologic subtype, tumor grade, tumor site, and extent of surgery.
In a multivariate analysis using the Cox proportional-hazards regression model, the following factors were independent adverse prognostic factors (P<0.05): age <1 year at diagnosis (hazard ratio [HR], 1.96; 95% CI, 1.49–2.59), surgery other than GTR (HR, 2.18; 95% CI, 1.78–2.67), histology other than astrocytoma (HR, 1.42; 95% CI, 1.19–1.67), radiotherapy (HR, 1.92; 95% CI, 1.67– 2.20), brainstem tumor (HR, 1.86; 95% CI, 1.62–2.19), and high tumor grade (HR, 6.13; 95% CI, 5.39–6.98).
The same model was tested separately using original SEER grading or histology-based grading for tumors not graded through by the SEER. High grade tumor remained significant in both models but with variable hazard ratios (2.61 for SEER grades and 4.83 for histology-based grading); all other factors remained significant.
The findings within each age group were similar to the overall findings; tumor grade was the most significant prognostic factor in all patients older than 1 year. Among patients < 1 year old at diagnosis, surgery other than GTR was the most significant adverse prognostic factor (HR, 5.05; 95% CI, 1.56–16.37) and high tumor grade (HR, 3.58; 95% CI, 2.08–6.18) was the second most significant adverse prognostic factor.
We analyzed the outcomes of patients who were diagnosed in 3 arbitrary eras; 1) from 1973 to 1985 (n=1359, 22%), 2) from 1986 to 1995 (n=1617, 26%) and 3) from 1996 to 2005 (n=3236, 52%). The 5-year survival estimates for patients diagnosed in these 3 eras were 63% ±1.3%, 72% ±1.1% and 75% ± 0.9%, respectively (P<0.001). Interestingly, the use of radiotherapy decreased dramatically from 64% in the first era to 25% in the last era (P<0.001). When tested in the multivariate model mentioned above, diagnosis before 1986 was not a significant factor in the model (P=0.15).
We looked at the histologies of gliomas diagnosed in the 3 eras. Significant changes occurred in the distribution of reported CNS gliomas; most noticeable, was the decrease of NOS astrocytoma (from 47% of reported gliomas in era 1 to 13% in era 3). This generic diagnosis was largely replaced with more specific pilocytic astrocytoma and anaplastic astrocytoma which together accounted for 10% of gliomas in era 1 and 45 % of gliomas in the last era. Astroblastoma accounted for 3.6% of tumors reported in the first era but only of 0.2% of tumors reported in the 3rd era.
The 6212 cases of pediatric glioma in the SEER 17 database (70% of all pediatric CNS tumors diagnosed during the years 1973 through 2005) allowed us to perform a population-based analysis of clinical features and outcome in the arbitrarily defined age groups (<1 year, 1–3 years, 3–5 years, and 5–20 years). We observed significant differences across these groups in tumor histology, grade, and primary site, although the distribution of tumor grade and the predominance of cerebral tumors were similar in patients < 1 year old and those 5 to 20 years old (Fig. 2B, C).
Among patients with low-grade gliomas (n=3419, 55.5%), grade I predicted better survival than grade II (Fig. 3 A) except among infants (Fig 4B). Reports of the prognostic value of grade I vs. grade II LGG are inconsistent. Some studies have found no difference in outcome between grades I and II,6–8 possibly because of the small number of subjects. A larger study (n= 278) showed that tumor grade (after pathology review) significantly influenced survival estimates, which were 92% for pilocytic astrocytoma, 86% for glioma not otherwise specified, and 48% for diffuse astrocytoma (P< 0.0001).4 Interestingly, our study found that age less than one year at diagnosis of grade I and II glioma had a negative impact on survival (Fig. 4B). Further, survival of patients with grade I gliomas was significantly better in the 1–3 and 3–5–-year age groups than in patients <1 year old (log-rank test for trend, P=0.0033; Fig. 4B). Few previous studies have addressed the negative impact of age less than 5 years on progression-free survival, but not on overall survival in pediatric LGG. 5,14
High-grade gliomas represented 17% of the studied tumors; however, their frequency differed according to primary site and age (Fig. 1B). Most high-grade tumors occurred in the cerebrum and brainstem, and fewer occurred in children 1 to 5 years old than in other age groups. Younger patients with high-grade tumors, particularly grade III, had higher survival estimates than did older patients (log-rank test for trend, P=0.067; Fig. 4B). Only 3 studies of children younger than three years with HGG have been reported, and they included only 16 to 39 subjects.15, 18, 19 Ours reports on the largest group to date of patients less than 3 years old with HGG (99 patients) (Table 2) to show improved survival in this age group.
Among patients with HGG, the extent of surgery was a major factor in survival. Patients with HGG who underwent GTR (23%) had the best survival in all age groups. Both GTR and grade were shown to influence the survival of patients with HGG in the largest studies reported to date, the Children’s Cancer Group (CCG)-943, and CCG-945 studies. 9,10 CCG-943 included 58 patients, 18 with AA and 40 with GBM; the latter group had significantly worse survival (p = 0.012). Patients who underwent only biopsy (n=11) had significantly worse survival than those who had partial resection (n=39) or GTR (n=8) (p < 0.001). In CCG-945 (172 children aged 18 months to 21 years), histologic subtype (AA vs. GBM) and percent resection (> 90% vs. <90%) were significantly associated with better prognosis (p < 0.02 and p < 0.04, respectively). Our larger, population-based analysis of 485 patients with grade III glioma and 552 with grade IV glioma confirmed these findings.
As expected, we found that brainstem gliomas carried the poorest prognosis (Fig. 4C). Interestingly, however, survival was inversely associated with age. Patients less than one year old had the best outcome, followed by age 1–3 years (Fig. 4C; log-rank test for trend, P= 0.0036). There has been only one reported study to date of infantile brainstem glioma; this report describes 10 patients, only one of whom was less than one year old.12 In that study the 3-year survival was69% ± 19% which is higher than other groups. Another study on pontine gliomas by Wagner et al found that age younger than 4 years (n= 13) was also associated with better prognosis.22 The positive impact of age on brain stem gliomas has been an area of debate with cases of spontenous regression in the neonatal peroid.23 Our study reports on the largest group of infantile glioma so far; 136 less than 3-year old ( 26 less than one year old). We believe this provides a basis for further research on this unique group of patients.
This study, like other population-based studies, was limited by the lack of central pathology review, which is considered important in confirming both low-grade and high-grade pediatric gliomas.4, 20, 21 In the CCG-945 study, 70 (28%) of 250 tumors originally designated as high-grade gliomas were found to be low-grade gliomas on central pathology review, and these patients fared better than the rest of the HGG cohort.20 However, after these 70 tumors were excluded from analysis, the final conclusions remained the same.21 The much greater size of our study population suggests that the absence of central pathology review was unlikely to confound our analysis. In addition, the importance of pathology review of LGGs is controversial. Fisher et al. reported a 39% (97/246) rate of discordance in their study of LGGs, whereas Gajjar et al. had only 2% discordance in their cohort of 145 tumors.4, 5
Our study was also limited by the lack of complete data about radiotherapy and surgery. The use of radiotherapy increased gradually with age at diagnosis (from 12.4% in patients <1 year old to 42% in children > 5 years old, P<0.0001). The use of radiotherapy was independently associated with poorer survival, but this finding is likely to reflect other prognostic factors, including resectability, anatomic site, tumor grade, and relation to nearby critical structures, that influenced the decision to use radiotherapy. Further, the majority of tumors with available grade in our cohort were LGGs (77%), for which radiation therapy is usually deferred or used only for recurrent or high-risk tumors. Signs and symptoms at presentation and association with neurofibromatosis may also have been factors in considering radiotherapy but were not available for analysis.
Notwithstanding its limitations, the SEER database provides a useful tool for the study of rare pediatric CNS tumors. Inclusion of more data about treatment, associated conditions such as neurofibromatosis, tumor size, and extent of disease will allow a better understanding of these tumors as well as other rare childhood cancers.
This work was supported in part by grant CA21765 from the U.S. Publish Health Service; Musicians Against Childhood Cancer (MACC); The Noyes Brain Tumor Foundation; The Ryan McGhee Foundation; the American Lebanese Syrian Associated Charities (ALSAC); and the King Hussein Cancer Foundation (KHCF).
The authors thank Sharon Naron for the scientific editing of this manuscript. |
<urn:uuid:5ded0e08-3746-4a87-8cc9-69c4d7a08bdb> | seed | Haemachromatosis: Treatment, symptoms, advice and help
Haemachromatosis is a form of iron overload disease which may be either hereditary or acquired. The intestinal tissues in a normal individual absorb adequate iron which is needed by the body. But in affected individuals, the intestinal absorption of iron exceeds the requirement. Subsequently this excess iron gets deposited in body tissues, resulting in a disorder called ‘haemachromatosis’.
Haemachromatosis: Incidence, age and sex
Haemachromatosis which is inherited, is usually present since birth but appears clinically only during adulthood. The caucasians of Northern European descent are more susceptible to haemachromatosis. Men are more prone to be afflicted with haemachromatosis, as compared with women.
Signs and symptoms of haemachromatosis: Diagnosis
The predominant symptom of haemachromatosis is pain in large joints, which can be accompanied by exhaustion and abdominal pain. As the disease progresses, jaundice, irregular heart rhythm and impotence may be noted. Women may complain of early menopause. The skin may become grey or bronze due to iron deposition.
The diagnosis of haemachromatosis is a difficult one. Specific blood tests like total iron binding capacity and serum ferritin may be recommended to detect the condition. A special genetic testing can be considered to discover mutation in HFE gene.
Causes and prevention of haemachromatosis
Haemachromatosis is most commonly hereditary, wherein it is due to primary iron overload. In occasional disorders like thalassemia and haemolytic anaemia, secondary iron overload takes place due to excessive destruction of red blood cells. This results in haemachromatosis which is acquired in nature. The inherited form of haemachromatosis occurs due to mutation in HFE gene which regulates the amount of iron absorption in body. The defect causes the body to absorb excess iron which gets stored in various organs like liver, heart and pancreas and subsequently damage them. Iron is an essential part of haemoglobin which transports oxygen from lungs to tissues.
Haemachromatosis, if left untreated may lead to damage of various organs. Liver damage may result in cirrhosis or even liver failure. Damage to heart may result in cardiac arrythmias or heart failure. Like wise pancreatic damage causes onset of diabetes. In fact, a combination of diabetes and bronze skin is characteristically known as ‘bronze diabetes’.
Timely detection of disease is of utmost importance so that it can be effectively managed before any irreversible organ damage is done. The evaluation and subsequent management requires multi-disciplinary approach including an internist, endocrinologist, hepatologist, cardiologist, haematologist and gastroenterologist. The first and foremost step in treatment is to eliminate excess iron from body which is done by a procedure called phlebotomy. In this procedure, regular (almost 2 times a week) removal of small amount of blood is done. This is done for several weeks along with regular monitoring of blood ferritin level. When this level normalises, then frequency of removal of blood is reduced to 2 to 4 times a month. Moreover, alcohol avoidance and a diet limited in iron may also contribute to improvement in individual’s condition. Early diagnosis and treatment may prevent any organ damage. |
<urn:uuid:2e4478cd-4e85-4f56-982c-4ba272a1ad92> | seed | STDs and Viral Hepatitis
Transmission of Hepatitis A virus (HAV) during sexual activity occurs due to fecal-oral contact or contamination. Measures typically used to prevent the transmission of other STDs (e.g., use of condoms) do not prevent HAV transmission. Vaccination is the most effective means of preventing HAV transmission among persons at risk for infection.
Among adults seeking treatment in STD clinics, as many as 10%–40% have evidence of past or current Hepatitis B virus (HBV) infection. Many of these infections could have been prevented through universal vaccination during delivery of STD prevention or treatment services. A study of adults diagnosed with acute Hepatitis B found that 39% had sought care or been screened for an STD before they were infected with HBV, indicating a significant missed opportunity to vaccinate at-risk persons when they first access STD prevention or treatment services.
Although not common, Hepatitis C virus (HCV) can be transmitted through sexual activity. The factors found to be associated with sexual transmission of HCV are sex with multiple partners, presence of other STDs, or sex with trauma. Case-control studies have reported an association between acquiring HCV infection and exposure to a sex contact with HCV infection or exposure to multiple sex partners. Surveillance data also indicate that 15%–20% of persons reported with acute HCV infection have a history of sexual exposure in the absence of other risk factors.
Guidelines and Recommendations
Sexually Transmitted Diseases Treatment Guidelines 2010
MMWR 2010;59(RR-12) - Includes chapters on Hepatitis A, B, and C.
Hepatitis B Vaccination Recommendations for Adults; Appendix
PDF version [PDF - 40 pages]: (with appendices) |
<urn:uuid:7eea53e1-a658-404f-9187-b2057604f94e> | seed | News & Events
FDA NEWS RELEASE
FOR IMMEDIATE RELEASE
FDA Requests Boxed Warnings on Older Class of Antipsychotic Drugs
The U.S. Food and Drug Administration today exercised its new authority under the Food and Drug Administration Amendments Act of 2007 (FDAAA) to require manufacturers of "conventional" antipsychotic drugs to make safety-related changes to prescribing information, or labeling, to warn about an increased risk of death associated with the off-label use of these drugs to treat behavioral problems in older people with dementia.
In 2005, the FDA announced similar labeling changes for "atypical" antipsychotic drugs. At that time, Boxed Warnings, the FDA's strongest, were added. The Boxed Warning will now be added to an older class of drugs known as "conventional" antipsychotics. The warning for both classes of drugs will say that clinical studies indicate that antipsychotic drugs of both types are associated with an increased risk of death when used in elderly patients treated for dementia-related psychosis.
"It is important that health care professionals and consumers have the most up-to-date drug safety information," said Thomas Laughren, M.D., director of the FDA's Division of Psychiatry Products in the Center for Drug Evaluation and Research. "The prescribing information for all antipsychotic drugs will be updated to describe the risk of death in elderly patients being treated for symptoms associated with dementia."
Antipsychotic drugs commonly are categorized into two classes, the older "conventional" antipsychotics and the newer "atypical" antipsychotics. Both classes of drugs are dopamine receptor antagonists that work by blocking the action of naturally occurring dopamine in the brain. They differ primarily in their side effects, with the atypical drugs having a lower incidence of neurological side effects such as involuntary movements or "tics."
Neither class of antipsychotic is FDA-approved for use in the treatment of dementia-related symptoms, which can include forgetfulness, poor memory, and an inability to recognize familiar objects, sounds, or people. The drugs are FDA-approved primarily for the treatment of symptoms associated with schizophrenia. The decision to use antipsychotic medications in the treatment of patients with symptoms of dementia is left to the discretion of the physician. Such use is often called "off-label" use and falls within the practice of medicine.
Recently, two observational epidemiological studies were published that examined the risk of death in elderly patients with dementia who were treated with conventional antipsychotic drugs. The investigators compared the risk for death with use of an atypical antipsychotic versus either no antipsychotic or the use of a conventional antipsychotic. These studies have limitations that preclude reaching a definitive conclusion about comparative death rates for atypical and conventional antipsychotic drugs. Nevertheless, the FDA has concluded that these studies, along with the earlier evidence for atypical antipsychotic drugs, suggest that both classes of drugs should be considered to have an increased risk of death when used in elderly patients treated for dementia-related psychosis.
An explanation of the data and advice for treating patients is available in an FDA notice to health care professionals being issued today.
The FDA today issued letters to the manufacturers of both types of antipsychotic drugs, under the new authority of FDAAA, notifying the manufacturers that they should make changes to drug labeling. Manufacturers of both classes of drugs are being asked to change labeling so that all of the drugs carry uniform warning language. Manufacturers of these drugs are required to submit new language to the FDA within 30 days, or to provide a reason why they do not believe such labeling changes are necessary. If they do not submit new language, FDAAA provides strict timelines for resolving the issue and allows the agency to initiate an enforcement action if necessary.
People taking antipsychotic drugs should not abruptly stop taking them. Caregivers and patients should talk to the patient's health care professionals about any concerns.
The medications involved in this action are:
Conventional Antipsychotic Drugs
For more information, see
FDA Information for Healthcare Professionals: Antipsychotics
FDA Historical Information on Atypical Antipsychotic Drugs |
<urn:uuid:e6f491d4-225c-4217-87f5-b79740971203> | seed | Our sense of smell plays a large role in everyday life. It lets us enjoy pleasant scents, such as flowers and food, but it also helps us detect dangerous smells, such as gas or fire. Smell can also help us recall long-forgotten memories. Not surprisingly, we often don’t realize how important it is to us until we lose it because of a disorder or a bad cold.
How does our sense of smell work?
Our smell is part of our chemosensory system, which also includes taste. High inside the nose, we have a group of specialized cells--called olfactory sensory neurons—and each expresses one odor receptor which connects directly to the brain. When microscopic molecules in our environment reach these receptors, they send a message to the brain which then identifies the smell. Smells reach the olfactory sensory neurons in two ways--through the nostrils directly or through the roof of your throat that connects to the nose.
The common chemical sense also influences our smell. The common chemical senses are composed of thousands of nerve endings on the moist areas of the eyes, nose, mouth and throat help us sense irritating substances. For instance, when an onion makes us cry or peppermint tingles and cools our mouth, we are experiencing the common chemical sense.
[TAKE THE QUIZ: Is it a Cold? The Flu? Allergies? Bronchitis?]
Why is it important?
A loss of smell can be indicative of a more serious health problem.
Roughly 1 to 2 percent of people in North America say they have a smell disorder, and the likelihood increases with age. Men are more likely than women to experience a problem, and many people with a smell disorder also notice they have problems with taste. Smell disorders either cause people to lose their ability to smell or it changes the way they perceive an odor. Something that once smelled pleasant can be distorted to smell bad. Hyposmia is a reduced ability to detect odors, and anosmia is the inability to detect any odors at all.
What happens when we lose our smell due to a cold or allergies?
A recent study published in the journal Nature Neuroscience looked at how the brain responded to a short-term loss of smell, and found that brain activity rapidly changes in the olfactory regions to ensure that our sense of smell is just as sharp when our nose recovers.
For one week, researchers blocked the noses of 14 participants while they lived in a special low-odor hospital room. After the smell deprivation, researchers saw two regions of the brain that reacted – there was an increase of activity in the orbital frontal cortex and decreased activity in the piriform cortex. When the participants were allowed to smell again, they were immediately able to perceive odors due to the brain activity during the seven days of deprivation. A week later, the brain’s response to odor had returned to pre-experiment levels, showing that the olfactory system is agile in response to changes. The researchers pointed out that this is different from other senses, such as sight, which takes much longer to recover after deprivation. They hypothesized that the olfactory system has adapted because smell deprivation is a common occurrence because of allergies and viral infections.
[SLIDESHOW: 7 Tips for Dealing with Seasonal Allergies]
Is smell connected to taste?
Smell and taste are closely linked because they are both part of the chemosensory system, and many people who think they have a taste disorder actually have a smell disorder. When your nose is stuffed due to a cold or allergies, food odors cannot reach the sensory cells and the flavor is lost. Without these olfactory sensory neurons, flavors such as chocolate or oranges are difficult to distinguish.
Sometimes when smell is impaired people will change their eating habits to include more salt, which can be problematic for people with high blood pressure or kidney disease.
Is smell linked to other health conditions?
There are many health conditions that can affect the sense of smell, including sinus and upper respiratory infections, polyps in the nasal cavities, frontal head injuries, hormone issues, dental problems, exposure to certain chemicals, medications such as antihistamines and antibiotics, radiation for the treatment of neck cancers and aging. More serious conditions that affect the nervous system can also cause loss of smell, such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Plus, smell disorders can also be a sign of obesity, diabetes, hypertension and malnutrition. Smoking can likewise affect our sense of smell, and loss of smell can also lead to depression.
Loss of smell is one of the first signs of Alzheimer’s disease. However, a study published in the Journal of Neuroscience in 2011 found that it may be possible to restore. Researchers discovered that removing a certain plaque-forming protein, called amyloid beta, restored the sense of smell in mice. To remove the protein, the mice were given a liver x-receptor agonist. After two weeks on the drug, the mice were able to process smells normally. Then after withdrawal from the drug for a week, the mice could not smell normally. This protein has been found to accumulate first in the parts of the brain associated with smell long before it builds up in areas associated with cognition and coordination. Researchers believe that this could lead to earlier diagnosis and treatment of Alzheimer’s patients.
Can it have an effect on emotional health?
The loss of smell can have such an impact on quality of life that it can lead to depression. But it’s not the only emotional or psychological effect that can occur. One study published in March 2012 in Chemosensory Perception found that anxious people have a heightened sense of smell. Researchers exposed 14 young adults to three types of smell: a pure neutral odor, a mixture of neutral odors and a negative odor mixture. They were asked to identify the presence or absence of these odors while in an MRI scanner. During this time, they also measured arousal level by the skin’s ability to conduct electricity, and measured breathing patterns. Participants were asked to rate their anxiety level after the odor test, while they were still in the scanner. When the researchers analyzed the brain images, they found that as anxiety levels rose, the ability to detect negative odors accurately also increased.
Another study, which was published in PLoS ONE in March 2012 found that people who were born without the sense of smell had higher social insecurity and an increased risk of depression.
National Institute of Deafness and Other Communication Disorders. (2012, April 22). “Smell Disorders.” Retrieved from http://www.nidcd.nih.gov/health/smelltaste/pages/smell.aspx
n.p. (2012, August 13). "Brain Changes After A Stuffed Nose Protect The Sense Of Smell." Medical News Today. Retrieved from http://www.medicalnewstoday.com/releases/248941.php
n.p. (2011, December 1). "Loss Of Sense Of Smell, Early Sign Of Alzheimer's, Reversed In Lab." Medical News Today. Retrieved from http://www.medicalnewstoday.com/releases/238456.php
Springer. (2012, March 26). "Sense Of Smell Boosted By Anxiety." Medical News Today. Retrieved from http://www.medicalnewstoday.com/releases/243302.php
Public Library of Science. (2012, March 23). "Those Without A Sense Of Smell Suffer Enhanced Social Insecurity." Medical News Today. Retrieved from http://www.medicalnewstoday.com/releases/243216.php |
<urn:uuid:65a39a02-1365-4b7a-a5d8-a4e291685ec7> | seed | Revista Panamericana de Salud Pública
Print version ISSN 1020-4989
Screening for colorectal cancer. Rev Panam Salud Publica [online]. 2002, vol.12, n.4, pp. 291-295. ISSN 1020-4989. http://dx.doi.org/10.1590/S1020-49892002001000022.
This piece summarizes new recommendations from the Preventive Services Task Force of the United States of America concerning screening for colorectal cancer (CRC). These recommendations update and replace ones that were issued in 1996. The Task Force strongly recommends that physicians carry out CRC screening tests for both men and women who are 50 years of age or older. The Task Force found fair or good evidence that: 1) several screening methods are effective in reducing mortality from CRC, 2) the benefits of screening outweigh its risks, although the quality of the tests, the magnitude of the benefits, and the potential harms vary according to the method, and 3) periodic fecal occult blood testing (FOBT) reduces mortality from CRC. In addition, there is fair evidence that sigmoidoscopy, either alone or in combination with FOBT, reduces CRC mortality. There is no direct evidence that screening colonoscopy is effective in reducing CRC mortality, nor is it clear if the greater accuracy of colonoscopy in comparison to other tests compensates for its additional complications, inconvenience, and costs. Double-contrast barium enema is less sensitive than colonoscopy, and there is no direct evidence that it is effective in lowering mortality rates. There are insufficient data to determine which screening strategy is best in terms of the balance of benefits, potential harms, and cost-effectiveness. Regardless of the strategy chosen, CRC screening is likely to be cost-effective (less than US$ 30 000 per year of life gained).
Keywords : cáncer colorrectal; colonoscopia; enema de bario; sangre oculta en heces; sigmoidoscopia. |
<urn:uuid:2dc467ca-0dfe-4013-8ddf-54daf42171a8> | seed | In a record-linkage study, Joel Ray and colleagues examine the association between diagnostic imaging during pregnancy and later childhood cancers.
The association between fetal exposure to major radiodiagnostic testing in pregnancy—computed tomography (CT) and radionuclide imaging—and the risk of childhood cancer is not established.
Methods and Findings
We completed a population-based study of 1.8 million maternal-child pairs in the province of Ontario, from 1991 to 2008. We used Ontario's universal health care–linked administrative databases to identify all term obstetrical deliveries and newborn records, inpatient and outpatient major radiodiagnostic services, as well as all children with a malignancy after birth. There were 5,590 mothers exposed to major radiodiagnostic testing in pregnancy (3.0 per 1,000) and 1,829,927 mothers not exposed. The rate of radiodiagnostic testing increased from 1.1 to 6.3 per 1,000 pregnancies over the study period; about 73% of tests were CT scans. After a median duration of follow-up of 8.9 years, four childhood cancers arose in the exposed group (1.13 per 10,000 person-years) and 2,539 cancers in the unexposed group (1.56 per 10,000 person-years), a crude hazard ratio of 0.69 (95% confidence interval 0.26–1.82). After adjusting for maternal age, income quintile, urban status, and maternal cancer, as well as infant sex, chromosomal or congenital anomalies, and major radiodiagnostic test exposure after birth, the risk was essentially unchanged (hazard ratio 0.68, 95% confidence interval 0.25–1.80).
Although major radiodiagnostic testing is now performed in about 1 in 160 pregnancies in Ontario, the absolute annual risk of childhood malignancy following exposure in utero remains about 1 in 10,000. Since the upper confidence limit of the relative risk of malignancy may be as high as 1.8 times that of an unexposed pregnancy, we cannot exclude the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic.
Please see later in the article for the Editors' Summary
In industrialized countries, childhood cancer (any form of cancer in a child aged 14 years or under) remains a major cause of death. With the exception of a few known risk factors, such as acquired genetic predisposition to cancer, which accounts for about 10% of all childhood cancers, the etiology of most childhood cancer remains unknown. There is thought to be an association between exposure to ionizing radiation in pregnancy and the subsequent risk of development of cancer in the exposed mother's child, but the evidence base to support this association is conflicting. For example, studies examining maternal exposure to plain radiographs in pregnancy and subsequent childhood cancer are inconsistent. Furthermore, although their use has dramatically increased over the past two decades, little is known about the cancer risk related to certain types of radiodiagnostic tests, such as CT and radionuclide imaging, both of which expose the fetus to considerably higher doses of radiation than plain radiographs administered at the same anatomical level.
Why Was This Study Done?
Many women could be exposed to major radiodiagnostic tests, such as those used in emergency situations, before they are aware that they are pregnant, as almost 50% of pregnancies are unplanned. This situation means that it is important to determine the subsequent cancer risk to any child exposed to maternal radiodiagnostic tests before birth.
What Did the Researchers Do and Find?
The researchers conducted a retrospective population-based cohort study of women who delivered a live infant in Ontario, Canada between April 1, 1992 and March 31, 2008. The basis of the research was an anonymized database for the whole province of Ontario, where universal health care, including prenatal care and radiodiagnostic testing, is available to all residents. Database characteristics allowed the researchers to link maternal radiation exposure (a major radiodiagnostic test performed on the mother up to one day before her delivery date) in a specific (index) pregnancy to a subsequent malignancy in the child. After birth, maternal-infant pairs were only followed up if the infant was delivered at term, weighed 2,500 g or more, and survived for at least 30 days.
The researchers were able to follow up 1,835,517 maternal-child pairs. The overall rate of exposure to major radiodiagnostic testing in pregnancy was 3.0 per 1,000 and occurred at an estimated mean gestational age of 15.7 weeks. A total of four childhood cancers occurred in the exposed group and 2,539 cancers in the unexposed group corresponding to a crude hazard ratio of 0.69, which did not significantly change after adjustments were made for potential confounding factors, such as maternal age, sex, and the presence of any chromosomal or congenital anomalies in the infant. The overall prevalence of childhood cancer following exposure to CT or radionuclide imaging in pregnancy is under 0.07%, giving an incidence rate of 1.13 per 10,000 person-years.
What Do These Findings Mean?
These findings can help inform clinicians and mothers about the risk of childhood malignancy following major radiodiagnostic testing in pregnancy. The absolute risk appears to be low, while the relative risk is not materially higher than that of unexposed controls. However, as the upper confidence limit of the relative risk of malignancy may be a maximum of 1.8 times that of an unexposed pregnancy, the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic cannot be excluded. Because this finding means that a very slight risk may exist, beta hCG testing should continue to be done in all potentially pregnant women before undergoing major radiodiagnostic testing, and lead apron shielding used in all women of reproductive age, whether or not known to be pregnant. In addition, nonradiation-emitting imaging, such as MRI and ultrasonography, should be considered first, when clinically appropriate. However, some pregnant women will still be faced with the decision to undergo CT or nuclear imaging because the test is clinically warranted. The findings of this study suggest that when clinically indicated, major radiodiagnostic testing in pregnancy should be performed, along with brief counseling to help lessen the anxiety experienced by an expectant mother before and after the birth of her child.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000337.
For information for patients and caregivers on radiodiagnostic testing, see The Royal College of Radiologists
The National Cancer Institute provides information about childhood cancer
CureSearch for Children's Cancer provides additional information about research into childhood cancer |
<urn:uuid:43d22898-3f33-41cb-897b-625ab3236060> | seed | Tips from Other Journals
Prognosis of Children with Vertically Acquired HCV
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Am Fam Physician. 2000 Jun 1;61(11):3394-3396.
Hepatitis C virus (HCV) infection has become the most common cause of community-acquired and post-transfusion non-A, non-B hepatitis. A majority of those persons subsequently develop long-term liver disease that may lead to hepatocellular cancer. Interferon is becoming the standard treatment in patients with long-term HCV infection, but only a minority show a long-term response to therapy. Perinatal transmission of HCV infection can occur, but the consequences are not clearly quantified. A network of European health care centers was recently established to clarify issues about vertically acquired HCV infection. This study describes the natural history of perinatal HCV infection through a retrospective analysis of prospectively collected data from the health care centers that are a part of this network.
The study followed 104 children born to mothers who were known to be infected with HCV. The children were seen within the first two weeks of birth. Excluded were children with human immunodeficiency virus (HIV) infection, hepatitis B co-infection or a history of blood transfusion. The diagnosis was confirmed by the persistence of HCV-specific antibody beyond 18 months of age and/or the detection of HCV-RNA in serum by polymerase chain reaction (PCR) test on at least two separate occasions. These two criteria are consistent with Centers for Disease Control and Prevention guidelines. The children were followed clinically and with laboratory monitoring every three to six months for the first two years of life, then every six to 12 months thereafter. Of note, most of the mothers of these children were co-infected with HIV.
The children were followed for a mean duration of 49 months (range: six to 153 months). PCR analyses for detection of HCV-RNA in serum were conducted in all children. Based on the presence or absence of viremia over time, three groups of children were identified. Three patterns among the children were observed. The first group included 54 children in whom persistent viral HCV-RNA was present in all samples tested. The second group included 44 children in whom serum HCV-RNA was below detection levels by PCR. The third group included six children in whom HCV-RNA was undetectable, but who showed persistent HCV-specific antibody beyond 18 months of age.
Clinical signs of infection or illness were observed in only four children. Two children were found to have hepatomegaly; one child had atopic dermatitis, and one child developed type 1 diabetes (formerly known as insulin-dependent diabetes mellitus). None of the children exhibited problems with growth or a reduction in quality of life.
Serum alanine aminotransferase (ALT) levels were recorded for 90 of the 104 children. The mean serum ALT levels were highest during the first two years of life and declined substantially thereafter. Most of the infected children showed transient or persistent increases in ALT activity with significant ALT concentration variations in individual patients after two years.
In 20 children, a liver biopsy was performed, with the most common reasons being persistent elevation of serum ALT or HCV-RNA levels. The histologic features varied and included steatosis and portal lymphoid agregates. None of the 20 children had severe liver damage, but three children showed a certain degree of fibrosis. No apparent correlation was seen between HCV-RNA and serum ALT levels and degree of histologic abnormalities.
Four children received treatment with interferon, and one child with intermittent viremia was treated with interferon for 12 months. During treatment, serum ALT levels were normal, but they relapsed when treatment stopped. One child who was PCR-negative at months 3, 6 and 10, was PCR-positive when tested a day after treatment was stopped. Two other children remained HCV-RNA negative: one at 25 months and one at 52 months after discontinuing treatment.
The authors conclude that most children who acquire HCV infection through vertical transmission have a high rate of long-term infection. The figure in this cohort of children was approximately 90 percent. However, the degree of liver injury appears to be less severe in these children than in adults. The authors believe that this observation supports the theory that hepatocellular injury from HCV infection is immune-mediated and not a result of the direct cytopathic effects of the virus.
Tovo PA, et al. Persistence rate and progression of vertically acquired hepatitis C infection. J Infect Dis. February 2000;181:419–24.
Copyright © 2000 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact [email protected] for copyright questions and/or permission requests.
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<urn:uuid:8bf9b6a9-f523-4f45-887d-cb5dabb3eb47> | seed | A dysmorphic feature is a difference of body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, genetic syndrome, or birth defect. Dysmorphology is the study of dysmorphic features, their origins and proper nomenclature. One of the key challenges in identifying and describing dysmorphic features is the use and understanding of specific terms between different individuals. Clinical geneticists and pediatricians are usually those most closely involved with the identification and description of dysmorphic features, as most are apparent during childhood.
Dysmorphic features can vary from isolated, mild anomalies such as clinodactyly or synophrys to severe congenital anomalies, such as heart defects and holoprosencephaly. In some cases, dysmorphic features are part of a larger clinical picture, sometimes known as a sequence, syndrome or association. Recognizing the patterns of dysmorphic features is an important part of a geneticist's diagnostic process, as many genetic disease present with a common collection of features. There are several commercially available databases that allow clinicians to input their observed features in a patient to generate a differential diagnosis. These databases are not infallible, as they require on the clinician to provide their own experience, particularly when the observed clinical features are general. A male child with short stature and hypertelorism could have several different disorders, as these findings are not highly specific. However a finding such as 2,3-toe syndactyly is raises the index of suspicion for Smith-Lemli-Opitz Syndrome
Dysmorphic features are invariably present from birth, although some are not immediately apparent upon visual inspection. They can be divided into groups based on their origin, including malformations (abnormal development), disruptions (damage to previously normal tissue), deformations (damage caused by an outside physical force) and dysplasias (abnormal growth or organization within a tissue).
- Reardon, W.; Donnai, D. (2007). "Dysmorphology demystified". Archives of Disease in Childhood - Fetal and Neonatal Edition 92 (3): F225–F229. doi:10.1136/adc.2006.110619. PMC 2675338. PMID 17449858.
- Maitra, Anirban; Kumar, Vinay (2004). "Diseases of Infancy and Childhood". In Kumar, Vinay; Abbas, Abul L.; Fausto, Nelson. Robbins and Coltran Pathologic Basis of Disease (in English) (7th ed.). Philadelphia: Elsevier. pp. 469–508. ISBN 978-0-7216-0187-8.
- j.-p., F.; De Ravel, T. D. (2002). "London Dysmorphology Database, London Neurogenetics Database and Dysmorphology Photo Library on CD-ROM \Version 3] 2001". Human Genetics 111 (1): 113. doi:10.1007/s00439-002-0759-6. PMID 12136245.
- Nowaczyk, M. J.; Waye, J. S. (2001). "The Smith-Lemli-Opitz syndrome: A novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology". Clinical genetics 59 (6): 375–386. doi:10.1034/j.1399-0004.2001.590601.x. PMID 11453964. |
<urn:uuid:2daa84e7-0697-4c9a-88fe-7363cc9820ed> | seed | Although a relatively uncommon cancer, ovarian cancer is often diagnosed at a stage where the cancer has spread beyond the ovary. Such cases often have a poor prognosis.
Ovarian cancer in Australia: an overview, 2010 provides a comprehensive picture of national statistics on ovarian cancer using a range of data sources, with the latest available data and trends over time presented. Throughout this report, the term 'ovarian cancer' refers to invasive ovarian cancers; borderline tumours are not included.
The number of ovarian cancer cases is increasing
In 2006, ovarian cancer was the ninth most commonly diagnosed cancer among Australian women (excluding non-reportable skin cancers) and the second most commonly diagnosed gynaecological cancer, with a total of 1,226 ovarian cancer cases diagnosed. Ovarian cancer is mainly a disease of postmenopausal women, with six in ten (60%) cases diagnosed in women aged 60 years and over.
The number of ovarian cancer cases increased by 47% between 1982 and 2006 (from 833 cases to 1,226 cases) due to an ageing and growing population. It is anticipated that the number of new cases will continue to increase, with an estimated 1,434 women expected to be diagnosed with ovarian cancer in 2015.
Nonetheless, the age-standardised incidence rate of ovarian cancer decreased significantly by 14% between 1982 and 2006 (from 12.4 to 10.7 new cases per 100,000 females).
The rate of death from ovarian cancer has fallen
A total of 795 women died from ovarian cancer in 2006, making it the sixth most common cause of cancer-related death for Australian women, and the most common cause of gynaecological cancer death, representing over half (55%) of such deaths.
The age-standardised mortality rates for ovarian cancer decreased significantly by 26% between 1968 and 2006 (from 9.1 to 6.7 deaths per 100,000 females). In addition, the 2006 mortality rate was the lowest rate observed for any year to date. Possible reasons for the decrease in the mortality rate over time include the observed decline in the incidence rate, improvements in access to and quality of treatments, and change over time in the types of ovarian cancers occurring among women. However, the data also indicate that the decline in the mortality rate was not observed for all age groups, with the ovarian cancer mortality rate for older women (those aged 70 years and over at death) increasing rather than decreasing over the period considered.
The prognosis of women with ovarian cancer has improved
The prognosis for women with ovarian cancer is relatively poor. Women who were diagnosed with ovarian cancer between 2000 and 2006 were 40% as likely to live five years after diagnosis as their counterparts in the general population. Significantly poorer survival was seen for older women, with 5-year relative survival estimates ranging from a high of 86% for those aged less than 30 years when diagnosed with ovarian cancer to a low of 15% for those aged 80 years or older at diagnosis. Possible reasons for poorer survival of older women include a greater likelihood that these women were diagnosed with advanced stage cancer and/or with more-aggressive types of cancers, as well as a greater likelihood of co-morbidities. Differences by age in the treatment provided to those with ovarian cancer are also believed to be a factor.
Improvement in the prognosis of those diagnosed with ovarian cancer has occurred over time, with the 5-year relative survival rate increasing significantly from 33% in 1982-1987 to 40% in 2000-2006. Nonetheless, the improvements in survival were focused on women in the middle age groups, with no significant change in the survival estimates over time for those aged less than 40 years and those aged 80 years and over. |
<urn:uuid:ee167e17-f494-4e3a-acc4-4de4bc4c8654> | seed | Tips from Other Journals
Normal Control in Pregnant Women with Hypothyroidism
Am Fam Physician. 2004 Mar 1;69(5):1228-1229.
An estimated 2.5 percent of pregnant women in the United States have hypothyroidism. Even subclinical hypothyroidism has been associated with adverse pregnancy outcomes. The fetus depends on maternal thyroid hormone until fetal thyroid function begins at about 10 to 12 weeks’ gestation, but some reliance on maternal thyroxine (T4) continues throughout pregnancy. Low maternal T4 levels at 12 weeks’ gestation have been linked to impaired psychomotor development in infants. In several studies, maternal hypothyroidism has been associated with lower IQ scores in children. Because T4 metabolism fluctuates during pregnancy, adequate control of thyroid function may be underestimated. As a result, pregnant women may be inadequately treated, with adverse effects on the fetus. Blazer and colleagues studied thyroid function in the neonatal stage of children born in an Israeli university medical center to determine the adequacy of treatment of pregnant women with hypothyroidism.
The authors studied 259 infants born during a six-year period to mothers who were being treated for hypothyroidism. The mothers of 208 infants had been treated before conception for primary hypothyroidism. The remaining 51 were diagnosed with gestational hypothyroidism and began treatment during pregnancy. Those in the control group were 139 infants born to mothers who had at least two documented normal thyroid tests during pregnancy. The two groups of mothers were matched for age, parity, smoking, and hypertension. Blood samples were collected between 25 and 48 hours or 49 and 120 hours after birth for determination of thyroid-stimulating hormone (TSH) and free T4 levels.
The study and control infants were similar in gestational age and Apgar scores at delivery; however, birth weight and head circumferences were significantly smaller in the study group. TSH and T4 levels were significantly higher in the study group than in control patients (see accompanying table). Between 49 and 120 hours after birth, 44.7 percent of study infants had free T4 levels higher than the 95th percentile of control patients, and 16.8 percent of study infants had significantly higher TSH levels. The levels of neonatal TSH after 48 hours of birth correlated with maternal pregnancy TSH levels. Three infants in the study group had thyroid dysgenesis, a rate significantly higher than expected, and one infant had a loss of TSH receptor function.
The authors conclude that the pituitary-thyroid axis of newborns is significantly affected by maternal hypothyroidism. The finding of significant abnormalities in neonatal infants despite apparently satisfactory thyroid management for the mothers raises concerns that current standards of care may be inadequate for pregnant women with thyroid conditions. The authors call for more stringent monitoring and adjustment of therapy for such mothers and long-term neurodevelopmental follow-up of their infants.
The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.
Blazer S, et al. Maternal hypothyroidism may affect fetal growth and neonatal thyroid function. Obstet Gynecol. August 2003;102:232–41.
Copyright © 2004 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact [email protected] for copyright questions and/or permission requests.
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<urn:uuid:0a430059-91c0-420b-bde3-ed59f85884c2> | seed | Nanosized particles developed at the School of Medicine offer hope of replacing numerous medical tests, scans or surgeries with a simple injection.
Samuel A. Wickline
The tiny spheres can travel through the bloodstream deep into the body to locate and highlight tumors undetectable by typical methods. While at the tumor site, the nanoparticles can deliver therapeutic agents to destroy the tumor.
To advance this promising technology, the National Cancer Institute (NCI) has awarded $16 million over five years to the School of Medicine to establish the Siteman Center of Cancer Nanotechnology Excellence (SCCNE).
The NCI also awarded funding for six other Centers of Cancer Nanotechnology Excellence (CCNEs) around the United States.
The SCCNE will research and apply nanotechnology for the diagnosis and treatment of cancer.
The center will be headed by Samuel A. Wickline, M.D., professor of medicine and of cellular biology in the School of Medicine; of biomedical engineering in the School of Engineering & Applied Science; and of physics in Arts & Sciences. He and Gregory M. Lanza, M.D., Ph.D., associate professor of medicine, developed nanoscale particles that can home in on tumor cells to carry imaging agents and drug therapies directly to tumor sites.
Capable of supporting a wide variety of homing, imaging and therapeutic agents, nanotechnology offers several advantages over traditional techniques.
It can provide more-accurate visualization and characterization of tumors, revealing even tiny tumors in medical scans. It has the ability to focus chemotherapeutic drugs exclusively at tumor sites to alleviate unpleasant or risky side effects. And it offers more precise adaptation of treatment to the biochemical and molecular features of each patient's disease.
"We've entered an era of precisely targeted and individualized cancer therapy," Wickline said. "Our nanotechnology will strongly affect the practice of medicine.
"And the grant from the NCI will allow us to build a highly effective collaborative network to bring the technology rapidly to clinical use in the treatment of cancer."
In addition to developing general oncology applications, the SCCNE will focus its efforts on breast cancer and melanoma detection and treatment. Some projects planned for the center include:
• Targeting of multiple tumors for early detection of cancer;
• A nanoparticle-based contrast agent for ultrasound imaging and therapy of tumors;
• Statistical tools to model the behavior of nanoparticles in the body; and
• Novel nanoscale sensors for rapidly screening potential anticancer drugs in single cells.
"The investment in cancer-related nanotechnology by the NCI is a show of confidence that this technology will truly advance cancer treatment," said Larry J. Shapiro, M.D., executive vice chancellor for medical affairs and dean of the School of Medicine. "By bringing these creative laboratory innovations to practical medical application, the SCCNE will become a vital part of the School of Medicine's BioMed 21 initiative."
The NCI began supporting the application of nanotechnology to cancer more than seven years ago. Within the past year, the institute created the NCI Alliance for Nanotechnology in Cancer (nano.cancer.gov) as a comprehensive initiative to translate nanotechnology research into clinical practice in cancer medicine. The establishment of the seven CCNEs is part of this initiative.
"With the advent of the Centers of Cancer Nanotechnology Excellence, we are particularly looking forward to new nanotech-based therapeutic delivery systems that could enhance the efficacy and tolerability of cancer treatments — an advance that would greatly benefit cancer patients," said Anna Barker, Ph.D., the NCI's deputy director.
Each CCNE is a multi-institutional hub. The SCCNE is a collaboration including the School of Medicine and the Siteman Cancer Center, the University of Illinois, several private-sector companies including Kereos Inc., and large multinational corporations including Philips Medical Systems.
The SCCNE will be housed in a newly constructed biotechnology laboratory complex on the east edge of the Medical Campus. Developed by CORTEX — the Center of Research, Technology & Entrepreneurial Exchange — the building is scheduled for completion in January.
The other six CCNEs are at the University of North Carolina; the University of California, San Diego; Emory University and Georgia Institute of Technology (joint center); Harvard University and Massachusetts General Hospital (joint center); Northwestern University; and California Institute of Technology. |
<urn:uuid:e618da93-709b-4463-96d4-6add7818ed4b> | seed | Bowing of the long bones
Campylobacteriosis is disease caused by gram negative spiral-shaped bacteria.
Most human illness is caused by Campylobacter jejuni, but human illness can also
be caused by other species. Campylobacteriosis is characterized by diarrhea,
cramping, abdominal pain, and fever within two to five days after exposure to raw or undercooked poultry, unpasteurized milk, or water
contaminated with the organism. Infection with Campylobacter jejuni
appears to increase the risk for developing Guillian-Barré syndrome and reactive
2. Allos BM. Association between Campylobacter infection and Guillain-Barré
syndrome. J Infect Dis 1997;176:S125-8.
Swelling and accumulation of fluid (edema) in the scalp of infants born
vaginally. The swelling usually disappears within 24 to 48 hours.
A collection of blood caused by rupture of blood vessels between the skull and the periosteum
(the membrane surrounding a bone). The blood does not cross the joints of the
skull, because it is trapped between the periosteum and bone. Subtle skull
fractures may underlie a cephalhematoma. The condition generally resolves over several weeks.
The ratio of the bi-parietal diameter (BPD) to the occipito-frontal diameter
(OFD) X 100. The normal range is 70 to 86. A cephalic index of less than
considered dolichocephaly. An index of greater than 86 is considered to be
Cephalopelvic disproportion (CPD)
The infant's head is too large to pass through the mother's pelvis. Cephalopelvic disproportion is usually diagnosed
when labor fails to progress (cervical dilation and effacement have stopped) and
is unresponsive to oxytocin
Certified nurse midwife (CNM)
A registered nurse with at least 1-2 years of nursing experience who has received additional training in delivering babies and
providing prenatal and postpartum care to women. They are certified by the
American College of Nurse-Midwives (ACNM).
A history of passive and painless dilation (opening) of the cervix in the second trimester leading to preterm delivery.
The cervix appears to be "short", with a length of less than 2 cm, on
Lower narrow part of the uterus that opens into the vagina..
Cesarean section (C-section)
An incision made through the abdomen and uterus for the purpose of delivering
one or more fetuses. The incision on the abdomen may be vertical or transverse.
The incision made on the uterus may not be in the same direction as the
abdominal incision. The three most common types of uterine incisions are:
transverse (Kerr) See illustration
most common incision. This incision is easy to repair and is associated with
the lowest probability of rupture or dehiscence in a subsequent pregnancy
vertical (Kronig) See illustration
when lower uterine segment is undeveloped or for premature breech
Classical See illustration
- This incision may be used when a back down transverse lie
that cannot be converted to breech or cephalic presentation, inability to
expose the lower uterine segment, premature breech presentation, and
anterior placenta previa.
Bluish discoloration of the vaginal tissue and cervix caused by
accumulation of blood (venous congestion). Chadwick's sign may be seen as
early as six weeks of pregnancy.
A positive pregnancy test ( elevated hCG level in the blood or urine) before
pregnancy can be verified by ultrasound. Often used to refer to a pregnancy that
has failed before reaching a size large enough to be seen on sonogram.
Chloasma (mask of pregnancy, melasma)
Blotchy areas of darkened skin over the the forehead, cheeks and upper lips associated with pregnancy or with the use of contraceptives.
Exposure to ultraviolet (UV) rays from the sun or tanning salons intensifies the
pigment changes. The areas of darkened skin usually fade several months
after delivery or discontinuation of the contraceptive.
Inflammation of the fetal membranes and amniotic fluid usually associated
with a bacterial infection. The bacteria responsible are usually those that are
normally present in the vagina. The presence of fever, uterine tenderness, and
foul vaginal discharge help to confirm the clinical diagnosis of chorioamniotis.
The outermost of the two fetal membranes that gives rise to the placenta.
Chorionic Villus Sampling (CVS)
Removal of cells that line the placenta, the chorionic villi, through the cervix
using a catheter or through the abdomen using a needle. The material obtained
may be tested for Down syndrome and other disorders. The procedure is
usually performed between the 10th and 12th weeks of pregnancy .
Structures in the ventricles (spaces) of the
brain that produce the cerebrospinal fluid. Each plexus is made up of a network
of capillary blood vessels covered by transporting epithelial cells.
Choroid plexus cyst
of fluid in the choroid plexus believed to
be caused by abnormal folding of the epithelium lining of the choroid plexus
which traps fluid and debris .
Structures made of of tightly coiled DNA (deoxyribonucleic acid) found in the
nucleus of a cell. DNA is a chemical substance that carries
the instructions for making living organisms and determines characteristics such as
hair and eye color. Human beings normally
have 23 pairs of chromosomes in every cell.
insertion proximally from the edge of the placenta
creates a folded and thickened
placental margin that appears as a
associated with the placental edge
during ultrasound examination.
Circumvallate placenta has been associated
with premature labor, stillbirth, hemorrhage and placental abruption.
The accuracy of sonographic diagnosis for revealing circumvallation
appears to be limited
Suzuki S.Clinical significance of pregnancies with circumvallate placenta.J
Obstet Gynaecol Res. 2008 Feb;34(1):51-4.
Harris RD, et al. Accuracy of prenatal sonography for detecting circumvallate
placenta. AJR Am J Roentgenol. 1997 Jun;168(6):1603-8.
Cleft lip and palate (orofacial cleft)
A gap of the lip or lip and palate (roof of the mouth) caused by failure of
the lip or the lip and palate to grow together.
The lip and primary palate
close during the 4th to 7th weeks of gestation.
The secondary palate begins to close the 6th week and is completed
between the 9th and 12th weeks of gestation
Cleft lips are unilateral
or bilateral. See
1. Moore KL. The branchial
apparatus and the head and neck. In: Moore KL, editor. Before we are born: basic
embryology and birth defects. 3rd edition. Philadelphia: WB Saunders; 1989. p.
2. Sandler TW. Langmans’s Medical Embryology, 7th ed.Baltimore: William and
Deviation or deflection of the fingers. The term most often refers to curving of the little finger toward the fourth finger (the ring finger). Clinodactyly can be inherited as a normal variant, or be associated with chromosomal abnormalities like Down syndrome.
Club foot (Talipes equinovarus)
The foot is turned inward. Both feet are affected in 50% of cases. The defect
may be corrected surgically.
Club foot occurs in about 1
in 700 to 800 births.
In a small number of cases, clubfoot may be seen in
association with spina bifida or as part of a skeletal dysplasia. The estimated
risk of recurrence in future children is 3 to 8% if 1 child is affected and 10%
if 1 child and 1 parent are affected.
Thin, yellow, milky fluid
secreted by the breasts in the last weeks of pregnancy and the first few days after
delivery. Colostrum contains high levels of maternal antibodies.
Enlargement of the occipital horns of the lateral ventricles in the brain.
Time elapsed since the day of conception.
To be related through a recent common ancestor
( a close blood relative ).
( also known as percutaneous umbilical blood sampling)
Insertion of a needle through the mother's abdomen and into the umbilical
cord. The procedure is performed to obtain fetal blood for testing. The risk of
miscarriage from the procedure is reported to be 1 to 2%.
Corpus luteum (CL)
yellow colored structure that the develops from cells of the empty egg
follicle after the egg is released.
The corpus luteum secretes progesterone which prepares the lining of the
uterus for implantation by the embryo.
Premature closing of joints or sutures in the skull. Craniosynostosis may
occur as an isolated finding or may be associated with a syndrome
such as Apert, Chotzen, Pfeiffer, Carpenter, and Crouzon syndromes
The appearance of the infant's scalp at the vaginal opening during labor.
A condition characterized by thick mucus build
up in the lungs and digestive tract. The mucus in the lungs causes inflammation
and infections leading to the formation of scar tissue (fibrosis) and cysts in
the lungs. Cystic fibrosis (CF) also affects the pancreas, liver, intestines, sinuses, and sex
channel that transports chloride ions into and out of cells, and is involved in
the production of sweat, mucus, digestive enzymes, and tears.
There are more than 1,000 mutations of the CFTR
CF is caused by mutations in the CFTR gene (cystic fibrosis transmembrane conductance
and is passed
through the genes from parents to children in autosomal recessive pattern of inheritance
The CFTR gene provides instructions for making
Single or multiple sac-like structures caused by abnormal development of the lymphatic system. Cystic hygromas occur
most often about the neck. More than half of fetuses with cystic hygromas diagnosed
in utero have Turner syndrome (one x chromosome).
Cytomegalovirus (CMV) infection
Cytomegalovirus (CMV) is a common virus transmitted by
direct person-to-person contact through saliva, breast
milk, or urine.
CMV is a member of the herpesvirus group, which also
includes herpes simplex virus,
Epstein-Barr virus , and
varicella-zoster virus. Persons infected with the virus may experience a mononucleosis-like syndrome with prolonged fever, extreme fatigue, body aches, and
sometimes a mild hepatitis.
Once infected with CMV the virus may remain inactive within the body for many
years. Recurrent disease occasionally occurs.
Transmission to the fetus occurs in 30-40% of cases of
primary maternal infections, and 0.5-1% of recurrent infections.
Findings on ultrasound that would raise the possibility of a severe CMV
infection include very high or very low levels of
amniotic fluid , fluid collections in the abdomen (ascites), dense
appearing (echogenic) bowel, growth restriction, very small head
of the fluid filled chambers of the brain ventriculomegaly or
hydrocephaly), or calcium deposits in the brain or liver.
Infants of mother who
experience recurrent infection with CMV during pregnancy tend to be only mildly
affected by the virus if at all. |
<urn:uuid:df068d24-b963-4586-807e-5f5780c9ed93> | seed | From Wikipedia, the free encyclopedia - View original article
|This article needs additional citations for verification. (January 2010)|
|This article needs attention from an expert in Medicine. (January 2010)|
A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body. As primary cancer treatments such as surgery, radiation therapy and chemotherapy have become more effective in the past few decades, people with cancer are living longer after initial treatment than ever before. However, brain metastases still occur in many patients months or even years after their original cancer treatment. Brain metastases have a poor prognosis for cure, but modern treatments are allowing patients to live months and sometimes years after the diagnosis.
Often, patients have no obvious symptoms to alert them that their cancer has spread to the brain. Follow-up doctor visits and brain scans may be needed to determine the presence of brain metastases.
Brain metastases can cause a wide variety of symptoms, many of which are also present in minor, more common conditions. They include:
Treatment for brain metastases is primarily palliative, with the goals of therapy being reduction of symptoms and prolongation of life. However, in some patients, particularly younger, healthier patients, aggressive therapy consisting of open craniotomy with maximal excision, aggressive chemotherapy, and radiosurgical intervention (gamma knife radiosurgery) may be attempted.
Symptomatic care should be given to all patients with brain metastases, as they often cause severe, debilitating symptoms. Treatment consists mainly of:
Radiotherapy plays a critical role in the treatment of brain metastases, and includes whole-brain irradiation, fractionated radiotherapy, and radiosurgery. For decades, whole brain irradiation has been advocated for patients with multiple lesions, a life expectancy of less than three months, or a low Karnofsky performance score, and it does appear at least somewhat effective. However, it often causes severe side effects, including radiation necrosis, dementia, toxic leukoencephalopathy, partial to complete hair loss, nausea, headaches, and otitis media. In children this treatment may cause mental retardation, psychiatric disturbances, and other neuropsychiatric effects.
Brain metastases are often managed surgically, with maximum surgical resection followed by stereotactic radiosurgery or whole-brain irradiation delivering superior survival compared to whole brain irradiation alone. Therefore, in patients with one metastatic brain lesion, limited, absent, or controlled systemic disease, a life expectancy of at least 3 months and good performance status might be expected.
Stereotactic radiosurgery is being increasingly utilized for the treatment of a limited number of brain metastases. Stereotactic radiosurgery alone or with whole brain radiation therapy has been shown to achieve excellent local tumor control. Addition of stereotactic radiosurgery to whole brain radiation can increase the control rate and functional status of patients.
Chemotherapy is rarely used for the treatment of brain metastases, as chemotheraputic agents penetrate the blood brain barrier poorly. However, some cancers such as lymphomas,small cell lung carcinomas and breast cancer are highly chemosensitive and chemotherapy may be used to treat extracranial sites of metastatic disease in these cancers. An experimental treatment for brain metastases is intrathecal chemotherapy, a technique in which a chemotheraputic drug is delivered via intralumbar injection into the cerebrospinal fluid. However, it is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of brain metastases.
The prognosis for brain metastases is variable. It depends on the type of primary cancer, the age of the patient, the absence or presence of extracranial metastases, and the number of metastatic sites in the brain. For all patients combined, median survival is only 2.3 months. However, in some patients, such as those with no extracranial metastases, those who are younger than 65, and those with a single site of metastasis in the brain only, prognosis is much better, with median survival rates of up to 13.5 months. |
<urn:uuid:d91982df-a50f-4e6c-abb8-ec4502752679> | seed | TOKYO--Genetics researchers received a new tool today. A database of annotated, full-length human complementary DNAs (cDNAs), compiled by an international team led by Japanese researchers, has been opened for public access. The database is expected to be a boon for research related to drug development, gene hunting, molecular evolution, and comparative genomics.
cDNA is basic tool of biotechnology. It's a lab-made copy of an organism's DNA--crucially, just the protein-coding parts--that researchers concoct using an enzyme called reverse transcriptase. Normally, DNA is transcribed into RNA, then edited and made into proteins. Reverse transcriptase goes the other way around, building a gene from its messenger RNA. That enables researchers to create copies of active genes without having to hunt through the unedited genome.
The new database pools and builds on information from six major cDNA projects, including the Mammalian Gene Collection of the U.S. National Institutes of Health, the German Human cDNA project, work at the Chinese National Human Genome Center in Shanghai, and three projects in Japan. Takashi Gojobori, deputy director of the Japan Biological Information Research Center in Tokyo, says that scientists involved in the various projects were looking for ways to make their work more accessible to all researchers and to augment the value of individual collections. "One project can't cover everything, but put them all together and they are very complementary," he says.The database includes data on more than 20,000 unique cDNA sequences, including everything known about function, structure, tissue expression patterns, disease relationships, and orthologs in common experimental animals. Researchers who want a copy of a particular cDNA clone can contact the appropriate institute. A second annotating marathon held last November produced data on 15,000 additional clones, which will be uploaded as soon as they are processed. The database is also prepared to accept submissions. Analysis of the annotated data has already led to the identification of several thousand previously unidentified candidate genes.Gojobori imagines the database as the ultimate repository of information on cDNAs and sees it as one of Japan's major contributions to the field. Japan was late getting started on its contribution to human genome sequencing efforts, contributing only about 6% of the total. In contrast, the three Japanese projects contributed about 60% of the cDNA data going into the H-Invitational Database. "I think Japanese researchers wanted to make a unique contribution to genomic efforts," he says.
The cDNA database |
<urn:uuid:24fd0808-2a5f-4bfc-bb04-80cf00b27a38> | seed | As a central pathway in metabolism, glycolysis has been highly conserved across multiple species from archaea to humans. The omnipresence of the glycolytic enzymes makes for a crude but standardized genomic measuring stick, comprising an ideal platform for studying pseudogenes.
Despite the high degree of conservation in the glycolytic enzymes, there is much more variation in their pseudogene abundances. Some genomes, like chicken, zebrafish, pufferfish, fruitfly, and worm, have very few or none, while others, like mouse and rat, have hundreds. The differences in pseudogene abundances alone suggests significant differences in the processes of gene expression, duplication, and retrotransposition in the different genomes. Previous studies have suggested that the difference lies in the prolonged lampbrush stage of oogenesis in mammalians as compared to non-mammalian organisms [48
Most glycolytic pseudogenes are processed and can be assumed to be retrotransposed from an mRNA intermediate. It is possible that certain sequences intrinsic to the GAPDH and LDH genes may predispose them to be preferentially retrotranscribed, inserted, and preserved in the genome. These pseudogenes are classified as processed and not duplicated indicating their formation was the result of a retrotransposition event of the parent gene, rather than a duplication event. However, we must consider the possibility of formation of a processed pseudogene through a retrotransposition event and its subsequent duplication giving rise to so called "duplicated-processed" pseudogenes. Thus, while duplicated pseudogenes result from the duplication of parent gene, duplicated-processed pseudogenes result from the duplication of a processed pseudogene [50
]. One way to differentiate processed pseudogenes from duplicated-processed pseudogenes is to check if the segments of the genome surrounding a pair of processed pseudogenes are also similar. Hence, we checked for the presence of 60 processed pseudogenes of human GAPDH in duplicated regions of the genome called segmental duplications [52
]. A pair of processed pseudogenes located in segmental duplication pairs indicates that one of the pseudogenes was likely formed by the duplication of the other one and hence is a duplicated-processed pseudogene (Figure ). We identified eight duplicated-processed pseudogenes by this analysis, listed in Additional File 1
. However, six of those eight pseudogenes occupy > 77% of the segments that are duplicated and could be the result of independent retrotransposition events. In this scenario perhaps the high sequence similarity of these segments led to their annotation as segmental duplications.
Figure 6 Aetiology of a duplicated-processed pseudogene. Alternative aetiology of a processed pseudogene. A parent gene is first retrotransposed into a processed pseudogene. Then the processed pseudogene undergoes segmental duplication to produce a duplicated-processed (more ...)
As a coincident finding, GAPDH has many more biological roles outside glycolysis as compared to the other glycolytic enzymes. For example, GAPDH functions in DNA repair, telomeric DNA binding, transcriptional regulation, nuclear RNA export, apoptosis, membrane fusion, phosphorylation, tubulin bundling, and sperm motility [53
]. Because the molecular processes of retrotransposition are separate from the enzymatic functionalities, we can only speculate that the preponderance of non-glycolytic roles may be correlated to the enrichment of GAPDH pseudogenes.
In an intergenomic analysis, GAPDH pseudogenes have about five- to six-fold greater abundance in the rodent genomes as in the primate genomes even though overall the mouse genome was found to have about half as many pseudogenes as the human genome [3
]. The mouse genome has higher rates of nucleotide substitution, insertion, and deletion [33
] than the human genome, leading to a higher rate of pseudogene decay. However, the higher rate of pseudogene decay seems to have preferentially spared the GAPDH pseudogenes.
To further characterize the molecular history of pseudogenes in the human, chimpanzee, mouse, and rat genomes, it was necessary to identify the pseudogenes that were most likely present prior to the primate-rodent ancestral divergence. We used orthologous genes to identify regions of synteny between primate-rodent genome pairs. This approach is based on the assumption that gene-coding regions are much less variable than intergenic regions because of functional constraints and are therefore more reliably matched between genome pairs.
The scarcity of GAPDH pseudogenes syntenic between the primate and rodent genomes suggests an increase in retrotranspositional activity after the primate-rodent divergence 91 million years ago, which is consistent with the findings of previous investigators [6
]. In order to achieve more detail in the timeline and provide further corroboration, we used Kimura's two-parameter model of nucleotide substitution to estimate the rates of change in the GAPDH genes and pseudogenes and thereby calculate the insertion date of each pseudogene. The creation dates formed three distinct distributions centered at 42.0, 36.3, and 25.9 million years ago in the human, mouse, and rat genomes, respectively, signifying a burst in retrotranspositional activity around those times. Kimura's model assumes neutrally evolving sequences, as in many pseudogenes [42
], but some may initially be subject to natural selection [12
] and the ages of these pseudogenes may be underestimated. In the human genome, the bursts in retrotranspositional activity may coincide with the "Alu burst" that occurred about 40 million years ago in primate genomes [60
]. By examining the sensitivity of our pseudogene pipeline, as decribed under Methods, we found that the number of pseudogenes does not vary significantly with the threshold for sequence identity or BLAST score when compared to the parent gene. Thus, we believe this dating method accurately reflects all GAPDH pseudogenes and is not significantly biased towards longer and therefore younger pseudogenes. |
<urn:uuid:86ef7f02-0fdb-4ac5-ba7f-47130509d02d> | seed | Follow Us:Follow Us on Twitter Like Us on Facebook Follow Us on Google+ Watch videos on our Youtube channel
Thyroid Nodule Treatment
Nodules can be caused by a variety of factors including an overgrowth of normal tissue, cysts or inflammation. Most nodules are benign but for a small majority of patients (5-7%), these nodules may be cancerous. In a patient with a known thyroid nodule, the initial step is to determine the risk for cancer. High-risk features include:
- Being male under the age of 40
- A history of radiation therapy to the head or neck
- Big lymph nodes in the neck
- Problems swallowing
- Problems speaking
- A family history of thyroid cancer
The next step is an ultrasound of the thyroid to determine the size of the nodule(s) and if it has certain characteristics that increase the possibility of it being cancer. An ultrasound-guided fine needle aspiration biopsy is then performed to obtain tissue from the thyroid nodule to determine whether the nodule is benign or malignant.
The specimen obtained from the fine needle aspiration is examined by a pathologist. There are four general categories of possible results for a FNA: 1) Benign, 2) Malignant, 3) Nondiagnostic, 4) Indeterminate. If the lesion is benign, the patient is monitored via ultrasound for the growth of the nodule(s) or development of new nodules. If there is growth, another biopsy may be performed. If the lesion is malignant, the patient is referred to one of the Thyroid Cancer Center surgeons for removal of the thyroid.
About 10% of the time, the pathologist is unable to provide a diagnosis due to lack of specimen from the aspiration. An indeterminate biopsy result confers an increased risk for malignancy and your doctor will discuss the benefits and risks of surgery versus monitoring.
Usually, the entire thyroid is removed (total thyroidectomy), although in selected instances, only a part of the gland may be removed. At surgery, lymph nodes also may be removed to determine any possible spread of the tumor beyond the thyroid gland. Subsequent therapy depends upon the findings at the time of surgery. Some patients may merely be placed on thyroid hormone and followed with blood tests and ultrasound examinations, while other will receive radioactive iodine to destroy the residual thyroid tissue and then be followed with blood tests and ultrasounds.
Using this type of therapy, the majority of cancers will be either cured or controlled and less than 20 percent will recur. Most of the time, residual cancer can be treated with additional surgery or radioactive iodine. Occassionally, external beam radiation (EBRT) may be needed to treat thyroid cancers that cannot be fully resected or that persist despite RAI treatment. Lastly, there are clinical trials with newer therapies such as targeted chemotherapies that a patient may qualify for if they have aggressive disease. |
<urn:uuid:d7e03e28-b813-4611-8776-27916be41aaa> | seed | The vast majority of life on earth is microbial, and the vast majority of these microbial species have not been cultured in the laboratory (1
). Consequently, our primary source of information about most microbial species consists of fragments of their DNA sequences. The DNA encoding the 16S rRNA gene has been widely used to specify bacterial taxa, since the region can be amplified using PCR primers that bind to conserved sites in most or all species, and large databases are available relating 16S rRNA sequences to bacterial phylogenies. As the cost of sequencing decreases, especially through techniques such as pyrosequencing [(2
) and references therein], methods for comparing different communities based on the sequences they contain become increasingly important. In particular, techniques such as UniFrac (3
) allow us to compare many microbial samples in terms of the phylogeny of the microbes that live in them. Such methods are particularly valuable as we begin to search for gradients that affect microbial distribution, and thus need to characterize many communities in an efficient and cost-effective fashion. Gradients of interest include different disease states in humans or animal models (4
), or physical or chemical gradients in natural environments such as temperature or nutrient gradients in hot springs (5
Our ability to apply phylogenetic diversity measures such as UniFrac to microbial community data relies on our ability to build phylogenetic trees from fragments of the 16S rRNA sequence. Because the accuracy of phylogenetic reconstruction depends sensitively on the number of informative sites, and tends to be much worse below a few hundred base pairs [see, for example, (6
)], the short sequence reads produced from pyrosequencing, which are 100 nt on average for the GS 20 (Genome Sequencer 20 DNA Sequencing System, 454 Life Sciences, Inc., Bradford, CT, USA) and 200–300 nt for the newer GS FLX (Genome Sequencer FLX System, 454 Life Sciences, Inc., Bradford, CT,USA), may be unsuitable for performing phylogenetically based community analysis. However, this limitation can be at least partially overcome by using a reference tree based on full-length sequences, such as the tree from Phil Hugenholtz's 16S rRNA ARB Database (7
), and then using an algorithm such as parsimony insertion (8
) to add the short sequence reads to this reference tree. These procedures are necessarily approximate, and may lead to errors in phylogenetic reconstruction that could affect later conclusions about which communities are more similar or different. One substantial concern is that because different regions of the rRNA sequence differ in variability (9
), conclusions drawn about the similarities between communities from different studies might be affected more by the region of the 16S rRNA that was chosen for sequencing than by the underlying biological reality.
Here we address these effects directly by asking how primer choice affects our ability to recover patterns of similarity between microbial communities obtained using full-length or near-full-length 16S rRNA sequences, using two complementary strategies. First, we ask whether microbial communities that come from a globally dispersed set of over 200 different physical locations (10
), including soil, fresh water and marine sediment, form distinct clusters by habitat type or instead cluster by which region of the 16S rRNA was sequenced. Second, we test for the recovery of UniFrac clusters from near-full-length sequences for three different studies: a set of communities from lean and obese mice (4
), a set of communities from the gastrointestinal tract of three healthy human individuals (11
) and a set of sequences from the Guerrero Negro microbial mat [Harris, J.K., Walker, J.J. and Pace, N.R. unpublished data, and (12
)]. In each case, we ask whether the same relationships would have been recovered if a smaller fragment of the sequence had been used. In particular, we are concerned with the trade-off that pyrosequencing offers: given finite resources, is it more efficient to collect a large number of 100-base 16S rRNA fragments, or to collect a smaller number of near-full-length rRNA sequences using traditional methods? |
<urn:uuid:f1e235f4-7a17-48f7-9ee9-708bd7ce130f> | seed | SUMMARY PARAGRAPH for CMD1
Calmodulin (also referred to as CaM) is a small, essential Ca2+ binding protein encoded by CMD1 that regulates many processes including response to various stress conditions, mating, budding, and actin-based processes (7). This wide range of roles is possible because calmodulin undergoes a conformational change upon calcium binding. The apo-calcium form has a very different structure than the calcium bound form and thus binds to a different set of protein targets (7). Although calmodulin is essential (3, 4), the essential functions mediated by calmodulin do not require calcium-binding, as cells with mutant forms of calmodulin which lack the ability to bind Ca2+ are viable and have only minor defects in growth and morphology in standard laboratory conditions (11). Some of the Ca2+-dependent targets of calmodulin only become essential in response to various stress conditions (7). Thus calmodulin has many targets, both Ca2+-dependent and Ca2+-independent.
Ca2+-independent roles of Calmodulin
Ca2+-independent targets of calmodulin, some of which are essential genes, play roles in the organization and formation of the spindle pole body (SPB), karyogamy, actin cytoskeletal organization and bud emergence, endocytosis, and microautophagy. Calmodulin localizes to the central plaque of the spindle pole body through its interaction with Spc110p (12, 13). Binding by calmodulin is required for correct localization of the essential Spc110p component to the SPB and thus the formation of the SPB (7, 14) and also for karyogamy (15). Calmodulin also interacts with Myo2p, one of two type V myosin heavy chains (16). Through its interaction with Myo2p, calmodulin is required for polarized growth of yeast cells and inheritance of the vacuole by daughter cells (7). Calmodulin may also interact with the other type V heavy chain encoded by Myo4p (7). Through interactions with both the unconventional type I myosin, encoded by MYO5, and Arc35p, a component of the Arp2/3 complex, calmodulin is also required for receptor-mediated endocytosis (17, 2, 7). Calmodulin is also involved in microautophagy, a role which may be mediated by Vtc2p and Vtc3p (18).
Ca2+-dedependent roles of Calmodulin
Calmodulin also has multiple Ca2+-dependent targets, including calcineurin and calmodulin-stimulated protein kinases. Calcineurin, or PP2B, is a Ca2+ and calmodulin dependent phosphatase that is highly conserved amongst eukaryotic organisms and regulates many different processes. Calcineurin is composed of a heterodimer of a catalytic A subunit, encoded by CMP2 and CNA1, and a regulatory B subunit, encoded by CNB1, which is an EF-hand domain protein related to calmodulin. When stimulatory levels of Ca2+ are present, calcium-bound calmodulin binds to the A subunit, displacing an autoinhibitory domain of the A subunit. In yeast, calcineurin regulates at least three different processes: a stress-activated transcriptional pathway, calcium homeostasis, and the G2 to M transition of the cell cycle. Calmodulin also regulates calcium and calmodulin dependent kinases, of which there are two in S. cerevisiae, encoded by CMK1 and CMK2. In the presense of calcium and calmodulin, they become autophosphorylated and can phosphorylate many different substrates. The calmodulin-dependent kinases regulate a number of different stress responses, including response to mating pheromone, response to organic acids, and tolerance to heat stress (7).
Other roles of Calmodulin
Calmodulin plays additional roles in the cell, and it is not yet clear whether these processes are dependent on or independent of calcium. Calmodulin plays a role in vacuole fusion. Some calmodulin mutants display abnormal vacuolar morphologies, calmodulin binds to vacuoles in a Ca2+-dependent manner, and in vitro assays indicate that calmodulin is required for a post-docking step in vacuole fusion (6). However, it is not clear whether this process requires calcium as a non-calcium binding mutant shows normal vacuolar morphology in vivo (7) and variable results have been obtained in assays testing whether the non-calcium binding mutant protein supports vacuolar fusion in vitro (9). The effect of calmodulin on vacuolar fusion may be due to its affects on remodelling of the actin cytoskeleton (19). Overexpression of Mss4p, a phosphatidylinositol-4-phosphate 5-kinase involved in the organization of the actin cytoskeleton, suppresses the actin cytoskeleton defects of a particular calmodulin mutation, which also causes reduced levels of phosphatidylinositol (4,5)-bisphosphate (8).
Structure of calmodulin and comparison with those from other organims
Calmodulin is a highly conserved protein found in all eukaryotes, including animals, plants, and fungi. While the amino acid sequences of calmodulins from multicellular organisms are more than 90% identical, that from S. cerevisiae is significantly diverged, with only 60% identity to vertebrate calmodulins. Calmodulin contains four EF-hand domains; in most species, including S. pombe, each motif chelates one Ca2+ ion. However, in calmodulin from S. cerevisiae, the fourth motif is divergent and does not bind calcium, making it the only yet characterized calmodulin to bind less than four Ca2+ ions. Despite these structural differences between calmodulin of S. cerevisiae and other organisms, its basic functions appear to be conserved (7).
Last updated: 2007-07-24 |
<urn:uuid:76da8241-5189-4a87-8e62-467652c77f3f> | seed | Oligoarticular juvenile arthritis is the most common form of juvenile idiopathic arthritis (JIA), representing nearly 50% of cases. Its prevalence is estimated at 1-10 in 6,500 children, with an annual incidence of 1-20 in 1,000,000 children. Oligoarticular juvenile arthritis is more common in girls (80% of cases), with onset occurring between ages 2 and 4. It is usually asymmetrical and affects between one and a maximum of four joints, predominantly those of the lower limbs (knee or foot). Pain is not a constant feature in young children and the most common reasons for seeking medical advice are an increase in the volume of the joint and/or limping. The association of this form of arthritis with nonsymptomatic iridocyclitis (no pain or visible redness) is a specific feature, present in a third of cases. Thus, it is important to perform an initial slit-lamp examination with regular ophthalmologic follow-up. The biological findings associated with the inflammatory syndrome are variable: antinuclear factor tests are positive in 70-80% of cases but their specificity remains undetermined and levels are relatively low. Oligoarticular juvenile arthritis is an autoimmune disorder, but the exact disease mechanism and triggering factors are unknown. However, the disease has been associated with HLA class II antigens, HLA DR3 and DRB1*08. The diagnostic criteria for the disease were established in 2001 at the last international meeting in Edmonton. Oligoarticular juvenile arthritis is defined as the presence of arthritis affecting between one and four joints in the first six months following disease onset. There are two subgroups: persistent oligoarticular arthritis (involvement of less than four joints) and extensive oligoarticular arthritis (involving more than five joints or more, after the first six months since onset). The exclusion criteria are: the presence of systemic arthritis or psoriasis in the patient, or a family history of psoriasis in one of the parents or first-degree relative; HLA B27-positivity in males with onset of arthritis after 6 years of age; and detection of rheumatoid factor IgM in two test samples taken three months apart. Other exclusion criteria include: the presence of ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory enteropathy or acute anterior uveitis in the patient or a family history of one of these conditions in a parent or first-degree relatives. The presence of iridocyclitis and/or antinuclear factors (without fever or psoriasis) are strong diagnostic indicators. The differential diagnosis should include infectious arthritis and other inflammatory diseases, as well as haematooncologic diseases that may lead to arthritis (e.g. connective tissue diseases and acute leukaemia). Treatment is best managed by a paediatric rheumatologist in collaboration with physiotherapists and ophthalmologists. Initial treatment revolves around administration of NSAIDS. In cases resistant to NSAIDS, intraarticular injection (under sedation or general anaesthesia in children under 3 years of age) of delayed-action corticoids (triamcinolone hexacetonide) is required and gives good results. The use of disease-modifying antirheumatic drugs (salazopyrine or tumour necrosis factor (TNF)-alpha) is only recommended in cases with extensive involvement or those that are refractory to other forms of treatment. The ophthalmologic manifestations should be treated with mydriatic eye drops and corticosteroids, or with general corticotherapy for very severe forms. In total, 50% of cases are non-progressive by adulthood. Joint sequelae are minor (possible asymmetry in the length of the lower limbs). In half of the cases, the joint disease and eye manifestations remain progressive (often with polyarticular extension, a risk of cartilage/bone damage and reduced visual acuity). In 10% of cases, the iridocyclitis causes amblyopia.
Last update: January 2007 |
<urn:uuid:caf8061b-3325-4030-b3c9-06c85ac3ec28> | seed | In Pakistan, only 59-73% of children 12-23 months of age are fully immunized. This randomized, controlled trial was conducted to assess the impact of a low-literacy immunization promotion educational intervention for mothers living in low-income communities of Karachi on infant immunization completion rates.
Three hundred and sixty-six mother-infant pairs, with infants aged ≤ 6 weeks, were enrolled and randomized into either the intervention or control arm between August - November 2008. The intervention, administered by trained community health workers, consisted of three targeted pictorial messages regarding vaccines. The control group received general health promotion messages based on Pakistan's Lady Health Worker program curriculum. Assessment of DPT/Hepatitis B vaccine completion (3 doses) was conducted 4-months after enrollment. A Poisson regression model was used to estimate effect of the intervention. The multivariable Poisson regression model included maternal education, paternal occupation, ownership of home, cooking fuel used at home, place of residence, the child's immunization status at enrollment, and mother's perception about the impact of immunization on child's health.
Baseline characteristics among the two groups were similar. At 4 month assessment, among 179 mother-infant pairs in the intervention group, 129 (72.1%) had received all 3 doses of DPT/Hepatitis B vaccine, whereas in the control group 92/178 (51.7%) had received all 3 doses. Multivariable analysis revealed a significant improvement of 39% (adjusted RR = 1.39; 95% CI: 1.06-1.81) in DPT-3/Hepatitis B completion rates in the intervention group.
A simple educational intervention designed for low-literate populations, improved DPT-3/Hepatitis B vaccine completion rates by 39%. These findings have important implications for improving routine immunization rates in Pakistan.
Vaccinating infants against childhood communicable diseases is one of the most cost-effective public health interventions worldwide . Pakistan's Expanded Program on Immunization (EPI) schedule involves administrating BCG/OPV at birth, three doses of DPT/OPV/Hepatitis B vaccines at 6, 10 and 14 weeks of age, and measles vaccine at 9 and 15 months of age. In Pakistan, children receive vaccinations through EPI at fixed primary health centers. Additional supplementary activities are undertaken through outreach efforts, such as National Immunization Days. Recently, Pakistan has added the Haemophilus influenzae type b vaccine to be administered with the three doses of DPT/Hepatitis B vaccines. Despite recent efforts, immunization coverage rates in Pakistan remain low, with 59-73% of children aged 12 - 23 months receiving all three doses of DPT/Hepatitis B vaccine [2,3]. Therefore, low-cost innovative interventions, which can be implemented within Pakistan's existing health care infrastructure, are needed.
Many studies have looked at factors that affect immunization completion rates. Low parental, specifically maternal literacy and knowledge regarding vaccines and immunization schedule, poor socioeconomic status, and residence in rural areas are associated with low immunization coverage [4-12]. Health provider factors that have been associated with increased immunization drop-out rates include parental difficulty of access to healthcare services and inadequate supervision of healthcare staff at health facilities [4-6,8]. Retention of proof of immunization by the infants' families has been associated with improved immunization coverage and facilitates documentation of vaccination status [6,10,11].
Increasing health awareness, knowledge about diseases, and their prevention or management has successfully improved many different health outcomes in high-income countries, especially among less literate populations [13-16]. Educational interventions promoting vaccine use have also proven cost-effective in improving immunization coverage rates in these settings [17,18]. However, there is limited data available from low-income countries . Usman et al recently reported findings from a randomized controlled trial in urban Pakistan evaluating the effect of center-based education to mothers of infants presenting at primary healthcare centers for first dose of DPT vaccine. The 2-3 minutes education session, conducted by trained study staff, emphasized the importance of completing the immunization schedule, and improved immunization completion rates by 31% among the cohort of infants whose mothers presented to an immunization center for their first vaccine .
To our knowledge, no study has looked at the impact of home-based vaccine promotion education among a population of mothers of newborns at high risk for not seeking immunization services for their children. Our study aims to close this gap. The main objective of this study was to assess the effect of short, home-based information sessions on importance of vaccines on DPT-3/Hepatitis B immunization rates in low-income urban and peri-urban communities in Karachi, Pakistan known for very low demand and care-seeking for vaccination services.
This was a multi-site community-based, randomized controlled educational intervention trial conducted at five low-income sites in Karachi. Among these, one community was urban, whereas the other four were peri-urban, located about 45 minutes travel outside of Karachi. The population in the study areas has low literacy, with only 24% of the population being literate. The total combined population of all five study sites is approximately 260,000, with high infant and maternal mortality rates. The major income generating activities include fishing and livestock rearing, or employment in local small industries (garment and leather).
The Department of Pediatrics and Child Health, Aga Khan University has well-established household-based surveillance for pregnancy and neonatal outcomes in these areas. A demographic surveillance round of the entire area is completed every three months. All pregnant women identified during this surveillance are visited frequently around the time of birth so that new births can be captured.
Eligibility and enrollment of participants
All mothers living in the study areas, and having a live child ≤ 6 weeks old, were eligible to be enrolled in the study. Twin births, infants > 6 weeks of age, or infants born to mothers living outside the study surveillance areas were excluded. The cutoff of 6 weeks was used to ensure that the intervention was implemented before the first dose of DPT/Hepatitis B came due.
Mothers of possibly eligible infants were identified through computerized surveillance databases of pregnant women and newborns maintained at each site. Families were approached with the help of local women, trained as community health workers (CHWs). The CHWs also obtained verbal consent from the mother of each eligible infant. The study protocol was approved by the Ethical Review Committee of the Aga Khan University. Informed consent was obtained from each participant at enrollment, and no breaches of confidentiality occurred.
Each mother-infant pair, who consented to participate in the study, was assigned a unique study identification number. Information on household demographics and socio-economic status was collected using a pre-tested structured questionnaire. Data collected on the infant included age, sex, place of birth, and health status. The baseline interview also recorded mother's knowledge and beliefs about vaccines. A follow-up questionnaire was used to assess the outcome. Subjects were enrolled from August 2008 to November 2008. Study participants were followed up for assessment of outcome from December 2008 to March 2009, with each individual mother-infant pair approached four months after the educational intervention session.
Randomization lists, stratified for each of the five enrollment sites were generated by a computer and provided to the CHWs Upon consent, mother-infant pairs were assigned either to intervention or control arms through block randomization (n = 4), according to the computer-generated list. As the intervention was educational, blinding of study staff and participants was not possible. Outcome assessment was done by an investigator (BH) at each participant's house, four months after initial enrollment. The investigator was blinded to the exposure status of participants.
To address the needs of low literacy populations, easy-to-understand pictorial cards, using very simple language, to convey three key messages as part of the educational intervention were designed. The first key message highlighted how vaccines save children's lives. The second message provided logistic information about the address and location of the local vaccination centers. The third key message emphasized the significance of retaining immunization cards, and the role they could play at the time of the child's school admissions. A copy of these pictorial messages was left with the mother. These messages took about 5 minutes to impart, and were given by the trained CHWs to each participant at their household.
The control group verbally received the general health promotion messages adapted from the curricula developed by the Pakistan Ministry of Health for the Lady Health Worker Program. These messages included information on hand-washing, breast-feeding, clean water, benefits of using oral rehydration solutions during diarrhea, bringing the infant to nearby health center when there are symptoms of acute respiratory illnesses, importance of antenatal check-ups for mothers, and some general information on vaccines. These messages were also given by trained CHWs. The length of each educational session in the control group was approximately 10-15 minutes.
The study outcome in each study group was the immunization status of DPT-3/Hepatitis B at 4 months after enrollment (4 to 5 months of infant's age). Immunization rates of DPT-3/Hepatitis B vaccines for intervention and control groups were assessed by an investigator, and were divided into two categories:
1) Infants receiving all three doses of DPT/Hepatitis B vaccines (assessed through vaccination cards) were considered "DPT-3/Hepatitis B fully immunized".
2) Infants missing any dose of DPT/Hepatitis B or who had lost their vaccination cards were termed"DPT-3/Hepatitis B non-immunized".
A participant was considered to be "DPT-3/Hepatitis B fully immunized" only if the mother/caretaker of the child was able to produce an EPI-issued or another health facility-issued vaccination card. Verbal responses of mothers regarding vaccine receipt without documentation on a vaccination card were not considered satisfactory evidence of their infant being fully immunized.
We assumed a DPT-3/Hepatitis B immunization rate of 55% in the control group, and hypothesized a difference of 15% in the immunization rates between the intervention and control group. With 80% power and α = 0.05, we estimated a sample size of 163 in each arm. Adjusting for possible lost to follow-up, we enrolled 183 mother-infants pairs in each study group.
Statistical analysis was performed using SAS Version 9.2 (SAS Institute, Inc., Cary, NC). Baseline characteristics of study participants were compared using proportions. Unadjusted risk ratio (RR) and 95% confidence interval (CI) were estimated for the study outcome (DPT-3/Hepatitis B fully immunized) using bivariate Poisson regression [19,20]. A multivariable Poisson regression model was built to assess the association between the study outcome, the study group and all other variables which were considered to be significantly associated with the study outcome at the bivariate level (p ≤ 0.20). All variables, having bivariate association with the study outcome (p ≤ 0.20) were also tested for interaction. The final model was interpreted using adjusted RR and corresponding 95% CI. The number needed to treat (NNT) in order to increase the completion of DPT-3/Hepatitis B immunization by one child was also estimated [21,22].
A total of 1157 mother-infant pairs were identified from surveillance databases at the five community sites were approached, and assessed for eligibility. Among these, 479 (41.4%) did not meet inclusion criteria, whereas 312 (27%) declined participation in the study (Figure 1), resulting in 366 (183 in each study arm) children being available for randomization. Four infants were lost to follow-up from the intervention group, and five were lost to follow-up from the control group during the study period and were excluded from the analysis. Therefore, 179 enrolled infants were included in the analysis from the intervention group and 178 from the control group (Figure 1). The distribution of enrolled mother-infant pairs among the five study sites was weighted to represent population size in each area and was as follows: Community A = 103; Community B = 96; Community C = 71; Community D = 47; and Community E = 40.
Figure 1. Flow diagram of study participant screening, allocation and follow-up.
The distribution of baseline characteristics of the participants in the intervention and control arms is summarized in Table 1. No significant differences were observed between the two groups, although the proportion of mothers who had received no formal education was higher in the control group compared to those in the intervention group (75% vs. 66%). History of receipt of BCG vaccine and OPV (first dose) at birth was similar in both groups (76.4% in the control group vs. 77.1% in the intervention group). After the 4-month follow-up period, 129 (72.1%) infants in the intervention group had completed primary immunization with three doses of DPT and Hepatitis B vaccines compared to 92 (51.7%) in the control group. Therefore, DPT-3/Hepatitis B immunization rates in the intervention group were improved by 39% (unadjusted RR = 1.39; 95% CI: 1.07 - 1.82) (Table 2). Vaccination cards were retained by 81% of the study participants in the intervention group, and by 69.1% of the participants in the control group.
Table 1. Distribution of baseline characteristics of study participants
Table 2. Effect of home-based vaccine education to mothers on study outcome
In the multivariable model, the child's immunization status at enrollment was the only variable significantly associated with the study outcome (p < 0.05). Adjusting for this variable did not change the effect estimate (adjusted RR = 1.39; 95% CI: 1.06 - 1.81) (Table 2). Place of residence of the study participants (urban vs. semi-urban) was not associated with the study outcome (p = 0.08).
The number needed to treat (NNT) in order to increase the completion of DPT-3/Hepatitis B immunization by 1 child was also calculated. An estimated 5 mothers need to be educated in order to have one more child complete his/her DPT-3/Hepatitis B vaccinations.
We also assessed if our results were subject to misclassification bias due to the requirement of documentation of vaccine receipt through vaccination cards for the infant to be classified as fully immunized at outcome assessment, and those without vaccination card as not fully immunized. There were 10 cases (3 in the intervention group and 7 in the control group) that could have been misclassified as "DPT-3/Hepatitis B non-immunized" due to lack of a vaccination card, but whose mothers recalled receipt of all three doses. Including these 10 children in the "DPT-3/Hepatitis B fully immunized" group, 132 (73.7%) infants in the intervention group had completed primary immunization with three doses of DPT and Hepatitis B vaccine, compared to 99 (55.6%) in the control group. Therefore, DPT-3/Hepatitis B immunization rates in the intervention group were improved by 33% (unadjusted RR = 1.33; 95% CI: 1.02 - 1.72). In the multivariable model, the child's immunization status at enrollment was the only variable significantly associated with the study outcome (p < 0.05). After adjusting for it, DPT-3/Hepatitis B immunization rates in the intervention group were improved by 32% (adjusted RR = 1.32; 95% CI: 1.02 - 1.71).
This study demonstrates that providing vaccine-related targeted education to mothers at home is an effective and practical strategy to improve childhood immunization rates in low literacy settings such as ours. In this randomized controlled trial, a significant improvement in infant DPT-3/Hepatitis B vaccine immunization rates was observed in the group of mothers who received home-based education on the importance of vaccines, compared to those who received standard health promotion messages only.
In low-income countries, efforts to improve infant vaccination completion rates have focused primarily on supply and/or provider factors, with little focus on creating demand for infant immunization services. The major thrust of the supply-side interventions to improve vaccination rates has been through mass immunization campaigns. These campaigns have been successful in improving vaccine coverage rates . However, there are certain drawbacks of mass campaigns such as those done for polio vaccine in Pakistan and other developing countries [24-26]. They lead to a misconception on the parents' part that the child will be delivered all vaccines at home , and can result in a decline in the number of visits to the immunization centers, paradoxically driving down routine immunization coverage rates. Furthermore, these mass immunization campaigns have resulted in declining performance of routine EPI activities in Pakistan.
Educational interventions have been successful in raising awareness regarding vaccine and increasing demand. Jacobson et al were successful in increasing pneumococcal vaccine coverage rates among the elderly, by using low-literacy pamphlets encouraging study participants to "ask your doctor about the pneumonia shot". Kimura et al were able to increase influenza vaccine coverage among workers in long-term care facilities with the help of an educational campaign and provision of free vaccines. In Pakistan, Usman et al reported an increase of 31% in DPT3 completion among infants of mothers who received primary healthcare center-based education on their first immunization visit.
The success of educational interventions in modifying health-seeking behavior may also be attributed to the focused nature of the interventions. This is certainly true in our study. The intervention group received a 5-minute educational session, focusing on the importance of immunization for a child's health. The control group, on the other hand, received a 10-15 minute verbal session on general child health promotion. Therefore, the group receiving the focused message may have been more likely to understand and retain its content, and modify their behavior, compared to the control group who may have had "information overload".
We observed that maternal knowledge/perception regarding importance of vaccines was significantly associated with higher DPT-3/Hepatitis B immunization rates (RR = 2.11; 95% CI: 1.33 - 3.34). Our results are consistent with findings of other studies [4,9-11]. Surprisingly, infants living in rented houses (considered a crude proxy for lower socioeconomic status) were more likely to have received all 3 doses of DPT-3/Hepatitis B vaccines as compared to infants living in houses owned by their families (RR = 1.26; 95% CI: 0.93 - 1.71). However, this association is not significant. Another explanation could be that many of the households in these populations are considered illegal squatters but claim ownership of the land on which they've built their house. Therefore, paradoxically, households in rental accommodation could actually be socio-economically better-off.
It is worth noting that even with the educational intervention specific to vaccines, only 72% of infants were fully immunized in the intervention group. This is because our study included very low-income, low-literacy populations of Sindh province where baseline immunization rates are 48% , much lower than the national reported figure of 73% . The national average is a composite figure, including more prosperous and literate parts of the Pakistani population and the large province of Punjab which has a more functional EPI system and estimated vaccine coverage of 65% . National surveys may overestimate or over-report vaccine coverage rates . Different immunization centers use different vaccination cards, which differ in the design and method of recording proof of vaccination. This makes it difficult for data collectors to accurately determine an infant's immunization status. Furthermore, verbal reports, in lieu of vaccination cards, are often accepted as proof of immunization, but our experience using serological confirmation shows poor correlation between verbal recall and serological immunity . Therefore, the true vaccine coverage rate for Pakistani children may be closer to the figure of 59% estimated by the recent Demographic and Health Survey of Pakistan . Although ascertaining the reasons for low vaccine coverage was beyond the scope of this study, many barriers to improving immunization coverage remain in low-income communities and need to be systematically addressed.
Our study also has a few limitations. First, the third key message provided education on retaining vaccination cards. Therefore, mothers in the intervention group were 17% more likely to save the card and provide proof of vaccination for outcome assessment. However, as shown above, using the stringent proof-of-vaccination via card to determine outcome did not bias our results significantly if infants with maternal recall of vaccine receipt were also included as fully immunized. Including these infants as fully immunized, DPT-3/Hepatitis B immunization rates in the intervention group were still 18 percentage points higher than the control group.
A second limitation is the lack of blinding of CHWs and participants as the intervention was educational in nature. However, the investigator (BH) assessing the outcome four months after the intervention was administered was blinded to the exposure status of the study participants. Furthermore, chances of spillover effect, or contamination between the intervention and control arms were minimized by choosing mother-infant pairs from five different communities in Karachi, lowering the probability that households participating in our study with an eligible newborn would be located close to each other. We also observed a trend for mothers in the intervention group to be more educated compared to those in the control group (34% vs. 25%). However, this difference was not statistically significant and other measures of parental knowledge about vaccines did not favor the control group. Our study also had a high refusal rate (27%) which may have excluded participants less likely to accept vaccines from the trial. However, the most common stated reason for refusal was absence of the child's father when study staff visited the household for initial recruitment.
Our educational intervention has the potential to be cost-effective. The cost of the intervention per CHW was estimated to be Pakistan Rs. 80 ($1). This includes the cost of laminated colored pictorial cards used by the CHWs to educate the mothers in the intervention group, as well as pamphlets of the pictorial messages left at each participant's house. We also estimated the cost of scaling-up this intervention nationally, through the Lady Health Worker Program. Given that there are 100,000 lady health workers working all over Pakistan, we estimate that the cost of the national scale-up will be approximately $200,000 for the national program ($100,000 for the cards and pamphlets, and $100,000 for training sessions).
This study offers firm evidence that providing home-based focused education to mothers regarding the importance of vaccines, through pictorial messages using very simple language, is effective in improving infant immunization rates in low-income and low-literacy populations. Our trial intervention offers novel options to the current vaccine coverage enhancement efforts in low-income countries like Pakistan. Given the low "number needed to treat" to increase immunization completion by 20%, this intervention may prove to be quite cost-effective. The National Lady Health Worker Program is an ideal platform for building a more focused immunization promotion campaign, similar to what we designed, and drive up the demand for infant immunization services in Pakistan. However, the operational and logistical challenges involved in large-scale implementation of such an intervention need further evaluation.
EPI: Expanded Program on Immunization; BCG: Bacillus Calmette-Guérin; OPV: Oral Polio Vaccine; DPT: Diphtheria Pertussis Tetanus; CHW: Community health worker.
The authors declare that they have no competing interests.
AO provided the design and execution of the data analysis, as well as wrote the manuscript. BH contributed to manuscript writing and supervised field operations. ARS supervised manuscript preparation. AA supervised data analysis. AKMZ contributed to the design of the study, data analysis, and manuscript writing. All authors have read and approved the final manuscript.
A. Owais and B. Hanif were supported by a grant from the Fogarty International Center, National Institute of Health, USA (Grant number: ID43 TW0075 85-01).
Commun Dis Rep CDR Wkly 1993, 3:137. PubMed Abstract
UNICEF: The State of the World's Children Special Edition: Celebrating 20 Years of the Convention on the Rights of the Child. UNICEF; 2009. PubMed Abstract
Maekawa M, Douangmala S, Sakisaka K, Takahashi K, Phathammavong O, Xeuatvongsa A, Kuroiwa C: Factors affecting routine immunization coverage among children aged 12-59 months in Lao PDR after regional polio eradication in western Pacific region.
P N G Med J 1992, 35:179-185. PubMed Abstract
World Health Forum 1988, 9:336-340. PubMed Abstract
East Afr Med J 2009, 86:323-329. PubMed Abstract
Kimura AC, Nguyen CN, Higa JI, Hurwitz EL, Vugia DJ: The effectiveness of vaccine day and educational interventions on influenza vaccine coverage among health care workers at long-term care facilities.
S Afr Med J 2001, 91:249-254. PubMed Abstract
Zaidi AKM, Khan TA, Akram DS: Early Childhood Health and Survival in Pakistan: A Situation Analysis of Programs and Recommendations. In Maternal and Child Health in Paksitan: Challenges and Opportunities. Edited by Bhutta ZA. Karachi: Oxford University Press; 2004:47-83.
Lim SS, Stein DB, Charrow A, Murray CJ: Tracking progress towards universal childhood immunisation and the impact of global initiatives: a systematic analysis of three-dose diphtheria, tetanus, and pertussis immunisation coverage.
The pre-publication history for this paper can be accessed here: |
<urn:uuid:2afb9877-0bb9-4dfc-83fe-c4797ab0e844> | seed | Imagine going to your doctor with a crippling condition that simply won't improve only to be ignored, called a faker, or written off as “delusional.” It happens more than you may think. People stricken with the mysterious and controversial Morgellons disease often have to deal with such distressing attitudes despite the fact that there are reports of the condition in every state and in 15 countries worldwide.What is Morgellons disease?
Morgellons is a condition with unexplained dermopathy (disease of the skin) and manifests with a range of skin symptoms that are debilitating and frightening. People suffering with Morgellons experience the following symptoms:
- Sores or rashes on the skin accompanied by intense itching
- The feeling of crawling sensations underneath or on the skin described as insects moving, biting, or stinging.
- Black or white stringy threads or fibers on or in the skin.
- Debilitating fatigue
- Joint pain
- Mental fogginess or short-term memory loss
- Vision changes
Those affected with Morgellons describe the condition as maddening. The open skin lesions heal very slowly and in the meantime may ooze out blue, black, red, or white threads or fibers that can be as thick as spaghetti strands. Trying to remove the fibers cause shooting pains that radiate from the sore.The Morgellons controversy.
Other than anecdotal reports, experts really don’t know much more about Morgellons. Some health professionals believe that it is a specific condition and future research will confirm it. Others hold to the idea that the signs and symptoms of Morgellons are actually symptoms of a mental illness
. Others still refuse to acknowledge it until more research reveals more about the condition. All agree that diagnosing what is actually going on is a difficult task.
One reason the diagnosis is often difficult is because Morgellons shares many characteristics with other diseases such as liver and kidney disease, Lyme disease
, alcohol abuse, or a mental illness such as schizophrenia
. Some medical professionals believe Morgellons is actually delusional parasitosis - a type of mental illness whereby one imagines his or her body is infested with parasites.
So what is the answer?
Since the symptoms of Morgellons are diverse and complex, in 2006 the CDC undertook a thorough and ongoing investigation along with Kaiser Permanente's Northern California Division of Research. The primary goals are to learn more about who may be affected with the condition, the symptoms, and what factors may contribute to it. During the investigation scientists will attempt to finally determine the clinical and epidemiological features of Morgellons, examine skin biopsies for affected patients, identify the fibers or threads from those affected, and finally estimate rates of illness among the population.
The validity of Morgellons disease has yet to be resolved. Whether it is a real disease with a biological basis or another name for delusional parasitosis, until the results are in Morgellons will remain a mystery. |
<urn:uuid:26f47765-c3db-4de9-bc7a-be45706fa698> | seed | THIS CLINICAL TRIAL1 compared the effectiveness of weekly vs daily administration of iron plus folic acid for the treatment of anemia in adolescent Nepalese girls, a population with an extremely high prevalence of anemia. The study was conducted in a single government-run school in Dharan, an urban foothill town in Nepal. Girls from the 8th to 12th grades aged 11 to 18 years were enrolled. Baseline characteristics measured included sociodemographic variables, diet (vegetarian vs nonvegetarian), history of parasites, menarcheal status, anthropometrics, and presence of specific physical abnormalities. The baseline prevalence of anemia in this population was 69%. Subjects were randomized to 1 of 3 groups: group A (n = 70) received supplementation with tablets containing 350 mg of ferrous sulfate and 1.5 mg of folic acid once a day for 90 to 100 days; group B (n = 67) received the same combination on a fixed day once a week for 14 weeks, supervised by 1 of the investigators; and group C (n = 72) received no treatment during the study period. Of the 225 girls enrolled, 209 met inclusion criteria, and 181 completed the trial. The primary outcomes included prevalence of anemia (defined as hematocrit <36%), mean hematocrit, and net change in hematocrit for each group from baseline to 15 days after completion of therapy. The prevalence of anemia declined from 68.6% and 70.1% in groups A and B to 20.0% and 13.4%, respectively (P<.001). In group C, the control group, the prevalence went from 68.1% to 65.3% (P = .81). Mean hematocrit and net changes in mean hematocrit also increased significantly in both treatment groups compared with the control group. Increases in all outcomes between the daily and weekly observed treatment regimens were statistically equivalent.
We evaluated this study using standards of design, analysis, and results for therapeutic trials described in the "Users' Guide" series published in the Journal of the American Medical Association.2,3 The focus is on the quality of the study, the validity of its results, and the generalizability of the outcomes.
The study was a randomized controlled trial. All students in grades 8 through 12 were initially enrolled, and 209 who met eligibility criteria were randomized. Though the authors state that subjects were randomly assigned to 1 of 3 groups, they do not state which method of randomization was used (eg, random number table). The resulting 3 study groups were roughly equivalent in size, and Table 1 from the study indicates that the demographic characteristics of the 3 groups were similar. These results suggest that, whichever randomization process was used, it was successful in creating 3 equivalent study groups. In the "Results" section, the authors state that all 3 groups were "matched" for age, anthropometrics, and personal and sociodemographic characteristics but do not state whether this was intentional matching in the formal epidemiological sense (ie, in order to control for bias in those factors involved in the match). Rather, it seems more likely that the groups were found to be matched on analysis, which is demonstrated by the fact that the 3 groups were statistically similar with regard to baseline characteristics (Table 1).
The authors account for all of the subjects in the study. Their text and figure clearly explain the reasons for the differences between the number originally registered (225) and the number eventually randomized (209). They state that 10 subjects met defined medical exclusion criteria and 6 refused participation. Of those randomized, 181 (87%) completed the trial, and reasons for loss of subjects are explicitly described (ie, severe adverse effects, noncompliance to treatment, and nonavailability for final hematocrit measurement). The authors indicate that they performed an "intention-to-treat" analysis. Intention-to-treat is the appropriate method of analysis to use for a randomized controlled trial because it presents the effect seen due to the treatment assigned, regardless of patient compliance or availability for follow-up.3
Ideally, therapeutic trials are double-blind. In this study, subjects were blind to whether they were anemic but not to their treatment assignment. Blinding subjects to their treatment assignment could have been accomplished if subjects in group B had taken placebo pills on the days they were not receiving their once-weekly combination of iron and folic acid and if subjects in group C had taken placebo pills every day. The authors state that incidence "of adverse effects [italics ours] could have been better analyzed if we had administered placebos to our control group" but do not address potential biases introduced by not blinding subjects to their treatment assignments. It is possible that subjects may have crossed over from one treatment group to another. For instance, because subjects in group A were not as explicitly supervised as those in group B, they may have been less conscientious about taking their medication daily, knowing that their friends were only taking their medication weekly. If daily administration of iron is more effective than weekly but many of the subjects in group A actually did not take iron daily, it may have biased the results against showing a difference.
The second component of double-blinding keeps the investigators from knowing subjects' treatment assignments. Investigators were not blinded to treatment assignments in this study. However, it is unlikely that this significantly affected the results because the outcomes measured were relatively objective (ie, hematocrit values and a clear definition of anemia: hematocrit <36%).
Table 1 indicates that groups A, B, and C were similar with respect to demographics, anthropometrics, menstrual history, past medical history, a variety of sociodemographic characteristics, and specific physical examination findings (ie, pallor, xeropthalmia, and goiter). Most importantly, the prevalence of anemia is similar among groups. The fact that these groups are similar, with respect to known prognostic factors, lends strength to the validity of the study results. Notably absent from baseline measures are indicators of iron deficiency (eg, microcytosis, serum ferritin, and free erythrocyte protoporphyrin). The authors comment that in a population with such a high prevalence of anemia, it can be assumed that iron deficiency anemia is the root cause. However, if iron deficiency was not evenly distributed among the 3 groups, it may have confounded the study results.
The major difference in treatment among groups was in documentation of compliance, though this was intentional. Direct observation of weekly therapy in group B assured compliance, whereas the compliance of group A with the daily regimen is unknown. If treatment were similarly observed in both groups and this lead to improved compliance in group A, it is possible that hematocrit levels in group A may have improved more than in group B.
Other possible differences in treatment among groups are not discussed. The use of additional vitamins or medications may have differed among the 3 groups. Additionally, the experience of the groups during the 15-day period after the trial prior to follow-up hematocrit evaluation may have differed. In both these situations, it is likely that any differences were offset through randomization, thus minimizing the possibility of bias.
The study found a dramatic decrease in the prevalence of anemia with the use of daily or weekly iron plus folic acid. All 3 groups had very similar rates of anemia at baseline (68%-70%). At follow-up, the control group had a similar anemia prevalence of 65.3%, whereas the intervention groups had rates of 20.0% and 13.4%, respectively. This equates to an absolute risk reduction of 45.3% for group A and 51.9% for group B. The number needed to treat for group A (daily supplementation) is 2.2. This means that for every 2 to 3 patients in group A treated for anemia, 1 will no longer be anemic. For group B (weekly supplementation) the number needed to treat is 1.92. For every 2 patients in group B treated for anemia, 1 will no longer be anemic.
Although the treatment effect of both regimens was impressive, the authors' aim was to see whether supervised weekly iron and folic acid supplementation was as effective as daily supplementation. The ability of a study to demonstrate that 2 treatments are equivalent is based on its power. The authors do not discuss sample size calculations. They do not state a priori what magnitude of difference in effect size between daily and weekly regimens would be clinically important to detect. With sample sizes of 70 in group A and 67 in group B, this study has a 90% probability of detecting a difference of 25% or more. Thus, in this study there is a chance of a type II error (ie, failure to reject the null hypotheses that the 2 regimens are equally effective when they actually are not). If public health officials feel that a difference in treatment effect of less than 25% might be important, then this study lacks adequate power.
As mentioned previously, 2 of the difficulties with this study are the assumption that most patients with anemia had iron deficiency anemia and that ferrous sulfate and folic acid were supplied simultaneously. Because additional tests were not performed to confirm that the anemia was caused by iron deficiency, we cannot be certain that the reduction in anemia is directly due to the treatment introduced. Specifically, we do not know whether iron or folic acid supplementation is the primary reason for a reduction in the prevalence of anemia.
Precision is usually expressed using confidence intervals. This study did not report confidence intervals for the binomial results of presence or absence of anemia posttreatment. The reduction in anemia in the 2 intervention groups was pronounced, and the P values were less than .001. This implies that there is a 99.9% confidence that these results were not due to chance alone.
There are 2 issues of generalizability to consider in interpreting this study. The first is the appropriateness of applying the findings to other populations of adolescent girls in developing countries with high rates of anemia. It is important to recognize that this study was conducted in a single government school in a small foothill town in Nepal. Whether the findings would be similar in larger samples of girls, in other regions of Nepal or other developing countries, and in non–school-based populations cannot be determined.
The application of the results of this study to adolescents in developed countries such as the United States is even more problematic. This population had a very high prevalence of anemia, as well as underlying medical conditions not commonly seen in the United States (eg, other nutritional deficiencies, parasitic infections, and goiter). The prevalence of iron deficiency in US adolescent girls is 9% to 11%, and the prevalence of iron deficiency anemia is 2% to 5%.4 Thus, the effect size that could be expected from empirical treatment of school-based populations of adolescent girls in this country with iron and folic acid would be far smaller.
It is difficult to apply these results to individual patients in the United States. In addition to the differences in anemia prevalence and nutritional health, there is only limited evidence that early treatment of anemia in the adolescent US population can reduce morbidity. Trials from developing countries have reported conflicting results as to the benefit of iron supplementation on work productivity, psychomotor function tests, subjective well-being, and other outcomes. In addition, none of these studies have examined the benefits of treating mild cases of anemia, which were common in this current study.5
Iron supplementation is relatively inexpensive, and it may improve some clinical outcomes. The adverse effects of iron therapy include gastrointestinal symptoms, iron overload in patients with an underlying iron storage disorder, and the potential for an intentional or unintentional overdose, which can be fatal. Currently, the US Preventive Services Task Force states that "There is insufficient evidence to recommend for or against routine testing for anemia in . . . asymptomatic persons, but recommendations against such screening may be made on the grounds of low prevalence, cost, and potential adverse effects."5 Routine screening of nonpregnant adolescents is not advocated by most organizations. Some organizations recommend screening for high-risk populations, such as adolescents with increased risk from heavy menses, weight loss, or nutritional deficits. The American Academy of Pediatrics currently recommends that hemoglobin or hematocrit be measured at least once for all menstruating adolescents, preferably at age 15 years.6
This study is a well-conducted clinical trial. It addresses a prevalent health problem in developing countries, and it demonstrates the effectiveness of an alternative treatment approach to anemia that may be advantageous in certain populations. The greatest limitation of this study is the relatively unique population that is employs. Nevertheless, public health officials interested in the treatment of anemia can potentially use this study to justify similar approaches in larger, more diverse populations.
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<urn:uuid:aa313d35-9a75-4b07-965f-545503e1a09b> | seed | Doctors can minimise the risks of taking epilepsy drugs by women who are considering pregnancy, claims a major international study published today in The Lancet Neurology.
An 11-year study gathering results from 33 countries has shown that taking four of the most commonly prescribed seizure-control drugs at the beginning of pregnancy is associated with a dose-dependent increased risk of major birth defects.
The findings claim to be the first to provide a multivariable analysis of the risks associated with individual drugs and their doses, so will help doctors identify the safest effective treatment for women with epilepsy who wish to become pregnant.
Between 0.3% and 0.7% of all pregnancies are in women with epilepsy and most of these women need to use antiepileptic drugs during pregnancy because uncontrolled seizures can harm the mother and fetus.
Previous research has suggested epilepsy drugs (particularly valproic acid) can increase the risk of birth defects, but until now, studies have not adequately compared the risks associated with different doses or assessed the influence of potential confounders such as a family history of birth defects or severity of epilepsy.
Researchers led by the Karolinska Institute in Sweden and the University of Pavia in Italy investigated the association between the use of carbamazepine, lamotrigine, valproic acid (valproate), and phenobarbital at different doses and the risk of major birth defects detected up to the end of the first year after birth.
They studied 3,909 pregnant women using data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP).
A total of 230 pregnancies associated with major birth defects were identified by the end of the first year after birth such as heart defects and spina bifida.
Analysis showed there was a growing rate of birth defects associated with increasing dose for all drugs.
The rate was lowest for low doses of the drugs lamotrigine (less than 300 mg per day) and carbamazepine (less than 400 mg per day).
The highest doses of valproic acid (1,500 mg per day or greater) and phenobarbital (150 mg per day or day or greater) posed the highest risk to the fetus, with particularly high rates of birth defects recorded in pregnancies exposed to valproic acid 1,500 mg per day or greater.
The authors said: “Our results show that dose selection is as crucial as the choice of drug…[and] gives the prescriber the possibility of assessing how teratogenic [ability to cause birth defects] risks at that dose compare with the risk associated with alternative treatments at various doses.”
They added a caution over the results, saying: “It should be emphasised, however, that, irrespective of which of the four investigated drugs was prescribed, the vast majority of women gave birth to perfectly healthy children.”
In an accompanying comment, Professor W Allen Hauser from Columbia University, New York, USA said: “The findings are important to the clinician treating people with epilepsy because they provide specific information not only on the drug but also on the dose.
“The data provide another reason for use of the lowest dose of a drug associated with optimum seizure control.” |
<urn:uuid:0cdb24e6-8ea7-49fe-95ae-dd483b94fab9> | seed | PEDIATRIC EAR INFECTIONS
Acute otitis media (AOM), commonly known as an ear infection, is the most common bacterial infection of pediatric patients. It is estimated that nearly 85% of children have at least one episode of AOM before their first birthday. However, most children “outgrow” these infections by age three or four.
To understand why most children stop having AOM, one needs to know about the Eustachian tube. The Eustachian tube is a narrow channel that connects the middle ear space to the back of the nose, just behind the soft palate. It functions to maintain an appropriate amount of pressure within the middle air space. In young children, the tube is prone to dysfunction because of two main reasons.
First, the Eustachian tube is very small and narrow, especially in younger children, and is very prone to becoming blocked. The most common reason for the blockage is adjacent tissue swelling from allergies or viral respiratory infections. This causes negative pressure within the middle ear space, and allows fluid to develop. This fluid is a good median for bacteria to invade and grow, causing AOM.
Secondly, the Eustachian tube sits in a horizontal plane in small children. As the child grows, the tube changes to sit in a more vertical position, which prevents bacteria from the nose and throat from reaching the middle ear space. Therefore, by being in a more horizontal plane, the younger child is more prone to AOM.
While infections are the mainstay of Eustachian tube dysfunction, there are some patients that develop middle ear fluid but do not develop infection. This is known as otitis media with effusion. If this recurs or persists for over 3 months, then this is called chronic serous otitis media (CSOM).
Symptoms of AOM are classic for an “earache”: fever, irritability, pulling on the ear, decreased appetite, and purulent drainage (possible if the ear drum ruptures). These episodes often coincide with an upper respiratory infection. Symptoms of CSOM are often difficult to notice if they are not accompanied by infections. However, these patient typically have a mild to moderate hearing loss, which can be manifested by speech and language delay. Both conditions, AOM and CSOM, can easily be diagnosed by a physician evaluating the patient with an otoscope.
Other important testing that should be performed during an evaluation for recurrent AOM or CSOM is a hearing test. The most commonly-used tests include a tympanogram, audiogram, or otoacoustic emission testing.
Treatment options for an episode of AOM include oral antibiotics, as well as ototopical antibiotic (ear drops) if there is concern of ear drum rupture. If the problem becomes recurrent or chronic, then surgical treatment is necessary.
The mainstay of therapy for recurrent AOM and CSOM is myringotomy and ear tube placement. Indications include 3 episodes of AOM in 6 months or 4 episodes in 12 months, or CSOM with hearing loss based on testing. The ear tube is placed using general mask anesthesia (no breathing tube or IV medicines are used) in an operating room. The procedure is done in approximately 10 minutes on an outpatient basis. Tubes are effective in 98% of children at reducing AOM and CSOM. In general, ear tubes typically fall out on their own between 6 and 12 months.
There are very few complications of ear tube placement. The most common is purulent drainage from the tube by infection. This is treated with antibiotic ear drops, and sometimes oral antibiotics. This complication is reduced by keeping the ears dry as possible while the tubes are present. Many children wear ear plugs, which can be purchased at a pharmacy, during bathing and swimming. Very rarely, this becomes a recurrent problem and the tube needs removed as bacteria have become adherent to the ear tube.
Another possible complication, which occurs in 1 to 2 percent, is a residual hole in the ear drum that may need repaired surgically. This is why it is important to have follow-up evaluations by the otolaryngologist.
Once the tube falls out, will my child need another set or ear tubes placed? In general, approximately 20 percent of children will need another set of ear tubes placed due to recurrent AOM or the redevelopment of CSOM.
Although earaches (AOM) are very common in young children, most resolve with antibiotics. However, if it does become a recurrent or chronic problem, then ear tube placement is a very successful treatment option. Any questions or concerns can be further discussed with your local ENT physician.
Dr. Robert Wilson, ENT
Hours of Operation
Monday to Friday
8:30 a.m. to 5:00 p.m.
Phone Number: (270) 769-5551 |
<urn:uuid:f539ab4c-af1d-4ec7-ae7d-6e4402dfeb53> | seed | Older men whose melanoma is detected by a physician are more likely to have thinner and therefore more treatable tumors at diagnosis, according to results of a new survey. A second analysis of the same survey data finds that physician detection of thin melanoma is more common in those who are 65 or older, have cancers on their backs or who have a history of atypical moles.
Melanoma is becoming more common and mortality rates from melanoma are steadily increasing among older men, according to background information in one of the articles. Tumor thickness at diagnosis strongly predicts the management and outcomes of melanoma, and the thickest tumors (4 millimeters or thicker) are increasingly common in white men age 60 and older. "Rigorous assessment of behavioral, social and medical access factors that differ between men 40 years or older with thinner vs. thicker melanomas may identify potential modifiable variables," the authors write. "A clearer understanding of these factors provides fundamental knowledge for additional studies and public health messages aimed at earlier melanoma detection in this high-risk subset of men."
In one study, Susan M. Swetter, M.D., of Stanford University Medical Center, Calif., and colleagues surveyed 227 men age 40 and older between 2004 and 2006, within three months of their melanoma diagnosis. The men responded to questions about their previous melanoma awareness, skin examination practices, how their cancer was discovered and social and medical care factors.
Of the 227 men, 57 (25.1 percent) had tumors thicker than 2 millimeters. These men were more likely to have less than a high school education, less likely to have a history of atypical nevi (moles) and their melanomas were more often discovered by the patient themselves or a friend or family member than by a physician. Men with thinner melanomas were more likely to have previous knowledge of melanoma, have paid attention to skin cancer detection information, be interested in health topics and be aware of the importance of physician skin examination. Tumor thickness was not associated with patients' age, whether or not they were married or lived with a partner, skin cancer history, sun sensitivity or the anatomic location of the cancer.
Overall, few patients were aware of melanoma warning signs (less than 20 percent), practiced skin self-examination (less than 50 percent) or used the Internet (less than 14 percent) as a source of skin cancer information.
"For men 40 years or older, who constitute more than half of all melanoma deaths in the United States, we have identified at least two key variables (physician skin examination and improved public awareness, particularly for patients in lower socioeconomic groups) as major targets for new interventions to promote earlier melanoma detection," the authors write. "Public education, in particular targeting less-educated, middle-aged and older men for improved self-examination and physician skin surveillance, should become an integral component of skin cancer risk reduction strategies promoted by cancer advocacy organizations."
In another study, Alan C. Geller, M.P.H., R.N., of Boston University, and colleagues report a separate analysis of the same survey data. Patients whose melanomas were detected by a physician tended to be older—57 percent were 65 years or older, compared with 42 percent of patients who detected cancer themselves and 34 percent whose cancer was detected by another non-physician. This may be because older patients visit their physicians more frequently, providing more opportunities for skin examination, and they may rely more heavily on physician skin evaluation because they tend to have poorer eyesight and are less likely to have a partner.
Forty-six percent of physician-detected melanomas, 16 percent of self-detected melanomas and 57 percent of melanomas detected by other means were on the patient's back; these back-of-the-body melanomas were smaller than 2 millimeters in 92 percent of physician-detected cases, 63 percent of self-detected cases and 76 percent of those detected by other means.
"Skin screenings of at-risk middle-aged and older American men can be integrated into the routine physical examination, with particular emphasis on hard-to-see areas, such as the back of the body," the authors conclude. "'Watch your back' professional education campaigns should be promoted by skin cancer advocacy organizations and should incorporate the importance of physician screening and the benefit of spouse or partner assistance for early detection of melanoma, particularly in the high-risk population of middle-aged and older men."
Editorial: Physicians Must Help Men Overcome Barriers to Care
"A growing body of sex-specific studies shows a trend among men, especially white middle-class men, of delaying seeking help when they become ill," writes June K. Robinson, M.D., of Northwestern University Feinberg School of Medicine, Chicago, and editor of Archives of Dermatology, and colleagues in an accompanying editorial. "By delaying seeking care, men present at a later stage of melanoma when it is no longer treatable."
"The tasks associated with seeking help from physicians, such as relying on others, admitting a need for help or appearing vulnerable, may be in conflict with some individuals' societal and normative beliefs that men are self-reliant, physically tough, invincible and in control of their destiny. For example, some men may be thought of as the 'strong, silent type'; thus, they are reluctant to make a fuss over a little mole or to admit their fear that something could be wrong, even to themselves."
"This latter issue leads to the question of how physicians can interact with their patients in a manner that overcomes some of these interpersonal and psychological barriers to improve treatment outcomes," the authors write. Building strong, trusting physician-patient relationships, using appropriate patient education materials, asking patients about their concerns and demonstrating empathy may improve the care of all patients with melanoma.
This study was supported in part by a National Cancer Institute grant to Dr. Robinson.
- Swetter et al. Melanoma in Middle-aged and Older Men: A Multi-institutional Survey Study of Factors Related to Tumor Thickness. Archives of Dermatology, 2009; 145 (4): 397 DOI: 10.1001/archdermatol.2008.603
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13 Respiratory disease
The lungs, with their combined surface area of greater than 500 m2, are directly open to the external environment. Thus structural, functional or microbiological changes within the lungs can be closely related to epidemiological, environmental, occupational, personal and social factors. Primary respiratory diseases are responsible for a major burden of morbidity and untimely deaths, and the lungs are often affected in multisystem diseases.
Respiratory symptoms are the most common cause of presentation to the family practitioner. Asthma occurs in more than 10% of British children; bronchial carcinoma is the most common fatal malignancy in the developed world; the lung is the major site of opportunistic infection in those immunocompromised by the acquired immunodeficiency syndrome (AIDS) or by anti-allograft and anticancer chemotherapeutic regimens; and the spectre of tuberculosis, particularly the emergence of multiple drug-resistant strains, is back with us.
A number of important research advances have occurred in recent years. The discovery of the genetic mechanism of cystic fibrosis provides a novel opportunity to develop gene therapy strategies to replace the defective gene. The lung is especially favoured for gene therapy since its airway epithelial cells are accessible to nebulised particles and the extensive microvascular pulmonary capillary endothelium is available to intravenously delivered agents. Finally, recent advances in our understanding of the cellular and molecular mechanisms underlying diseases such as asthma and the acute (formerly adult) respiratory distress syndrome (ARDS) are likely to lead to rational, mechanism-based therapy within the foreseeable future.
pages 483 - 486
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
APPLIED ANATOMY AND PHYSIOLOGY
Figure 13.1 The major bronchial divisions and the fissures, lobes and segments of the lungs. The position of the oblique fissure is such that the left upper lobe is largely anterior to the lower lobe. On the right side the transverse fissure separates the upper from the anteriorly placed middle lobe which is matched by the lingular segment on the left side. The site of the lobe determines whether physical signs are mainly anterior or posterior. Each lobe is composed of two or more bronchopulmonary segments, i.e. the lung tissue supplied by the main branches of each lobar bronchus. BRONCHOPULMONARY SEGMENTS: Right-Upper lobe (1) Anterior (2) Posterior (3) Apical. Middle lobe (1) Lateral (2) Medial. Lower lobe (1) Apical (2) Posterior basal (3) Lateral basal (4) Anterior basal (5) Medial basal. Left-Upper lobe (1) Anterior (2) Apical (3) Posterior (4) Lingular. Lower lobe (1) Apical (2) Posterior basal (3) Lateral basal (4) Anterior basal.
Figure 13.2 The acinus-the basic gas exchange unit of the lung.
The upper respiratory tract includes the nose, nasopharynx and larynx. It is lined by vascular mucous membranes with ciliated epithelium on their surfaces. The lower respiratory tract includes the trachea and bronchi. These form an interconnecting tree of conducting airways eventually joining, via around 64 000 terminal bronchioles, with the alveoli to form the acini. The lower respiratory tract is lined with ciliated epithelium as far as the terminal bronchioles. The larynx and large bronchi are supplied with sensory nerve receptors involved in the cough reflex.
Some knowledge of the patterns of branching of the lobar and segmental bronchi is necessary for interpreting investigations, including chest radiographs and CT scans. Major bronchial and pulmonary divisions are shown in Figure 13.1. (See also bronchoscopic appearances in Fig. 13.8, p. 492.)
The acinus is the gas exchange unit of the lung (see Fig. 13.2) and comprises branching respiratory bronchioles leading to clusters of alveoli. The alveoli are lined mostly with flattened epithelial cells (type I pneumocytes), but there are some, more cuboidal, type II pneumocytes. The latter produce surfactant, a mixture of phospholipids, which acts to reduce surface tension and counteract the tendency of alveoli to collapse. Type II pneumocytes also display a remarkable capacity to divide and reconstitute the type I pneumocytes after lung injury.
The right ventricle pumps blood against the relatively low pulmonary vascular resistance. Blood flows through a rich capillary network, intimately adjacent to alveoli (see Fig. 13.2), facilitating gas exchange. Increased pulmonary vascular resistance-due, for example, to thromboembolism (see p. 562) or to destructive changes caused by chronic obstructive pulmonary disease (COPD, see p. 508)-results in right ventricular hypertrophy, and eventually right heart failure (cor pulmonale) ensues.
GAS EXCHANGE, VENTILATION, BLOOD FLOW AND DIFFUSION
Gas exchange in the lungs is suboptimal unless there is sufficient ventilation, distributed uniformly to different parts of the lungs and matched by uniform distribution of blood flow. Furthermore, abnormal diffusion of oxygen or carbon dioxide across the alveolar-capillary membrane impairs gas exchange.
In clinical practice the important consequences of impaired gas exchange are hypoxaemia and hypercapnia.
Hypercapnia (PaCO2 > 6 kPa) is generally caused by conditions resulting in alveolar hypoventilation or ventilation-perfusion mismatch (see Box 13.1). Hypoventilation may be caused by depression of the respiratory centre in the medulla; in contrast, stimulation of the respiratory centre causes hypocapnia and respiratory alkalosis (see Box 13.2). Ventilation-perfusion mismatch is thought to be largely responsible for the hypercapnia of COPD and severe asthma.
13.1 COMMON CAUSES OF HYPERCAPNIA (RAISED PaCO2)
Central sleep apnoea
Chronic obstructive airways disease (COPD)
13.2 SOME INFLUENCES ON THE RESPIRATORY CENTRE
Upper brain-stem lesions Central neurogenic hyperventilation
Input from receptors Pain; muscles and joints; pulmonary afferents
Increased PaCO2 Via central and peripheral chemoreceptors
Increased arterial [H+] Via peripheral chemoreceptors
Decreased PaO2 (< 8 kPa at rest) Via peripheral chemoreceptors
Sedative drugs Opiates, benzodiazepines
13.3 COMMON CAUSES OF HYPOXAEMIA
Ventilation-perfusion mismatch (poorly ventilated lung)
Alveolar underventilation (raised PaCO2)
Impairment of diffusion (less important at rest)
Right-to-left shunts (circulatory channels bypassing lungs)
Reduced oxygen-carrying capacity of blood (PaO2 may be normal) (anaemia; inactivated haemoglobin)
Corrected by oxygen
Causes of hypoxaemia are shown in Box 13.3. Blood flow wasted on perfusing poorly ventilated lung is probably the most important of these and contributes to the hypoxaemia found, for example, in bronchial obstruction (due to secretions, mucosal oedema, bronchoconstriction or tumours), destruction of elastic tissue (e.g. emphysema), pulmonary collapse, consolidation, fibrosis or oedema, and chest wall deformities. In conditions where the area of alveolar-capillary interface available for gas exchange is reduced (e.g. emphysema), impaired diffusion may contribute to hypoxaemia. This effect may not be significant at rest, but may limit the amount of oxygen which can be taken up during exercise.
Hypoxaemia due to ventilation-perfusion mismatch, hypoventilation or diffusion impairment is reversed by giving oxygen. In right-to-left shunts-as, for example, in congenital heart diseases and pulmonary vascular anomalies-blood does not pass through alveolar capillaries and therefore oxygen does not fully correct the hypoxaemia. Hypoxaemia also occurs if the oxygen-carrying capacity of the blood is reduced-as, for example, in anaemia or carbon monoxide poisoning.
The normal arterial PaO2 is over 12 kPa at the age of 20 and falls to around 11 kPa at 60. Above this age a further fall in PaO2 of up to 1.3 kPa may occur on lying down because of closure of small airways in the dependent regions of the lungs.
Under physiological conditions hypoxaemia and hypercapnia both stimulate ventilation. In some patients with COPD, tolerance to chronic hypercapnia ensues, and in such patients administration of high concentrations of oxygen removes the remaining hypoxaemic stimulus for ventilation, resulting in worsening hypercapnia. Patients with COPD who have chronic hypercapnia should therefore receive, if required, low concentrations of oxygen (e.g. 24-28%), adjusted according to arterial blood gas analysis (see p. 512). Patients with pure asthma do not have chronic hypercapnia and it is therefore safe, and indeed important, to give high concentrations of oxygen during exacerbations of asthma (see p. 520).
Integration link: Oxyhemoglobin dissociation curve
Taken from Physiology 5e
Integration link: Emphysema - pathology
Taken from General & Systematic Pathology 4e
Each day our lungs are directly exposed to more than 7000 litres of air which contain varying amounts of inorganic and organic particles as well as potentially lethal bacteria and viruses. In general terms, physical mechanisms including cough are particularly important in defence of the upper airways, whereas the lower airways are protected by complex mucociliary mechanisms, by the antimicrobial properties of surfactant and the lung-lining fluids, and by resident alveolar macrophages.
Most large particles are removed from inspired air by the nose, which is composed of a 'stack' of fine aerodynamic filters comprising fine hairs and columnar ciliated epithelium which cover the turbinate bones. The larynx acts as a sphincter during cough and expectoration and is an essential mechanism protecting the lower airways during swallowing and vomiting.
Figure 13.3 The mucociliary escalator. Scanning electron micrograph of the respiratory epithelium showing large numbers of cilia (C) overlaid by the mucus 'raft' (M).
13.4 PROTECTIVE AGENTS IN THE LUNG-LINING FLUID
Surfactant proteins-bacterial opsonisation
Immunoglobulins (IgA, IgG, IgM)-bacterial opsonisation, generation of the immune response
Complement-bacterial opsonisation, generation of the inflammatory response
Bactericidal proteins-bacterial killing
Proteinase inhibitors-protection of host tissues during the inflammatory response
Particles with a diameter greater than 0.5µm that survive passage through the nose will be trapped by the lining fluid of the trachea and bronchi and cleared by the 'mucociliary escalator' (see Fig. 13.3). This highly effective small particle clearance mechanism works by a complex interaction between cilia, which are a series of small projections on the surface of respiratory epithelial cells, and mucus, which forms a 'raft' on top of the cilia. Particles are trapped by the mucus which is then swept by the cilia in a cephalic direction. Other important functions of mucus include dilution of noxious substances, lubrication of the airways, and humidification of inspired air. Mucus is mostly secreted by goblet cells within the respiratory epithelium and is composed of the mucus glycoproteins and a variety of other proteins (see Box 13.4) which, although present in low concentrations, play an important role in the defence of the bronchial tree. A number of factors reduce mucociliary clearance by interfering with ciliary function or by causing actual ciliary damage. These include pollutants, cigarette smoke, local and general anaesthetic agents, bacterial products and viral infection. There is also a rare autosomal recessive condition (1 in 30 000 live births) called primary ciliary dyskinesia, which is characterised by repeated sinusitis and respiratory tract infections which progress to persistent lung suppuration and bronchiectasis, thus reinforcing the importance of ciliary clearance in antibacterial lung defences.
Surfactant and other defensive proteins
In addition to its surface active properties which are so important in lung mechanics, surfactant contains a number of proteins, including surfactant protein A, which can opsonise bacteria and other particles, rendering them susceptible to phagocytosis by macrophages. Lung-lining fluids also contain other defensive proteins (see Box 13.4) including immunoglobulins, complement, defensins (powerful antibacterial peptides) and a variety of antiproteinases (including a1-antitrypsin) which play an important role in protecting healthy tissues from damage which would be incurred by the release of proteinases from inflammatory cells during the inflammatory response.
Figure 13.4 Alveolar macrophages. Scanning electron micrograph showing alveolar macrophages (arrow) patrolling the alveolar spaces of the lung.
These multipotent cells normally patrol the interior of the alveoli (see Fig. 13.4), where they display a formidable array of mechanisms by which they recognise and destroy bacteria and other foreign particles. The remarkably versatile resident macrophage can also 'call in reinforcements' by generating mediators which cause an inflammatory response and attract granulocytes and monocytes. It may also generate an immune response by presenting antigens and by releasing specific lymphokines. Finally, the alveolar macrophage exerts important scavenging functions in the clearance of dead bacteria and other cells during the aftermath of infection and inflammation. Nevertheless, it is important to appreciate that the excessive or uncontrolled release of some of these powerful macrophage products may cause disordered inflammation or scarring responses which are likely to be important in the pathogenesis of a variety of inflammatory diseases including asthma, COPD and other inflammatory/scarring conditions of the lung, e.g. fibrosing alveolitis.
ISSUES IN OLDER PEOPLE
The vast reserve capacity of the respiratory system means a significant reduction in function can occur with ageing with only minimal effect on normal breathing, but the ability to combat acute respiratory disease is reduced.
Lung volumes fall gradually with age; the FEV1/VC ratio falls by around 0.2% per year from 70% at the age of 40-45 years. The decline is less rapid in men.
There are reduced ventilatory responses to hypoxia and hypercapnia in old age, so older people may be less tachypnoeic for any given fall in PaO2 or rise in PaCO2.
Reduced numbers of glandular epithelial cells lead to a reduction in protective mucus and thus impaired defences against infection.
Maximum oxygen uptake declines with age due to a combination of changes in the respiratory and cardiovascular systems. This leads to a reduction in cardiorespiratory reserve and exercise capacity.
The chest wall becomes less mobile due to reduced intervertebral disc spaces and ossification of the costal cartilages; respiratory muscle strength and endurance also decline. These changes only become important in the presence of other respiratory disease.
Ageing leads to reduced elastic recoil in the small airways, which causes a tendency for these to collapse during expiration, particularly in dependent areas of the lungs, thus reducing ventilation and increasing ventilation-perfusion mismatch.
INVESTIGATION OF RESPIRATORY DISEASE
It is essential to take a detailed history from the patient, and much can be learned from a careful physical examination (see Box 13.5). Routine haematological and biochemical investigations can provide indices of infection, immunosuppression and evidence of metastasis of lung tumours, but a number of special investigations are often required in the diagnosis and monitoring of lung disease.
The 'plain' chest radiograph
Many diseases, including bronchial carcinoma and pulmonary tuberculosis, cannot be detected at an early stage without a radiograph of the chest. A lateral film provides additional information about the likely nature and situation of a pulmonary, pleural or mediastinal abnormality. Comparison with previous radiographs may help to distinguish between a 'new' or progressive change which is thus potentially serious, and 'old' or static abnormalities which may be of no importance. In some diseases, such as COPD and asthma, there is often no radiographic abnormality. In these diseases functional assessment (see p. 493) is of much more value in detecting abnormality.
Computed tomography (CT)
13.5 SUMMARY OF TYPICAL PHYSICAL SIGNS IN THE MORE COMMON RESPIRATORY DISEASES
Pathological process Movement of chest wall Mediastinal displacement Percussion note Breath sounds Vocal resonance Added sounds
Consolidation (as in lobar pneumonia) Reduced on side affected None Dull High-pitched bronchial Increased; whispering pectoriloquy Fine crepitations1 early; coarse crepitations later
Collapse due to obstruction of a major bronchus Reduced on side affected Towards lesion Dull Diminished or absent Reduced or absent None
Collapse due to peripheral bronchial obstruction Reduced on side affected Towards lesion Dull High-pitched bronchial Increased; whispering pectoriloquy None early; coarse crepitations later
Localised fibrosis and/or bronchiectasis Slightly reduced on side affected Towards lesion Impaired Low-pitched bronchial Increased Coarse crepitations
Cavitation (usually associated with consolidation or fibrosis) Slightly reduced on side affected None, or towards lesion Impaired Bronchial Increased; whispering pectoriloquy Coarse crepitations
Pleural effusion Empyema Reduced or absent (depending on size) on side affected Towards opposite side Stony dull Diminished or absent (occasionally bronchial) Reduced or absent (occasionally increased) Pleural rub in some cases (above effusion)
Pneumothorax Reduced or absent (depending on size) on side affected Towards opposite side Normal or hyper-resonant Diminished or absent (occasionally faint bronchial) Reduced or absent Tinkling crepitations when fluid present
Bronchitis (acute or chronic) Normal or symmetrically diminished None Normal Vesicular with prolonged expiration Normal Rhonchi,2 usually with some coarse crepitations
Bronchial asthma Symmetrically diminished None Normal Vesicular with prolonged expiration Normal or reduced Rhonchi, mainly expiratory and high-pitched
Bronchopneumonia Symmetrically diminished None May be impaired Usually harsh vesicular with prolonged expiration Normal Rhonchi and coarse crepitations
Diffuse pulmonary emphysema Symmetrically diminished None Normal or hyper-resonant Diminished vesicular with prolonged expiration Normal or reduced Expiratory rhonchi
Interstitial lung disease Symmetrically diminished None Normal Harsh vesicular with prolonged expiration Usually increased End-inspiratory crepitations not influenced by coughing
1 Crepitations = crackles.
2 Rhonchi = wheeze.
This has virtually taken over from conventional tomography in centres where it is available. Conventional tomography was valuable in determining the position and size of a pulmonary nodule or mass and whether calcification or cavitation was present. It was also useful in localising lesions for percutaneous needle biopsy and in assessing the mediastinum and thoracic cage. In all of these examples, however, computed tomography is more sensitive and accurate. CT is now routinely used in the pre-operative assessment of patients with lung cancer, particularly for assessing mediastinal spread, and the presence of metastases in the liver or adrenals. Its value in imaging the mediastinum can be greatly enhanced by using an intravenous contrast which outlines the mediastinal vessels. High-resolution CT is particularly useful in diagnosing interstitial fibrosis, and in identifying bronchiectasis (see Fig. 13.5).
The main value of this technique is in the detection of pulmonary thromboemboli. 133Xe gas is inhaled (the ventilation scan) and 99mTc-labelled macroaggregates of albumin, or albumin microspheres, are injected intravenously, the particles becoming transiently trapped in pulmonary microvessels and providing the 'perfusion' scan. Pulmonary emboli can be detected as a 'filling defect' in the perfusion scan (see Fig. 13.6), but patients with asthma, COPD or other forms of obstructive airways disease may also have disordered pulmonary vascular distribution. However, in these patients the ventilation scan shows defects which match the areas of reduced perfusion on the perfusion scan, whereas the perfusion defects in pulmonary embolism are not matched to defects on the ventilation scan. Ventilation-perfusion scanning is also useful in pre-operative assessment of the functional effects of lung cancer and bullae.
Positron emission tomography (PET)
Whole-body PET with 18-fluorodeoxyglucose (FDG) is showing considerable utility in the investigation of pulmonary nodules and in staging mediastinal lymph node involvement and distal metastatic disease in patients with lung cancer. Recent studies have shown that FDG-PET can prevent unnecessary surgery in 20% of patients with non-small-cell lung cancer.
Figure 13.5 Computed tomography of the thorax. This scan shows extensive dilatation of the bronchi (bronchiectasis) with thickened walls (arrows) in both lower lobes.
Figure 13.6 Lung ventilation and perfusion scintigraphy. A Multiple perfusion defects present in left upper zone and right mid-zone of perfusion scan. B Normal ventilation scan. The appearances in A indicate a high probability of recent pulmonary embolism.
Figure 13.7 Normal digital subtraction pulmonary angiogram of the right lung.
This is the definitive method of diagnosing pulmonary emboli, particularly in the acutely ill and shocked patient or when ventilation-perfusion scans are equivocal. Conventional pulmonary angiography is performed by passing contrast medium down a catheter inserted via the femoral vein into the main pulmonary artery. This catheter can also be used to measure pulmonary artery pressure and instil thrombolytic agents such as streptokinase. Digital subtraction angiography (DSA) is a technique whereby images obtained before contrast injection are digitised and subtracted from post-contrast images, thus removing bones and other background structures from the final digital images. This technique is more sensitive and requires much less contrast to obtain high-quality images (see Fig. 13.7). Other techniques for imaging the pulmonary arteries include the use of contrast-enhanced spiral CT-'CT pulmonary angiography'-which is increasingly used in the diagnosis of pulmonary thromboembolism (see p. 562).
The larynx may be inspected indirectly with a mirror or directly with a laryngoscope. Fibreoptic instruments allow a magnified view to be obtained.
The trachea (see Fig. 13.8) and larger bronchi are inspected by a bronchoscope of flexible fibreoptic or rigid type. Rigid bronchoscopy usually requires general anaesthesia. Structural changes, such as distortion or obstruction, can be seen. Abnormal tissue in the bronchial lumen or wall can be biopsied, and bronchial brushings, washings or aspirates can be taken for cytological or bacteriological examination. The range of vision is limited by the calibre of the subsegmental bronchi, but peripheral lesions can sometimes be reached by flexible biopsy forceps directed under fluoroscopic control. Small biopsy specimens of lung tissue taken by forceps passed through the bronchial wall (transbronchial biopsies) may reveal sarcoid granulomata or malignant diseases and may be helpful in diagnosing certain bronchocentric disorders (e.g. extrinsic allergic alveolitis, cryptogenic organising pneumonia), but are generally too small to be of diagnostic value in diffuse interstitial lung disease (see p. 552).
The mediastinoscope is introduced through a small incision at the suprasternal notch to give a view of the upper mediastinum. Biopsy of some mediastinal nodes is possible, which may be of value in obtaining a diagnosis and in determining whether a bronchial carcinoma has spread to the mediastinum and is, therefore, inoperable.
Pleural aspiration and biopsy
Figure 13.8 Bronchoscopic appearances of the lower trachea, carina and the right and left main bronchi.
Pleural aspiration and biopsy using an Abram's needle is a 'blind' procedure but often provides histological evidence of the cause of a pleural effusion. Transthoracic needle biopsy (with radiological guidance) may be useful in obtaining a cytological diagnosis from a peripheral lung lesion. In difficult cases, thoracoscopy may be necessary to obtain diseased tissue; the recent introduction of video-assisted thoracoscopic lung biopsy reduces the need for thoracotomy in cases of interstitial lung disease when lung biopsy is required (see p. 552).
The tuberculin test (see p. 537) may be of value in the diagnosis of tuberculosis. Skin hypersensitivity tests are useful in the investigation of allergic diseases.
IMMUNOLOGICAL AND SEROLOGICAL TESTS
The presence of pneumococcal antigen (revealed by counterimmunoelectrophoresis) in sputum, blood or urine may be of diagnostic importance. Exfoliated cells colonised by influenza A virus (see p. 525) can be detected by fluorescent antibody techniques. In blood, high or rising antibody titres to specific organisms (such as Legionella, Mycoplasma, Chlamydia or viruses) may eventually clinch a diagnosis suspected on clinical grounds. Precipitating antibodies may be found as a reaction to fungi such as Aspergillus (see p. 540) or to antigens involved in allergic alveolitis (see p. 556).
Sputum, pleural fluid, throat swabs, blood and bronchial washings and aspirates can be examined for bacteria, fungi and viruses. In some cases, as when Mycobacterium tuberculosis is isolated, the information is diagnostically conclusive but in other circumstances the findings must be interpreted in conjunction with the results of clinical and radiological examination.
HISTOPATHOLOGICAL AND CYTOLOGICAL EXAMINATION
Histopathological examination of biopsy material (obtained from pleura, lymph node or lung) often allows a 'tissue diagnosis' to be made. This is of particular importance in suspected malignancy or in elucidating the pathological changes in interstitial lung disease (see p. 550). Important causative organisms, such as M. tuberculosis, Pneumocystis carinii or fungi, may be identified in bronchial washings, brushings or transbronchial biopsies.
Cytological examination of exfoliated cells in sputum, pleural fluid or bronchial brushings and washings or of fine-needle aspirates from lymph nodes or pulmonary lesions can support a diagnosis of malignancy but a tissue biopsy is necessary in most cases to confirm the diagnosis. Cellular patterns in bronchial lavage fluid may help to distinguish pulmonary changes due to sarcoidosis (see p. 552) from those caused by fibrosing alveolitis (see p. 555) or allergic alveolitis (see p. 556).
LUNG FUNCTION TESTING
Pulmonary function tests are used to aid diagnosis, assess functional impairment and monitor treatment or progression of disease. Common abbreviations used in pulmonary function testing are shown in Box 13.6. Simple spirometry should be a routine procedure carried out by all doctors when assessing a patient who is breathless.
13.6 ABBREVIATIONS USED IN PULMONARY FUNCTION TESTING
Abbreviation Stands for
FEV1 Forced expiratory volume in 1 second
FVC Forced vital capacity
VC Vital capacity (relaxed)
PEF Peak (maximum) expiratory flow
TLC Total lung capacity
FRC Functional residual capacity
RV Residual volume
TLCO Gas transfer factor for carbon monoxide
KCO Transfer coefficient for carbon monoxide
Spirometry and peak flow
The forced expiratory volume in 1 second (FEV1) and vital capacity (VC) are obtained from maximal forced and relaxed expirations into a spirometer. The results are compared with predicted values based on age, sex, height and ethnic group. The FEV1/VC ratio is also a useful diagnostic aid, with values of less than 70% defining airflow obstruction (see Box 13.7). Acute reversibility testing using inhaled short-acting ß2-adrenoceptor agonists (e.g. salbutamol or terbutaline) should be carried out when airflow obstruction is seen; full reversibility is diagnostic of asthma (see p. 513). Peak expiratory flow (PEF) monitored via a small portable meter can be usefully recorded by patients at home or at work in order to assess asthma control on an objective basis. Peak flow monitoring can be used by patients as a basis for self-management plans. Serial measures show any circadian changes, and responses to occupational exposure or therapy are of value in both the diagnosis and the management of asthma.
The plotting of flow versus volume during both maximal expiratory and inspiratory manoeuvres is of major help in differentiating central airflow obstruction (leading to stridor) from diffuse airflow obstruction as seen in COPD and asthma.
13.7 PATTERNS OF ABNORMAL VENTILATORY CAPACITY
Asthma Emphysema Lung fibrosis
FEV1 Low Low Low
VC Low Low Low
FEV1/VC Low Low Normal
DLCO Normal Low Low
KCO Normal Low Low
TLC High High Low
RV High High Low
Measurement of total lung capacity and residual volume is best performed using a whole body plethysmograph, but can be measured by a helium dilution method. In general, restrictive defects lead to reduced values, and obstructive defects to increased values (see Box 13.7 and Fig. 13.9).
Measurement of diffusing capacity
The diffusing capacity (DLCO) is a measure of the lung's ability to transfer gas from alveoli to blood. The test utilises uptake of carbon monoxide from a single breath of 0.3% mixture in air; this gas is chosen because it combines rapidly with haemoglobin and provides a true estimate of diffusion across the alveolar capillary membrane. The diffusing capacity is reduced in patients with disease principally affecting alveoli such as fibrosing alveolitis or emphysema. The transfer coefficient (KCO) is a measure of diffusing capacity expressed per volume of ventilated lung during the single breath test and is useful to confirm that a low DLCO is due to alveolar disease rather than maldistribution of ventilation. High values of DLCO may be seen in alveolar haemorrhage.
Arterial blood gases and oximetry
Figure 13.9 Normal lung volumes and schematic tidal flow-volume curves. A Volume-time plot during tidal breathing (I), forced inspiration (II) and forced expiration (III). B Schematic tidal flow-volume curve in a normal subject and in a patient with COPD and moderate airflow obstruction.
The measurement of hydrogen ion concentration, PaO2 and PaCO2, and derived bicarbonate concentration of arterial blood is essential in assessing the degree and type of respiratory failure and for measuring overall acid-base status. Use of a pulse oximeter allows a non-invasive continuous method of assessing oxygen saturation in patients who require continuous monitoring in order to assess hypoxaemia and its response to therapy, including supplemental oxygen.
Formal exercise testing with measurement of metabolic gas exchange and respiratory and cardiac responses using cycle ergometry or treadmill exercise is useful in providing a detailed analysis of both pulmonary and cardiac function in the breathless patient. Exercise challenge with measurement of spirometry before and after can also be helpful in demonstrating exercise-induced asthma. Finally, the 6-minute walk test or 'shuttle' test can provide a simple but objective assessment of disability and response to treatment.
pages 486 - 494
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > MAJOR MANIFESTATIONS OF LUNG DISEASE
MAJOR MANIFESTATIONS OF LUNG DISEASE
Cough is the most frequent symptom of respiratory disease. It is caused by stimulation of sensory nerves in the mucosa of the pharynx, larynx, trachea and bronchi. Sensitisation of the normal cough reflex is also observed following viral infections, oesophageal reflux, post-nasal drip, 'cough variant' asthma and in 10-15% of patients (particularly women) taking angiotensin-converting enzyme (ACE) inhibitors. Rarely, cough may also arise following stimulation of the parietal pleura: for example, during the aspiration of a pleural effusion. The nature and characteristics of cough originating at various levels of the respiratory tract are given in Box 13.8.
Origin Common causes Nature/characteristics
Pharynx Post-nasal drip Usually persistent
Larynx Laryngitis, tumour, whooping cough, croup Harsh, barking, painful, persistent, often associated with stridor
Trachea Tracheitis Painful
Bronchi Bronchitis (acute) and COPD Dry or productive, worse in mornings
Asthma Dry or productive, worse at night
Bronchial carcinoma Persistent (often with haemoptysis)
Lung parenchyma Tuberculosis Productive, often with haemoptysis
Pneumonia Dry initially, productive later
Bronchiectasis Productive, changes in posture induce sputum production
Pulmonary oedema Often at night (may be productive of pink, frothy sputum)
Interstitial fibrosis Dry, irritant and distressing
The explosive quality of a normal cough is lost in patients with severe airflow obstruction, respiratory muscle paralysis or vocal cord palsy. Paralysis of a single vocal cord gives rise to a prolonged, low-pitched, inefficient 'bovine' cough accompanied by hoarseness. Patients with sensitisation of the cough reflex typically have symptoms induced by changes in air temperature or exposure to cigarette smoke or perfumes. Coexistence of stridor indicates partial obstruction of a major airway (e.g. laryngeal oedema, tumour or an inhaled foreign body) and requires urgent investigation and treatment. Sputum production is common in patients with acute or chronic cough and its nature and appearance can provide valuable clues as to the aetiology (see p. 485).
Acute or transient cough most commonly relates to viral-induced lower respiratory tract infection, post-nasal drip resulting from rhinitis or sinusitis, or throat-clearing secondary to laryngitis or pharyngitis. Acute cough occurring in the context of more serious diseases such as pneumonia, aspiration, congestive heart failure or pulmonary embolism is usually easy to diagnose due to the presence of other clinical features.
Patients with chronic cough often represent more of a diagnostic challenge, especially those individuals with a normal examination, chest radiograph and lung function studies. In this context, most cough can be explained by post-nasal drip secondary to nasal or sinus disease; asthma, where cough may be the principal or exclusive clinical manifestation; or gastro-oesophageal reflux. The latter cause may require ambulatory pH monitoring or a prolonged trial of anti-reflux therapy (see p. 775) to diagnose. Bordetella pertussis infection in adults can also result in protracted cough and should always be suspected in those in close contact with children. While less than 1% of patients with a bronchogenic carcinoma have a normal chest radiograph on presentation, fibreoptic bronchoscopy or spiral CT of the airways is advisable in most adults with otherwise unexplained cough of recent onset (especially in smokers) as this may reveal a small intrabronchial tumour or unexpected foreign body (see Fig. 13.10).
Figure 13.10 Bronchoscopic appearances of inhaled foreign body (tooth) with a covering mucous film.
Breathlessness or dyspnoea can be defined as an unpleasant subjective awareness of the sensation of breathing. It is a common symptom of cardiac and respiratory disease, but it may occur as a result of disorders of other systems, e.g. diabetic ketoacidosis or severe anaemia.
Breathless patients with asthma or COPD often also describe a 'tight chest'. Pleural pain (see p. 499) of any cause is associated with limitation of breathing.
13.9 PHYSIOLOGICAL BASIS OF DYSPNOEA
Increased ventilatory drive
? PaCO2-e.g. COPD
? PaO2-e.g. cyanotic congenital heart disease, asthma, COPD
Acidaemia-e.g. diabetic ketoacidosis, lactic acidosis
Reduced ventilatory capacity
? Lung volume, e.g. restrictive lung diseases-pneumonia, pulmonary oedema, interstitial lung diseases
? Resistance to airflow, e.g. asthma, COPD, upper airway or laryngeal obstruction
In broad physiological terms, patients usually perceive discomfort either from an increased ventilatory rate or drive, which can be provoked by a variety of factors, or from any disease which causes sufficient reduction of ventilatory capacity (see Box 13.9). Other factors, however, including the stimulation of intrapulmonary receptors (e.g. J receptors), augment the ventilatory response in many bronchopulmonary disorders.
It follows that dyspnoea often has a multifactorial aetiology, e.g. acute respiratory infections may stimulate the respiratory rate as a consequence of fever, hypoxaemia and, in severe cases, by acidaemia or hypercapnia. They may also reduce ventilatory capacity by increasing bronchial resistance and by restricting ventilation because of pleural pain.
While it is useful to understand the physiological basis of dyspnoea, patients often present either as an emergency with acute breathlessness (with prominent symptoms even at rest) or with chronic dyspnoea on exertion, and it is useful therefore to describe the causes of dyspnoea in this fashion (see Box 13.10).
13.10 SOME CAUSES OF DYSPNOEA
System Acute dyspnoea at rest Chronic exertional dyspnoea
Cardiovascular *Acute pulmonary oedema (see p. 377) Chronic heart failure (see p. 377)
Myocardial ischaemia (angina equivalent) (see p. 378) Myocardial ischaemia (angina equivalent) (see p. 378)
Respiratory *Acute severe asthma *COPD
*Acute exacerbation of COPD *Chronic asthma
*Pneumothorax Bronchial carcinoma
*Pneumonia Interstitial lung disease (sarcoidosis, fibrosing alveolitis,
*Pulmonary embolus extrinsic allergic alveolitis, pneumoconiosis)
Acute respiratory distress syndrome Chronic pulmonary thromboembolism
Inhaled foreign body (especially in the child) Lymphatic carcinomatosis (may cause intolerable dyspnoea)
Lobar collapse Large pleural effusion(s)
Laryngeal oedema (e.g. anaphylaxis)
Others Metabolic acidosis (e.g. diabetic ketoacidosis, lactic acidosis, uraemia, overdose of salicylates, ethylene glycol poisoning) Severe anaemia
Psychogenic hyperventilation (anxiety or panic-related)
*Denotes a common cause.
AN APPROACH TO THE DIFFERENTIAL DIAGNOSIS IN THE PATIENT WITH CHRONIC EXERTIONAL DYSPNOEA
Chronic obstructive pulmonary disease (COPD)
There is usually a history of exertional dyspnoea, often associated with wheeze, over many months or years, with a steady decline in exercise capacity (e.g. initially breathlessness on hills and stairs, but eventually after walking a few paces on the flat). Chronic cough productive of sputum, usually most troublesome in the mornings, is the rule and there is often a history of recurrent acute exacerbations, usually in the winter months. In late disease orthopnoea, nocturnal breathlessness and ankle swelling may supervene as a result of the development of cor pulmonale.
Central cyanosis at rest or after minimal exertion, wheeze and pursing of the lips during expiration, and intercostal indrawing during inspiration are common examination findings. The antero-posterior diameter of the chest may be increased (barrel chest) and there may be a reduced crico-sternal distance with a 'tracheal tug' on inspiration.
The chest radiograph may show signs of hyperinflation and/or bullae; arterial blood gases may reveal hypoxaemia, hypercapnia and a raised plasma bicarbonate, indicating compensated type II respiratory failure. It is important to note that patients presenting with type II respiratory failure (see p. 506) may not be distressed by breathlessness. There will often be a severe obstructive defect on spirometry, with a low FEV1 and little, if any, improvement after bronchodilator therapy.
It is often difficult to differentiate breathlessness due to heart disease from that caused by lung disease. A history of cough, wheezing and nocturnal breathlessness may occur in cardiac failure as well as in patients with lung disease. A history of angina or hypertension may be useful in implicating a cardiac cause (see Fig. 13.11).
On examination, an increase in heart size as judged by a displaced apex beat, a raised jugular venous pressure (JVP) and cardiac murmurs may implicate cardiac disease (although these signs can occur in severe cor pulmonale). The chest radiograph may show cardiomegaly and an ECG may provide evidence of left ventricular disease. Arterial blood gases may be of value, since in the absence of an intracardiac shunt or obvious pulmonary oedema the PaO2 in cardiac disease is not usually reduced significantly and the PaCO2 is low or normal.
Interstitial or alveolar disease of the lung
A large number of conditions can cause interstitial lung disease (see p. 550), which may be difficult to distinguish from other conditions including infiltrating malignancy and certain opportunistic lung infections (see Box 13.74, p. 551). It is imperative to elicit a detailed history, including lifetime occupation and exposure to birds and other sources of organic agents which may provoke lung disease. The chest radiograph is nearly always abnormal, but early changes may be very subtle. Pulmonary function tests usually show a restrictive defect (reduced vital capacity) and reduced gas transfer. Arterial blood gases may show hypoxaemia, or haemoglobin desaturation may be detected by oximetry, particularly during formal exercise testing, which may be valuable in early disease; the PaCO2 is seldom elevated, even in advanced disease.
Diseases of the chest wall or respiratory muscles
These are usually obvious on history, examination and chest radiography. Other rarer causes of alveolar hypoventilation, e.g. brain-stem defects, primary alveolar hypoventilation and alveolar hypoventilation in gross obesity, may cause disordered breathing and cyanosis, but these conditions are not usually associated with breathlessness. Bilateral diaphragmatic weakness or palsy results in breathlessness that is characteristically worse on lying; this is associated with a drop in the vital capacity. Patients with major chest wall abnormalities, or problems with ventilatory drive or muscle strength tend to develop problems initially during sleep, with nocturnal hypoxaemia and hypercapnia which resolve during the day.
As will be considered below, pulmonary thromboembolism often presents with acute breathlessness with or without chest pain. However, chronic pulmonary thromboembolic disease (see p. 562) should be suspected in patients who present with more gradual onset of breathlessness, in particular those with a previous history of thromboembolic events or those with marked exertional breathlessness but a relatively normal chest radiograph. Leg swelling and an elevated JVP may arouse suspicion but clearly can also occur in cardiac failure.
Breathlessness which is not caused by organic disease of the heart or lungs is also relatively common. It creates a particularly difficult clinical problem when it occurs in patients with pre-existing disease, such as asthma or heart disease. It is possible in most patients to ascertain by careful questioning whether the sensation of breathlessness is different from that caused by exertion in the past, or dyspnoea associated with any pre-existing lung or heart disease.
Figure 13.11 Features that can distinguish cardiac from non-cardiac dyspnoea. N.B. Non-cardiac dyspnoea may coexist with occult or symptomatic heart disease. Psychological factors may amplify cardiac or non-cardiac symptoms or occur in isolation.
Psychogenic breathlessness is usually described as an 'inability to get enough air into the lung' and this leads to extra deep breaths having to be taken. This form of breathlessness rarely disturbs sleep, but may be present after waking for another reason. Symptoms occur predominantly at rest and may even be relieved by exercise. Specialist centres use a number of features to develop a 'points' score in the assessment of this problem, often called anxiety-related hyperventilation-see Box 13.11. Occasionally, formal exercise testing may be required to be confident that patients have breathlessness which does not have an organic cause.
13.11 SOME FACTORS POINTING TO PSYCHOGENIC HYPERVENTILATION
'Inability to take a deep breath'
Frequent sighing/erratic ventilation at rest
Short breath-holding time in the absence of severe respiratory disease
Difficulty in performing/inconsistent spirometry manoeuvres
High score on Nijmegen anxiety questionnaire
Induction of symptoms during submaximal hyperventilation
Resting end-tidal CO2 < 4.5%
Overt 'hysterical' or panic-related hyperventilation is associated with paraesthesia in the hands and feet, cramps and carpopedal spasm due to acute respiratory alkalosis; it can present as a respiratory emergency but rarely creates a diagnostic problem. It must always, however, be included in the differential diagnosis of acute-onset breathlessness (see Box 13.10). It is best treated with oxygen and reassurance delivered in a quiet environment rather than by rebreathing into a bag as formerly suggested.
AN APPROACH TO THE PATIENT WITH ACUTE SEVERE DYSPNOEA
Acute severe breathlessness is one of the most common medical emergencies. The presentation is often dramatic and it is easy for the inexperienced clinician to be disconcerted. Although there are usually a number of possible causes, attention to the history and a rapid but careful examination will usually suggest a diagnosis which can often be confirmed by routine investigations, including chest radiograph, electrocardiogram (ECG) and arterial blood gases. Some specific features aiding in the diagnosis of important causes of acute severe breathlessness are considered in detail in Box 13.12.
13.12 DIFFERENTIAL DIAGNOSIS OF ACUTE SEVERE DYSPNOEA
Condition History Signs Chest radiography Arterial blood gases ECG Other tests
Left ventricular failure Chest pain Orthopnoea Palpitations
*A previous cardiac history Central cyanosis JVP (? or?)
*Sweating Cool extremities
*Dullness and crepitations at bases Cardiomegaly
*Upper zone vessel enlargement
*Overt oedema/pleural effusions ? Pa O2 ? Pa CO2 Sinus tachycardia
*Signs of myocardial infarction Arrhythmia *Echocardiography (? left ventricular function)
Massive pulmonary embolus Recent surgery or other risk factors Chest pain Previous pleurisy
*Dizziness Severe central cyanosis
*Absence of signs in the lung (unless previous pulmonary infarction) Shock (tachycardia, reduced blood pressure) May be subtle changes only Prominent hilar vessels
*Oligaemic lung fields ?Pa O2 ? Pa CO2 Sinus tachycardia S1Q3T3 pattern ? T (V1-V4) Right bundle-branch block *Echocardiography
*CT pulmonary angiography
Acute severe asthma *History of previous episodes, asthma medications, wheeze Tachycardia and pulsus paradoxus Cyanosis (late)
*? peak flow, rhonchi *Hyperinflation only (unless complicated by pneumothorax) ? Pa O2 ? Pa CO2 (until late) Sinus tachycardia (bradycardia with severe hypoxaemia -late)
Acute exacerbation of COPD *Previous episodes (admissions) If in type II respiratory failure, may not be distressed Cyanosis
*Signs of COPD (barrel chest, intercostal indrawing, pursed lips, tracheal tug)
*Signs of CO2 retention (warm periphery, flapping tremor, bounding pulses) *Hyperinflation Signs of emphysema Signs of events precipitating exacerbation ? or ? Pa O2 In type II failure Pa CO2 ?, with ¯ ? [H+] and ¯ ?bicarbonate Nil, or signs of right ventricular failure (in cor pulmonale)
Pneumonia *Prodromal illness
*Pleurisy Fever, confusion
*Consolidation Cyanosis (only if severe) *Pneumonic consolidation ? Pa CO2 ? Pa O2 Tachycardia ? CRP ? White cell count Sputum and blood culture
Metabolic acidosis *Evidence of diabetes/renal disease
*Overdose of aspirin or ethylene glycol Fetor (ketones)
*Hyperventilation without physical signs in heart or lungs
*Dehydration Air hunger (Kussmaul's respiration) Normal *Pa O2 normal ? Pa CO2 ? pH (¯ H+)
Psychogenic (a diagnosis of exclusion) Previous episodes *Not cyanosed
*No heart signs
*No lung signs Carpopedal spasm Normal *Pa O2 normal ? Pa CO2
*pH normal or ¯ ?(H+ ?) End-tidal PaCO2
*Low exercise tolerance test
*Denotes a valuable discriminatory feature.
Figure 13.12 CT showing retrosternal multinodular goitre (small arrow) causing acute severe breathlessness and stridor due to tracheal compression (large arrow).
It is important to ascertain the rate of onset and severity of the breathlessness and whether associated cardiovascular symptoms (chest pain, palpitations, sweating and nausea) or respiratory symptoms (cough, wheeze, haemoptysis, stridor-see Fig. 13.12) are present. A previous history of repeated episodes of left ventricular failure, asthma or exacerbations of COPD is valuable. Recent intake of drugs or a history of other diseases (renal disease, diabetes or anaemia) should be established. In the severely ill patient it may be necessary to obtain a brief history from friends, relatives or ambulance personnel. In children, particularly pre-school toddlers, the possibility of inhalation of a foreign body (see Fig. 13.10, p. 495) or acute epiglottitis should always be considered.
The severity of the condition should be assessed immediately by the level of consciousness, degree of central cyanosis, evidence of anaphylaxis (urticaria or angio-oedema), patency of the upper airway, ability to speak (in single words or sentences), and the cardiovascular status assessed by heart rate and rhythm, blood pressure and degree of peripheral perfusion. Examination should then be targeted on digital clubbing, clinical evidence of anaemia or polycythaemia, and any clinical features of diabetes, renal failure or any other chronic disease. A detailed examination of the respiratory system should include the respiratory rate, clinical evidence of CO2 retention, pattern of breathing, position of the trachea, degree and symmetry of chest expansion, and whether there are areas of hyper-resonance or dullness on percussion. Breath sounds should be compared on each side of the chest and at the bases, and the presence of abnormal sounds noted. The peak expiratory flow should be measured whenever possible. Leg swelling may suggest cardiac failure or venous thrombosis.
Chest pain is a major and frequent manifestation of both cardiac and respiratory disease and is considered in detail on page 372. In general, however, lung disease only gives rise to chest pain when there is pleural or chest wall involvement and hence tends to be predominantly peripheral (see Box 13.13). Central chest pain or tightness is a feature of acute airways obstruction in asthma and COPD or may reflect disorders of the oesophagus (see p. 775) or thoracic aorta (see p. 448). Tracheitis produces severe upper chest pain worse on coughing. Persistent dull central chest pain is also a feature of malignant disease affecting the mediastinum.
13.13 DIFFERENTIAL DIAGNOSIS OF CHEST PAIN
Myocardial ischaemia (angina)
Mitral valve prolapse syndrome
Massive pulmonary embolus
Connective tissue disorders
Intercostal muscle injury
Costochondritis (Tietze's syndrome)
Epidemic myalgia (Bornholm disease)
Prolapsed intervertebral disc
Thoracic outlet syndrome
Coughing up blood, irrespective of the amount, is an alarming symptom and nearly always brings the patient to the doctor. A clear history should be taken to establish that it is true haemoptysis and not haematemesis or epistaxis (nosebleed). Haemoptysis must always be assumed to have a serious cause until appropriate investigations have excluded bronchial carcinoma, thromboembolic disease, tuberculosis etc. (see Box 13.14).
13.14 CAUSES OF HAEMOPTYSIS
Parasites (e.g. hydatid disease, flukes)
Lung vascular disease
Goodpasture's syndrome (see p. 614)
Idiopathic pulmonary haemosiderosis
Acute left ventricular failure
Many episodes of haemoptysis are unexplained, even after full investigation, and are likely to be caused by simple bronchial infection. A history of repeated small haemoptyses, or blood-streaking of sputum, is highly suggestive of bronchial carcinoma. Chronic fever and weight loss may suggest tuberculosis. Pneumococcal pneumonia is often the cause of 'rusty'-coloured sputum but can cause frank haemoptysis, as can all the pneumonic infections which lead to suppuration or abscess formation (see p. 530). Bronchiectasis and intracavitary aspergilloma (see p. 541) can cause catastrophic bronchial haemorrhage and in these patients there may be a history of previous tuberculosis or pneumonia in early life. Pulmonary thromboembolism is a common cause of haemoptysis and should always be considered. Major risk factors include immobilisation, malignant disease of any organ, cardiac failure and pregnancy.
Physical examination may reveal clues as to the underlying diagnosis, e.g. finger clubbing in bronchial carcinoma or bronchiectasis; other signs of malignancy such as cachexia, hepatomegaly, lymphadenopathy etc.; fever or signs of consolidation and pleurisy in pneumonia or pulmonary infarction; leg signs of deep venous thrombosis in a minority of patients with pulmonary infarction; and signs of systemic diseases including rash, purpura, haematuria, splinter haemorrhages, lymphadenopathy or splenomegaly in the uncommon systemic diseases which may be associated with haemoptysis.
In catastrophic acute haemoptysis, the patient should be nursed on the side of the suspected source of bleeding, haemodynamically resuscitated and then bronchoscoped. Ideally this is performed under general anaesthesia using a rigid bronchoscope which allows optimal bronchial suction and can be used to maintain adequate ventilation during anaesthesia. Angiography and bronchial arterial embolisation (see Fig. 13.13), or even emergency pulmonary surgery, can be life-saving in the acute situation.
Figure 13.13 Bronchial artery angiography. An angiography catheter has been passed via the femoral artery and aorta into an abnormally dilated right bronchial artery (arrows). Contrast is seen flowing into the lung. This patient had post-tuberculous bronchiectasis affecting the right upper lobe and presented with massive haemoptysis. Bronchial artery embolisation was successfully carried out.
In the vast majority of cases, however, the haemoptysis itself is not life-threatening and it is possible to follow a logical sequence of investigations which include:
Chest radiograph, which may give clear evidence of a localised lesion including pulmonary infarction, a tumour (malignant or benign), pneumonia or tuberculosis.
Full blood count and other haematological tests including clotting screen.
Bronchoscopy, which will often be necessary to exclude a central bronchial carcinoma (not visible on the chest radiograph) and to provide a tissue diagnosis in other cases of suspected bronchial neoplasia.
Ventilation-perfusion ([Vdot]/[Qdot]) lung scan, which is helpful in establishing a diagnosis of suspected pulmonary thromboembolic disease. CT pulmonary angiography may be necessary in patients with pre-existing lung disease where interpretation of the [Vdot]/[Qdot] scan can be difficult.
CT, which is particularly useful in investigating peripheral lesions seen on the chest radiograph which may not be accessible to bronchoscopy and facilitates accurate percutaneous needle biopsy where indicated.
THE SOLITARY RADIOGRAPHIC PULMONARY LESION
Patients frequently present because they have been found to have an abnormal chest radiograph. A common clinical problem is created by the adult with few or no symptoms, who has been found to have a single peripheral lesion (nodule) detected by chest radiography. There are many causes of the 'peripheral radiograph shadow', some of which are shown in Box 13.15. Primary bronchial carcinoma is the most likely cause in a middle-aged or elderly adult, particularly if a smoker.
13.15 THE SOLITARY PULMONARY NODULE
'Pseudotumour'-fluid collection in a fissure
Aspergilloma (usually surrounded by air 'halo')
The single most important investigation is examination of previous radiographs, if they exist, since if a lesion has been present for more than 2 years and has not changed, it can be assumed to be non-malignant. If there are no previous radiographs or if previous films are normal, CT can be of great value in defining the lesion more precisely, demonstrating the presence of calcification and cavitation within it, and identifying whether other smaller lesions exist in other areas of the lung which may not be apparent on the conventional radiograph. The injection of intravenous contrast medium at the time of the CT provides information regarding the vascularity of the lesion, with malignant tumours tending to show greatest contrast enhancement. CT will also show hilar and mediastinal lymphadenopathy, which is important in the staging of a primary bronchial carcinoma. A positive 18FDG-PET scan (see p. 491) is also suggestive of a malignant lesion.
Bronchoscopy is unlikely to allow direct inspection of a peripheral lesion, but a diagnosis of malignant disease or infection can be achieved by examination of bronchial washings and brushings obtained from the segment of lung in which the lesion is seen on the chest radiograph or CT. Biopsy of the lesion via the bronchoscope may be possible with the aid of radiographic screening. Percutaneous needle biopsy under CT guidance has proved to be the most effective procedure for the diagnosis of solitary pulmonary nodules with few complications (pneumothorax and haemorrhage). On occasion, a definitive diagnosis can only be made by surgical resection.
Whenever bacterial infection is included in the clinical differential diagnosis, an antibiotic should be given during the period in which the investigations are being performed; the patient should then undergo a repeat radiograph to see whether there has been a reduction in size of the opacity. In elderly patients in whom a primary malignant lesion is suspected, but who are considered unfit for any form of curative treatment, observation by repeat radiograph at intervals of a few weeks may be the most appropriate management decision.
This term is used when serous fluid accumulates in the pleural space. The presence of frank pus (empyema) or blood (haemothorax) in the pleural space represents separate conditions; empyema is considered elsewhere (see p. 569). In general, pleural fluid accumulates as a result of either increased hydrostatic pressure or decreased osmotic pressure ('transudative effusion', as seen in cardiac, liver and renal failure), or from increased microvascular permeability due to disease of the pleural surface itself or injury in the adjacent lung ('exudative effusion'). Some causes of pleural effusion are shown in Boxes 13.16 and 13.17.
Pleural effusion may be unilateral or bilateral. Bilateral effusions often occur in cardiac failure, but are also seen in patients with connective tissue diseases and hypoproteinaemia. The likely cause of the majority of pleural effusions can usually be identified if a careful history is taken and a comprehensive clinical examination performed.
Particular attention should be paid to recent history of respiratory infection, the presence of heart, liver or renal disease, smoking history, occupation-for example, exposure to asbestos, contact with tuberculosis, and risk factors for thromboembolism such as recent immobilisation or operation.
13.16 CAUSES OF PLEURAL EFFUSION
Pneumonia ('para-pneumonic effusion')
Subdiaphragmatic disorders (subphrenic abscess, pancreatitis etc.)
Hypoproteinaemia (nephrotic syndrome, liver failure, malnutrition)
Connective tissue diseases (particularly systemic lupus erythematosus and rheumatoid arthritis)
Acute rheumatic fever
Post-myocardial infarction syndrome
Meigs' syndrome (ovarian tumour plus pleural effusion)
Asbestos-related benign pleural effusion
13.17 PLEURAL EFFUSION: MAIN CAUSES AND FEATURES
Cause Appearance of fluid Type of fluid Predominant cells in fluid Other diagnostic features
Tuberculosis Serous, usually amber-coloured Exudate Lymphocytes (occasionally polymorphs) Positive tuberculin test
Isolation of M. tuberculosis from pleural fluid (20%)
Positive pleural biopsy (80%)
Malignant disease Serous, often blood-stained Exudate Serosal cells and lymphocytes Often clumps of malignant cells Positive pleural biopsy (40%)
Evidence of malignant disease elsewhere
Cardiac failure* Serous, straw-coloured Transudate Few serosal cells Other evidence of left ventricular failure
Response to diuretics
Pulmonary infarction* Serous or blood-stained Exudate (rarely transudate) Red blood cells Eosinophils Evidence of pulmonary infarction
Source of embolism
Factors predisposing to venous thrombosis
Rheumatoid disease* Serous Turbid if chronic Exudate Lymphocytes (occasionally polymorphs) Rheumatoid arthritis; rheumatoid factor in serum
Cholesterol in chronic effusion; very low glucose in pleural fluid
Systemic lupus erythematosus (SLE)* Serous Exudate Lymphocytes and serosal cells Other manifestations of SLE
Antinuclear factor or anti-DNA in serum
Acute pancreatitis Serous or blood-stained Exudate No cells predominate High amylase in pleural fluid (greater than in serum)
Obstruction of thoracic duct Milky Chyle None Chylomicrons
*Effusion often bilateral.
Symptoms and signs of pleurisy often precede the development of an effusion, especially in patients with underlying pneumonia, pulmonary infarction or connective tissue disease. Frequently, however, the onset is insidious. Breathlessness is the only symptom related to the effusion and the severity depends on the size and rate of accumulation of the fluid. The physical signs in the chest are those of fluid in the pleural space-namely, reduced chest wall movement on the affected side, stony dullness on percussion, and reduced or absent breath sounds and vocal resonance. Large effusions cause displacement of the trachea and mediastinum to the opposite side.
The chest radiograph shows a dense uniform opacity in the lower and lateral parts of the hemithorax, shading off above and medially into translucent lung (see Fig. 13.14). Occasionally, the fluid is localised below the lower lobe ('subpulmonary effusion'), the appearances simulating an elevated hemidiaphragm. A localised opacity may be seen when the effusion is loculated-for example, in an interlobar fissure.
Figure 13.14 Pleural effusion. Chest radiograph showing the characteristic opacification of a large left-sided effusion.
This investigation is invaluable in differentiating between a loculated pleural effusion and pleural tumour and allows examination of the diaphragm and subdiaphragmatic space. It also helps to localise an effusion prior to aspiration and pleural biopsy.
Pleural aspiration and pleural biopsy
Absolute proof that an effusion is present can be obtained only by the aspiration of fluid. Since the chances of obtaining a diagnosis from pleural biopsy material are much greater than by examination of the pleural liquid alone, pleural biopsy is always indicated whenever a diagnostic aspiration of pleural fluid is performed. Ideally, ultrasound or CT should be used to indicate the most appropriate site for pleural aspiration and biopsy. If these are not readily available, the pleural biopsy needle should be inserted through an intercostal space at the area of maximum dullness on percussion and at the site of maximum radiological opacity as shown by postero-anterior and lateral films. At least 50 ml of fluid should be withdrawn initially, aliquots being placed in separate containers for microbiological examination (including culture for tuberculosis), cytology and biochemical examination. Whenever there is a strong suspicion of tuberculosis, a large volume of pleural liquid should be submitted to the laboratory. Pleural biopsies should be taken after the initial pleural fluid sample has been aspirated for diagnostic purposes and before further drainage is undertaken.
The appearance of the fluid can be straw-coloured, blood-stained, purulent or chylous. Knowledge of the biochemical characteristics of pleural fluid can be very valuable in determining the aetiology of a pleural effusion. The most useful indices to measure are protein, lactate dehydrogenase, glucose and pH (see Fig. 13.15). The predominant cell type (neutrophil, eosinophil, lymphocyte, red blood cell) provides useful information, and fluid should always be examined for malignant cells.
Estimation of the total and differential peripheral blood leucocyte count, a tuberculin test and examination of the sputum for tubercle bacilli should be routine in most situations. A chest radiograph may disclose an underlying pulmonary lesion and indicate its nature. If the lung is obscured by a massive effusion, the radiograph should be repeated after the fluid has been aspirated. Other investigations which may be of help include bronchoscopy, biopsy or aspiration of enlarged regional lymph nodes, thoracoscopy and serological tests for antinuclear and rheumatoid factors.
The main diagnostic features and more important causes of pleural effusion are shown in Box 13.17.
Aspiration of pleural fluid may be necessary to relieve breathlessness. It is inadvisable to remove more than 1 litre on the first occasion because 're-expansion' pulmonary oedema occasionally follows the aspiration of larger amounts. A pneumothorax may be produced even by a careful operator, and a chest radiograph must always be taken after the procedure.
Treatment of the underlying cause-for example, heart failure, pneumonia, pulmonary embolism or subphrenic abscess-will often be followed by resolution of the effusion. However, certain conditions require special measures as detailed below.
Para-pneumonic pleural effusion
Figure 13.15 Pleural effusion. Biochemical characteristics.
Pleural effusions complicating pneumonia require complete and often repeated aspiration to ensure that an empyema has not developed and that one does not develop, and to reduce the extent of pleural thickening.
Tuberculous pleural effusion
Patients with tuberculous effusions should always receive antituberculosis chemotherapy (see p. 538). Aspiration is required initially if the effusion is large and causing breathlessness. The addition of prednisolone 20 mg daily by mouth for 4-6 weeks in patients with large effusions will promote rapid absorption of the fluid, obviate the need for further aspiration and may prevent fibrosis.
Effusions caused by malignant infiltration of the pleural surfaces usually reaccumulate rapidly. To avoid the distress of repeated aspirations, an attempt should be made to drain all fluid via an intercostal tube and then obliterate the pleural space (pleurodesis) by the injection of substances which produce an inflammatory reaction and extensive pleural adhesions. The agents most frequently used are talc and tetracycline.
A variety of respiratory disorders manifest themselves during sleep. For example, nocturnal cough and wheeze are characteristic features of asthma, and the hypoventilation that occurs during normal sleep can exacerbate respiratory failure in patients with restrictive lung disease such as kyphoscoliosis, diaphragmatic palsy, muscle weakness (e.g. muscular dystrophy) or intrinsic lung disease (e.g. COPD, pulmonary fibrosis). In contrast, a small but important group of disorders cause problems only during sleep. Patients with such disorders have normal lungs and day-time respiratory function but have either abnormalities of ventilatory drive (central sleep apnoea) or upper airway obstruction (obstructive sleep apnoea) that are manifested during sleep. Of these, the obstructive sleep apnoea/hypopnoea syndrome is by far the most common and important disorder.
THE SLEEP APNOEA/HYPOPNOEA SYNDROME
It is now recognised that 2-4% of the middle-aged population suffer from recurrent upper airway obstruction during sleep. Due to the ensuing sleep fragmentation they experience day-time sleepiness, especially in monotonous situations, and this results in a threefold increased risk of road traffic accidents and a ninefold increased risk of single-vehicle accidents.
The problem results from recurrent occlusion of the pharynx during sleep, most often starting at the level of the soft palate. On inspiration the pressure in the throat is subatmospheric. During wakefulness upper airway dilating muscles-including the palatoglossus and genioglossus-actively contract during each inspiration to preserve airway patency. During sleep, muscle tone declines and the ability of the upper airway dilating muscles to maintain pharyngeal patency falls. In most people sufficient tone persists to result in uncompromised breathing during sleep. However, in those who for some reason have a narrow throat when awake, upper airway muscle tone is more important and when it falls during sleep the airway narrows. If the narrowing is slight, turbulent flow and vibration occur, resulting in snoring; around 40% of middle-aged men and 20% of middle-aged women snore. If the upper airway narrowing progresses to the point of occlusion or near-occlusion, sleeping subjects increase respiratory effort to try to breathe until the increased effort transiently awakens them, so briefly that they have no recollection, but long enough for the upper airway dilating muscles to open the airway again. Then a series of deep breaths are taken before the subject rapidly returns to sleep, snores and becomes apnoeic once more. This recurrent cycle of apnoea, awakening, apnoea, awakening etc. may repeat itself many hundreds of times per night and result in severe sleep fragmentation. The awakenings are associated with surges in blood pressure which may lead to an increased frequency of hypertension, ischaemic heart disease and stroke.
Predisposing factors to the sleep apnoea/hypopnoea syndrome include being male, which doubles the risk, probably due to a testosterone effect on the upper airway, and obesity, found in about half the patients and having the effect of narrowing the throat by parapharyngeal fat deposits. Nasal obstruction or anomalies of the upper airway can further exacerbate the problem. Acromegaly and hypothyroidism also predispose individuals to this condition by causing submucosal infiltration and narrowing of the upper airway. The condition is often familial, and in these families the maxilla and mandible are back-set, thus narrowing the upper airway. Alcohol and sedatives predispose to snoring and apnoeas by relaxing the upper airway dilating muscles.
Excessive day-time sleepiness is the principal symptom and snoring is virtually universal. The patient usually feels that he or she has been asleep all night but wakes unrefreshed. Bed partners report loud snoring in all body positions and will often have noticed multiple breathing pauses (apnoeas). Difficulty with concentration, impaired cognitive function and work performance, depression, irritability and nocturia are other features.
Provided that the sleepiness does not result from inadequate time in bed or from shift work etc., any person who falls asleep during the day when not in bed, who complains that his or her work is impaired by sleepiness, or who is a habitual snorer with multiple witnessed apnoeas should be referred to a sleep or respiratory specialist. A more quantitative assessment of day-time sleepiness can be obtained by questionnaire (see Box 13.18).
13.18 EPWORTH SLEEPINESS SCALE
How likely are you to doze off or fall asleep in the situations described below? Use the following scale to choose the most appropriate number for each situation:
0 = would never doze
1 = slight chance of dozing
2 = moderate chance of dozing
3 = high chance of dozing
Sitting and reading
Sitting, inactive in a public place (e.g. a theatre or a meeting)
As a passenger in a car for an hour without a break
Lying down to rest in the afternoon when circumstances permit
Sitting and talking to someone
Sitting quietly after a lunch without alcohol
In a car, while stopped for a few minutes in the traffic
Normal subjects average 5.9 (S.D. 2.2) and patients with severe obstructive sleep apnoea average 16.0 (S.D. 4.4)
Figure 13.16 Sleep apnoea/hypopnoea syndrome: overnight oxygen saturation trace. The left panel shows the trace of a 46-year-old patient during a night when he slept without continuous positive airway pressure (CPAP) and had 53 apnoeas plus hypopnoeas/hour, 55 brief awakenings/hour and marked oxygen desaturation. The right panel shows the next night when he slept with a CPAP of 10 cm H2O delivered through a tight-fitting nasal mask which abolished his breathing irregularity and awakenings and improved his oxygenation.
Overnight studies of breathing, oxygenation and sleep quality are diagnostic (see Fig. 13.16) but the level of complexity of investigations will vary depending on the probability of diagnosis, differential diagnosis and resources. The current threshold for diagnosing the sleep apnoea/hypopnoea syndrome is 15 apnoeas/hypopnoeas per hour of sleep, where an apnoea is a 10-second or longer breathing pause and a hypopnoea a 10-second or longer 50% reduction in breathing.
13.19 DIFFERENTIAL DIAGNOSIS OF PERSISTENT SLEEPINESS
Lack of sleep
Inadequate time in bed
Extraneous sleep disruption (e.g. babies/children)
Excessive caffeine intake
Physical illness (e.g. pain)
Sleep apnoea/hypopnoea syndrome
Periodic limb movement disorder (recurrent limb movements during non-REM sleep, frequent nocturnal awakenings)
Sleepiness with relatively normal sleep
Idiopathic hypersomnolence (rare)
Neurological lesions (e.g. hypothalamic or upper brain-stem infarcts or tumours)
A number of other conditions can cause day-time sleepiness but these can usually be excluded by a careful history (see Box 13.19). Narcolepsy is a rare cause of sleepiness, occurring in 0.05% of the population (see p. 1133), and is associated with cataplexy (when muscle tone is lost in fully conscious people in response to emotional triggers and they may flop over-see p. 1133), hypnagogic hallucinations (hallucinations at sleep onset) and sleep paralysis. Idiopathic hypersomnolence occurs in younger individuals and is characterised by long nocturnal sleeps.
In a few patients advice to avoid evening alcohol and lose weight suffices, but most need to use continuous positive airway pressure (CPAP) delivered by a nasal mask every night at home. CPAP keeps the throat open by making the upper airway pressure above atmospheric. The pressure for CPAP is set in the laboratory to the lowest that will prevent apnoeas, hypopnoeas and awakenings. The effect is often dramatic (see Fig. 13.16) and CPAP results in improvements in symptoms, day-time performance, quality of life and survival. Unfortunately, 30-50% of patients are poorly compliant or do not tolerate such therapy. There is no evidence that upper airway surgery has any role in the management of this condition but mandibular advancement devices may be effective in some patients.
Respiratory failure results from a disorder in which lung function is inadequate for the metabolic requirements of the individual. Its classification into type I and type II relates to the absence or presence of hypercapnia (raised PaCO2). A summary of respiratory failure and its characteristic blood gas abnormalities is shown in Box 13.20.
Management of acute type I respiratory failure
The most common causes of acute type I respiratory failure (PaO2 < 8.0 kPa) are listed in Box 13.21.
All patients should be treated with a high-concentration (= 35%) of oxygen delivered by an oronasal mask. Young children may need to be treated in oxygen tents, since few of them tolerate masks. Very ill patients may require immediate ventilatory support, often involving tracheal intubation and mechanical ventilation (see p. 204). Effective management requires prompt diagnosis and treatment of the underlying disorder. Close monitoring is essential and arterial blood gases taken on presentation should be repeated within 20 minutes to establish that treatment has achieved acceptable PaO2 levels. If there is no improvement despite treating the underlying condition, an early decision about mechanical ventilation is necessary. In acute left ventricular failure, in massive pulmonary embolism and when pulmonary infarction or pneumonia is the cause of pleural pain, treatment with opiates is entirely appropriate, but these drugs should never be used in asthma or COPD, except immediately prior to and during assisted mechanical ventilation.
13.20 RESPIRATORY FAILURE
Type I (PaO2 <> 6.6 kPa)
Acute Chronic Acute Chronic
Typical blood gases PaO2?? PaO2? PaO2? PaO2?
PaCO2 ? or ? PaCO2 ? PaCO2¯? PaCO2?
pH ? or ? pH ? pH? pH? or ?
HCO3 ? HCO3 ? HCO3 ? HCO3?
Causes Acute asthma Emphysema Acute severe asthma COPD
Pulmonary embolus Lung fibrosis Acute epiglottitis Primary alveolar hypoventilation
Pulmonary oedema Lymphangitis Inhaled foreign body Kyphoscoliosis
ARDS carcinomatosa Respiratory muscle paralysis Ankylosing spondylitis
Pneumothorax Right-to-left shunts Flail chest injury
Pneumonia Anaemia Sleep apnoea
Therapy Treat underlying disorder Treat underlying disorder Treat underlying disorder Treat underlying disorder
High-concentration O2 Controlled long-term O2 Controlled low-concentration O2 Controlled long-term O2
Mechanical ventilation if necessary Mechanical ventilation (or tracheostomy) if necessary Mechanical ventilatory support if necessary
13.21 COMMON CAUSES OF ACUTE TYPE I RESPIRATORY FAILURE
Acute severe asthma (causes type II failure when life-threatening)-see page 519
Acute exacerbation of COPD (also causes type II failure)-see page 512
Left ventricular failure and other causes of pulmonary oedema-see page 377
Pulmonary embolism-see page 562
Pneumonia-see page 526
Pneumothorax-see page 570
ARDS-see page 198
Management of type II respiratory failure
In acute type II respiratory failure, also known as asphyxia, CO2 retention occurs (PaCO2 > 6.6 kPa) and causes severe acute respiratory acidosis (see Box 13.20). Treatment is aimed at immediate or very rapid reversal of the precipitating event-e.g. dislodgement of a laryngeal foreign body or tracheostomy, fixation of ribs in a flail chest injury, reversal of narcotic poisons, treatment of acute severe asthma etc. In some cases it will be necessary to support ventilation temporarily by means of non-invasive ventilation (see p. 204) or intubation and mechanical ventilation if the condition causing respiratory failure cannot immediately be reversed.
13.22 SOME CAUSES OF 'ACUTE ON CHRONIC' TYPE II RESPIRATORY FAILURE
Retention of secretions
Rib fractures/intercostal muscle tears
Central nervous system depression (narcotic drugs)
The most common cause of chronic type II respiratory failure is COPD. Here CO2 retention may occur on a chronic basis, the potential for acidaemia being corrected by renal conservation of bicarbonate, which results in the plasma pH remaining within the normal range. The status quo is often maintained until there is a further pulmonary insult (see Box 13.22), such as an exacerbation of COPD which precipitates an episode of 'acute on chronic' respiratory failure.
The further acute increase in PaCO2 results in acidaemia and worsening hypercapnia, and may lead to drowsiness and eventually coma. The principal aim of treatment in type II respiratory failure is to achieve a safe PaO2 (PaO2 > 7.0 kPa) without inducing extremes of PaCO2 or pH while identifying and treating the precipitating condition (see Box 13.22). It is important to note that in the patient who already has severe lung disease, only a small insult may be required to tip the balance towards catastrophic respiratory failure. Moreover, in contrast to acute severe asthma, a patient with type II respiratory failure due to COPD may not be overtly distressed despite being critically ill with severe hypoxaemia, hypercapnia and acidaemia.
In the initial assessment it is important to evaluate the patient's conscious level and his or her ability to respond to commands, particularly the ability to cough effectively. This may give a preliminary indication of whether intubation and tracheal suction may be necessary to clear secretions or whether physiotherapy will be helpful. The decision regarding mechanical ventilation can be complex and difficult. Ideally, an early decision should be made, based mainly on whether there is a potentially remediable precipitating condition (see Box 13.22) and whether the patient is likely to regain an acceptable quality of life. It is important to remember that while physical signs of CO2 retention (confusion, flapping tremor, bounding pulses etc.) can be helpful if present, they are often unreliable; there is no substitute for arterial blood gases in the assessment of initial severity and response to treatment.
13.23 ASSESSMENT AND MANAGEMENT OF 'ACUTE ON CHRONIC' TYPE II RESPIRATORY FAILURE
N.B. Patient may not appear distressed despite being critically ill.
Conscious level (response to commands, ability to cough)
CO2 retention (warm periphery, bounding pulses, flapping tremor)
Airways obstruction (wheeze, intercostal indrawing, pursed lips, tracheal 'tug')
Right heart failure (peripheral oedema, raised JVP, hepatomegaly, ascites)
Background functional status and quality of life
Signs of precipitating event (see Box 13.22)
Arterial blood gases (severity of hypoxaemia, hypercapnia and acidaemia)
Maintenance of airway
Treatment of specific precipitating event (see Box 13.22)
Frequent physiotherapy ± pharyngeal suction
Controlled oxygen therapy
Start with 24% controlled-flow mask
Aim for a PaO2 = 7 kPa (a PaO2 < 5 is very dangerous)
If PaCO2 continues to rise or patient cannot achieve a safe PaO2 without severe hypercapnia and acidaemia, respiratory stimulants (e.g. doxapram) or mechanical ventilatory support may be required
Prompt intervention may occasionally be necessary for some precipitating conditions, e.g. intercostal tube drainage of pneumothoraces or injection with local anaesthetic for fractured ribs and torn muscles; such interventions can result in a dramatic improvement of respiratory function (see Box 13.23). Generally, however, treatment is empirical and includes low-concentration controlled oxygen therapy (24-28% oxygen), physiotherapy, bronchodilators, broad-spectrum antibiotics and diuretics (see p. 512). While the dangers of hypercapnia should not be under-estimated, it is important to recognise that severe hypoxaemia must be reversed if the patient is not to suffer potentially fatal arrhythmias or severe cerebral complications. The aim of oxygen therapy is not necessarily to achieve a normal PaO2; even a small increment of increase in the PaO2 will often have a greatly beneficial effect on oxygen delivery to tissues since the arterial values of these patients are often on the very steep part of the oxygen saturation curve. If controlled oxygen treatment causes an increase in the PaCO2 associated with a reduction in pH, invasive or non-invasive ventilatory support (see p. 203) may be required. Doxapram (1.5-4 mg min-1) by slow intravenous infusion should only be used as a respiratory stimulant where non-invasive ventilation is not available or is poorly tolerated, or in those with reduced respiratory drive due to sedatives or anaesthetic agents. Even in these circumstances this agent provides only minor and transient improvements in arterial blood gas parameters.
The delivery of oxygen to tissue mitochondria is controlled by factors exerting influences at various levels, including: inspired oxygen concentration (FiO2); alveolar ventilation; ventilation-perfusion distribution within the lung; haemoglobin and concentrations of agents such as carbon monoxide which may bind to haemoglobin; influences on the oxygen-haemoglobin dissociation curve (see p. 192); cardiac output; and distribution of capillary blood flow within the tissues.
Many of the causes of hypoxaemia (see Box 13.21) are corrected by increasing the FiO2, but right-to-left shunting, either through circulatory channels bypassing the lung or through parts of the lung in which the alveoli are inaccessible to inspired oxygen, is less susceptible to such therapeutic approaches. The increased amount of dissolved oxygen carried by the blood which has perfused alveoli with a high PaO2 can saturate the haemoglobin in small quantities of shunted blood, but persistence of cyanosis when 100% oxygen is breathed indicates that the shunt is larger than 20% of the cardiac output.
The consequences of severe hypoxaemia include: systemic hypotension, pulmonary hypertension, polycythaemia, tachycardia, and undesirable cerebral consequences ranging from confusion to coma.
The objectives of oxygen therapy are:
to overcome the reduced partial pressure and quantity of oxygen in the blood
to increase the quantity of oxygen carried in solution in the plasma, even when the haemoglobin is fully saturated.
100% oxygen is both irritant and toxic if inhaled for more than a few hours. Premature infants develop retrolental fibroplasia and blindness if exposed to excessive concentrations. In adults, pulmonary oxygen toxicity (as manifested by pulmonary oedema) would not be expected to occur unless the patient had been treated with inappropriately high concentrations of oxygen for more than 24 hours.
Oxygen should always be prescribed in writing with clearly specified flow rates or concentrations.
High concentrations for short periods, such as 60% oxygen via a high-flow mask, are particularly useful in acute type I respiratory failure such as commonly occurs in pneumonia or asthma.
Low concentrations, via a 24% or 28% controlled-flow mask, are the most accurate method of delivering controlled oxygen therapy, particularly in type II respiratory failure. However, when a low concentration of oxygen is required continuously for more than a few hours, 1-2 litres per minute delivered via nasal double cannulae allows patients to eat and to undergo physiotherapy etc. while continuing to receive oxygen. When high-flow masks are used, the oxygen should be humidified by passing it over warm water. This is not necessary with low-flow masks or nasal cannulae, as a high proportion of atmospheric air is mixed with oxygen.
Chronic oxygen delivery from cylinders delivered to the home, or more conveniently from an oxygen concentrator, is often given via a low-concentration mask or nasal cannulae. Assessment for long-term oxygen therapy requires that patients should have a PaO2 of less than 7.3 kPa breathing air and an FEV1 of less than 1.5 litres in the steady state (i.e. at least 1 month since the previous exacerbation) (see p. 512). Long-term oxygen delivery has also been achieved by transtracheal microcatheters which have proved to be both oxygen-saving and of cosmetic benefit.
Patients with initially severe respiratory failure (type I or type II) or those who fail to improve despite optimal medical therapy may require mechanical ventilation. The various types of invasive (via an endotracheal tube) or non-invasive (via a face or nasal mask) ventilation are detailed on page 204. In many patients with respiratory failure, intermittent positive pressure ventilation (IPPV) with full sedation is indicated but nasal positive pressure ventilation (NPPV), delivered by a nasal mask, has proved to be of great value in the treatment of acute on chronic and chronic respiratory failure. Patients who benefit most from long-term (usually nocturnal) NPPV are those with skeletal deformity, especially kyphoscoliosis, and neuromuscular disease. However, NPPV can also be of value in some patients with central alveolar hypoventilation. It is now in widespread use in the acute situation in patients with COPD and type II respiratory failure, usually to try to avoid tracheal intubation and IPPV, but also in weaning such patients from mechanical ventilation.
Lung transplantation is now an established treatment for carefully selected patients with advanced cardiopulmonary disease unresponsive to medical treatment. Transplantation of both heart and lungs was the first successful approach for many disorders (see Box 13.24). However, improved surgical techniques and the shortage of donor organs have led to the development of isolated lung transplantation using double or single lungs. More recently, living lobar transplantation has been introduced. Single-lung transplantation is best applied for older patients with emphysema and patients with intrapulmonary restrictive disorders such as lung fibrosis. It is contraindicated in patients with chronic bilateral pulmonary infection, such as cystic fibrosis and bronchiectasis, where bilateral lung transplantation is the favoured option. Combined transplantation of the heart and lungs remains necessary for the treatment of patients with advanced congenital heart disease such as Eisenmenger's syndrome and is preferred by some surgeons for the treatment of primary pulmonary hypertension unresponsive to prostenoid therapy.
13.24 SOME INDICATIONS FOR HEART-LUNG TRANSPLANTATION
Parenchymatous lung disease
Langerhans cell histiocytosis
Pulmonary vascular disease
Primary pulmonary hypertension
Thromboembolic pulmonary hypertension
Eisenmenger's syndrome (see p. 470)
pages 494 - 508
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > OBSTRUCTIVE PULMONARY DISEASES
OBSTRUCTIVE PULMONARY DISEASES
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Chronic obstructive pulmonary disease is the internationally preferred term encompassing chronic bronchitis and emphysema. By definition COPD is a chronic, slowly progressive disorder characterised by airflow obstruction (FEV1 < 80% predicted and FEV1/VC ratio <70%) which does not change markedly over several months. The impairment of lung function is largely fixed but may be partially reversible by bronchodilator therapy. Historically, the term 'chronic bronchitis' was used to define any patient who coughed up sputum on most days of at least 3 consecutive months for more than 2 successive years (provided other causes of cough had been excluded) and 'emphysema' referred to the pathological process of a permanent destructive enlargement of the airspaces distal to the terminal bronchioles. Although 'pure' forms of these two conditions do exist, there is considerable overlap in the vast majority of patients.
Integration link: COPD
Taken from General & Systematic Pathology 4e
The death rate from COPD currently exceeds 25 000/year (> 20-fold higher than asthma) in England and Wales and this condition accounts for over 10% of all hospital medical admissions in the United Kingdom.
Aetiology and natural history
The single most important cause of COPD is cigarette smoking although in developing countries exposure to smoke from biomass and solid fuel fires is also important. Smoking is thought to have its effect by inducing persistent airway inflammation and causing a direct imbalance in oxidant/antioxidant capacity and proteinase/antiproteinase load in the lungs. Individual susceptibility to smoking is, however, very wide, with only 15% of smokers likely to develop clinically significant COPD. Recent studies have also emphasised the strong familial risks associated with the development of COPD, with the incidence of disease in an individual who smokes and has an affected sibling being 4.7 times that of matched controls. A small additional contribution to the severity of COPD has been reported in patients exposed to dusty or polluted air. An association also exists between low birth weight, bronchial hyper-responsiveness and the development of COPD. Alpha1-antitrypsin deficiency can cause emphysema in non-smokers but this risk is increased dramatically in enzyme-deficient patients who smoke. Stopping smoking slows the average rate of the decline in FEV1 from 50-70 ml/year to 30 ml/year (i.e. equal to non-smokers) (see Fig. 13.17). Interestingly, there is no evidence that acute exacerbations or drug therapy affect the rate of decline of the FEV1.
Figure 13.17 Model of annual decline in FEV1 with accelerated decline in susceptible smokers. When smoking is stopped, subsequent loss is similar to that in healthy non-smokers.
Figure 13.18 The pathology of emphysema. A Normal lung. B Emphysematous lung showing gross loss of the normal surface area available for gas exchange.
Most patients develop airway wall inflammation, hypertrophy of the mucus-secreting glands and an increase in the number of goblet cells in the bronchi and bronchioles with a consequent decrease in ciliated cells. There is, therefore, less efficient transport of the increased mucus in the airways. Airflow limitation reflects both mechanical obstruction in the small airways and loss of pulmonary elastic recoil. Loss of alveolar attachments around such airways makes them more liable to collapse during expiration.
Emphysema is usually centriacinar, involving respiratory bronchioles, alveolar ducts and centrally located alveoli. More rarely, panacinar emphysema (see Fig. 13.18) or paraseptal emphysema develops, with the latter responsible for blebs on the lung surface and/or giant bullae. Pulmonary vascular remodelling caused by persistent hypoxaemia results in pulmonary hypertension and right ventricular hypertrophy and dilatation.
Integration link: Emphysema - pathology
Taken from General & Systematic Pathology 4e
13.25 CLASSIFICATION AND DIAGNOSIS OF COPD
Severity Spirometry Symptoms
Mild FEV1 60-79% predicted Smoker's cough ± exertional breathlessness
Moderate FEV1 40-59% predicted Exertional breathlessness ± wheeze, cough ± sputum
Severe FEV1 < 40% predicted Breathlessness, wheeze and cough prominent, swollen legs
The clinical state is dictated largely by the severity of disease (see Box 13.25). The initial symptoms are usually repeated attacks of productive cough, usually after colds during the winter months, which show a steady increase in severity and duration with successive years until cough is present all the year round. Thereafter, patients suffer recurrent respiratory infections, exertional breathlessness, regular morning cough, wheeze and occasionally chest tightness. Sputum may be scanty, mucoid, tenacious and occasionally streaked with blood during infective exacerbations. Frankly purulent sputum is indicative of bacterial infection, which often occurs in these patients. Breathlessness is aggravated by infection, excessive cigarette smoking and adverse atmospheric conditions.
In patients with mild to moderate disease the respiratory examination may be normal. However, variable numbers of inspiratory and expiratory rhonchi, mainly low- and medium-pitched, are audible in most patients. Crepitations (crackles) which usually, but not always, disappear after coughing may be audible over the lower zones.
Physical signs associated with severe disease are outlined in Box 13.26. These reflect pulmonary hyperinflation, hypoxaemia, the development of cor pulmonale (pulmonary hypertension and right heart failure) and polycythaemia.
Integration link: "Pink puffers" and "blue bloaters"
Taken from General & Systematic Pathology 4e
Pulmonary bullae are thin-walled airspaces created by rupture of alveolar walls. They may be single or multiple, large or small, and tend to be situated subpleurally. Rupture of subpleural bullae may cause pneumothorax (see p. 570), and occasionally bullae increase in size, compress functioning lung tissue and further embarrass pulmonary ventilation. Respiratory failure and cor pulmonale are generally late complications in COPD patients.
Pulmonary function tests
The diagnosis and classification of COPD rest on objective demonstration of airways obstruction by spirometric testing (see Box 13.25). An abnormal FEV1 (< 80% predicted), with an FEV1/VC ratio of < 70% and little variation in serial PEF, strongly suggests COPD. A normal FEV1 excludes the diagnosis. The relationship between FEV1 and PEF is poor in COPD, and PEF in particular may under-estimate the degree of airflow obstruction in these patients.
Reversibility testing to salbutamol and ipratropium bromide is necessary to detect patients with substantial increases in FEV1 who really have asthma, and to establish the post-bronchodilator FEV1 which is the best predictor of long-term prognosis. Significant reversibility is defined as a 15% and at least 200 ml increase in FEV1. Evidence of a similar objective response to a course of oral prednisolone (30 mg daily for 2 weeks) should also be performed in all patients with COPD.
13.26 CLINICAL ABNORMALITIES IN PATIENTS WITH ADVANCED AIRFLOW OBSTRUCTION
Rhonchi, especially on forced expiration
A reduction in the length of the trachea palpable above the sternal notch
Tracheal descent during inspiration (tracheal 'tug')
Contraction of the sternomastoid and scalene muscles on inspiration
Excavation of the suprasternal and supraclavicular fossae during inspiration, together with indrawing of the costal margins and intercostal spaces
Increased antero-posterior diameter of the chest relative to the lateral diameter; loss of cardiac dullness
Loss of weight common (often stimulates unnecessary investigation)
Pursed lip breathing-physiological response to decrease air trapping
Flapping tremor and bounding pulse (due to hypercapnia)
Peripheral oedema which may indicate cor pulmonale
Raised JVP, right ventricular heave, loud pulmonary second sound, tricuspid regurgitation
Lung volumes show an increase in total lung capacity (TLC) and residual volume (RV) due to gas trapping; the carbon monoxide transfer factor and coefficient are markedly reduced in patients with a severe emphysema component. Alveolar underventilation causes a fall in PaO2 and often a permanent increase in PaCO2, especially in severe cases. Measurement of arterial blood gases should be performed in all patients with severe COPD (FEV1 < 40% predicted).
Exercise tests are of little diagnostic value but can provide an objective assessment of exertional dyspnoea.
Figure 13.19 Gross emphysema. High-resolution CT showing emphysema most evident in the right lower lobe.
COPD cannot be diagnosed on a chest radiograph but this investigation is useful in excluding other pathology. In moderate and severe COPD the chest radiograph typically shows hypertranslucent lung fields with disorganisation of the vasculature, low flat diaphragms or 'terracing' of the hemidiaphragms and prominent pulmonary artery shadows at both hila. Bullae may also be observed. CT can be used to quantify the extent and distribution of emphysema (see Fig. 13.19) but its clinical value is currently restricted to the assessment of bullous emphysema and the potential for lung volume reduction surgery or lung transplantation (see p. 508). Patients with a1-antitrypsin deficiency typically display basal disease, compared with the predominantly apical disease seen in smokers with normal a1-antitrypsin levels.
Polycythaemia (see p. 904) may develop but should not be assumed to be secondary without measurement of PaO2. Venesection may be considered if the haematocrit is above 0.55.
The treatment of patients with stable COPD is outlined in Figure 13.20.
Reduction of bronchial irritation
It is of extreme importance that the patient who smokes should stop completely and permanently. Participation in an active smoking cessation programme, together with the use of nicotine replacement therapy, leads to a higher quit rate. In well-motivated patients bupropion (150 mg once daily increasing to 150 mg 12-hourly on day 7) commenced 1-2 weeks prior to stopping smoking is also a valuable adjunct to smoking cessation. Bupropion is contraindicated in those patients with a history of epilepsy or known CNS tumour and should only be used for 7-9 weeks (see Box 13.27).
Figure 13.20 Summary of management of COPD.
Telephone advice for patients wanting to stop smoking is available in the UK on:
NHS Smoking Helpline: 0800 1690169
QUIT: 0800 002200.
13.27 RECOMMENDATIONS FOR USING ANTI-SMOKING INTERVENTIONS*
Smokers who are not motivated to try to stop smoking
Record smoking status at regular intervals
Encourage change in attitude regarding smoking to improve motivation
Motivated light smokers (< 10/day)
Involve in anti-smoking support programme
Motivated heavy smokers (10-15/day)
As above plus nicotine replacement therapy (NRT) (minimum 8 weeks)
Motivated heavy smokers (> 15/day)
As above plus bupropion if NRT and behavioural support unsuccessful and patient remains motivated
Dusty and smoke-laden atmospheres should be avoided; this may involve a change of occupation.
Treatment of respiratory infection
Respiratory infection should be treated promptly because it aggravates breathlessness and may precipitate type II respiratory failure in patients with severe airflow obstruction. Purulent sputum is treated with amoxicillin 250 mg 8-hourly (clarithromycin 250-500 mg 12-hourly if penicillin-sensitive) pending sputum culture results. Co-amoxiclav 375 mg 8-hourly should be used if there is no response or if a ß-lactamase-producing organism is cultured. The usual causative organisms are Streptococcus pneumoniae or Haemophilus influenzae. A 5-10-day course of treatment is usually effective. Well-informed, reliable patients can be given a supply of one of these drugs and start a course of treatment on their own initiative when the need arises.
Continuous suppressive antibiotic treatment is not advised as it is apt to promote the emergence of drug-resistant organisms within the respiratory tract. Influenza immunisation should be offered to all patients each year.
Bronchodilator and anti-inflammatory therapy
COPD-role of regular inhaled corticosteroids
'Several large RCTs have found no evidence for a long-term beneficial effect of inhaled corticosteroid therapy on the annual decline in FEV1 in patients with smoking-related COPD.'
Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue to smoke. N Engl J Med 1999; 340:1948-1953.
Burge PS, Calvertey PM, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320:1297-1303.
Bronchodilator therapy with regular inhaled anticholinergic agents and short-acting ß2-agonists taken as required provides useful symptomatic relief in the majority of patients. In moderate and severe COPD these agents should be used regularly and in combination, and low-dose inhaled steroids considered in patients with severe COPD and frequent exacerbations requiring hospital admission. These latter agents should not be used routinely (see EBM panel). Theophyllines and long-acting ß2-adrenoceptor agonists are of limited value in COPD but may produce small increases in exercise tolerance and quality of life. There is no role for other anti-inflammatory drugs. It is vital to check inhaler use as many patients with COPD struggle to use metered-dose inhalers (MDIs) effectively; dry powder inhalers or large-volume spacer devices are often preferable. The use of home nebulisers to deliver high doses of bronchodilator drugs is controversial. Treatment is expensive and may have important side-effects; however, a few patients may show significant objective or subjective improvements with such treatment.
Exercise should be encouraged and outpatient-based pulmonary rehabilitation programmes, while not affecting the FEV1, can improve exercise performance and reduce breathlessness. Obesity, poor nutrition, depression and social isolation should be identified and, if possible, improved. Expectorants, cough suppressants and mucolytic agents are of no proven benefit. Sedatives and opiate-based analgesic preparations are contraindicated.
Long-term domiciliary oxygen therapy
13.28 PRESCRIPTION OF LONG-TERM OXYGEN THERAPY (LTOT) IN COPD
Arterial blood gases measured in clinically stable patient on optimal medical therapy on at least two occasions 3 weeks apart
PaO2 < 7.3 kPa irrespective of PaCO2 and FEV1 < 1.5 litres
PaO2 7.3-8 kPa plus pulmonary hypertension, peripheral oedema or nocturnal hypoxaemia
Patient stopped smoking
Use at least 15 hours/day at 2-4 litres/min to achieve PaO2 > 8 kPa without an unacceptable rise in PaCO2
COPD-role of long-term domiciliary oxygen therapy (LTOT)
'Two RCTs have demonstrated that long-term oxygen therapy (used for = 15 hours/day) in patients with COPD and chronic and severe hypoxaemia improves survival, reduces secondary polycythaemia and prevents the progression of pulmonary hypertension. LTOT did not improve survival in patients with moderate hypoxaemia or in those with arterial desaturation occurring only at night.'
Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxaemic chronic obstructive lung disease. A clinical trial. Ann Intern Med 1980; 93:391-398.
MRC Working Group. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681-686.
Crockett AJ, Cranston JM, Moss JR, Alpers JH. Domiciliary oxygen for COPD (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.brit-thoracic.org.uk
Long-term low-concentration oxygen therapy (2 litres/min by nasal cannulae) decreases pulmonary hypertension, reduces secondary polycythaemia, improves neuropsychological health and, most importantly, prolongs life in hypoxaemic COPD patients. The most efficient method of providing oxygen in this way is by an oxygen concentrator. Low-concentration oxygen should be administered for 15 hours or more per 24 hours. The criteria for the prescription of long-term oxygen therapy are given in Box 13.28.
Medical assessment and clearance are required in all patients who are dyspnoeic on walking 50 m. In practice, all patients with a resting PaO2 on air of < 9.0 kPa will require supplemental oxygen since at usual in-flight cabin pressures equivalent to an altitude of 5000-8000 feet the PaO2 of such patients will fall below 7 kPa. Hypercarbia or gross hypoxaemia while breathing air (PaO2 < 6.7 kPa) is a relative contraindication to air travel. Additional hazards include expansion of non-functioning emphysematous bullae and abdominal gases and drying of bronchial secretions.
A very small group of patients are suitable for surgical intervention. Young patients, particularly those with a1-antitrypsin deficiency and severe disease, should be considered for lung transplantation (usually single-lung), and surgical removal of expanding or very large bullae may be indicated in some patients. Lung volume reduction surgery, in which the most severely affected areas of emphysematous lung are removed in order to improve pulmonary mechanics, particularly by enhancing diaphragmatic function, is currently under assessment.
Treatment of acute COPD exacerbations
13.29 MANAGEMENT OF ACUTE COPD EXACERBATIONS
In the community
Add or increase bronchodilator therapy
Antibiotics (see p. 511)
Oral corticosteroids if patient already on oral corticosteroids, if previous response to such treatment, if airflow obstruction fails to respond to bronchodilator therapy or if first presentation of disease (prednisolone 30 mg daily for 1 week)
Check arterial blood gases (ABGs), chest radiograph, ECG, full blood count, urea and electrolytes; measure FEV1 + peak flow; send sputum for culture
Oxygen: 24-28% via mask, 2 litres/min by nasal prongs; check ABGs within 60 mins and adjust according to PaO2 (try to keep = 7.5 kPa) and PaCO2/pH
Bronchodilators: nebulised ß2-adrenoceptor agonist (+ ipratropium bromide if severe) 4-6-hourly. If no response consider i.v. aminophylline infusion
Oral corticosteroids: indicated as above
Diuretics: indicated if JVP elevated and oedema present
If pH <> 6, consider ventilatory support (invasive or non-invasive IPPV, see p. 508). If patient continuing to deteriorate despite non-invasive ventilation support, and endotracheal intubation not indicated (e.g. previous poor quality of life, significant comorbidity), doxapram can be considered
Prophylactic subcutaneous low molecular weight heparin
N.B. All patients should be reviewed 4-6 weeks after hospital discharge to assess ability to cope at home, FEV1, inhaler technique and understanding of treatment, and the potential need for LTOT or a home nebuliser.
The assessment and management of type I and type II respiratory failure are detailed on page 505. Acute exacerbations of COPD can present as increased sputum volume and purulence, increased breathlessness and wheeze, chest tightness and sometimes fluid retention. The differential diagnosis includes pneumonia, pneumothorax, left ventricular failure, pulmonary embolism, lung cancer and upper airway obstruction. The management of an acute COPD exacerbation is outlined in Box 13.29. Any patient with severe breathlessness, cyanosis, worsening oedema, impaired conscious level or poor social circumstances should be referred for hospital admission.
COPD EXACERBATIONS-role of non-invasive ventilation
'RCTs have demonstrated that the early use of non-invasive ventilation of patients with an acute exacerbation of COPD associated with mild to moderate respiratory acidosis (arterial pH 7.25-7.35, PaCO2 > 6 kPa) reduces the need for endotracheal intubation, the length of hospital stay and the in-hospital mortality.'
Brochard L, Mancebo J, Wysocki M, et al. Non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995; 333:817-822.
Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet 2000; 355:1931-1935.
The best guide to the progression of COPD is the decline in FEV1 over time (normally 30 ml/year). The prognosis is inversely related to age and directly related to the post-bronchodilator FEV1. Patients with atopy have a significantly better survival but to date no drug treatment (aside from long-term oxygen therapy) has been shown to affect disease outcome. Pulmonary hypertension in COPD implies a poor prognosis. The mean survival of patients admitted with an acute exacerbation of COPD associated with an elevated PaCO2 that reverts to normal on recovery is 3 years.
Asthma is defined as a disorder characterised by chronic airway inflammation and increased airway responsiveness resulting in symptoms of wheeze, cough, chest tightness and dyspnoea. It is characterised functionally by the presence of airflow obstruction which is variable over short periods of time or is reversible with treatment. It is not a uniform disease but rather a dynamic clinical syndrome which has a number of clinical patterns. Many patients with well-controlled asthma are asymptomatic with normal lung function between exacerbations, although even these patients have evidence of chronic airway inflammation and hyper-responsiveness. By contrast, in some patients with chronic asthma the asthma progresses, leading to irreversible obstruction of the airways (see Box 13.30).
13.30 CARDINAL PATHOPHYSIOLOGICAL FEATURES OF ASTHMA
Usually reverses spontaneously or with treatment
Exaggerated bronchoconstriction to a wide range of non-specific stimuli, e.g. exercise, cold air
Eosinophils, lymphocytes, mast cells, neutrophils; associated oedema, smooth muscle hypertrophy and hyperplasia, thickening of basement membrane, mucous plugging and epithelial damage (see Fig. 13.22, p. 515)
Asthma is common and its prevalence is increasing. Studies using objective measurements of lung function, airway responsiveness and symptoms suggest that about 7% of adults and up to 15% of children in the UK have asthma. There is considerable interest in the reasons for the increase in the prevalence of asthma, most probably relating to changes in the indoor environment including early exposure to air allergens and cigarette smoke, fewer childhood infections and changes in diet. There is a wide variability in the geographical prevalence of asthma, with the highest rates observed in New Zealand, Australia and the UK, and the lowest in countries such as China and Malaysia.
Asthma is multifactorial in origin, arising from the interaction of both genetic and environmental factors. Airway inflammation characterising asthma occurs when genetically susceptible individuals are exposed to environmental factors, but the exact processes may vary from patient to patient. The timing, intensity and mode of exposure to aero-allergens are important environmental factors which stimulate the production of IgE.
It has long been known that asthma and atopy run in families. Asthma which begins in childhood generally occurs in atopic individuals who produce significant amounts of IgE on exposure to small amounts of common antigens. This contrasts with those patients who develop asthma in adult life and who are non-atopic, so-called 'intrinsic' or late-onset asthma. First-degree relatives of asthmatic patients have a higher prevalence of asthma when compared to relatives of non-asthmatic patients. Atopic individuals demonstrate positive reactions to antigens delivered in skin prick tests and have a high prevalence of asthma, allergic rhinitis, urticaria and eczema. Several potential gene linkages (e.g. chromosome 11q13) to asthma and atopy have been suggested; however, the genetic contribution to asthma remains poorly defined. It possibly involves polygenic inheritance with several genes contributing to the asthmatic tendency in any one individual, and genetic heterogeneity where different combinations of genes lead to asthma in different individuals.
The importance of environmental factors in the aetiology of asthma has been particularly evident in studies of populations who have migrated from one country to another. The change to a modern, urban, economically developed society seems to be particularly associated with the development of asthma.
Indoor. The indoor environment is a particularly important cause of asthma in children since allergen exposure early in life appears to be important in determining sensitisation. House dust mites abound in carpets, soft furnishings and bedding, and pet-derived allergens are widespread in houses where dogs or cats are kept. Other allergens of relevance are fungal spores and cockroach antigens. Pollutants such as nitrogen dioxide are found in higher concentrations indoors than outside as a result of gas cookers. Sulphur dioxide and particulate pollutants are released from open fires. Passive exposure to cigarette smoke immediately following birth increases the risk of developing asthma.
Outdoor. Experimental and population studies have shown that nitrogen dioxide, ozone, sulphur dioxide and air-borne particulates exacerbate asthma symptoms. The predominant source of nitrogen dioxide comprises motor vehicle emissions and fuel-burning industries. Nitrogen dioxide reacts with sunlight and oxygen in a photochemical reaction to produce ozone. Sulphur dioxide is created by the burning of fossil fuels and emissions from diesel-powered vehicles. Such vehicles also contribute to the development of air-borne particulates. Finally, levels of grass and flower pollens vary considerably according to the atmospheric conditions, as do allergens from rapeseed, soya bean and other crops. Interactions between atmospheric pollutants, aero-allergens and climate will have important effects on asthma, with some studies showing exposure to air pollution increasing airway responsiveness to allergens. Several epidemics of acute asthma have been associated with thunderstorms in patients sensitised to both pollen and fungal antigens.
Work. Many agents encountered in the workplace may induce occupational asthma, e.g. isocyanates, epoxy resins and wood dust.
Beta2-adrenoceptor antagonists (ß-blockers) can induce bronchoconstriction even when administered in the form of eye drops. Hence ß-blockers should be avoided in patients with asthma or COPD. Approximately 10% of asthmatic patients develop bronchoconstriction when given salicylates (e.g. aspirin) or non-steroidal anti-inflammatory agents.
Many viral and bacterial infections of the respiratory system produce a transient increase in airway responsiveness in asthmatic patients. Viruses in particular are an important cause of asthma exacerbations.
Smoking during pregnancy is thought to increase the risk of developing atopic disease in infancy, and passive exposure to smoking has an adverse effect on asthma and other respiratory diseases.
Anxiety and psychosocial factors
Any cause of severe anxiety or stress (see p. 252) can exacerbate asthma, and acute emotion may provoke an acute attack, but there is no evidence that asthmatics are primarily psychologically disturbed.
Figure 13.21 Changes in peak flow following allergen challenge. A similar biphasic response is observed following a variety of different challenges. Occasionally an individual will develop an isolated late response with no early reaction.
Figure 13.22 Pathological changes in asthma. A Pathological changes seen in the bronchus of an asthmatic. B Histological section of bronchus in a patient with asthma, demonstrating pathological changes as illustrated in A. (I = inflammatory cells in bronchial tissues; SM = smooth muscle; BM = basement membrane; EP = epithelium; M = mucus in airway lumen) C Mucus plug expectorated by patient with acute severe asthma.
The inhalation of an allergen in a sensitised atopic asthmatic patient results in a two-phase bronchoconstrictor response (see Fig. 13.21). The inhaled allergen rapidly interacts with mucosal mast cells via an IgE-dependent mechanism, resulting in the release of mediators such as histamine and the cysteinyl leukotrienes which lead to bronchoconstriction. A full spectrum of inflammatory cells, however, are involved in the perpetuation of the chronic inflammatory reaction in the bronchial wall which characterises asthma. It is now known that epithelial and smooth muscle cells are also capable of releasing inflammatory mediators rather than acting solely as passive targets. All of these cells are also involved in the initiation of asthma in non-atopic patients. T lymphocytes are present in increased numbers in asthmatic airways and have an important role in the regulation of the inflammatory response. They are programmed to release inflammatory cytokines amongst which IL-4 and IL-5 are of importance since they both recruit eosinophils to the airway and delay apoptosis of these cells. This pattern of cytokine release, which also includes IL-15, GM-CSF and IL-10, identifies the T cells as being of TH2 subtype. Eosinophils are characteristically present in increased numbers in the airway. These cells release bioactive lipid mediators and oxygen radicals; their granules also contain toxic basic proteins including major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin and eosinophil peroxidase. The number of airway macrophages is also increased in asthma and these cells may be activated by a number of mechanisms including a low affinity IgE receptor. Epithelial shedding (see Fig. 13.22) is commonly observed in airway biopsies from asthmatic patients. This has long been recognised as a feature of fatal asthma. Microvascular leakage is also a feature and may be triggered by many inflammatory mediators. This results in plasma exudation into the lumen of the airways, contributing to mucous plugging, decreased mucociliary clearance, release of kinins and complement fragments and oedema of the airway wall which facilitates epithelial stripping. The increase in airway smooth muscle bulk around the airways appears to be a particularly important contributory factor in airflow obstruction. Likewise, airway inflammation induces an imbalance between cholinergic and peptidergic neuronal control, causing exaggerated bronchoconstrictor responses. As a result of the ongoing airway inflammation, therefore, the asthmatic airway wall is thickened by oedema, cellular infiltration, increased smooth muscle mass and hypertrophy of mucus-secreting glands. With increasing severity and chronicity of the disease, remodelling of the airway occurs, leading to fibrosis of the airway wall, fixed narrowing of the airway and a reduced response to bronchodilator medication. Although in clinical practice patients with asthma are sometimes classified as having 'extrinsic' asthma (occurring in relation to inhalation of environmental antigens) or 'intrinsic' asthma (occurring without any definable relationship to an environmental antigen), the pathological features of the airway inflammation are identical. It is likely that the inflammatory cascade of asthma can be initiated by a variety of different factors in different patients.
Typical symptoms of asthma comprise wheeze, breathlessness, cough and a sensation of chest tightness. These symptoms may occur for the first time at any age, and may be episodic or persistent. Patients with episodic asthma are usually asymptomatic between exacerbations, which occur during viral respiratory tract infections or after exposure to allergens. This pattern of asthma is commonly seen in children or young adults who are atopic. In other patients the clinical pattern is of persistent asthma with chronic wheeze and breathlessness. This may sometimes make it difficult to distinguish from wheeze due to COPD or more unusual causes, e.g. cardiac failure. (Note that acute pulmonary oedema or an inhaled foreign body in a child can cause acute wheeze which can mimic acute severe asthma-see below.) This pattern is more common in older patients with adult-onset asthma who are non-atopic and typifies intrinsic asthma. The variable nature of symptoms is a characteristic feature. Typically, there is a diurnal pattern (see Fig. 13.23), with symptoms and peak expiratory flow measurement being worse in the early morning. Symptoms such as cough and wheeze often disturb sleep and the term 'nocturnal asthma' emphasises this. Cough may be the dominant symptom and the lack of wheeze or breathlessness may lead to a delay in making the diagnosis of so-called 'cough variant asthma'. Symptoms may be specifically provoked by exercise ('exercise-induced asthma'). All of these descriptive clinical terms are useful in emphasising the characteristic features of asthma particular to each patient and highlight the fact that asthma is not a uniform static disease but a broad dynamic syndrome.
Acute severe asthma
This term has replaced status asthmaticus as a description of life-threatening attacks of asthma. Patients are usually extremely distressed, using accessory muscles of respiration, are hyperinflated and tachypnoeic. Respiratory symptoms are accompanied by tachycardia, pulsus paradoxus (loss of pulse pressure on inspiration due to reduced cardiac return as a consequence of severe hyperinflation) and sweating. In very severe asthma central cyanosis occurs and airflow may have become so restrictive that rhonchi are no longer produced. The presence of a silent chest and bradycardia in such patients is an ominous sign.
A diagnosis of asthma is made on the basis of a compatible clinical history plus a demonstration of variable airflow obstruction (see Box 13.31) which may classically be seen as 'morning dipping' of the peak expiratory flow (see Fig. 13.23).
Figure 13.23 'Morning dipping'. Serial recordings of peak expiratory flow (PEF) in patients with COPD and asthma. Note sharp overnight fall (morning dip) and subsequent rise during the day in patients with asthma, which does not occur in patients with COPD.
13.31 MAKING A DIAGNOSIS OF ASTHMA
Compatible clinical history plus either/or:
= 15% improvement in FEV1 or PEF following administration of a bronchodilator (see Fig. 13.24) or
= 15% spontaneous change in PEF during 1 week of home monitoring (see Fig. 13.23)
In more difficult situations where the above tests are negative, an exercise test, a histamine or methacholine bronchial provocation test (see p. 517), an occupational exposure test or a trial of oral corticosteroids (e.g. prednisolone 30 mg daily for 2 weeks) may be required. An elevated sputum or peripheral blood eosinophil count, or an increased serum level of total or allergen-specific IgE (radioallergosorbent test-RAST) may also be helpful. It is particularly important, however, to be aware that wheeze is audible in many conditions other than asthma.
Pulmonary function tests
Figure 13.24 Reversibility test. Forced expiratory manoeuvres before and 20 minutes after inhalation of a ß2-adrenoceptor agonist. Note the increase in FEV1 from 1.0 to 2.5 litres.
Figure 13.25 Exercise-induced asthma. Serial recordings of forced expiratory volume in 1 second (FEV1) in a patient with bronchial asthma before and after 6 minutes of strenuous exercise. Note initial slight rise on completion of exercise, followed by sudden fall and gradual recovery. Adequate warm-up exercise or pre-treatment with a ß2-adrenoceptor agonist, nedocromil sodium or a leukotriene antagonist (e.g. montelukast sodium) often protects against exercise-induced symptoms.
Measurement of the FEV1/VC ratio or PEF provides a fairly reliable indication of the degree of airflow obstruction, and can also be used to determine whether and to what extent it can be relieved by bronchodilator drugs (see Fig. 13.24). These parameters are also used to examine whether asthma is provoked by exercise (see Fig. 13.25), hyperventilation or occupational exposure. Serial recordings of PEF are useful in distinguishing patients with chronic asthma from those with fixed or irreversible airflow obstruction associated with COPD. In asthma there is usually a marked diurnal variation in PEF, the lowest values being recorded in the mornings ('morning dipping') (see Fig. 13.23). Serial PEF recordings are also invaluable in the assessment of a patient's response to corticosteroid therapy and in the long-term monitoring of patients with poorly controlled disease. They are also essential in monitoring response to treatment in acute severe asthma.
Measurement of bronchial reactivity can be of value in diagnosing asthma and in assessing the effects of treatment. This can be achieved by administering increasing concentrations of substances such as histamine and methacholine by inhalation until there is a 20% fall in FEV1 or PEF. This concentration is called the PC20. Patients with asthma show evidence of bronchoconstriction at much lower concentrations than normal subjects.
In an acute attack of asthma the lungs appear hyperinflated. Between episodes the chest radiograph is usually normal. In long-standing chronic cases the appearances may be indistinguishable from hyperinflation caused by emphysema and a lateral view may demonstrate a 'pigeon chest' deformity. Occasionally, when a large bronchus is obstructed by tenacious mucus, there is an opacity caused by lobar or segmental collapse.
A chest radiograph should be performed in all patients with acute severe asthma. This is especially important if there is poor response to treatment and assisted ventilation is being contemplated, since pneumothorax is a rare but potentially fatal complication. The chest radiograph may rarely show mediastinal, pericardial or subcutaneous emphysema in patients with acute severe asthma.
Allergic bronchopulmonary aspergillosis may complicate chronic persisting asthma (see p. 540) and produce areas of segmental/subsegmental collapse and proximal bronchiectasis.
Arterial blood gas analysis
Measurements of arterial blood gas pressures (PaO2 and PaCO2) are indispensable in the management of patients with acute severe asthma.
Successful management of asthma mandates that the patient or parents of a child with asthma understand the nature of the condition and its treatment. Patient education should begin at the time of diagnosis and be revisited in every subsequent consultation between patient, doctor or nurse. Education involves the patient understanding the nature of asthma, the practical skills necessary to manage asthma successfully and the adoption of appropriate actions in response to deteriorating asthma. It is important for patients to appreciate differences between reliever (bronchodilator) and preventer (anti-inflammatory) medications and patients should be fully capable of using their inhaler devices. Use of a peak flow meter provides patients with an objective measure of airway obstruction and allows them to monitor the effect of treatment and the severity of exacerbations. There is clear evidence that the development of a personalised asthma action plan for patients improves outcome and this should be discussed individually with patients.
ASTHMA-role of self-management plans
'Self-management plans advising asthmatic patients how to respond to worsening symptoms or PEF lead to less need for emergency medical care, less time off work and a better quality of life.'
Lahdensno A, Halahtela T, Herals J, et al. Randomised comparison of guided self-management and traditional treatment of asthma over one year. BMJ 1996; 312:748-752.
Ignacio-Garcia J, Gonzalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995; 151:353-359.
Avoidance of precipitating factors
There are few instances in which a single agent can be identified as a cause of an asthma exacerbation; however, where possible, measures can be taken to prevent or reduce allergen exposure, such as avoiding contact with household pets.
Desensitisation is a highly specialised technique in which repeated injections of an allergen are given in an attempt to produce blocking antibody of IgG type which can prevent the allergen from binding to specific IgE on mast cells. It is most commonly used in well-documented life-threatening anaphylactic reactions to insect stings; there is little evidence of its benefit in asthma and this form of therapy has largely been abandoned in the UK because of the attendant risks.
Management of chronic persistent asthma
Treatment should be stepped up or down as required, with PEF monitoring being key to such decisions. The patient should be allowed to select the best inhaler device for himself or herself, and compliance and inhaler technique must be checked at every opportunity. All metered dose inhalers (MDIs) which remain the most cost-effective inhaler devices will be reformulated over the next few years to replace conventional chlorofluorocarbon (CFC) propellants with hydrofluoroalkanes (HFAs). While these products are equally effective and as safe as current CFC-containing MDIs, the aerosol characteristics are different and this may be noticed by patients. In patients with mild to moderate asthma (on step 1-3 medication-see below and Fig. 13.26) the aim of treatment should be to abolish or minimise all symptoms, permit unrestricted exercise and prevent exacerbations. In patients with more severe disease (on step 4-5 medication) the aim should be to achieve the best possible and most stable PEF, to improve symptoms and exercise capacity, and to reduce the need for bronchodilator drug use as far as possible with the least adverse effects from the drugs used.
Step 1 Occasional use of inhaled short-acting ß2-adrenoceptor agonist bronchodilators
Figure 13.26 Concept of step-up and step-down drug treatment in asthma.
Short-acting bronchodilators, such as salbutamol or terbutaline, are used by inhalation as required for the relief of occasional minor symptoms. If the patient is using ß2-adrenoceptor agonists more than once daily, move to step 2. Beta2-adrenoceptor agonist therapy alone is only recommended if it is used occasionally and when this allows the patient to lead an active normal life free from nocturnal and exercise-induced asthmatic symptoms.
Step 2 Regular inhaled anti-inflammatory agents
Inhaled short-acting ß2-adrenoceptor agonists are used as required and the patient is commenced on a regular inhaled steroid (beclometasone dipropionate, budesonide or fluticasone propionate) up to 800 µg daily (or 400 µg daily for fluticasone propionate). Alternatively, sodium cromoglicate or nedocromil sodium can be used instead of an inhaled corticosteroid, but these drugs are rarely effective outside childhood.
INHALED SHORT-ACTING ß2-ADRENOCEPTOR AGONISTS-regular versus as-needed treatment
'Systematic review of 24 RCTs found that regularly scheduled as opposed to as-needed use of short-acting inhaled ß2-adrenoceptor agonists in people with mild intermittent asthma provides no additional clinical benefit.'
Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol [salbutamol] in mild asthma. Asthma Clinical Network. N Engl J Med 1996; 335:841-847.
Walters EH, Walters J. Inhaled short-acting beta2-agonist use in asthma: regular vs as needed treatment (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Step 3 High-dose inhaled corticosteroids, or low-dose inhaled corticosteroids plus a long-acting inhaled ß2-adrenoceptor agonist
Inhaled short-acting ß2-adrenoceptor agonists are used as required plus an inhaled corticosteroid in the dose range 800-2000 µg daily. Alternatively, a long-acting ß2-adrenoceptor agonist (e.g. formoterol (eformoterol) fumarate 6 µg 12-hourly or salmeterol 50 µg 12-hourly) or a sustained-release theophylline may be added. When corticosteroids are inhaled in high dose via a conventional pressurised MDI, the use of a large-volume spacer (holding chamber) is recommended. When dry powder inhalers are used, mouth-rinsing and gargling with spitting out of the rinsing liquid after each treatment should be encouraged. Spacers and mouth-rinsing are recommended to decrease gastrointestinal absorption of swallowed drug, and to lower the risk of developing the local side-effect of oropharyngeal candidiasis. Recent studies have suggested that the addition of a long-acting ß2-adrenoceptor agonist is more effective in improving symptoms, improving lung function and reducing exacerbations than increasing the dose of inhaled corticosteroids.
CHRONIC ASTHMA-role of long-acting ß2-adrenoceptor agonists
'RCTs have found that in patients whose asthma is poorly controlled by inhaled corticosteroids, the addition of a long-acting ß2-adrenoceptor agonist improves symptoms and lung function and reduces exacerbations.'
Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344:219-224.
Pauwels RA, Lofdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 387:1405-1411.
Further information: www.brit-thoracic.org.uk
Step 4 High-dose inhaled corticosteroids and regular bronchodilators
Inhaled short-acting ß2-adrenoceptor agonists are used as required with an inhaled corticosteroid (800-2000 µg daily) plus a sequential therapeutic trial of one or more of:
inhaled long-acting ß2-adrenoceptor agonist (e.g. salmeterol 50 µg 12-hourly or formoterol fumarate (eformoterol fumarate) 12 µg 12-hourly)
leukotriene receptor antagonist (e.g. montelukast sodium)
inhaled ipratropium bromide or oxitropium bromide
long-acting oral ß2-adrenoceptor agonist (sustained-release salbutamol or terbutaline preparations)
high-dose inhaled ß2-adrenoceptor agonists
sodium cromoglicate or nedocromil sodium.
The role of anti-IgE antibody therapy in patients with severe atopic asthma is under evaluation.
Step 5 Addition of regular oral corticosteroid therapy
Step 4 treatment is given plus regular prednisolone tablets prescribed in the lowest amount necessary to control symptoms as a single daily dose in the mornings.
Using this 'stepwise' approach to asthma management (see Fig. 13.26), the initial treatment for each patient should be chosen individually depending upon severity of disease. In general, it is better to start with a treatment regimen which is likely to achieve disease control rapidly and then 'step down' rather than to start with inadequate treatment and then have to 'step up'. Patient compliance is also likely to be better when symptom control is achieved rapidly. Regular review is important and if there has been good symptomatic control for 3-6 months a step down should be made. This is of particular importance in those taking oral and high-dose inhaled corticosteroids (steps 3-5).
Short-course oral corticosteroid treatments
Short courses of 'rescue' oral corticosteroids are often required to regain control of symptoms. For adults, 30-60 mg of prednisolone can be given initially and the same dose continued in a single daily dose each morning until 2 days after control is re-established. In children, a dose of 1-2 mg/kg body weight can be used. Tapering of the dose to withdraw treatment is not necessary unless given for more than 3 weeks. Indications for 'rescue' courses include:
symptoms and PEF progressively worsening day by day
fall of PEF below 60% of the patient's personal best recording
onset or worsening of sleep disturbance by asthma
persistence of morning symptoms until midday
progressively diminishing response to an inhaled bronchodilator
symptoms severe enough to require treatment with nebulised or injected bronchodilators.
Increase in dose of inhaled corticosteroid
Doubling the dose of inhaled corticosteroids is often advised to control minor exacerbations of asthma not severe enough to warrant treatment with oral prednisolone. This appears to be effective in many cases.
Management of acute severe asthma
The aims of management are to prevent death, to restore pulmonary function to the patient's best as quickly as possible, to maintain optimal pulmonary function and to prevent early relapse. The features of acute severe asthma are shown in Box 13.32.
13.32 IMMEDIATE ASSESSMENT OF ACUTE SEVERE ASTHMA
Features of severity
Pulse rate > 110 per min
Unable to speak in sentences
PEF < 50% of expected
N.B. Apparent distress and respiratory rate may be misleading.
Exhaustion, confusion, reduced conscious level
Arterial blood gases in life-threatening asthma
A normal (5-6 kPa) or high CO2 tension
Severe hypoxaemia (< 8 kPa), especially if being treated with oxygen
A low pH or high [H+]
PEF should be recorded immediately in all patients unless they are too ill to cooperate. PEF measurements are most easily interpreted when expressed as a percentage of the predicted normal value or of the previous best value obtained on optimal treatment. When neither of these is known, decisions have to be made on the absolute value recorded, remembering that normal values vary with age, sex and height. In a previously fit asthmatic patient, recordings of <200 l/min are indicative of severe disease, and values of <100 l/min must be taken as evidence of life-threatening asthma.
Immediate treatment (see Fig. 13.27)
Oxygen. Oxygen should be given at the highest concentration available (usually 60%). High-concentration oxygen therapy does not cause or aggravate carbon dioxide retention in asthma, and the presence of carbon dioxide retention must not be interpreted as a contraindication for the use of high-concentration oxygen treatment. Thereafter, the concentration of oxygen used can be adjusted according to the arterial blood gas measurements. A PaO2 of > 8.5-9 kPa should be maintained if possible.
High doses of inhaled ß2-adrenoceptor agonists. When possible, ß2-adrenoceptor agonists should be nebulised using oxygen. Salbutamol 2.5-5 mg or terbutaline 5-10 mg should be given initially and repeated within 30 minutes if necessary. When treatment is given outside hospital and oxygen is not available, an air compressor can be used to drive the nebuliser. An alternative method of giving high doses of ß2-adrenoceptor agonists in general practice is multiple actuations of an MDI into a large-volume spacer device.
Systemic corticosteroids. Systemic corticosteroids are necessary for the treatment of all cases of acute severe asthma. Oral prednisolone 30-60 mg (or intravenous hydrocortisone 200 mg if the patient is unable to swallow or vomiting) should be given initially.
Figure 13.27 Immediate treatment of patients with acute severe asthma.
ACUTE ASTHMA-use of intravenous aminophylline
'Two SRs of RCTs examining the effect of adding intravenous aminophylline to initial standard therapy with nebulised ß2-adrenoceptor agonists and systemic corticosteroids in acute asthma failed to demonstrate any beneficial effect of aminophylline. The frequency of adverse effects was also higher with aminophylline.'
Parameswaran K, Beida J, Rowe BH. Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Hart SP. Should aminophylline be abandoned in the treatment of acute asthma in adults? QJM 2000; 93:761-765.
Use of intravenous aminophylline is not recommended (see EBM panel).
13.33 CONTINUED MANAGEMENT OF ACUTE SEVERE ASTHMA
If features of severity persist:
Ipratropium bromide 0.5 mg should be added to the nebulised ß2-adrenoceptor agonist
Continue nebulised ß2-adrenoceptor agonist treatment every 15-30 minutes as necessary. Reduce to 4-hourly once clear clinical response
Magnesium sulphate (25 mg/kg i.v., maximum 2 g)
13.34 INDICATIONS FOR ASSISTED VENTILATION IN ACUTE SEVERE ASTHMA
Deterioration of arterial blood gas tensions despite optimal therapy
PaO2 < 8 kPa and falling
PaCO2 > 6 kPa and rising
pH low and falling (H+ high and rising)
Exhaustion, confusion, drowsiness
All patients must be closely supervised and oxygen therapy continued. If features of severity persist, additional measures may be required (see Box 13.33). Systemic corticosteroid treatment with oral prednisolone 30-60 mg daily is recommended for patients responding to treatment, but intravenous hydrocortisone 200 mg 6-hourly should be continued in the seriously ill. Mechanical ventilation is necessary as a life-saving procedure in a few patients. Indications for endotracheal intubation and intermittent positive pressure ventilation are shown in Box 13.34.
Monitoring of treatment
PEF recordings should be made every 15-30 minutes to assess early response and as necessary thereafter. In hospital PEF values should be charted 4-6-hourly before and after inhaled bronchodilator treatments throughout the period of hospital stay.
Repeat measurement of arterial blood gas tensions and pH or H+ within 1-2 hours is necessary in all patients if the first arterial sample showed features of life-threatening disease (see Box 13.33). Continuous monitoring of oxygen saturation by pulse oximetry is valuable in all patients to help assess response. Oximetry may also prevent the need to repeat an arterial puncture in some patients.
The prognosis of individual asthma attacks is generally good. There is occasionally a fatal outcome, especially if treatment is inadequate or delayed. Spontaneous remission is fairly common in episodic asthma, particularly in children, but rare in chronic asthma. Seasonal fluctuations can occur in both types of asthma. Atopic subjects with episodic asthma are usually worse in the summer when they are more heavily exposed to antigens, while chronic asthmatic patients are usually worse in winter months because of the increased frequency of viral infections.
Prior to discharge from hospital, patients should have been taking discharge medication (i.e. changed from nebulised drugs) for 24 hours and have a PEF of 75% predicted or personal best over that period. They should also have their own PEF meter, a written self-management plan, an adequate supply of medication and an appointment to be reviewed by their GP within 7 days.
Aetiology and pathogenesis
Bronchiectasis is the term used to describe abnormal dilatation of the bronchi. It is usually acquired (see Box 13.35) but may result from an underlying congenital defect of immune or ciliary function.
13.35 CAUSES OF BRONCHIECTASIS
Ciliary dysfunction syndromes
Primary ciliary dyskinesia (immotile cilia syndrome)
Primary hypogammaglobulinaemia (see p. 795)
Pneumonia (complicating whooping cough or measles)
Allergic bronchopulmonary aspergillosis (see p. 540)
In the UK the symptoms of bronchiectasis can often be tracked back to a severe bacterial infection in childhood consequent upon whooping cough or measles. World-wide, pulmonary tuberculosis remains the most common cause of bronchiectasis.
Bronchiectasis may be due to bronchial distension resulting from the accumulation of pus beyond a lesion obstructing a major bronchus, such as compression by tuberculous hilar lymph nodes, an inhaled foreign body or a bronchial tumour. Recurrent infection and chronic obstruction by viscid mucus are both factors in causing bronchiectasis in cystic fibrosis (see p. 522). Rarely, it may be the result of congenital dysfunction of the cilia, which is a feature of, for example, Kartagener's syndrome (bronchiectasis, sinusitis and transposition of the viscera), or immunoglobulin deficiency.
The bronchiectatic cavities may be lined by granulation tissue, squamous epithelium or normal ciliated epithelium. There may also be inflammatory changes in the deeper layers of the bronchial wall and hypertrophy of the bronchial arteries. Chronic inflammatory and fibrotic changes are usually found in the surrounding lung tissue.
Bronchiectasis may involve any part of the lungs but the more efficient drainage by gravity of the upper lobes usually produces less serious symptoms and complications than when bronchiectasis involves the lower lobes.
The groups of clinical features that occur in more severe cases are shown in Box 13.36.
Physical signs in the chest may be unilateral or bilateral. If the bronchiectatic airways do not contain secretions and there is no associated lobar collapse, there are no abnormal physical signs. When there are large amounts of sputum in the bronchiectatic spaces numerous coarse crepitations can be heard over the affected areas. When collapse is present the character of the physical signs depends on whether or not the proximal bronchus supplying the collapsed lobe is patent (see Box 13.5, p. 490).
13.36 SYMPTOMS OF BRONCHIECTASIS
Due to accumulation of pus in dilated bronchi
Chronic productive cough usually worse in mornings and often brought on by changes of posture. Sputum often copious and persistently purulent in advanced disease
Due to inflammatory changes in lung and pleura surrounding dilated bronchi
Fever, malaise and increased cough and sputum volume when spread of infection causes pneumonia, which is frequently associated with pleurisy. Recurrent pleurisy in the same site often occurs in bronchiectasis
Can be slight or massive and is often recurrent. Usually associated with purulent sputum or an increase in sputum purulence. Can, however, be the only symptom in so-called 'dry bronchiectasis'
When disease is extensive and sputum persistently purulent a decline in general health occurs with weight loss, anorexia, lassitude, low-grade fever, and failure to thrive in children. In these patients digital clubbing is common
Bacteriological and mycological examination of sputum
This is necessary in all patients but is especially important in bronchiectasis associated with cystic fibrosis and in any patient who has had numerous courses of antibiotics.
Bronchiectasis, unless very gross, is not usually apparent on a chest radiograph. In advanced disease the cystic bronchiectatic spaces may be visible. Abnormalities produced by associated pulmonary infection and/or collapse are evident. A diagnosis of bronchiectasis can only be made with certainty by CT (see Fig. 13.5, p. 491).
Assessment of ciliary function
A screening test can be performed in patients suspected of having a ciliary dysfunction syndrome by assessing the time taken for a small pellet of saccharin placed in the anterior chamber of the nose to reach the pharynx, when the patient can taste it. This time should not exceed 20 minutes and is greatly prolonged in patients with ciliary dysfunction. It is also possible to assess ciliary function by measuring ciliary beat frequency using biopsies taken from the nose. If ciliary function is thought to be impaired, the ciliary ultrastructure should also be determined by electron microscopy.
In addition to optimising treatment with inhaled bronchodilators and corticosteroids to enhance airway patency, the aim of this measure is to keep the dilated bronchi empty of secretions. Efficiently performed, it is of great value both in reducing the amount of cough and sputum and in preventing recurrent episodes of bronchopulmonary infection. In its simplest form, postural drainage consists of adopting a position in which the lobe to be drained is uppermost, thereby allowing secretions in the dilated bronchi to gravitate towards the trachea, from which they can readily be cleared by vigorous coughing. 'Percussion' of the chest wall with cupped hands aids dislodgement of sputum, and a number of mechanical devices are available which cause the chest wall to oscillate, thus achieving the same effect as postural percussion and chest wall compression. The optimum duration and frequency of postural drainage depend on the amount of sputum but 5-10 minutes once or twice daily is a minimum for most patients. Forced expiratory manoeuvres ('huffing and puffing') are of help in augmenting the expectoration of sputum.
The policy governing the use of antibiotics in most patients with bronchiectasis is the same as that in COPD (see p. 511). Some, especially those with cystic fibrosis, present difficult therapeutic problems because of secondary infection with bacteria such as staphylococci and Gram-negative bacilli, in particular Pseudomonas species. In these circumstances antibiotic therapy should be guided by the microbiological results but frequently requires the use of oral ciprofloxacin (250-750 mg twice daily) or ceftazidime by intravenous injection or infusion (100-150 mg/kg daily in three divided doses). The bronchi of some patients with cystic fibrosis also become colonised by Aspergillus fumigatus.
Surgery is only indicated in a small minority of individuals. These are usually young patients in whom the bronchiectasis is unilateral and confined to a single lobe or segment as demonstrated by CT. Unfortunately, many of the patients in whom medical treatment proves unsuccessful are also unsuitable for pulmonary resection because of either extensive bronchiectasis or coexisting chronic lung disease. Resection of areas of bronchiectatic lung has no role in the management of the progressive forms of bronchiectasis-for example, those associated with ciliary dysfunction and cystic fibrosis.
The disease is progressive when associated with ciliary dysfunction and cystic fibrosis, and inevitably causes respiratory failure and right ventricular failure. In other patients the prognosis can be relatively good if postural drainage is performed regularly and antibiotics are used judiciously.
As bronchiectasis commonly starts in childhood following measles, whooping cough or a primary tuberculous infection, it is essential that these conditions receive adequate prophylaxis and treatment. The early recognition and treatment of bronchial obstruction are also particularly important.
Epidemiology and pathogenesis
Figure 13.28 Cystic fibrosis: basic defect in the pulmonary epithelium. A The CF gene codes for a chloride channel (1) in the apical (luminal) membrane of epithelial cells in the conducting airways. This channel is normally controlled by cyclic adenosine monophosphate (cAMP) and indirectly by ß-adrenoceptor stimulation. It is one of several apical ion channels which together control the quantity and solute content of airway-lining fluid. Normal channels appear to inhibit the adjacent epithelial sodium channels (2). B In CF, one of many CF gene defects causes absence or defective function of this chloride channel (3). This leads to reduced chloride secretion and loss of inhibition of sodium channels with excessive sodium resorption (4) and dehydration of the airway lining. The resulting abnormal airway-lining fluid is believed to predispose to infection by mechanisms which are not fully understood.
Cystic fibrosis (CF) is the most common severe autosomal recessive disease in Caucasians, occurring with a carrier rate of 1 in 25 and an incidence of about 1 in 2500 live births (see p. 344). CF is the result of mutations affecting a gene (located on the long arm of chromosome 7) which encodes for a chloride channel known as cystic fibrosis transmembrane conductance regulator (CFTR), which is essential for the regulation of salt and water movement across cell membranes. The most common CFTR mutation in northern European and American populations is d508, but numerous mutations have now been identified in this region. The genetic defect causes an increased sodium chloride content in sweat and increased electrical potential difference across the respiratory epithelium which can be detected in the nose (see Fig. 13.28). This results in much increased viscosity of secretions in the lung and other organs, which causes ciliary dysfunction and chronic bronchial infection. Recurrent exacerbations of bronchial infection predispose to bronchial wall damage, eventually causing bronchiectasis, often predominantly in the upper lobes initially but subsequently in all areas of both lungs, with the end result of death from respiratory failure. There are also disorders in the gut epithelium, and in the pancreas and liver (causing intestinal malabsorption, diabetes and hepatic cirrhosis). Most men with CF are infertile due to failure of development of the vas deferens. Population carrier screening is feasible but unlikely to affect overall patient numbers significantly. However, early diagnosis can be achieved by neonatal screening, and in some cases by amniocentesis.
13.37 COMPLICATIONS OF CYSTIC FIBROSIS
Distal intestinal obstruction syndrome
Increased frequency of gallstones
Diabetes (11% of adults)
Lung function is normal at birth, which leads to the hope that if the basic defect can be corrected by gene therapy many of the sequelae (see Box 13.37) might be avoided. Bronchiectasis, however, usually develops at a young age. Initially, the bacteria associated with CF are those expected in bronchiectasis of other causes (see p. 521), but infection with Staphylococcus aureus tends to be early in CF and the majority have Pseudomonas infection at an early age. Repeated lung infections, inflammation and scarring almost inevitably lead to respiratory failure and death.
The management of established cystic fibrosis is that of severe bronchiectasis (see opposite). All patients with cystic fibrosis who produce sputum should have regular chest physiotherapy, which should be performed more frequently during exacerbations. Lung infections are usually predominantly caused by Pseudomonas species and Staph. aureus. Unfortunately, the bronchi of many CF patients eventually become colonised with pathogens which are resistant to most antibiotics; Pseudomonas aeruginosa and Burkholderia cepacia (previously known as Pseudomonas cepacia) are the main culprits. Infections with Haemophilus influenzae can be treated with a number of antibiotics and Staph. aureus should be treated with flucloxacillin or erythromycin. Patients requiring frequent courses of intravenous antibiotics for the control of Pseudomonas infections can, with benefit, be taught self-administration via an in-dwelling central venous port and cannula, implanted subcutaneously in the chest wall to allow intravenous therapy at home. Nebulised antibiotic therapy, mainly with colistin, is used between exacerbations in an attempt to suppress chronic pseudomonal infection.
CYSTIC FIBROSIS-role of nebulised anti-pseudomonal antibiotics
'Meta-analysis of RCTs demonstrates that nebulised anti-pseudomonal antibiotic therapy improves lung function and decreases the risk of infective exacerbations and hospitalisation in patients with cystic fibrosis and Pseudomonas aeruginosa infection. The long-term benefit and impact of such treatment on quality of life and survival remain to be determined.'
Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340:23-30.
Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.update-software.com/ccweb/cochrane/revabstr/ab001021.htm
Treatment with nebulised recombinant human DNAase (rhDNAase) has been available since 1994. The aim of this therapy is to solubilise DNA derived from disintegrated inflammatory cells, which is a major contributor to the viscosity of bronchial secretions in CF, in which it is present in abundance. This therapy has been shown to improve pulmonary function and increase well-being in a subgroup of patients, and perhaps also to reduce the number of infective exacerbations. There is also some evidence that it can reduce the neutrophil elastase load and, therefore, decelerate bronchial wall tissue damage. It has to be emphasised that this treatment is very expensive and is not of benefit to all patients, which makes clinical selection of patients for such treatment difficult. Aerosol a1-antitrypsin treatment has been used to reduce the neutrophil elastase load, but this form of therapy is even less established than rhDNAase.
A number of patients with cystic fibrosis develop symptoms of bronchospasm, which can be treated effectively with bronchodilators following appropriate reversibility tests. Allergic bronchopulmonary aspergillosis (see p. 540) is also a well-recognised complication of CF. It is also common for 'atypical mycobacteria' to be cultured from the sputum of CF patients, but it is frequently difficult to determine whether these organisms are causing disease, or are benign 'colonisers' of the bronchiectatic airways which do not require specific therapy.
The prognosis of CF has greatly improved in the last decade, mainly because of better control of bronchial sepsis and maintenance of nutrition. The median survival of patients with CF is now predicted to be at least 40 years for children born in the 1990s. Organ transplantation remains last-resort therapy for patients with end-stage disease.
The potential for somatic gene therapy
The discovery of the CF gene and the fact that the lung defect is located in the respiratory epithelium (which is accessible by inhaled therapy) presents an exciting opportunity for gene therapy. The CF gene could be 'packaged' within a liposome or incorporated by genetic engineering into a modified viral vector and delivered to the respiratory epithelium with the aim of correcting the genetic defect. The feasibility of this approach is currently under investigation and initially promising results have been obtained in preliminary studies of the CF gene delivered to the nasal mucosa of CF patients. Studies of the delivery of the gene to the bronchi are in progress.
ISSUES IN OLDER PEOPLE
OBSTRUCTIVE PULMONARY DISEASE
Both COPD and asthma are common in old age and are not mutually exclusive. A bias towards misdiagnosis of COPD rather than asthma is well recognised in elderly men and those of lower socio-economic class.
Older people with poor vision have difficulty reading PEFmeters.
Older people perceive acute bronchoconstriction less well than younger patients, so their description of symptoms is not a reliable indicator of severity, and 'on demand' bronchodilators may not be appropriate as a first step in treatment.
The beneficial effects of stopping smoking on the rate of loss of lung function decline with age but remain valuable up to the age of 80.
Most older people cannot use metered dose inhalers because of difficulty coordinating and triggering the device. Even mild cognitive impairment virtually precludes their use. Spacer devices are much preferred by patients. Frequent demonstration and reinstruction in the use of all devices are required.
Mortality rates for acute asthma are higher in old age, partly because patients under-estimate the severity of bronchoconstriction and develop less tachycardia and pulsus paradoxus for the same degree of bronchoconstriction.
Advanced age in itself is not a barrier to intensive care or mechanical ventilation in an acute episode of asthma or COPD, but a decision about this can be difficult and should be shared with the patient (if possible), relatives and general practitioner.
pages 508 - 524
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > INFECTIONS OF THE RESPIRATORY SYSTEM
INFECTIONS OF THE RESPIRATORY SYSTEM
Infections of the upper and lower respiratory tract continue to be a major cause of morbidity and mortality throughout the world, with patients at the extremes of age or with pre-existing lung disease or immune suppression being at particular risk. Viruses are the most frequent cause of upper respiratory illnesses, with bacteria being responsible for the majority of community- and hospital-acquired pneumonia in adults. Organisms such as Mycoplasma, Coxiella and Chlamydia are less common causes of severe pneumonia. Pulmonary infection by Mycobacterium tuberculosis, atypical mycobacteria and fungi results in diseases of a more chronic type. These are described separately.
UPPER RESPIRATORY TRACT INFECTIONS
13.38 THE COMMON AND MOST IMPORTANT UPPER RESPIRATORY TRACT INFECTIONS: CLINICAL FEATURES, COMPLICATIONS AND MANAGEMENT
Infection Clinical features Complications Management
Acute coryza (common cold) Rapid onset. Burning and tickling sensation in nose. Sneezing. Sore throat. Blocked nose with watery discharge. Discharge usually green/yellow after 24-48 hrs. Nasal allergy can give rise to similar clinical features Sinusitis. Lower respiratory tract infection (bronchitis/pneumonia). Hearing impairment, otitis media (due to blockage of eustachian tubes) Most do not require treatment. Paracetamol 0.5-1 g 4-6-hourly for relief of systemic symptoms. Nasal decongestant in some cases. Antibiotics not necessary in uncomplicated coryza
Acute laryngitis Often a complication of acute coryza. Dry sore throat. Hoarse voice or loss of voice. Attempts to speak cause pain. Initially, painful and unproductive cough. Stridor in children (croup) because of inflammatory oedema leading to partial obstruction of a small larynx Complications rare. Chronic laryngitis. Downward spread of infection may cause tracheitis, bronchitis or pneumonia Rest voice. Paracetamol 0.5-1 g 4-6-hourly for relief of discomfort and pyrexia. Steam inhalations may be of value. Antibiotics not necessary in simple acute laryngitis
Acute laryngo-tracheobronchitis (croup)* Initial symptoms like common cold. Sudden paroxysms of cough accompanied by stridor and breathlessness. Contraction of accessory muscles and indrawing of intercostal spaces. Cyanosis and asphyxia in small children, if appropriate treatment not given Asphyxia. Death. Superinfection with bacteria, especially Strep. pneumoniae and Staph. aureus. Viscid secretions may occlude bronchi Inhalations of steam and humidified air/high concentrations of oxygen. Endotracheal intubation or tracheostomy to relieve laryngeal obstruction and allow clearing of bronchial secretions. Intravenous antibiotic therapy for seriously ill (co-amoxiclav or erythromycin). Maintain adequate hydration
Acute epiglottitis Fever and sore throat, rapidly leading to stridor because of swelling of epiglottis and surrounding structures (infection with H. influenzae). Stridor and cough in absence of much hoarseness may distinguish acute epiglottitis from other causes of stridor Death from asphyxia which may be precipitated by attempts to examine the throat-avoid using a tongue depressor or any instrument unless facilities for endotracheal intubation or tracheostomy are immediately available Intravenous antibiotic therapy essential. Co-amoxiclav or chloramphenicol. Other measures as for acute laryngotracheobronchitis
Acute bronchitis and tracheitis Often follows acute coryza. Initially irritating unproductive cough accompanied by retrosternal discomfort of tracheitis. Chest tightness, wheeze and breathlessness when bronchi become involved. Tracheitis causes pain on coughing. Sputum is initially scanty or mucoid. After a day or so sputum becomes mucopurulent, more copious and, in tracheitis, often blood-stained. Acute bronchial infection may be associated with a pyrexia of 38-39°C and a neutrophil leucocytosis. Spontaneous recovery occurs over a few days Bronchopneumonia. Exacerbation of chronic bronchitis which often results in type II respiratory failure in patients with severe COPD. Acute exacerbation of bronchial asthma Specific treatment rarely necessary in previously healthy individuals. Cough may be eased by pholcodine 5-10 mg 6-8-hourly. In patients with COPD (see p. 508) and asthma (see p. 513) aggressive treatment of exacerbations may be required. Amoxicillin 250 mg 8-hourly should be given to previously healthy patients who are thought to be developing bronchopneumonia (see also p. 526)
Influenza (a specific acute illness caused by a group of myxoviruses- two common types, A and B) Sudden onset of pyrexia associated with generalised aches and pains, anorexia, nausea and vomiting. Degree of ill health ranges from mild to rapidly fatal. Usually harsh unproductive cough. Most patients do not develop complications and acute symptoms subside within 3-5 days, but may be followed by 'post-influenzal asthenia' which can persist for several weeks. During epidemics the diagnosis is usually easy. Sporadic cases may have to be diagnosed by virus isolation, fluorescent antibody techniques or serological tests for specific antibodies Tracheitis, bronchitis, bronchiolitis and bronchopneumonia. Secondary bacterial invasion by Strep. pneumoniae, H. influenzae and Staph. aureus may occur. Toxic cardiomyopathy may cause sudden death (rare). Encephalitis, demyelinating encephalopathy and peripheral neuropathy are also rare complications Bed rest is advisable until fever has subsided. Paracetamol 0.5-1 g 4-6-hourly can be used to relieve headache and generalised pains. Pholcodine 5-10 mg 6-8-hourly may be given to suppress cough. Specific treatment for pneumonia (see p. 528) may be necessary
*Whooping cough (caused by Bordetella pertussis) is often considered a disease of non-immunised children but it also occurs in sporadic 'epidemics' in middle life when immunisation effectiveness has waned. After a short, febrile tracheobronchitis (which itself is responsive to antibiotics), severe episodic paroxysmal coughing bouts, associated with laryngospasm and often leading to intercostal muscle tears or fractured ribs, may persist for many weeks.
13.39 RESPIRATORY INFECTIONS CAUSED BY VIRUSES
Clinical syndrome Usual cause (other causes in parentheses)
Epidemic influenza Influenza A and B
'Influenza-like' illness Adenoviruses, rhinoviruses (enteroviruses)
Sore throat Adenoviruses (enteroviruses, parainfluenza viruses, influenza A and B in partially immune)
Common cold (coryza) Rhinoviruses (coronaviruses, enteroviruses, adenoviruses, respiratory syncytial virus)
'Feverish' cold Rhinoviruses, enteroviruses (influenza A and B, parainfluenza viruses, respiratory syncytial virus)
Croup Parainfluenza 1, 2, 3 (rhinoviruses, enteroviruses)
Bronchitis Rhinoviruses, adenoviruses (influenza A and B)
Bronchiolitis Respiratory syncytial virus (parainfluenza 3)
Pneumonia Influenza A and B, chickenpox (respiratory syncytial virus, parainfluenza, measles and adenoviruses in children and elderly)
The clinical features, complications and management of the common and most important upper respiratory tract infections are summarised in Box 13.38. The vast majority of these illnesses, of which acute coryza (common cold) is by far the most common, are caused by viruses (see Box 13.39). Immunity is short-lived and virus-specific. Other viral infections include acute laryngitis and acute laryngotracheobronchitis. Bacterial infection is the usual cause of acute tonsillitis, otitis media and epiglottitis.
ACUTE UNCOMPLICATED UPPER RESPIRATORY TRACT INFECTIONS-role of antibiotics
'Two SRs of RCTs have found no evidence that antibiotics have a clinically important effect in patients with acute undifferentiated upper respiratory tract infections. Antibiotics can prevent the non-suppurative complications of ß-haemolytic streptococcal pharyngitis.'
Arrol B, Kenealy T. The use of antibiotics versus placebo in the common cold (Cochrane Review). Cochrane Library, issue 3, 1999. Oxford: Update Software.
Fahey T, Stocks N, Thomas T. Systematic review of the treatment of upper respiratory tract infection. Arch Dis Child 1998; 79:225-230.
INFLUENZA VACCINE-use in elderly people
'One SR of cohort studies and several recent RCTs have found that influenza vaccination reduces the risk of influenza and death in elderly people.'
Gross PA, Hermogenes AW, Sacks HS, et al. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med 1995; 123:518-527.
Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy of influenza vaccination in elderly persons living in the community. N Engl J Med 1994; 31:778-784.
Further information: www.clinicalevidence.org
Most patients with upper respiratory tract infections recover rapidly and specific investigation is indicated only in more severe illness. The possibility of acute epiglottitis, which represents a medical emergency, must be considered at all times (see Box 13.38). Viruses can be isolated from exfoliated cells collected on throat swabs, and may be identified retrospectively by serological tests. Certain viruses can be identified in exfoliated cells by the fluorescent antibody technique, allowing the pathogen to be identified more rapidly. Throat swabs may also be helpful if streptococcal pharyngitis is suspected, and examination of the blood will identify infectious mononucleosis (see p. 16). Radiographic examination may be required if an underlying chronic infection involving the sinuses is suspected.
Pneumonia is defined as an acute respiratory illness associated with recently developed radiological pulmonary shadowing which either is segmental or affects more than one lobe. As the setting in which a pneumonia develops has such major implications for the likely organisms involved and hence dictates the immediate choice of antibiotics, pneumonias are now classified as community-acquired, hospital-acquired, or those occurring in the immunocompromised host or damaged lung (including suppurative and aspirational pneumonia).
This form of pneumonia is responsible for over 1 000 000 admissions per year in the UK. Infection is usually spread by droplet inhalation and, while most patients affected are previously well, cigarette smoke, alcohol and corticosteroid therapy all impair ciliary and immune function. Other risk factors include old age, recent influenza infection, pre-existing lung disease and, for certain forms of pneumonia, contact with sick birds (Chlamydia psittaci) or farm environments (Coxiella burnetii). Knowledge of the patient's recent travel history and local epidemics is also valuable. Appropriate investigation allows a microbiological diagnosis to be made in approximately 60% of patients with pneumonia. 'Lobar pneumonia' is a radiological and pathological term referring to homogeneous consolidation (red hepatisation) of one or more lung lobes, often with associated pleural inflammation; bronchopneumonia refers to more patchy alveolar consolidation associated with bronchial and bronchiolar inflammation often affecting both lower lobes.
Patients present with a short illness of cough, fever and malaise, often associated with pleuritic chest pain which is occasionally referred to the shoulder or anterior abdominal wall. The cough is characteristically short, painful and at first dry, but later becomes productive and may become rust-coloured or even frankly blood-stained. The sudden onset of a high fever can result in rigors or, in children, vomiting or a febrile convulsion. Appetite is usually lost and headache is a frequent accompanying symptom. In patients with severe pneumonia confusion can be an early and dominant problem. Certain features may suggest a particular microbiological diagnosis (see Box 13.40).
13.40 CLINICAL AND RADIOLOGICAL CHARACTERISTICS OF COMMUNITY-ACQUIRED PNEUMONIAS CAUSED BY SPECIFIC ORGANISMS
Organism Frequency* Clinical features Radiological features
Streptococcus pneumoniae 30%(+) Young to middle-aged, rapid onset, high fever, rigors, pleuritic chest pain, herpes simplex labialis, 'rusty' sputum Lobar consolidation, one or more lobes
Chlamydia pneumoniae 10% Young to middle-aged, large-scale epidemics or sporadic, often mild, self-limiting disease Small segmental infiltrates
Associated sinusitis, pharyngitis, laryngitis
White cell count often normal, liver transaminases elevated
Usually diagnosed on serology
Mycoplasma pneumoniae 9% Children and young adults, autumn and 3-4-yearly cycles Patchy or lobar consolidation, hilar lymphadenopathy may be seen
Insidious onset, headaches, systemic features, often few signs in chest
Erythema nodosum, myocarditis, pericarditis, meningoencephalitis, rash, haemolytic anaemia
Legionella pneumoniae 5% Middle to old age, recent travel, local epidemics around point source, e.g. cooling tower Shadowing may spread despite antibiotics and often slow to resolve
Headache, malaise, myalgia, high fever, dry cough, gastrointestinal symptoms
Confusion, hepatitis, hyponatraemia, hypoalbuminaemia
Haemophilus influenzae 3% Often underlying lung disease, purulent sputum Bronchopneumonia
Staphylococcus aureus < 1% Coexistent debilitating illness Lobar or segmental. Abscess formation, residual cysts
Often complicates viral pneumonia
Can arise from, or cause, abscesses in other organs, e.g. osteomyelitis
Chlamydia psittaci < 1% Contact with sick birds Patchy lower lobe consolidation
Malaise, low-grade fever, protracted illness
Coxiella burnetii Farm or abattoir contact Multiple segmental opacities
Chronic course, influenza-like illness, dry cough, conjunctivitis, hepatomegaly, endocarditis
Klebsiella pneumoniae < 1% Systemic disturbance marked, widespread consolidation, often in upper lobes, purulent dark sputum, high mortality Expansion of affected lobes
Actinomyces israelii < 1% Mouth commensal Cervicofacial, abdominal or pulmonary infection, empyema, chest wall sinuses, pus with 'sulphur grains' Abscesses, pleural effusions and bone involvement
Primary viral pneumonias Influenza, parainfluenza and measles can cause pneumonia commonly complicated by bacterial infection Respiratory syncytial virus seen mainly in infancy Varicella (chickenpox) can cause severe pneumonia Chickenpox produces multiple miliary nodular shadows which may calcify
*No microbiological diagnosis established in approximately 40% of patients with community-acquired pneumonia admitted to hospital.
Physical signs include a significant pyrexia, tachycardia, tachypnoea, evidence of hypoxaemia and, not infrequently, hypotension and confusion. Pleurisy often results in diminution of respiratory movement and a pleural rub on the affected side. At a variable time after onset, generally within 2 days, signs of consolidation appear, with impairment of the percussion note and high-pitched bronchial breath sounds. When resolution begins, numerous coarse crepitations are heard, indicating liquefaction of the alveolar exudate. If a para-pneumonic pleural effusion develops, physical signs of fluid in the pleural space are usually found, but bronchial breath sounds can persist and the presence of an empyema (see p. 569) may be suspected only from the recurrence or persistence of pyrexia. Upper abdominal tenderness is sometimes apparent in patients with lower lobe pneumonia or if there is associated hepatitis.
The main objectives of investigating patients with a clinically based diagnosis of pneumonia are:
to obtain a radiological confirmation of the diagnosis
to exclude other conditions that may mimic pneumonia (see Box 13.41)
to obtain a microbiological diagnosis
to assess the severity of the pneumonia
to identify the development of complications.
In lobar pneumonia, the chest radiograph shows a homogeneous opacity localised to the affected lobe or segment; this usually appears within 12-18 hours of the onset of the illness (see Fig. 13.29). Radiological examination is also particularly helpful if a complication such as pleural effusion, intrapulmonary abscess formation or empyema is suspected. Hilar lymphadenopathy is occasionally seen in mycoplasma pneumonia, and lung cavities are more frequently observed in patients with staphylococcal or pneumococcal serotype 3 pneumonia. Follow-up radiological examination is essential as failure of a pneumonia to resolve may indicate underlying bronchial obstruction (e.g. a foreign body or carcinoma).
13.41 DIFFERENTIAL DIAGNOSIS OF PNEUMONIA
Often presents like bacterial pneumonia, but pyrexia usually less, cough not as troublesome, haemoptysis much more common and the source of embolism may be apparent
Acute pulmonary tuberculosis can simulate pneumonia, but patients seldom as acutely ill. Tuberculous pleurisy may also present like a bacterial pleural infection
Pulmonary oedema, especially if unilateral and localised, may be difficult to distinguish from pneumonia on the chest radiograph. Absence of fever and presence of heart disease favour a diagnosis of oedema
Inflammatory conditions below the diaphragm
Conditions such as cholecystitis, perforated peptic ulcer, subphrenic abscess, acute pancreatitis and hepatic amoebiasis may be mistaken for lower lobe pneumonia associated with diaphragmatic pleurisy
Pulmonary eosinophilia, intrathoracic manifestations of connective tissue disorders, acute allergic alveolitis, Wegener's granulomatosis
Every effort should be made to establish a microbiological diagnosis, as such information is invaluable in tailoring antibiotic therapy and in managing any complications. The identification of organisms such as Legionella pneumophila also has important public health implications. Rapid results can sometimes be obtained with 'bedside' complement fixation tests for antigen levels (for example, of H. influenzae and Pneumocystis carinii) in urine and other body fluids. In patients who are severely ill a microbiological diagnosis becomes essential and, if sputum cannot be obtained, an attempt should be made to aspirate secretions or washings from the trachea or lower respiratory tract either by bronchoscopy or by inserting a needle through the cricothyroid membrane. Some patients can be induced to produce sputum by the administration of nebulised hypertonic saline. A summary of the microbiological investigations required in patients with community-acquired pneumonia is provided in Box 13.42; see also Figure 13.30.
Arterial blood gas measurements
These should be measured in all patients admitted to hospital with a diagnosis of pneumonia.
General blood tests
A high neutrophil leucocytosis favours a diagnosis of bacterial (particularly pneumococcal) pneumonia; patients with pneumonia caused by atypical agents tend to have a marginally raised or normal white cell count. A marked leucopenia indicates either a viral aetiology or an overwhelming bacterial infection.
Assessment of disease severity
Figure 13.29 Pneumonia of the right middle lobe. A Postero-anterior (PA) view: consolidation in right middle lobe with characteristic opacification beneath the horizontal fissure and loss of normal contrast between the right heart border and lung. B Lateral view: consolidation confined to the anteriorly situated middle lobe.
It is essential that in every patient with a clinical diagnosis of pneumonia an assessment is made to determine the severity of the disease. The use of simple clinical and laboratory parameters can determine very accurately those at high risk of death (see Box 13.43) and forms an important guide to the level of patient monitoring required. This assessment also has an important bearing on antibiotic choice. As a simple guide, patients with two or more of the four cardinal markers of severity, namely a respiratory rate = 30, a diastolic blood pressure = 60 mmHg, a serum urea = 7 mmol/l or the presence of confusion, have a 36-fold higher risk of dying compared with those patients without such features. Likewise, it is important to appreciate that a higher proportion of patients with mycoplasma pneumonia die compared to those with pneumococcal pneumonia and that in the latter condition coexistent septicaemia increases the mortality rate significantly.
13.42 MICROBIOLOGICAL INVESTIGATIONS IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA
Severe community-acquired pneumonia
The above tests plus consider:
Tracheal aspirate, induced sputum, bronchoalveolar lavage, protected brush specimen or percutaneous needle aspiration. Direct fluorescent antibody stain for Legionella and viruses
Serology-Legionella antigen in urine. Pneumococcal antigen in sputum and blood. Immediate IgM for Mycoplasma
Cold agglutinins-positive in 50% of patients with Mycoplasma
Throat/nasopharyngeal swabs-helpful in children or during influenza epidemic
Pleural fluid-should always be sampled when present in more than trivial amounts, preferably with ultrasound guidance
Sputum-direct smear by Gram (see Fig. 13.30) and Ziehl-Neelsen stains. Culture and antimicrobial sensitivity testing
Blood culture-frequently positive in pneumococcal pneumonia
Serology-acute and convalescent titres to diagnose Mycoplasma, Chlamydia, Legionella and viral infections. Pneumococcal antigen detection in serum
Figure 13.30 Gram stain of sputum showing Gram-positive diplococci characteristic of Strep. pneumoniae (arrows).
With appropriate intervention most patients respond promptly to antibiotic treatment. Delayed recovery suggests either that some complication such as empyema has developed or that the diagnosis is incorrect. Alternatively, the pneumonia may be secondary to a proximal bronchial obstruction or recurrent aspiration which delays recovery.
Oxygen should be administered to all hypoxaemic patients, and high concentrations (=35%) should be used in all patients who do not have hypercapnia associated with advanced COPD. Assisted ventilation should be considered at an early stage in all patients who remain significantly hypoxaemic despite adequate oxygen therapy. Most patients with moderate to severe pneumonia also require intravenous fluids and occasionally inotrope support (see p. 203).
13.43 FEATURES ASSOCIATED WITH A HIGH MORTALITY IN PNEUMONIA
Age 60 years or older
Respiratory rate > 30/min
Diastolic blood pressure 60 mmHg or less
More than one lobe involved on chest radiograph
Presence of underlying disease
Hypoxaemia (PaO2 < 8 kPa)
Leucopenia (white blood cells < 4000 × 109/litre)
Leucocytosis (white blood cells > 20 000 × 109/litre)
Raised serum urea (> 7 mmol/l)
Positive blood culture
13.44 ANTIBIOTIC TREATMENT FOR COMMUNITY-ACQUIRED PNEUMONIA (CAP)
Amoxicillin 500 mg 8-hourly orally
If patient allergic to penicillin
Clarithromycin 500 mg 12-hourly orally or
Erythromycin 500 mg 6-hourly orally
If Staphylococcus is cultured or suspected
Flucloxacillin 1-2 g 6-hourly i.v. plus
Clarithromycin 500 mg 12-hourly i.v.
If Mycoplasma or Legionella is suspected
Clarithromycin 500 mg 12-hourly orally or i.v. or
Erythromycin 500 mg 6-hourly orally or i.v. plus
Rifampicin 600 mg 12-hourly i.v. in severe cases
Clarithromycin 500 mg 12-hourly i.v. or Erythromycin 500 mg 6-hourly i.v. plus
Co-amoxiclav 1.2 g 8-hourly i.v. or Ceftriaxone 1-2 g daily i.v. or Cefuroxime 1.5 g 8-hourly i.v. or Amoxicillin 1 g 6-hourly i.v. plus flucloxacillin 2 g 6-hourly i.v.
Antibiotics should be given as soon as a clinical diagnosis of pneumonia is made. If possible, culture specimens should be sent prior to starting antibiotics but such treatment should not be delayed if, for example, a sputum sample is not readily available. The antibiotic regimens currently recommended in uncomplicated and severe community-acquired pneumonia are detailed in Box 13.44. If Strep. pneumoniae is identified as the causative organism, benzylpenicillin 1-2 g 6-hourly (i.v.) can be used in place of amoxicillin. Oral cephalosporins should not be used in the management of community-acquired pneumonia as they do not penetrate well into sputum or bronchial fluids and do not cover likely organisms. Patients with proven Klebsiella pneumonia should be treated with gentamicin (dose according to patient age, weight, creatinine clearance and intended frequency of use) plus either ceftazidime 1 g 8-hourly (i.v.) or ciprofloxacin 200 mg 12-hourly (i.v. infusion). Chlamydia pneumoniae is a somewhat difficult organism to culture and hence most cases are diagnosed late or retrospectively on serological grounds. In proven or suspected (epidemic) cases, erythromycin or tetracycline is recommended. Psittacosis is treated with tetracycline 500 mg 6-hourly orally or 500 mg 12-hourly i.v., or erythromycin at an equivalent dose. Actinomycosis, which is now regarded as an anaerobic bacterial infection, responds best to benzylpenicillin 2-4 g 6-hourly (i.v.). Chickenpox pneumonia is usually treated with oral aciclovir 200 mg five times daily for 5 days.
In most cases of uncomplicated pneumococcal pneumonia a 7-10-day course of treatment is usually adequate, although treatment is usually required for 14 days or longer in patients with Legionella, staphylococcal or Klebsiella pneumonia.
Treatment of pleural pain
It is important to relieve pleural pain in order to allow the patient to breathe normally and cough efficiently. Mild analgesics such as paracetamol are rarely adequate and most patients require pethidine 50-100 mg or morphine 10-15 mg by intramuscular or intravenous injection. Opiates, however, must be used with extreme caution in patients with poor respiratory function.
Formal physiotherapy is not indicated in patients with community-acquired pneumonia; however, assisted coughing is important in patients who suppress cough because of pleural pain. The administration of analgesic drugs should be coordinated with this form of physiotherapy to optimise patient cooperation.
Assessing progress can be difficult in patients with pneumonia. Although the response to antibiotics may be rapid and dramatic, fever may persist for several days and the chest radiograph often takes several weeks or even months to resolve, especially in the elderly. Failure to respond to therapy may indicate use of the wrong antibiotic, mixed infection, bronchial obstruction, the wrong diagnosis (e.g. pulmonary thromboembolism) or the development of a complication (see Box 13.45).
13.45 COMPLICATIONS OF PNEUMONIA
Empyema-see page 569
Retention of sputum causing lobar collapse
Development of thromboembolic disease
Pneumothorax-particularly with Staph. aureus
Suppurative pneumonia/lung abscess-see below
ARDS, renal failure, multi-organ failure
Ectopic abscess formation (Staph. aureus)
Hepatitis, pericarditis, myocarditis, meningoencephalitis
Pyrexia due to drug hypersensitivity
SUPPURATIVE AND ASPIRATIONAL PNEUMONIA (INCLUDING PULMONARY ABSCESS)
Suppurative pneumonia is the term used to describe a form of pneumonic consolidation in which there is destruction of the lung parenchyma by the inflammatory process. Although microabscess formation is a characteristic histological feature of suppurative pneumonia, it is usual to restrict the term 'pulmonary abscess' to lesions in which there is a fairly large localised collection of pus, or a cavity lined by chronic inflammatory tissue, from which pus has escaped by rupture into a bronchus.
Suppurative pneumonia and pulmonary abscess may be produced by infection of previously healthy lung tissue with Staph. aureus or Klebsiella pneumoniae. These are, in effect, primary bacterial pneumonias associated with pulmonary suppuration. More frequently, suppurative pneumonia and pulmonary abscess develop after the inhalation of septic material during operations on the nose, mouth or throat under general anaesthesia, or of vomitus during anaesthesia or coma. In such circumstances gross oral sepsis may be a predisposing factor. Additional risk factors for aspiration pneumonia include bulbar or vocal cord palsy, achalasia or oesophageal reflux and alcoholism. Intravenous drug users are at particular risk of developing lung abscess, often in association with endocarditis affecting the pulmonary and tricuspid valves. Aspiration into the lungs of acid gastric contents can give rise to a severe haemorrhagic pneumonia often complicated by the acute respiratory distress syndrome (ARDS, see p. 198). The clinical features of a suppurative pneumonia are summarised in Box 13.46.
Bacterial infection of a pulmonary infarct or of a collapsed lobe may also produce a suppurative pneumonia or a lung abscess. The organism(s) isolated from the sputum include Strep. pneumoniae, Staph. aureus, Strep. pyogenes, H. influenzae and, in some cases, anaerobic bacteria. In many cases, however, no pathogens can be isolated, particularly when antibiotics have been given.
13.46 CLINICAL FEATURES OF SUPPURATIVE PNEUMONIA
Acute or insidious
Cough productive of large amounts of sputum which is sometimes fetid and blood-stained
Pleural pain common
Sudden expectoration of copious amounts of foul sputum occurs if abscess ruptures into a bronchus
High remittent pyrexia
Profound systemic upset
Digital clubbing may develop quickly (10-14 days)
Chest examination usually reveals signs of consolidation; signs of cavitation rarely found
Pleural rub common
Rapid deterioration in general health with marked weight loss can occur if disease not adequately treated
Chest radiograph features
There is a homogeneous lobar or segmental opacity consistent with consolidation or collapse. A large, dense opacity, which may later cavitate and show a fluid level, is the characteristic finding when a frank lung abscess is present. Occasionally, a pre-existing emphysematous bulla becomes infected and appears as a cavity containing an air-fluid level.
In many patients oral treatment with amoxicillin 500 mg 6-hourly is effective. If an anaerobic bacterial infection is suspected (e.g. from fetor of the sputum), oral metronidazole 400 mg 8-hourly should be added. Antibacterial therapy should be modified according to the results of microbiological examination of the sputum. Prolonged treatment for 4-6 weeks may be required in some patients with lung abscess. Removal or treatment of any obstructing endobronchial lesion is essential.
In contrast to uncomplicated community-acquired pneumonia, physiotherapy is of great value, especially when large abscess cavities have formed. It may not be possible to drain lower lobe cavities without postural coughing.
In most patients there is a good response to treatment and although residual fibrosis and bronchiectasis are common sequelae, these seldom give rise to serious morbidity. Abscesses that fail to resolve despite optimal medical therapy require surgical intervention.
Hospital-acquired or nosocomial pneumonia refers to a new episode of pneumonia occurring at least 2 days after admission to hospital. The term includes post-operative and certain forms of aspiration pneumonia, and pneumonia or bronchopneumonia developing in patients with chronic lung disease, general debility or those receiving assisted ventilation.
The factors predisposing to the development of pneumonia in a hospitalised patient are listed in Box 13.47. The elderly are particularly at risk and this condition now occurs in 2-5% of all hospital admissions.
13.47 FACTORS PREDISPOSING TO NOSOCOMIAL PNEUMONIA
Reduced host defences against bacteria
Reduced immune defences (e.g. corticosteroid treatment, diabetes, malignancy)
Reduced cough reflex (e.g. post-operative)
Disordered mucociliary clearance (e.g. anaesthetic agents)
Bulbar or vocal cord palsy
Aspiration of nasopharyngeal or gastric secretions
Immobility or reduced conscious level
Vomiting, dysphagia, achalasia or severe reflux
Bacteria introduced into lower respiratory tract
Dental or sinus infection
Intravenous cannula infection
The most important distinction between hospital- and community-acquired pneumonia is the difference in the spectrum of pathogenic organisms, with the majority of hospital-acquired infections caused by Gram-negative bacteria. These include Escherichia, Pseudomonas and Klebsiella species. Infections caused by Staph. aureus (including multidrug-resistant-MRSA-forms) are also common in hospital, and anaerobic organisms are much more likely than in pneumonia acquired in the community. This profile of organisms in part reflects the high rate of colonisation of the nasopharynx of hospital patients with Gram-negative bacteria, together with the poor host defences and general inability of the severely ill or semiconscious patient to clear upper airway and respiratory tract secretions.
The clinical features and investigation of patients with hospital-acquired pneumonia are very similar to community-acquired pneumonia (see pp. 526-528). In the elderly or debilitated patient who develops acute bronchopneumonia (or 'hypostatic pneumonia') symptoms of acute bronchitis are followed after 2 or 3 days by increased cough and sputum purulence associated with a rise in temperature. Breathlessness and central cyanosis may then appear, but pleural pain is uncommon. In the early stages the physical signs are those of acute bronchitis followed by the development of crepitations. There is a neutrophil leucocytosis and the chest radiograph shows mottled opacities in both lung fields, chiefly in the lower zones.
Adequate Gram-negative coverage is usually obtained with:
a third-generation cephalosporin (e.g. cefotaxime) plus an aminoglycoside (e.g. gentamicin)
a monocyclic ß-lactam (e.g. aztreonam) plus flucloxacillin.
Aspiration pneumonia can be treated with co-amoxiclav 1.2 g 8-hourly plus metronidazole 500 mg 8-hourly. The nature and severity of most hospital-acquired pneumonias dictate that these antibiotics are all given intravenously, at least initially.
Physiotherapy is of particular importance in the immobile and elderly, and adequate oxygen therapy, fluid support and monitoring are essential. The mortality from hospital-acquired pneumonia is high (approximately 30%).
PNEUMONIA IN THE IMMUNOCOMPROMISED PATIENT
13.48 COMMON CAUSES OF IMMUNE SUPPRESSION: ASSOCIATED LUNG INFECTION
Cause Lung infection
Neutropenia Cytotoxic drugs Staph. aureus
Agranulocytosis Gram-negative bacteria
Acute leukaemia Candida albicans
T cell defect (± B cell defect) Lymphoma C. albicans
Chronic lymphocytic Mycobacterium tuberculosis
leukaemia (CLL) Pneumocystis carinii
Immunosuppressive drugs Cytomegalovirus
Bone marrow transplants Staph. aureus
Splenectomy H. influenzae
Antibody production CLL Strep. pneumoniae
Myeloma H. influenzae
Pulmonary infection is common in patients receiving immunosuppressive drugs and in those with diseases causing defects of cellular or humoral immune mechanisms. For example, patients with AIDS are susceptible to many types of pneumonia, in particular Pneumocystis carinii (see p. 120). It is important to recognise, however, that the common pathogenic bacteria are responsible for the majority of lung infections in immunocompromised patients (see Box 13.48). Despite this, the Gram-negative bacteria, especially Pseudomonas aeruginosa, are more of a problem than Gram-positive organisms, and unusual organisms or those normally considered to be of low virulence or non-pathogenic may become 'opportunistic' pathogens. Likewise, infection is often due to more than one organism. Pneumocystis carinii and other fungi such as Aspergillus fumigatus (see pp. 540-542), viral infections, cytomegalovirus (see p. 30), herpesviruses, and infections with M. tuberculosis and other types of mycobacteria (see opposite) are all common causes of infection in patients who are immunocompromised.
The patient usually presents with fever, cough, breathlessness and infiltrates on the chest radiograph. Patients may develop non-specific symptoms, and a high index of suspicion is required to determine the site and nature of the infection. In general, the onset of symptoms tends to be less rapid in patients with opportunistic organisms such as Pneumocystis carinii and mycobacterial infections. In Pneumocystis carinii pneumonia symptoms of cough and breathlessness can be present several days or weeks before the onset of systemic symptoms or even a chest radiograph abnormality.
Lung biopsy offers the greatest chance of establishing a diagnosis if examination of sputum or bronchoalveolar lavage fluid has not revealed a pathogen. This, however, is a relatively high-risk and invasive procedure and should be reserved for patients in whom less invasive procedures fail to establish a diagnosis and in whom there has been no response to broad-spectrum antibiotic treatment. Some patients who cannot produce sputum can be induced to do so by the inhalation of nebulised hypertonic saline. Fibreoptic bronchoscopy should be performed early since a diagnosis can often be established by examination of lavage fluid, bronchial brushings or transbronchial biopsies.
Whenever possible, treatment should be based on an established aetiological diagnosis. In practice, however, the cause of the pneumonia is frequently not known when treatment has to be started. Hence, broad-spectrum antibiotic therapy is required (e.g. a third-generation cephalosporin, or a quinolone, plus an antistaphylococcal antibiotic, or an antipseudomonal penicillin plus an aminoglycoside) and this treatment is thereafter tailored according to the results of investigations and the clinical response. The management of P. carinii infection is detailed on page 121.
Tuberculosis (TB) remains the most common infectious disease in the world, with an estimated one-third of the population infected and 2.5 million deaths annually. In the mid-1980s, the falling global incidence reversed in both developed and developing nations (see Box 13.49). In 1999 there were an estimated 8.4 million new cases of tuberculosis world-wide (up 5% from 1997), with 3 million occurring in South-east Asia and 2 million in Africa (where two-thirds are HIV-infected). By 2005, WHO predicts there will be 10.2 million new cases and Africa will have more cases than any other region (up 10% annually). In England and Wales there has been a 21% increase in notifications since 1987. Annual rates of tuberculosis are highest amongst non-white ethnic groups (Indian subcontinent, black African and Chinese) and in urban areas. In 1998, over half of all notified patients were born outside the UK, one-third of cases occurred in young adults and an estimated 3.3% were HIV-coinfected. Apart from HIV, several other factors are recognised to increase the risk of individuals developing tuberculosis (see Box 13.50).
13.49 REASONS FOR THE INCREASING INCIDENCE OF PULMONARY TUBERCULOSIS
Ø HIV (mainly urban)
Ø Immigration from high prevalence areas
Ø Increasing life expectancy of the elderly
Ø Social deprivation (injection drug use, homelessness, poverty)
Ø Drug resistance (MDRTB)
Ø Reduced priority for TB control
o HIV (mainly urban)
o Population increase (75% predicted increase in India over 30 years)
o Lack of access to health care
o Poverty, civil unrest
o Ineffective control programmes
o Drug resistance (MDRTB)
13.50 FACTORS INCREASING THE RISK OF TUBERCULOSIS
1. Age (children > young adults)
2. First-generation immigrants from high prevalence countries
3. Close contacts of patients with smear-positive pulmonary tuberculosis
4. Chest radiograph evidence of self-healed tuberculosis
5. Primary infection < 1 year previously
4) Malignancy (especially lymphoma, leukaemia)
5) Type 1 diabetes mellitus
6) Chronic renal failure
7) Gastrointestinal disease associated with malnutrition (gastrectomy, jejuno-ileal bypass, cancer of the pancreas, malabsorption)
13.51 SITE-SPECIFIC MYCOBACTERIAL DISEASE
Pulmonary M. tuberculosis
Lymph node M. tuberculosis
Soft tissue/skin M. leprae
M. ulcerans (prevalent in Africa, northern Australia and South-east Asia) M. marinum
Disseminated (seen in immunodeficiency states) MAC (HIV-associated)
(MAC = Mycobacterium avium complex--M. scrofulaceum, M. intracellulare and M. avium)
Mycobacterium tuberculosis belongs to a complex of organisms with M. bovis (reservoir cattle) and African and Asian variants (reservoir humans); all cause clinical tuberculosis. In addition, other species of environmental mycobacteria (often termed 'atypical') may cause human disease (see Box 13.51). The sites commonly involved are the lungs, lymph nodes, skin and soft tissues. With the advent of HIV, disseminated infection with Mycobacterium avium complex (MAC) has become common when severe immunodeficiency exists (CD4 count < 50 cells/ml-see p. 121). Environmental mycobacteria are low-grade pathogens (with the exception of M. malmoense and M. ulcerans), tending to cause disease in the setting of immunocompromise or scarred lungs. The significance of an isolate depends on the species, site of isolation, number of isolates and whether or not there is a recognised association with the clinical presentation. Where the isolate is from a non-sterile site, multiple positive cultures are usually required to confirm infection.
Pathology and pathogenesis
Infection with M. tuberculosis occurs most frequently through inhalation of infected droplets, with the primary infection occurring in the lung (see Fig. 13.31). Occasionally, the tonsil, intestine or skin may be the site of primary disease. Following inhalation of M. tuberculosis, a small subpleural lesion (the Ghon focus) develops with rapid transport of bacilli to the regional (hilar) lymph nodes and the development of the primary complex. Non-specifically activated macrophages that have ingested the bacilli then aggregate and the lesions enlarge. At 2-4 weeks, two distinct T cell-mediated immune responses start. A delayed-type hypersensitivity reaction destroys non-activated macrophages containing bacilli but also results in tissue necrosis and caseation. Cell-mediated immunity results in macrophages being activated into epithelioid cells with the formation of granulomas seen at the periphery of the caseation. The virulence factors of M. tuberculosis have not been fully elucidated. The organism is versatile, with the ability to multiply rapidly outside cells within cavities, survive inside macrophages preventing fusion between the lysosome and phagosome, and survive in a relatively inactive state with only infrequent bursts of division.
Integration link: TB - histopathology
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
Figure 13.31 Primary pulmonary tuberculosis. (1) Spread from the primary focus to hilar and mediastinal lymph glands to form the 'primary complex', which in most cases heals spontaneously. (2) Direct extension of the primary focus-'progressive pulmonary tuberculosis'. (3) Spread to the pleura-tuberculous pleurisy and pleural effusion. (4) Blood-borne spread: few bacilli-pulmonary, skeletal, renal, genitourinary infection often months or years later; massive spread-miliary tuberculosis and meningitis.
13.52 TIMETABLE OF TUBERCULOSIS
Time from infection Manifestations
3-8 weeks Primary complex, positive tuberculin skin test
3-6 months Meningeal, miliary and pleural disease
Up to 3 years Gastrointestinal, bone and joint, and lymph node disease
Around 8 years Renal tract disease
From 3 years onwards Post-primary disease due to reactivation or reinfection
In 85-90% of cases the primary complex heals spontaneously in 1-2 months and the tuberculin skin test becomes positive. In 10-15%, multiplication of M. tuberculosis is not contained and lymph node enlargement results in either local pressure effects, lymphatic spread to the pleura or pericardium, or rupture into an adjacent bronchus or pulmonary blood vessel. Where dissemination has occurred, disease may progress rapidly to the development of miliary and meningeal tuberculosis. Also, foci of infection may be set up in bone, the lung, the genitourinary and gastrointestinal tracts, or lymph nodes, which may progress to clinical disease (see Box 13.52). However, 85-90% of patients develop latent infection (positive tuberculin test or radiographic evidence of self-healed tuberculosis). Within this group 5-10% reactivate during their life-time, resulting in post-primary disease. This is predominantly pulmonary (75%) and infectious (50% smear-positive). Re-exposure to smear-positive pulmonary tuberculosis may result in post-primary disease and accounts for up to one-third of all cases. The likelihood of infection after exposure (30%), development of progressive primary disease (30%) and reinfection from other infectious cases (50%) are all increased in HIV-infected individuals. Where good immune function is retained in HIV, clinical disease resembles classical post-primary tuberculosis. However, where significant immunodeficiency has occurred, the presentation is more likely to be disseminated or extrapulmonary (see Box 13.53 and opposite).
Integration link: Sequence of TB infection
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
13.53 TUBERCULOSIS IN HIV
Infection after exposure
Progressive primary disease after infection
Reactivation of latent infection
Reinfection with new strain
Reduced smear-positive rates in pulmonary TB
Atypical chest radiograph appearance
Increased disseminated disease
More extrapulmonary infection
Greater risk of adverse drug reactions
Clinical features: pulmonary disease
Primary pulmonary tuberculosis
Integration link: TB - gross pathology
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
Infection usually occurs in childhood and is generally asymptomatic; a few patients develop a self-limiting febrile illness. A history of contact with a person with active pulmonary tuberculosis is often obtained. Clinical disease results either from the development of a hypersensitivity reaction or from the infection pursuing a progressive course (see Box 13.54). Erythema nodosum may be the presenting feature of primary tuberculosis and is associated with a strongly positive tuberculin skin test. Progressive primary disease may appear during the course of the initial illness or after a latent interval of weeks or months. The features depend on the site affected (see below).
13.54 FEATURES OF PRIMARY TUBERCULOSIS
Infection (4-8 weeks)
§ Influenza-like illness
§ Skin test conversion
§ Primary complex
¨ Lymphadenopathy (hilar (often unilateral), paratracheal or mediastinal)
o Collapse (especially right middle lobe)
o Consolidation (especially right middle lobe)
o Obstructive emphysema
o Cavitation (rare)
¨ Pleural effusion
¨ Erythema nodosum
¨ Phlyctenular conjunctivitis
This is a severe infection often diagnosed late. The disease may start suddenly but more frequently there is a period of 2-3 weeks when fever, night sweats, anorexia, weight loss and a dry cough are present. Hepatosplenomegaly may be present (25%) and the presence of headache may indicate coexistent tuberculous meningitis. Auscultation of the chest is frequently normal, although with more advanced disease widespread crackles are evident. Choroidal tubercles occur in 5-10%. The chest radiograph reveals fine 1-2 mm lesions (millet seeds) throughout the lungs, although occasionally the appearances are coarser. Anaemia and leucopenia may be present. An unusual presentation seen usually in the elderly is 'cryptic' miliary tuberculosis (see Box 13.55).
13.55 PRESENTATION OF CRYPTIC TUBERCULOSIS
¨ Age over 60 years
¨ Intermittent low-grade pyrexia of unknown origin
¨ Unexplained weight loss, general debility (hepatosplenomegaly in 25-50%)
¨ Normal chest radiograph
¨ Blood dyscrasias; leukaemoid reaction, pancytopenia
¨ Negative tuberculin skin test
¨ Confirmation by biopsy (granulomata and/or acid-fast bacilli demonstrated) of liver or bone marrow
Post-primary pulmonary tuberculosis
13.56 CLINICAL PRESENTATION OF PULMONARY TUBERCULOSIS
§ Chronic cough, often with haemoptysis
§ Pyrexia of unknown origin
§ Unresolved pneumonia
§ Exudative pleural effusion
§ Asymptomatic (diagnosis on chest radiograph)
§ Weight loss, general debility
§ Spontaneous pneumothorax
13.57 CHRONIC COMPLICATIONS OF PULMONARY TUBERCULOSIS
M Massive haemoptysis
M Cor pulmonale
M Atypical mycobacterial infection
M Lung/pleural calcification
M Obstructive airways disease
M Bronchopleural fistula
M Empyema necessitans
M Anorectal disease
M Poncet's polyarthritis
Figure 13.32 Chest radiograph: major manifestations and differential diagnosis of pulmonary tuberculosis. Less common manifestations include pneumothorax, ARDS (see p. 198), cor pulmonale and localised emphysema.
Disease in adults is usually a result of post-primary disease. A subacute illness characterised by cough, haemoptysis, dyspnoea, anorexia and weight loss associated with fevers and night sweats is typical. Other clinical presentations are listed in Box 13.56. Auscultation of the chest frequently reveals localising signs but may be normal. The earliest radiological change is typically an ill-defined opacity situated in one of the upper lobes. Disease often involves two or more areas of lung and may be bilateral; as disease progresses, consolidation, collapse and cavitation develop to varying degrees (see Fig. 13.32). The presence of a miliary pattern or cavitation indicates active disease although there is a wide differential. In extensive disease, collapse may be marked and result in significant displacement of the trachea and mediastinum. Occasionally, a caseous lymph node may drain into an adjoining bronchus, resulting in tuberculous pneumonia. The complications of pulmonary tuberculosis are shown in Box 13.57.
Clinical features: extrapulmonary disease
The most common extrapulmonary site of disease is the lymph nodes. Cervical and mediastinal glands are affected most frequently, followed by axillary and inguinal; in 5% of patients, more than one region is involved. Disease may represent primary infection, spread from contiguous sites or reactivation of infection. Supraclavicular lymphadenopathy is usually a result of spread from mediastinal disease. The nodes are usually painless and initially mobile but become matted together with time. When caseation and liquefaction occur, the swelling becomes fluctuant and may discharge through the skin with the formation of a 'collar-stud' abscess and sinus formation. Approximately half of patients fail to show any constitutional features such as fevers and night sweats. The tuberculin skin test is usually strongly positive. During or after treatment, paradoxical enlargement, development of new nodes and suppuration may all occur but without evidence of continued infection; rarely, surgical excision is necessary. In non-immigrant children in the UK, most mycobacterial lymphadenitis is caused by environmental (atypical) mycobacteria, especially of the M. avium complex (see Box 13.51).
Tuberculosis can affect any part of the bowel and patients may present with a wide range of symptoms and signs (see Fig. 13.33). Upper gastrointestinal tract involvement is rare and is usually an unexpected histological finding in an endoscopic or laparotomy specimen. Ileocaecal disease accounts for approximately half of abdominal tuberculosis cases. Fever, night sweats, anorexia and weight loss are usually prominent and a right iliac fossa mass may be palpable. Up to 30% of cases present with an acute abdomen. Ultrasound or CT may reveal thickened bowel wall, abdominal lymphadenopathy, mesenteric thickening or ascites. Barium enema and small bowel enema reveal narrowing, shortening and distortion of the bowel with caecal involvement predominating. Diagnosis rests on obtaining histology by either colonoscopy or mini-laparotomy. The main differential diagnosis is Crohn's disease (see p. 808). Tuberculous peritonitis is characterised by abdominal distension, pain and constitutional symptoms. The ascitic fluid is exudative and cellular with a predominance of lymphocytes. Laparoscopy reveals multiple white 'tubercles' over the peritoneal and omental surfaces. Low-grade hepatic dysfunction is common in miliary disease when biopsy reveals granulomata. Occasionally, patients may be frankly icteric with a mixed hepatic/cholestatic picture.
Figure 13.33 Systemic presentations of extrapulmonary tuberculosis.
Disease occurs in two main forms (see Fig. 13.33 and p. 478): pericardial effusion and constrictive pericarditis. Fever and night sweats are rarely prominent and the presentation is usually insidious with breathlessness and abdominal swelling. Pulsus paradoxus, a very raised JVP, hepatosplenomegaly, prominent ascites and the absence of peripheral oedema are common to both types of disease. Pericardial effusion is associated with increased pericardial dullness and a globular enlarged heart on chest radiograph. Constriction is associated with atrial fibrillation (< 20%), an early third heart sound and pericardial calcification in 25%. Diagnosis is on clinical, radiological and echocardiographic grounds. The pericardial effusion is blood-stained in 85% of cases. Coexistent pulmonary disease is very rare, with the exception of pleural effusion. Open pericardial biopsy can be performed in patients with effusion where there is doubt about the diagnosis. The addition of corticosteroids has been shown to be beneficial when added to antituberculosis treatment (see below) for both.
Central nervous system disease
By far the most important form of central nervous system tuberculosis is meningeal disease. This is life-threatening and may be rapidly fatal if not diagnosed early. Clinical features, investigations and management are dealt with on page 1192.
Bone and joint disease
Tuberculosis of the spine usually presents with chronic back pain and typically involves the lower thoracic and lumbar spine (see Fig. 13.33). The infection starts as a discitis and then spreads along the spinal ligaments to involve the adjacent anterior vertebral bodies, causing angulation of the vertebrae with subsequent kyphosis. Paravertebral and psoas abscess formation is common. CT is valuable in gauging the extent of disease, the amount of cord compression, and the site for needle biopsy or open exploration if required. The major differential diagnosis is malignancy, which tends to affect the vertebral body and leave the disc intact. In the absence of spinal instability or cord compression, patients can be treated as outpatients. Tuberculosis can affect any joint, but most frequently involves the hip or knee. Presentation is usually insidious with pain and swelling; fever and night sweats are uncommon. Radiological changes are often non-specific but, as disease progresses, reduction in joint space and erosions appear.
Fever and night sweats are rare with renal tract tuberculosis and patients are often only mildly symptomatic for many years. Haematuria, frequency and dysuria are often present, with sterile pyuria found on urine microscopy and culture. In women, infertility from endometritis, or pelvic pain and swelling from salpingitis or a tubo-ovarian abscess may occur infrequently. In men, genitourinary tuberculosis may present as epididymitis or prostatitis.
Diagnosis (see Box 13.58)
Mycobacterial infection can be confirmed by direct microscopy of samples (Ziehl-Neelsen or auramine staining) and culture. Confirmation of the isolate as M. tuberculosis is obtained through standard culture methods (growth characteristics, pigment production and biochemical tests) or molecular DNA technology (hybridisation probes, polymerase chain reaction amplification). After decontamination, samples should be cultured on solid medium as well as into liquid medium, which provides more rapid growth. Drug susceptibility profiles can be obtained within 1-2 weeks of growth using the BACTEC system. Where MDRTB is suspected, molecular methods allow the detection of rifampicin resistance (a marker for multidrug resistance) in primary specimens as well as cultures. If a cluster of cases suggests a common source, fingerprinting of isolates with restriction-fragment length polymorphism (RFLP) or DNA amplification can help confirm this.
Primary tuberculosis in children is rarely confirmed by culture. In adults, direct microscopy is positive in 60% of pulmonary and 5-25% of extrapulmonary cases (highest for lymph node and lowest for meningeal disease). In 10-20% of patients with pulmonary disease and 40-50% of patients with extrapulmonary disease, culture is also negative and the diagnosis is clinical.
Control and prevention
13.58 DIAGNOSIS OF TUBERCULOSIS
§ Sputum (induced with nebulised hypertonic saline if not expectorating)
§ Gastric washing (mainly used for children)
§ Bronchoalveolar lavage
§ Transbronchial biopsy
¨ Fluid examination (cerebrospinal, ascitic, pleural, pericardial, joint)
¨ Tissue biopsy (from affected site; also bone marrow/liver may be diagnostic in patients with disseminated disease)
Ä Diagnostic test
è Circumstantial (ESR, C-reactive protein, anaemia etc.)
è Tuberculin skin test (low sensitivity/specificity; useful only in primary or deep-seated infection)
Ä Auramine fluorescence
è Nucleic acid amplification
Ä Solid (Löwenstein-Jensen, Middlebrook)
Ä Liquid (e.g. BACTEC)
è Response to empirical antituberculous drugs (usually seen after 5-10 days)
BCG (the Calmette-Guérin bacillus) is an attenuated vaccine derived from M. bovis, which was developed in 1921 (see pp. 1213-1214). Its protective efficacy is up to 80% for 10-15 years and is greatest for preventing disseminated disease in children. In the UK it is recommended for the following tuberculin skin test-negative groups:
Kall children 10-14 years of age
Kcontacts < 2 years old
Kimmigrants from countries where tuberculosis is endemic
Kinfants in high prevalence ethnic groups
Khealth-care workers at risk.
Only those who do not respond to tuberculin are vaccinated. Grade 3-4 tuberculin skin test responders should be referred for clinical and radiological examination. Tuberculin skin testing is usually performed using the Heaf or Mantoux technique (see Box 13.59 and Fig. 13.34). Some countries do not use BCG because they value the diagnostic sensitivity of the tuberculin skin test as a measure of recent primary infection. Occasional complications include a local BCG abscess and disseminated infection in immunocompromised persons.
Chemoprophylaxis is given to prevent infection progressing to clinical disease. It is recommended for children aged less than 16 years with strongly positive Heaf tests, children aged less than 2 years in close contact with smear-positive pulmonary disease, those in whom recent tuberculin conversion has been confirmed, and babies of mothers with pulmonary tuberculosis. It should be considered for HIV-infected close contacts of a patient with smear-positive disease. Rifampicin and isoniazid for 3 months, rifampicin and pyrazinamide for 2 months, or isoniazid for 6 months are all effective.
13.59 SKIN TESTING IN TUBERCULOSIS
Tests using purified protein derivative (PPD) False negatives
Heaf (read at 3-7 days) Severe TB (25% of cases negative)
Multipuncture method Newborn and elderly
Grade 1: 4-6 papules HIV (if CD4 count < 200 cells/ml)
Grade 2: Confluent papules forming ring Recent infection (e.g. measles) or immunisation
Grade 3: Central induration Malnutrition
Grade 4: > 10 mm induration Immunosuppressive drugs
Mantoux (read at 2-4 days) Using 10 tuberculin units: positive when
induration 5-14 mm (equivalent to Heaf grade 2)
and > 15 mm (Heaf grade 3-4)
In the UK an active contact-screening programme operates, beginning with compulsory notification of all tuberculosis cases. The aim of contact tracing is to identify a possible index case with clinical disease, other cases infected by the same index patient (with or without evidence of disease), and close contacts who should receive BCG vaccination. Approximately 10-20% of close contacts of patients with smear-positive pulmonary tuberculosis and 2-5% of those with smear-negative, culture-positive disease have evidence of tuberculosis infection. Close contacts of patients with pulmonary disease are seen in dedicated clinics where their BCG and clinical status is reviewed, Heaf tests are performed (except in those below 16 years of age), and the need for radiography is assessed. Outcomes include chemotherapy (for active disease), chemoprophylaxis (to prevent infection progressing to active disease), BCG immunisation or discharge.
Figure 13.34 Gradings of the Heaf test response.
A Negative. B Grade 1. C Grade 2. D Grade 3. E Grade 4.
13.60 TREATMENT OF TUBERCULOSIS AND DISSEMINATED MAC
Initial Months Continuation Months
New cases HRZE 2 HR 4
New cases: resource-poor settings HRZS or HRZE 2 HT1 or HE 6
Relapses and treatment failures HRZE2 2+ = 2 drugs3 6-10
MDRTB = 5 drugs4 24
Disseminated MAC = 4 drugs5 2-6 2 drugs6 12+
First-line drugs7: Ethambutol (E), isoniazid (H), rifampicin (R), pyrazinamide (Z), streptomycin (S), rifabutin, thiacetazone (T)1
Second-line drugs: Clarithromycin (or azithromycin), ofloxacin (or ciprofloxacin), protionamide (or ethionamide), cycloserine, capreomycin, para-aminosalicylic acid (PAS)
1 Thiacetazone is bacteriostatic and contraindicated in HIV.
2 Additional second-line agents may be indicated until sensitivities are known.
3 Guided by sensitivity results.
4 Dependent on sensitivities.
5 Ciprofloxacin, ethambutol, azithromycin, rifabutin is a recommended regimen.
6 When CD4 count > 100 cells/ml reduction to azithromycin and one other drug is safe.
7 HRZE and S can all be given by intermittent dosing (directly observed therapy).
Short-course therapy with 2 months of four drugs (rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) followed by 4 months of rifampicin and isoniazid is now recommended for all patients with new-onset, uncomplicated pulmonary or extrapulmonary tuberculosis (see Box 13.60). The fourth drug (ethambutol or streptomycin) can be omitted in patients in whom isoniazid resistance is unlikely (previously untreated white patients, presumed HIV-negative individuals and those having no contact with a possible patient with drug-resistant disease). Streptomycin is now rarely used in the UK but it is an important component of short-course treatment regimens in developing nations. Drugs should be given as a single daily dose before breakfast. Patients should be considered for longer treatment (9-12 months) where meningeal disease is present, there is HIV coinfection, or drug intolerance occurs and a second-line agent is substituted. Relapse is rare when the strain is fully sensitive (< 2%) and adherence to drug therapy is complete. In patients with a history of past treatment, four drugs must be used until the sensitivity results are obtained. In the UK drug resistance in newly diagnosed patients is uncommon (overall < 5%) and is more frequently observed in isolates from ethnic minority patients. The treatment of MDRTB is complex and depends on the sensitivity of the isolate. Five or more drugs are used and the patient must be admitted to a negative-pressure isolation room for treatment until deemed non-infectious.
Most patients can be treated at home, although where there is uncertainty about the diagnosis, intolerance of medication, questionable compliance, a background of adverse social conditions or a significant risk of MDRTB (culture positive after 2 months on treatment, contact with known MDRTB), patients should be admitted. Where drug resistance is not expected, patients can be assumed to be non-infectious after 2 weeks of quadruple therapy including rifampicin and isoniazid. Combined drug preparations (including rifampicin and isoniazid with or without pyrazinamide) reduce tablet load and allow relatively simple screening for compliance as the urine can be assessed visually for an orange-red colour. Directly observed therapy (DOT) is recommended where patients are unlikely to comply (alcoholics, injection drug users, the mentally ill and patients failing previous therapy), where there is multidrug resistance (as part of the continuation phase) and where there are language difficulties. In developing nations, DOT dispenses with the need for initial hospitalisation to receive streptomycin, is cost-effective and is less disruptive to patients' lives. Most importantly, it improves adherence. All the first-line agents can be given thrice weekly. Currently, WHO recommends DOT therapy for all patients with tuberculosis at a global level.
In choosing a suitable drug regimen, it is important to bear in mind underlying comorbidity (renal and hepatic dysfunction, eye disease, peripheral neuropathy and HIV as well as the potential for drug interactions (rifampicin is a potent cytochrome inducer). Baseline liver function and subsequent regular monitoring are important for patients with underlying liver disease treated with standard therapy including rifampicin, isoniazid and pyrazinamide, all of which are potentially hepatotoxic. Patients treated with the first-line drug rifampicin should always be warned that their urine, tears and other secretions will develop a bright orange/red coloration. Ethambutol should be used with caution in patients with renal failure, with appropriate dose reduction and monitoring of drug levels.
Corticosteroids are recommended in tuberculous pericarditis as they reduce the need for pericardiectomy in constrictive pericarditis and repeat aspiration or open surgical drainage in pericardial effusion. They are also advised for moderate to severe tuberculous meningitis. In patients with ureteric disease, pleural effusion, primary endobronchial disease or severe disseminated disease, corticosteroids should be considered, although the evidence is less certain. Surgery is still occasionally required (e.g. for massive haemoptysis, loculated empyema, constrictive pericarditis, lymph node suppuration, spinal disease with cord compression), but usually only after a full course of antituberculosis treatment.
PULMONARY TUBERCULOSIS-optimal choice of antituberculous drugs
'Two large RCTs have shown that 6 months of treatment are as effective as longer courses if a four-drug combination (isoniazid, rifampicin, pyrazinamide and ethambutol, or isoniazid, rifampicin, pyrazinamide and streptomycin) is used for 2 months followed by isoniazid and rifampicin for 4 months. One RCT has shown no difference between streptomycin and ethambutol as the fourth drug. One SR shows no difference between daily and thrice-weekly short course regimens.'
Global Tuberculosis Programme. Treatment of tuberculosis. Geneva: World Health Organisation; 1997 (WHO/TB/97.220).
British Thoracic Society. A controlled trial of 6 months' chemotherapy in pulmonary tuberculosis: results during the 36 months after the end of chemotherapy and beyond. Br J Dis Chest 1984; 78:330-336.
Mwandumba HC, Squire SB. Fully intermittent dosing with drugs for tuberculosis (Cochrane Review). Cochrane Library, issue 1, 2001. Oxford: Update Software.
Further information: www.clinicalevidence.org
CHEMOTHERAPY FOR TUBERCULOSIS-optimal duration of therapy
'RCTs have found no evidence of a difference in relapse rates between 6 and 9 months' chemotherapy in people with pulmonary tuberculosis. In contrast, SR of 9 trials comparing 6 months of treatment with shorter-duration regimens demonstrates consistently higher relapse rates (range 1-8%) in the shorter treatment arms. On the basis of such data, WHO recommends 6 months of treatment in all patients with active pulmonary tuberculosis infection.'
Gelband H. Regimens of less than six months for treating tuberculosis (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998; 53:536-548.
Further information: www.cochrane.co.uk
13.61 MAIN ADVERSE REACTIONS OF FIRST-LINE ANTITUBERCULOUS DRUGS
Isoniazid Rifampicin Pyrazinamide Streptomycin Ethambutol
Mode of action Cell wall synthesis DNA transcription Unknown Protein synthesis Cell wall synthesis
Major adverse reactions Peripheral neuropathy1 Febrile reactions Hepatitis 8th nerve damage Retrobulbar neuritis3
Hepatitis2 Hepatitis Gastrointestinal disturbance Rash Arthralgia
Gastrointestinal disturbance Hyperuricaemia
Less common adverse reactions Lupoid reactions Interstitial nephritis Rash Nephrotoxicity Peripheral neuropathy
Seizures Thrombocytopenia Photosensitisation Agranulocytosis Rash
Psychoses Haemolytic anaemia Gout
12-5%; reduced to 0.2% with supplementary pyridoxine.
3Reduced visual acuity and colour vision with higher doses; usually reversible.
21.5%; increased with age, slow acetylator status, rifampicin use and alcohol.
Adverse drug reactions occur in 10% of patients but are significantly more common where there is HIV coinfection (see Box 13.61).
In the absence of major complications, short-course therapy using four drugs initially is curative. Occasionally, patients die of overwhelming infection (usually miliary disease or bronchopneumonia) and some patients succumb to the later complications of tuberculosis (e.g. cor pulmonale). A few patients die unexpectedly soon after commencing therapy and it is possible that some of these individuals have subclinical hypoadrenalism that is unmasked by a rifampicin-induced increase in steroid metabolism. In HIV-associated tuberculosis, mortality is increased but mainly as a result of superimposed bacterial infection.
RESPIRATORY DISEASES CAUSED BY FUNGI
Most fungi encountered by humans are harmless saprophytes but some species may, in certain circumstances, infect human tissue or promote damaging allergic reactions.
The term 'mycosis' is applied to disease caused by fungal infection. Predisposing factors include metabolic disorders such as diabetes mellitus, toxic states (for example, chronic alcoholism), diseases in which immunological responses are disturbed such as AIDS, treatment with corticosteroids and immunosuppressive drugs, and radiotherapy. Local factors such as tissue damage by suppuration or necrosis and the elimination of the competitive influence of a normal bacterial flora by antibiotics may also facilitate fungal infection.
The diagnosis of fungal disease of the respiratory system is usually made by mycological examination of sputum-microscopic examination of stained films for fungal hyphae being extremely important-supported by serological tests and in some cases by skin sensitivity tests.
Most cases of bronchopulmonary aspergillosis are caused by Aspergillus fumigatus, but other members of the genus (A. clavatus, A. flavus, A. niger and A. terreus) occasionally cause disease. The conditions associated with Aspergillus species are listed in Box 13.62.
13.62 CLASSIFICATION OF BRONCHOPULMONARY ASPERGILLOSIS
Atopic (allergic) asthma (see p. 514)
Allergic bronchopulmonary aspergillosis (asthmatic pulmonary eosinophilia)
Extrinsic allergic alveolitis (Aspergillus clavatus)
Invasive pulmonary aspergillosis
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)
This is caused by hypersensitivity reactions to A. fumigatus involving the bronchial wall and peripheral parts of the lung. In the vast majority of patients it is associated with bronchial asthma, but it can occur in non-asthmatic patients and is a recognised complication of cystic fibrosis. It is one of the causes of pulmonary eosinophilia (see p. 560), since it is characterised by fleeting radiographic abnormalities associated with peripheral blood eosinophilia.
Fever, breathlessness, cough productive of bronchial casts and worsening of asthmatic symptoms can all be manifestations of ABPA, but frequently the diagnosis is suggested by abnormalities on routine chest radiographs of patients whose asthmatic symptoms are no worse than usual. When repeated episodes of ABPA have caused bronchiectasis, the symptoms and complications of that disease often overshadow those of asthma.
The disease is characterised by recurrent transient radiograph abnormalities of two main types: diffuse pulmonary infiltrates and lobar or segmental pulmonary collapse. Permanent radiographic changes of bronchiectasis ('tram-line', ring and 'gloved-finger' shadows) are seen predominantly in the upper lobes in patients with advanced disease.
The diagnostic features are shown in Box 13.63. Not all are required to make a confident diagnosis.
13.63 DIAGNOSTIC FEATURES OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
Asthma (in the majority of cases)
Peripheral blood eosinophilia > 0.5 × 109/litre
Presence or history of chest radiograph abnormalities
Positive skin test to an extract of A. fumigatus
Serum precipitating antibodies to A. fumigatus
Elevated total serum IgE
Fungal hyphae of A. fumigatus on microscopic examination of sputum
In the absence of safe and effective antifungal agents which can be given long-term, the main aims of therapy are:
suppression of the immunopathological responses to A. fumigatus with low-dose oral corticosteroid therapy (prednisolone 7.5-10 mg daily)
optimal control of associated asthma
prompt, effective management of exacerbations associated with new chest radiograph changes-prednisolone 40-60 mg daily and physiotherapy. If lobar collapse persists for more than 7-10 days, bronchoscopy to remove impacted mucus should be performed to prevent the development of bronchiectasis.
Inhaled air-borne spores of A. fumigatus may lodge and germinate in damaged pulmonary tissue, and an 'aspergilloma' (a ball of Aspergillus fungus) can form in any area of damaged lung in which there is a persistent abnormal space. The most common cause of such pulmonary damage is tuberculosis (see Fig. 13.35), but an aspergilloma can develop in an abscess cavity, a bronchiectatic space or even a cavitated tumour. Most, but not all, are caused by A. fumigatus.
An aspergilloma often produces no specific symptoms but may be responsible for recurrent haemoptysis, which is often severe. The presence of a fungus ball in the lung can also give rise to non-specific systemic features such as lethargy and weight loss.
The development of a fungal ball within a cavity produces a tumour-like opacity on radiograph. An aspergilloma can usually be distinguished from a peripheral bronchial carcinoma by the presence of a crescent of air between the fungal ball and the upper wall of the cavity. Aspergillomata may be multiple.
The diagnosis is usually suspected because of the chest radiograph findings. Serum precipitins to A. fumigatus can be demonstrated in virtually all patients. Sputum contains hyphal fragments on microscopy which are often only scanty, and is usually positive on culture. Less than 50% of patients exhibit skin hypersensitivity to extracts of A. fumigatus.
Figure 13.35 Aspergilloma in left upper lobe cavity. Aspergilloma demonstrated using conventional tomography. Rounded fungal ball (arrows) separated from the wall of the cavity by a 'halo' of air.
Specific antifungal therapy is of no value. Surgical removal of the aspergilloma is indicated in patients who have massive haemoptysis and in whom thoracotomy is not contraindicated because of poor respiratory reserve. Bronchial artery embolisation is an alternative approach to the management of recurrent haemoptysis.
INVASIVE PULMONARY ASPERGILLOSIS
Invasion of previously healthy lung tissue by A. fumigatus is uncommon but can produce a serious and often fatal condition which usually occurs in patients who are immunocompromised by either drugs or disease. The source of the infection can be an aspergilloma but this is by no means always so.
Spread of the disease to the lungs is usually rapid, with the production of consolidation, necrosis and cavitation. There is grave systemic disturbance. The formation of multiple abscesses is associated with the production of copious amounts of purulent sputum which is often blood-stained.
A much more indolent form of invasive pulmonary aspergillosis is now recognised.
Invasive pulmonary aspergillosis should be suspected in any patient thought to have severe suppurative pneumonia (see p. 530) which has not responded to antibiotic therapy. The diagnosis can be established by the demonstration of abundant fungal elements in stained smears of sputum. Serum precipitins can be demonstrated in some, but not all, patients.
ISSUES IN OLDER PEOPLE
In the developed world the vast majority of deaths from pneumonia occur in the elderly.
Older people are at increased risk of and from respiratory infection because of reduced immune responses, reduced respiratory muscle strength and endurance, altered mucus layer, poor nutritional status and the increased prevalence of chronic lung disease.
Influenza has a much higher complication rate, morbidity and mortality in old age. Vaccination significantly reduces morbidity and mortality in old age but uptake is poor.
Other medical conditions may also predispose to infection; for example, swallowing difficulties due to stroke increase the risk of aspiration pneumonia.
Elderly patients are more likely to present with atypical symptoms, especially confusion.
Most cases of tuberculosis in old age represent reactivation of previous, often unrecognised disease and may be precipitated by steroid therapy, diabetes mellitus and the factors above. Cryptic miliary tuberculosis is an occasional alternative presentation. Older people more commonly suffer adverse effects from antituberculous chemotherapy and require close monitoring.
If the diagnosis is established at an early stage, antifungal therapy can be successful. Amphotericin 0.25-1 mg/kg daily by slow intravenous infusion over 6 hours should be given in combination with flucytosine 150-200 mg/kg daily by mouth or by intravenous infusion, in four divided doses. The combination of flucytosine and amphotericin prevents resistance to flucytosine developing and allows a smaller daily dose of amphotericin to be used than would be possible if this drug was used on its own. Liposomal amphotericin is recommended when toxicity precludes the use of conventional amphotericin. Itraconazole has been used successfully in the treatment of invasive aspergillosis.
Histoplasmosis, coccidioidomycosis, blastomycosis and cryptococcosis
See pages 93-95.
pages 524 - 542
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > TUMOURS OF THE BRONCHUS AND LUNG
TUMOURS OF THE BRONCHUS AND LUNG
Between 1995 and 1996 there were more than 36 000 lung cancer deaths in the UK (see Box 13.64). Bronchial carcinoma is by far the most common (> 90%) lung tumour; by comparison, benign tumours of the lung are rare. Primary carcinomas of other organs, in particular the breast, kidney, uterus, ovary, testes and thyroid, may give rise to metastatic pulmonary deposits, as may an osteogenic or other sarcoma. Bronchial tumours also represent the most common cause of obstruction to a major bronchus (see Box 13.65).
13.64 THE BURDEN OF LUNG CANCER
36 000 deaths/year in the UK
25% of all cancer deaths
8% of all male deaths and 4% of all female deaths
More than threefold increase in deaths since 1950
Most rapidly increasing cause of cancer death in women
Most common cause of cancer death in men
After breast cancer, the second most common cause of cancer death in women in England and Wales
13.65 CAUSES OF LARGE BRONCHUS OBSTRUCTION
Bronchial carcinoma or adenoma (see Box 13.70)
Enlarged tracheobronchial lymph nodes (malignant or tuberculous)
Inhaled foreign bodies (especially right lung and in children)
Bronchial casts or plugs consisting of inspissated mucus or blood clot (especially asthma, haemoptysis, debility)
Collections of mucus or mucopus retained in the bronchi as a result of ineffective expectoration (especially post-operative following abdominal surgery)
Giant left atrium
Congenital bronchial atresia
Fibrous bronchial stricture (e.g. following tuberculosis)
Figure 13.36 Collapse of the right lung: effects on neighbouring structures. A Chest radiograph. B Artist's impression.
The clinical and radiological manifestations of bronchial obstruction (see Figs 13.36 and 13.37) depend on the site of the obstruction, whether the obstruction is complete or partial, the presence or absence of secondary infection, and the extent of pre-existing lung disease. Signs of displacement of the mediastinum or elevation of the diaphragm only occur if a major portion of the lung becomes collapsed. Bacterial infection affecting the distal lung is almost inevitable whenever a major bronchus is significantly obstructed. Hence pneumonia is often the first clinical manifestation of a bronchial carcinoma, even when the degree of obstruction is insufficient to cause collapse.
The cause of bronchial obstruction should be determined at bronchoscopy; this procedure also enables biopsy of abnormal tissue and the removal of foreign bodies, mucus plugs or tenacious secretions.
Figure 13.37 Radiological features of lobar collapse caused by bronchial obstruction. The dotted line in the drawings represents the normal position of the diaphragm. A The radiograph shows an example of left upper lobe collapse which is often the most difficult to identify; this is due to the hazy, ill-defined shadowing on the PA view. B The collapsed left upper lobe is more easily seen on the lateral view (line indicates posterior margin of collapsed left upper lobe). C Radiograph of collapsed left lower lobe (arrow) causing increased density behind heart and loss of normal clarity between lung and both the left hemidiaphragm and descending thoracic aorta.
PRIMARY TUMOURS OF THE LUNG
Cigarette smoking is by far the most important single factor in the causation of lung cancer. It is thought to be directly responsible for at least 90% of lung carcinomas, the risk being directly proportional to the amount smoked and to the tar content of cigarettes. For example, the death rate from the disease in heavy cigarette smokers is 40 times that in non-smokers. The effect of 'passive' smoking is more difficult to quantify but is currently believed to be a factor in 5% of all lung cancer deaths. Exposure to naturally occurring radon has been estimated to cause 5% of lung cancers. The incidence of lung cancer is also slightly higher in urban than in rural dwellers; this may reflect differences in atmospheric pollution (including tobacco smoke) or occupation since a number of industrial products (e.g. asbestos, beryllium, cadmium and chromium) are associated with lung cancer.
The incidence of bronchial carcinoma increased dramatically during the 20th century (see Fig. 13.38) and it is now the most common fatal malignancy in the developed world, with escalating incidences in the less developed world as the prevalence of cigarette smoking increases. The current data for lung cancer in the UK are shown in Box 13.64. It accounts for more than 50% of all male deaths from malignant disease and the incidence of lung cancer deaths is expected to climb over the next 10 years, with an increasing number unrelated to smoking.
Figure 13.38 Mortality trends from lung cancer in England and Wales, 1921-90 by age and year of death. A Males. B Females. Note the decline in mortality from lung cancer in men towards the end of this period, reflecting a change in smoking habit.
Bronchial carcinomas arise from the bronchial epithelium or mucous glands. The common cell types are listed in Box 13.66.
13.66 COMMON CELL TYPES OF BRONCHIAL CARCINOMA
Cell type %
When the tumour arises in a large bronchus, symptoms arise early, but tumours originating in a peripheral bronchus can attain a very large size without producing symptoms. Such a tumour, which is usually of the squamous type, may undergo central necrosis and cavitation, when it may have similar radiographic features to a lung abscess (see Fig. 13.39).
Bronchial carcinoma may involve the pleura either directly or by lymphatic spread and extend into the chest wall, invading the intercostal nerves or the brachial plexus and causing severe pain. The primary tumour, or tumour within lymph node metastases, may spread into the mediastinum and invade or compress the pericardium, oesophagus, superior vena cava, trachea, phrenic or left recurrent laryngeal nerves. Lymphatic spread to supraclavicular and mediastinal lymph nodes is also frequently observed. Blood-borne metastases occur most commonly in liver, bone, brain, adrenals and skin. Even a small primary tumour may cause widespread metastatic deposits and this is a particular characteristic of small-cell-type lung cancers.
Figure 13.39 Large cavitated bronchial carcinoma in left lower lobe.
Lung cancer may present in a number of different ways. Most commonly, symptoms reflect local involvement of the bronchus, but may also arise from spread to the chest wall or mediastinum, from distant blood-borne spread or, less commonly, as a result of a variety of non-metastatic paraneoplastic syndromes (see Box 13.67).
13.67 NON-METASTATIC EXTRAPULMONARY MANIFESTATIONS OF BRONCHIAL CARCINOMA
Inappropriate antidiuretic hormone (ADH) secretion causing hyponatraemia
Ectopic adrenocorticotrophic hormone (ACTH) secretion
Hypercalcaemia due to secretion of parathyroid hormone (PTH)-related peptides
Carcinoid syndrome (see p. 801)
Myasthenia (Eaton-Lambert syndrome, see p. 1185)
Hypertrophic pulmonary osteoarthropathy
Polymyositis and dermatomyositis
Cough is the most common early symptom; sputum is purulent if there is secondary infection. Bronchial obstruction may lead to pneumonia, and a recurrent pneumonia at the same site or one which is slow to respond to treatment, particularly in a cigarette smoker, should immediately suggest the possibility of bronchial carcinoma. A lung abscess may sometimes develop, leading to cough productive of large volumes of purulent sputum. A change in the character of the 'regular' cough of a smoker, particularly if it is associated with other new respiratory symptoms, should always alert the clinician to the possibility of bronchial carcinoma.
Haemoptysis is a common symptom, especially in tumours arising in large bronchi. Occasionally, central tumours invade large vessels, causing massive haemoptysis which may be fatal. Repeated episodes of scanty haemoptysis or blood-streaking of sputum in a smoker are highly suggestive of bronchial carcinoma and should always be investigated.
Breathlessness may reflect occlusion of a large bronchus, resulting in collapse of a lobe or lung or the development of a large pleural effusion. Stridor may occur where spread of the tumour to the subcarinal and paratracheal glands causes compression of the main bronchi or lower end of the trachea or, rarely, where the trachea is the site of the primary tumour.
Pleural pain usually reflects malignant invasion of the pleura, although it can reflect distal infection. Involvement of the intercostal nerves or brachial plexus may cause pain in the chest or upper limb along the appropriate nerve root distribution. Bronchial carcinoma in the apex of the lung ('superior sulcus tumour') may cause Horner's syndrome (ipsilateral partial ptosis, enophthalmos, a small pupil and hypohidrosis of the face) due to involvement of the sympathetic chain at or above the stellate ganglion, and/or Pancoast's syndrome (pain in the shoulder and inner aspect of the arm) caused by involvement of the lower part of the brachial plexus. Mediastinal spread may result in dysphagia.
The patient may also present with symptoms due to blood-borne metastases, such as focal neurological defects, epileptic seizures, personality change, jaundice, bone pain or skin nodules. Lassitude, anorexia and weight loss usually indicate the presence of metastatic spread. Finally, the patient may present with symptoms referable to the presence of a number of non-metastatic extrapulmonary manifestations (see Box 13.67). Hypercalcaemia is usually caused by squamous carcinoma and causes polyuria, nocturia, fatigue, constipation, confusion and occasionally coma. The most frequently encountered endocrine syndromes (inappropriate antidiuretic hormone (ADH) secretion and ectopic adrenocorticotrophic hormone (ACTH) secretion) are usually associated with small-cell lung cancer. Associated neurological syndromes may occur with any type of bronchial carcinoma.
Examination is usually normal unless there is significant bronchial obstruction, or the tumour has spread to the pleura or mediastinum. A tumour obstructing a large bronchus produces the physical signs of collapse (or occasionally obstructive emphysema) and may give rise to pneumonia that is characterised by a relative absence of physical signs and a slow response to treatment. A monophonic or unilateral rhonchus (wheeze) suggests the presence of a fixed bronchial obstruction, and the presence of stridor indicates obstruction at or above the level of the main carina. A hoarse voice associated with an ineffectual or 'bovine' cough usually indicates left recurrent laryngeal nerve palsy. Phrenic nerve paralysis causes unilateral diaphragmatic palsy and hence dullness to percussion and absent breath sounds at a lung base. Involvement of the pleura produces the physical signs of pleurisy or of pleural effusion (see p. 501). Bronchial carcinoma is also the most common cause of the superior vena cava syndrome, which presents initially as bilateral engorgement of the jugular veins and later as oedema affecting the face, neck and arms. Digital clubbing is often seen and may be a component part of a syndrome called hypertrophic pulmonary osteoarthropathy (HPOA), which is characterised by periostitis of the long bones, most commonly the distal tibia, fibula, radius and ulna. This gives rise to pain and tenderness in the affected joints and often pitting oedema over the anterior aspect of the shin. Radiographs of the painful bone show subperiosteal new bone formation. HPOA, while most frequently associated with bronchial carcinoma, can occur with other tumours and has been described in association with cystic fibrosis.
The main aims of investigation are to confirm the diagnosis, establish the histological cell type and define the extent of the disease.
The common radiological features of bronchial carcinoma are illustrated in Figure 13.40. Further investigation to obtain a histological diagnosis and determine operability is nearly always indicated.
Figure 13.40 Common radiological presentations of bronchial carcinoma. (See Box 13.68 for details.)
Bronchoscopy is usually the most useful investigation as it can provide tissue (biopsies and bronchial brush samples) for pathological examination and allow direct assessment of the proximity of central tumours to the main carina (see Fig. 13.41). If abnormal tissue is not visible at bronchoscopy, bronchial washings and directed biopsies can be taken from the lung segment in which the tumour is shown to be located on radiological examination. In patients who are not fit enough for a bronchoscopy, examination of sputum cytology can be a valuable diagnostic aid (see Fig. 13.42). Pleural biopsy is indicated in all patients with pleural effusions. If bronchoscopy fails to obtain a cytological diagnosis, percutaneous needle biopsy under CT guidance is appropriate for peripheral tumours or mediastinoscopy for patients with suspected mediastinal involvement. Not infrequently, thoracoscopy or thoracotomy is required to obtain a definitive histological diagnosis. In patients with metastatic disease the diagnosis can often be confirmed by needle aspiration or biopsy of enlarged lymph nodes, skin lesions, where indicated, liver or bone marrow.
13.68 COMMON RADIOLOGICAL PRESENTATIONS OF BRONCHIAL CARCINOMA
1 Unilateral hilar enlargement
Central tumour. Hilar glandular involvement. Beware-peripheral tumour in apical segment of a lower lobe can look like an enlarged hilar shadow on the PA radiograph
2 Peripheral pulmonary opacity (see p. 500)
Usually irregular but well circumscribed. May have irregular cavitation within it. Can be very large
3 Lung, lobe or segmental collapse
Usually caused by tumour within the bronchus causing occlusion. Lung collapse can be produced by compression of the main bronchus by enlarged lymph glands
4 Pleural effusion
Usually indicates tumour invasion of pleural space; very rarely a manifestation of infection in collapsed lung tissue distal to a bronchial carcinoma
5-7 Broadening of mediastinum, enlarged cardiac shadow, elevation of a hemidiaphragm
Paratracheal lymphadenopathy may cause widening of the upper mediastinum. A malignant pericardial effusion will cause enlargement of the cardiac shadow. If a raised hemidiaphragm is caused by phrenic nerve palsy, screening will show it to move paradoxically upwards when patient sniffs
8 Rib destruction
Direct invasion of the chest wall or blood-borne metastatic spread can cause osteolytic lesions of the ribs
Figure 13.41 Bronchoscopic view of a bronchogenic carcinoma. There is distortion of mucosal folds, partial occlusion of the airway lumen and abnormal tumour tissue.
Figure 13.42 Sputum sample showing a cluster of carcinoma cells. There is keratinisation, showing orangeophilia of the cytoplasm, and non-keratinised forms are also seen. The nuclei are large and 'coal-black' in density. These are the features of squamous cell bronchogenic carcinoma.
After establishing a histological diagnosis, investigations should focus on determining whether the tumour is operable. This requires excluding involvement of central mediastinal structures or spread of tumour to distant sites and ensuring that the patient's respiratory and cardiac function is sufficient to allow surgical treatment (see Box 13.69). The propensity of small-cell lung cancer to metastasise early dictates that very few patients with this tumour type are suitable for surgical intervention and that more detailed pre-operative staging is advisable before resection is contemplated. Head CT, radionuclide bone scanning, liver ultrasound and bone marrow biopsy can be reserved for patients with clinical, haematological or biochemical evidence of tumour spread to such sites.
Cure can only be achieved by surgical resection. Unfortunately, in the majority of cases (approximately 85%) surgery is not possible or appropriate, and such patients can only be offered palliative therapy. Radiotherapy, and in some cases chemotherapy, can relieve distressing symptoms.
As discussed, careful staging is essential prior to surgical resection and equal attention must be given to the patient's respiratory reserve and cardiac status. This, coupled with improvements in surgical and post-operative care, now offers 5-year survival rates of > 75% in stage I disease (N0, tumour confined within visceral pleura) and 55% in stage II disease, which includes resection in patients with ipsilateral peribronchial or hilar node involvement.
13.69 CONTRAINDICATIONS TO SURGICAL RESECTION IN BRONCHIAL CARCINOMA
N.B. In otherwise fit individuals, direct extension of tumour into the chest wall, diaphragm, mediastinal pleura or pericardium or to within 2 cm of the main carina does not exclude surgery. Though surgically resectable, patients with N2 (ipsilateral mediastinal) nodes may require neoadjuvant or adjuvant therapy.
Distant metastasis (M1)
Invasion of central mediastinal structures including heart, great vessels, trachea and oesophagus (T4)
Malignant pleural effusion (T4)
Contralateral mediastinal nodes (N3)
FEV1 < 0.8 litres
Severe or unstable cardiac or other medical condition
While much less effective than surgery, radical radiotherapy can offer long-term survival in certain patients with bronchial carcinoma. It is of greatest value, however, in the palliation of distressing complications such as superior vena caval obstruction, recurrent haemoptysis, and pain caused by chest wall invasion or by skeletal metastatic deposits. Obstruction of the trachea and main bronchi can also be relieved temporarily by radiotherapy. Radiotherapy can be used in conjunction with chemotherapy in the treatment of small-cell carcinoma and is particularly efficient at preventing the development of brain metastasis in patients who have had a complete response to chemotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART), in which a similar total dose is given in smaller but more frequent fractions, offers better survival prospects than conventional schedules.
The treatment of small-cell carcinoma with combinations of cytotoxic drugs, sometimes in combination with radiotherapy, can increase the median survival of patients with this highly malignant type of bronchial carcinoma from 3 months to well over a year. Combination chemotherapy leads to better outcomes than single-agent treatment. In particular, oral etoposide leads to more toxicity and worse survival than standard combination chemotherapy. Current recommendations include i.v. cyclophosphamide, doxorubicin and vincristine or i.v. cisplatin and etoposide. The above regimens are given every 3 weeks for 3-6 cycles. Nausea and vomiting peak for 3 days after each cycle of chemotherapy and are best treated with 5-HT3 receptor antagonists (see p. 220).
The use of combinations of chemotherapeutic drugs requires considerable medical skill and expertise and it is recommended that such treatment should only be given under the supervision of clinicians experienced in such treatment. In general, chemotherapy is far less effective in non-small-cell bronchial cancers. However, recent studies in such patients using platinum-based chemotherapy regimens have shown a 30% response rate associated with a small increase in survival.
SMALL-CELL LUNG CANCER-role of prophylactic cranial irradiation
'Meta-analysis of seven RCTs has found that prophylactic cranial irradiation reduces the risk of developing brain metastases and improves survival in patients with small-cell lung cancer in complete remission.'
Auperin A, Arriagada R, Pignon J-P, et al. Prophylactic cranial irradiation for people with small-cell lung cancer in complete remission. N Engl J Med 1999; 341:476-484.
Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk
Laser treatment via a fibreoptic bronchoscope is essentially palliative, the aim being to destroy tumour tissue occluding major airways to allow re-aeration of collapsed lung. The best results are achieved in tumours of the main bronchi.
General aspects of management
As in other forms of carcinoma, effective communication, pain relief and attention to diet are important (see Ch. 5). Lung tumours can cause clinically significant depression and anxiety, and these may need specific therapy. Hypercalcaemia (see p. 715) is an uncommon but important complication of lung cancer, particularly squamous cell carcinoma. Treatment in the acute situation involves intravenous rehydration, maintenance of a good urine output and administration of bisphosphonates. Thereafter, steroids may be effective and mithramycin may be necessary to maintain a normal blood calcium. Demeclocycline can be useful for controlling inappropriate ADH secretion in patients with small-cell lung cancer. The management of malignant pleural effusions is outlined on page 503.
STAGE IV NON-SMALL-CELL LUNG CANCER-role of palliative chemotherapy
'Four SRs of RCTs have found that chemotherapy significantly prolongs 1-year survival in patients with stage IV non-small-cell lung cancer. The survival benefit is greatest with regimens containing cisplatin. Quality of life issues remain undefined.'
Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated individual patient data from 52 randomised clinical trials. BMJ 1995; 311:899-909.
Marino P, Pampallona S, Preatoni A, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994; 106:861-865.
Further information: www.meds.com/pdq/nonsmallcell_pro.html
13.70 RARER TYPES OF LUNG TUMOUR
Tumour Status Histology Typical presentation Prognosis
Adenosquamous carcinoma Malignant Tumours with areas of unequivocal squamous and adeno-differentiation Peripheral or central lung mass Stage-dependent
Carcinoid tumour (see p. 801) Low-grade malignant Neuro-endocrine differentiation Bronchial obstruction, cough 95% 5-year survival with resection
Bronchial gland adenoma Benign Salivary gland differentiation Tracheobronchial irritation/obstruction Local resection curative
Bronchial gland carcinoma Low-grade malignant Salivary gland differentiation Tracheobronchial irritation/obstruction Local recurrence occurs
Hamartoma Benign Mesenchymal cells, cartilage Peripheral lung nodule Local resection curative
Bronchoalveolar carcinoma Malignant Tumour cells line alveolar spaces Alveolar shadowing, productive cough Variable, worse if multifocal
The overall prognosis in bronchial carcinoma is very poor, with around 80% of patients dying within a year of diagnosis and less than 6% of patients surviving 5 years after diagnosis. The best prognosis is with well-differentiated squamous cell tumours which have not metastasised and are amenable to surgical treatment. The clinical features and prognosis of other less common benign and malignant tumours of the lung are given in Box 13.70.
SECONDARY TUMOURS OF THE LUNG
Blood-borne metastatic deposits in the lungs may be derived from many primary tumours (see p. 542). The secondary deposits are usually multiple and bilateral. Often there are no respiratory symptoms and the diagnosis is made by radiological examination. Breathlessness may be the only symptom if a considerable amount of lung tissue has been replaced by metastatic tumour. Endobronchial deposits are uncommon but can cause haemoptysis and lobar collapse.
PULMONARY LYMPHATIC CARCINOMATOSIS
Lymphatic infiltration may develop in patients with carcinoma of the breast, stomach, bowel, pancreas or bronchus. This grave condition causes severe and rapidly progressive breathlessness associated with marked hypoxaemia. The diagnosis is often suggested by the chest radiograph, which shows diffuse pulmonary shadowing radiating from the hilar regions, often associated with septal lines.
TUMOURS OF THE MEDIASTINUM
The mediastinum can be divided into four major compartments with reference to the lateral chest radiograph (see Fig. 13.43):
superior mediastinum-above a line drawn between the lower border of the 4th thoracic vertebra and the upper end of the body of the sternum
anterior mediastinum-in front of the heart
middle mediastinum-between the anterior and posterior compartments
posterior mediastinum-behind the heart.
Figure 13.43 The divisions of the mediastinum described in the diagnosis of mediastinal masses. (1) Superior mediastinum. (2) Anterior mediastinum. (3) Middle mediastinum. (4) Posterior mediastinum. Sites of the more common mediastinal tumours are also illustrated.
13.71 SOME CAUSES OF A MEDIASTINAL MASS
Persistent left superior
Germ cell tumour
Hernia through the diaphragmatic foramen of Morgagni
A variety of conditions can present radiologically as a mediastinal mass (see Box 13.71).
Benign tumours and cysts arising within the mediastinum are frequently diagnosed when radiological examination of the chest is undertaken for some other reason. In general, they do not invade vital structures but may cause symptoms by compressing the trachea or occasionally the superior vena cava. A dermoid cyst may very occasionally rupture into a bronchus.
13.72 SYMPTOMS AND SIGNS PRODUCED BY MALIGNANT INVASION OF THE STRUCTURES OF THE MEDIASTINUM
Trachea and main bronchi
Stridor, breathlessness, cough, pulmonary collapse
Dysphagia, oesophageal displacement or obstruction on barium swallow examination
Left recurrent laryngeal nerve
Paralysis of left vocal cord giving rise to hoarseness and 'bovine' cough
Superior vena cava
SVC obstruction results in non-pulsatile distension of neck veins, oedema and cyanosis of head, neck, hands and arms. Dilated anastomotic veins on chest wall
Pericarditis and/or pericardial effusion
Malignant mediastinal tumours are distinguished by their power to invade as well as compress structures such as bronchi and lungs (see Box 13.72). As a result, even a small malignant tumour can produce symptoms, although as a rule the tumour has attained a considerable size before this happens. Included in this category are mediastinal lymph node metastases, lymphomas, leukaemia, malignant thymic tumours and germ-cell tumours. Aortic and innominate aneurysms have destructive features resembling those of malignant mediastinal tumours.
A benign mediastinal tumour generally appears as a sharply circumscribed opacity situated mainly in the mediastinum but often encroaching on one or both lung fields (see Fig. 13.44). A malignant mediastinal tumour seldom has a clearly defined margin and often presents as a general broadening of the mediastinal shadow. CT together with MRI are the investigations of choice for mediastinal tumours.
Figure 13.44 Large mass (intrathoracic goitre-arrows) extending from right upper mediastinum.
Bronchoscopy should be carried out in most patients because bronchial carcinoma is a common cause of mediastinal tumour by secondary lymphatic spread.
If enlarged lymph nodes are suspected in the anterior mediastinum, tissue from these nodes can be removed for histological examination by mediastinoscopy. However, surgical exploration of the chest with removal of part or all of the tumour is often required to obtain a histological diagnosis.
Benign mediastinal tumours should be removed surgically because most produce symptoms sooner or later. Some of them, particularly cysts, may become infected, while others, especially neural tumours, have the potential to undergo malignant transformation. The operative mortality is low provided there is not a relative contraindication to surgical treatment, such as coexisting cardiovascular disease, COPD or extreme age.
The treatment of lymphoma and leukaemia is described on pages 931 and 939 respectively. The management of malignant thymomas is surgical. Lymph node metastases from bronchial carcinoma often respond well, though temporarily, to radiotherapy or, in the case of small-cell carcinoma, to chemotherapy. Complications such as superior vena caval and tracheal obstruction can also be treated with radiotherapy or a combination of radiotherapy and chemotherapy, and the placement of internal stents is now possible for localised obstruction of both these structures.
ISSUES IN OLDER PEOPLE
Ageing is a major risk factor for the development of lung cancer.
Elderly patients tend to present with more advanced disease.
There is evidence that older patients are less likely to be referred for bronchoscopy or CT-guided needle biopsy than younger patients, although these procedures are well tolerated and safe even in very old patients. The only older patients who should not be referred are those with other significant pathology who are not fit for investigation or intervention.
The 5-year survival rates for older patients who undergo surgery for squamous cell carcinoma are little different from those for younger patients.
High-intensity chemotherapy regimens for small-cell carcinoma have high levels of toxicity in old age without significant survival benefits.
pages 542 - 550
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > INTERSTITIAL AND INFILTRATIVE PULMONARY DISEASES
INTERSTITIAL AND INFILTRATIVE PULMONARY DISEASES
INTERSTITIAL PULMONARY DISEASES
Interstitial lung diseases are a heterogeneous group of conditions caused by diffuse thickening of the alveolar walls with inflammatory cells and exudate (e.g. the acute respiratory distress syndrome-ARDS), granulomas (e.g. sarcoidosis), alveolar haemorrhage (e.g. Goodpasture's syndrome, see p. 614) and/or fibrosis (e.g. fibrosing alveolitis). Some are the result of exposure to known agents (e.g. asbestos), whereas in others, such as sarcoidosis, the cause is unknown. Lung disease may occur in isolation, or as part of a systemic connective tissue disorder-for example, in rheumatoid arthritis and systemic lupus erythematosus. Interstitial lung diseases may present acutely, as in acute drug reactions and ARDS, but more often the natural history is one of slowly progressive loss of alveolar-capillary gas exchange units over months or even years. This relentless progression of increased lung stiffness, disordered matching of ventilation and perfusion, and defects in gas transfer results in worsening exertional dyspnoea which, in many cases, eventually progresses to respiratory failure, pulmonary hypertension and death.
There is a very wide range of causes of interstitial lung disease (see Box 13.73). Some, like sarcoidosis, are quite common whereas others are rare. Despite the different causes and pathological processes involved, many interstitial lung diseases give rise to similar symptoms, physical signs, radiological changes and disturbances of pulmonary function and are therefore worthy of collective consideration. Nevertheless, the various underlying aetiologies present very different implications for prognosis and therapy. Moreover, interstitial lung diseases may be confused with other conditions with similar clinical and radiological features (see Box 13.74). Therefore a general approach to interstitial lung disease will be considered before a more detailed description of some specific disorders.
13.73 SOME CAUSES OF INTERSTITIAL LUNG DISEASE
Cryptogenic fibrosing alveolitis
Exposure to organic dusts, e.g. farmer's lung, bird fancier's lung
Exposure to inorganic dusts, e.g. asbestosis, silicosis
As part of systemic inflammatory disease, e.g. ARDS, fibrosing alveolitis in connective tissue disorders
Some forms of pulmonary eosinophilia
Exposure to irradiation and drugs
Rare disorders, e.g. alveolar proteinosis, Langerhans cell histiocytosis
13.74 CONDITIONS WHICH MIMIC INTERSTITIAL LUNG DISEASES
Parasites, e.g. filariasis
Leukaemia and lymphoma
Diagnosis of interstitial lung disease: a general approach
The first task is to differentiate the disorder from other conditions which can mimic interstitial lung diseases (ILDs) (see Box 13.74), and then to determine which of the many causes of ILD is implicated. Establishing a diagnosis is important for a number of reasons. Firstly, there are prognostic implications; for example, sarcoidosis is frequently self-limiting (see p. 552), whereas cryptogenic fibrosing alveolitis (CFA, see p. 555) is most often fatal. Secondly, establishing a specific diagnosis will avoid inappropriate treatment; for example, the powerful immunosuppressive regimens used for some cases of cryptogenic fibrosing alveolitis would be undesirable if the underlying condition was asbestosis or extrinsic allergic alveolitis (see p. 556). Thirdly, some ILDs can be expected to respond better than others to treatment, e.g. a good symptomatic response to corticosteroids could be predicted in sarcoidosis, whereas the prognosis would need to be much more guarded in cryptogenic fibrosing alveolitis. Finally, a lung biopsy taken when the patient is already established on empirical immunosuppressive therapy is not only associated with a higher morbidity and mortality, but the tissue obtained is more difficult to interpret histologically; it is desirable, therefore, to be confident about the diagnosis before starting any therapy.
Establishing a diagnosis often presents a considerable clinical challenge, necessitating meticulous attention to the history and physical signs together with the judicious and selective use of investigations (see Fig. 13.45).
Figure 13.45 Algorithm for the investigation of patients with interstitial lung disease following initial clinical and chest radiograph examination. (CFA = cryptogenic fibrosing alveolitis; UIP = usual interstitial pneumonia; TBB = transbronchial biopsy; HRCT = high-resolution CT)
The duration of disease may sometimes be difficult to ascertain. In the early stages particularly, gradually progressive shortness of breath on exertion may be the only symptom, and hence the patient may not present clinically until there is quite extensive lung pathology. It is clearly important to elicit a detailed history of exposure to organic dusts, inorganic dusts and drugs, including the degree and duration of such exposure. A 'lifetime' occupational history is essential for this purpose. Contact with birds at home or in the working environment is the cause of the most common form of extrinsic allergic alveolitis, but such enquiry is easily overlooked. A history of rashes, joint pains or renal disease may suggest an underlying connective tissue disorder or vasculitis (see Ch. 20).
In many cases, especially in early disease, there may be few, if any, physical signs. In advanced disease tachypnoea and cyanosis may be obvious at rest, and there may be signs of pulmonary hypertension and right heart failure. Digital clubbing may be prominent, particularly in cryptogenic fibrosing alveolitis or asbestosis. There may be restriction of lung expansion and showers of end-inspiratory crepitations on auscultation over the lower zones posteriorly and laterally. Extrapulmonary signs, including lymphadenopathy or uveitis, may be present in sarcoidosis (see Box 13.75) and arthropathies or rashes may suggest an ILD occurring as a manifestation of a connective tissue disorder (see p. 559).
No single blood test is diagnostic for a particular interstitial lung disease. Some laboratory tests may be useful in indicating systemic disease or providing crude indices of disease activity. The ESR and C-reactive protein may be non-specifically elevated. Serological tests may be of value: antinuclear antibodies, rheumatoid factor etc. in connective tissue diseases, and antiglomerular basement membrane antibodies in Goodpasture's syndrome (see p. 614). Serum levels of angiotensin-converting enzyme (ACE) may be elevated in sarcoidosis, but the test is not specific for this condition.
The chest radiograph may show a fine reticular shadowing, a reticulonodular or even a nodular pattern of infiltration at the bases and periphery (see Fig. 13.46A). In advanced disease there may be cystic areas and honeycombing.
Figure 13.46 Cryptogenic fibrosing alveolitis. A Chest radiograph showing bilateral, predominantly lower zone and peripheral coarse reticulonodular shadowing and small lungs. B The CT shows honeycombing and scarring which is most marked peripherally.
High-resolution CT is extremely valuable in detecting early interstitial lung disease and assessing the extent and type of involvement (see Fig. 13.46B), and is also helpful in identifying hilar and paratracheal lymphadenopathy, particularly in sarcoidosis.
Bronchoalveolar lavage is not often of diagnostic value, but there are some important exceptions (see Fig. 13.45). Increased numbers of lymphocytes in bronchoalveolar lavage fluid occur in sarcoidosis and extrinsic allergic alveolitis, whereas a neutrophilia is suggestive of cryptogenic fibrosing alveolitis or pneumoconiosis. In the rare disease, alveolar proteinosis (see p. 562), copious lipoproteinaceous material is recovered in the lavage fluid and large numbers of iron-laden macrophages are seen in pulmonary haemosiderosis (see Box 13.84, p. 562).
Examination of biopsy material is an important diagnostic procedure in most cases. Bronchial and transbronchial biopsies obtained via the fibreoptic bronchoscope will usually establish the diagnosis in sarcoidosis and in some conditions which mimic ILDs, such as lymphatic carcinomatosis and certain infections. However, this approach provides only a small sample of tissue, and in less specific disorders such as cryptogenic fibrosing alveolitis a larger surgical biopsy sample is often necessary to yield a confident diagnosis. This can be obtained by limited thoracotomy or video-assisted thoracoscopy (VATS).
Sarcoidosis is a multisystem granulomatous disease. It is most common in colder climates (e.g. Scandinavian countries). The lung is affected in over 90% of cases. While the aetiology of sarcoidosis remains uncertain, it is associated with imbalance between subsets of T lymphocytes and other disturbances of cell-mediated immunity, but the relationship between these phenomena and sarcoidosis has not yet been explained. The lesions are histologically similar to tuberculous follicles, apart from the absence of caseation and tubercle bacilli, but there is no convincing evidence that the disease is caused by any of the mycobacteria. Chronic beryllium poisoning produces a disease which mimics sarcoidosis both pathologically and clinically but exposure to beryllium is now extremely uncommon. Histological changes resembling those of sarcoidosis are occasionally seen in individual organs, such as lymph nodes, in conditions such as carcinoma and fungal infections, but these localised 'sarcoid reactions' are not associated with systemic sarcoidosis.
The mediastinal and superficial lymph nodes, lungs, liver, spleen, skin, eyes, parotid glands and phalangeal bones are most frequently affected, but all tissues may be involved (see Figs 13.47 and 13.48). The characteristic histological feature consists of non-caseating epithelioid granulomas which usually resolve spontaneously; fibrosis occurs in up to 20% of cases of pulmonary sarcoidosis and it is impossible at present to identify this group of patients prospectively. The overall mortality rate of sarcoidosis is low (1-5%) and usually relates to the involvement of vital organs, particularly the heart. Calcium metabolism may be disturbed, causing hypercalciuria, hypercalcaemia and, rarely, nephrocalcinosis.
Figure 13.47 The range of possible systemic involvement in sarcoidosis.
13.75 PRESENTATION OF SARCOIDOSIS
Asymptomatic-abnormal routine chest radiograph (c. 30%) or abnormal liver function tests
Respiratory and constitutional symptoms (20-30%)
Erythema nodosum and arthralgia (20-30%)
Ocular symptoms (5-10%)
Skin sarcoid (including lupus pernio) (5%)
Superficial lymphadenopathy (5%)
Other (1%), e.g. hypercalcaemia, diabetes insipidus, cranial nerve palsies, cardiac arrhythmias, nephrocalcinosis
Figure 13.48 Pathological lesions in sarcoidosis. A Nasal cutaneous sarcoid lesions. B Histology of sarcoidosis in the lung, showing non-caseating granulomas (arrows).
Since sarcoid lesions can develop in almost any tissue, the mode of presentation can be quite variable (see Box 13.75). Patients can present with an 'acute' form of sarcoidosis with erythema nodosum, peripheral arthropathy, uveitis, bilateral hilar lymphadenopathy, lethargy and occasionally fever. Alternatively, the disease has a more insidious onset and presents with cough, exertional breathlessness or one of the protean extrapulmonary manifestations. Clubbing and cyanosis are unusual even in advanced pulmonary disease and, in contrast to cryptogenic fibrosing alveolitis, inspiratory crepitations are not a prominent feature.
Skin sensitivity to tuberculin is depressed or absent in most (but not all) patients, and the Mantoux reaction is, therefore, a useful 'screening' test; a strongly positive reaction to one tuberculin unit virtually excludes sarcoidosis. The presence of 'rim enhancement' with central necrosis in the lymph nodes on contrast-enhanced CT suggests tuberculous lymphadenopathy. Although the diagnosis can often be made with a fair measure of confidence from the clinical and radiological features (see Box 13.75), it should, if possible, be confirmed histologically by biopsy of an involved organ (e.g. superficial lymph node or skin lesion). Transbronchial lung biopsy confirms the diagnosis in 80-90% of cases, even in those with a normal chest radiograph and no pulmonary symptoms. Bronchoalveolar lavage usually yields fluid with an increased proportion of lymphocytes.
The plasma level of ACE is often elevated. While not specific for sarcoidosis, this test may be valuable in the assessment of disease activity and response to treatment. Lymphopenia, hypercalciuria and a moderately elevated ESR are also frequently observed. Hypercalcaemia may occur but seldom causes symptoms. The chest radiograph features have been used to stage sarcoidosis (see Box 13.76). A radionuclide scan using 67gallium is usually positive in patients with active disease and shows abnormal uptake in affected organs.
When parenchymal lung disease is significant there may be disordered pulmonary function tests with a reduction in gas transfer and typical restrictive abnormalities (see p. 493) occurring in more advanced disease, particularly if fibrosis has occurred.
In stage III and IV sarcoidosis assessment of disease progression is made by repeated measurement of lung volumes, carbon monoxide transfer factor and serial chest radiographs.
13.76 CHEST RADIOGRAPH CHANGES IN SARCOIDOSIS
Radiograph shows bilateral hilar enlargement, usually symmetrical; paratracheal nodes often enlarged
Spontaneous resolution within 1 year in the majority of cases. Often asymptomatic, but may be associated with erythema nodosum and arthralgia
Radiograph shows a combination of hilar glandular enlargement and pulmonary opacities which are often diffuse
Patients are breathless or have a cough. Spontaneous improvement occurs in the majority
Radiograph shows diffuse pulmonary shadows without evidence of hilar adenopathy
Disease less likely to resolve spontaneously
Can cause progressive ventilatory failure, pulmonary hypertension and cor pulmonale
Stage I and II disease usually resolves spontaneously and treatment is seldom required. Patients with persistent erythema nodosum, pyrexia and arthralgia may benefit from non-steroidal anti-inflammatory drugs. Short-term oral corticosteroid therapy is occasionally required for patients with severe systemic features, anterior uveitis or hypercalcaemia.
Symptomatic stage III pulmonary sarcoidosis and sarcoidosis involving the eyes or other vital organs (especially the heart or brain) usually need to be treated with corticosteroids, which may have to be continued for several years. Sarcoidosis typically responds rapidly to prednisolone 20-40 mg daily (see EBM panel); thereafter the disease is usually suppressed by a maintenance dose of 7.5-10 mg daily, or 20 mg on alternate days. Methotrexate and hydroxychloroquine are effective second-line or steroid-sparing agents.
PULMONARY SARCOIDOSIS-role of systemic steroids
'RCTs indicate that oral steroids improve symptoms, respiratory function and radiographic appearance in patients with stage II and III pulmonary sarcoidosis. However, these effects are small and there are no data beyond 2 years to indicate whether such therapy influences long-term disease progression.'
Gibson GJ, Prescott RJ, Muers MF, et al. The British Thoracic Society Sarcoidosis Study: effects of long term corticosteroid treatment. Thorax 1996; 51:238-247.
Paramothayan NS, Jones PW. Corticosteroids for pulmonary sarcoidosis (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
CRYPTOGENIC FIBROSING ALVEOLITIS
Cryptogenic fibrosing alveolitis (CFA; also referred to as idiopathic pulmonary fibrosis in North America) exemplifies many of the typical features of interstitial lung disease. By definition this form of fibrosing alveolitis is not associated with an overt systemic or connective tissue disorder. The Epstein-Barr virus and exposure to metal and wood dusts have been reported to be associated with the disease. CFA has an incidence of 6-10 per 100 000 per year and is about twice as common among cigarette smokers as in non-smokers. Men are also more commonly affected than women.
CFA is probably not a single disease entity and other forms of idiopathic interstitial lung disease are now recognised both clinically and pathologically (see Box 13.77). Such differentiation is important as many of these conditions have a much better response to corticosteroid therapy and a better prognosis.
13.77 HISTOLOGICAL SUBCLASSIFICATION OF IDIOPATHIC FORMS OF INTERSTITIAL LUNG DISEASE
Histological diagnosis Clinical diagnosis Notes
Usual interstitial pneumonia (UIP) Cryptogenic fibrosing alveolitis (CFA) See text
Poor response to corticosteroids
Non-specific interstitial pneumonia (NSIP) NSIP Uniform fibrosis and thickening of alveolar walls
Associated with underlying connective tissue disease and HIV infection
Good response to corticosteroids
Better prognosis than CFA
Respiratory bronchiolitis Respiratory bronchiolitis (interstitial lung disease) Invariable association with cigarette smoking
Accumulation of pigment-laden macrophages in respiratory bronchioles and adjacent alveoli
Good prognosis on stopping smoking
Diffuse alveolar damage (DAD) Acute interstitial pneumonia (AIP) Proteinaceous alveolar exudate, interstitial oedema and fibrosis, hyaline membranes
Desquamative interstitial pneumonia (DIP) DIP Alveolar wall thickening and mononuclear cell infiltration; alveoli filled with alveolar macrophages
Good initial response to corticosteroid therapy
Organising pneumonia Cryptogenic organising pneumonia (COP) Intraluminal organising fibrosis of distal airspaces, patchy distribution, preservation of lung architecture
Good response to corticosteroids
Macroscopically, the lungs show subpleural fibrosis and a honeycomb appearance, predominantly in the lower lobes and basolateral pleural regions. Microscopically, there is architectural disruption with temporal heterogeneity and characteristic fibroproliferative lesions representing the site of healing alveolar injury. There is variable mononuclear cell infiltration of the alveolar walls, fibrosis and smooth muscle proliferation.
CFA is predominantly a disease of the elderly, with a mean age at presentation of 69 years. Progressive exertional breathlessness is usually the presenting symptom, often accompanied by persistent dry cough. In 60% of patients digital clubbing is observed. Chest expansion may be poor and numerous bilateral end-inspiratory crepitations are audible on auscultation, particularly over the lower zones posteriorly.
Blood tests are of no value in confirming a diagnosis of CFA. However, rheumatoid factor and antinuclear factor can be detected in 30-50% of patients. The ESR and lactate dehydrogenase are elevated in most cases.
The chest radiograph shows diffuse pulmonary opacities which are usually most obvious in the lower zones and peripherally (see Fig. 13.46A, p. 552). The hemidiaphragms are high and the lungs appear small. In advanced disease the chest radiographs may show a 'honeycomb' appearance, in which diffuse pulmonary shadowing is interspersed with small cystic translucencies. 'Honeycomb lung' is also a characteristic feature of rare diseases such as Langerhans cell histiocytosis and tuberous sclerosis (see Box 13.84, p. 562). High-resolution CT can reveal a characteristic picture (see p. 552) and is particularly useful in early disease when chest radiograph changes may be slight or absent.
Pulmonary function tests show a restrictive ventilatory defect with proportionate reduction in VC and FEV1. The carbon monoxide transfer factor is low and there is an overall reduction in lung volume. In early disease there is arterial hypoxaemia on exercise; later, arterial hypoxaemia and hypocapnia are present at rest.
A firm diagnosis of CFA can usually be achieved on the basis of the history, clinical findings and characteristic high-resolution CT appearance (see Fig. 13.46B, p. 552). If doubt exists, an open lung biopsy is indicated. Bronchoalveolar lavage and transbronchial biopsy are generally unhelpful and do not allow the pathologist to differentiate between CFA and other forms of pulmonary fibrosis.
CFA has a high mortality rate, with survival beyond 5 years unusual; there are no RCTs of corticosteroids (or alternative immunosuppressive agents) in CFA but a proportion of patients do respond in terms of symptoms (50%) and lung function (25%) (see Box 13.77 for further details). Currently, such therapy is recommended in patients who are highly symptomatic or have rapidly progressive disease, have a predominantly 'ground-glass' appearance on CT or have a sustained fall of > 15% in their FVC or gas transfer over a 3-6-month period. The recommended initial treatment is combined therapy with prednisolone (0.5 mg/kg) and azathioprine (2-3 mg/kg).
Assessment of response to this treatment is by repeat measurement of lung volumes, transfer factor and chest radiograph. Immunosuppressive therapy should be withdrawn over a few weeks if there is no response. Should objective evidence of improvement be demonstrated the prednisolone dose can be reduced gradually to a maintenance dose of 10-12.5 mg daily.
The median survival time of patients with CFA is about 3.5 years. Most deaths occur in patients over the age of 55, with males predominating. The rate of disease progression varies considerably from death within a few months to survival with minimal symptoms for many years. Occasionally, the disease process may 'burn out', but in the majority of patients the disease is progressive, even in those who have responded to treatment. Lung transplantation (see p. 508) should be considered in young patients with advanced disease.
LUNG DISEASES DUE TO ORGANIC DUSTS
A wide range of organic agents may cause respiratory disorders (see Box 13.78). Disease results from a local immune response to animal proteins (e.g. bird fancier's lung) or fungal antigens in mouldy vegetable matter. The most common presentation has been termed extrinsic allergic alveolitis.
13.78 SOME EXAMPLES OF LUNG DISEASES CAUSED BY ORGANIC DUSTS
Disorder Source Antigen/agent
Farmer's lung* Mouldy hay, straw, grain Micropolyspora faenae
Bird fancier's lung* Avian excreta, proteins and feathers Avian serum proteins
Malt worker's lung* Mouldy maltings Aspergillus clavatus
Byssinosis Textile industries Cotton, flax, hemp dust
Inhalation ('humidifier') fever Contamination of air conditioning Thermophilic actinomycetes
Cheese worker's lung* Mouldy cheese Aspergillus clavatus Penicillium casei
Maple bark stripper's lung* Bark from stored maple Cryptostroma corticale
*Denotes lung disease presenting as extrinsic allergic alveolitis.
EXTRINSIC ALLERGIC ALVEOLITIS
In this condition the inhalation of certain types of organic dust produces a diffuse immune complex reaction in the walls of the alveoli and bronchioles.
The pathogenic mechanisms concerned in the production of extrinsic allergic alveolitis (EAA) are not fully understood. It is thought that the disease develops in sensitised individuals mainly through a type III Arthus reaction, although type IV mechanisms are probably also important. When the antigen is inhaled, the immune complexes formed in antibody excess are precipitated very rapidly. Deposition of these immune complexes results in complement activation, causing a localised inflammatory reaction in the alveolar walls. Immunofluorescence has shown IgG, IgA and complement to be fixed in the pulmonary tissues when biopsy specimens are examined in the acute stages. The presence of granulomata in the alveolar walls provides some evidence for a type IV response also being involved. Bronchoalveolar lavage fluid from patients with extrinsic allergic alveolitis usually shows an increase in the number of lymphocytes.
Some of the agents which produce EAA, their source, and the names given to the resulting disease are shown in Box 13.78. In the UK, 50% of reported cases of EAA occur in farm workers. If patients with this disorder continue to be exposed to the relevant antigen, they develop progressive lung fibrosis, leading to severe respiratory disability, pulmonary hypertension and cor pulmonale.
EAA should be suspected when anyone who is regularly or intermittently exposed to organic dust complains, within a few hours of re-exposure to the same dust, of influenza-like symptoms. These include headache, muscle pains, malaise, pyrexia, dry cough and breathlessness without wheeze. When exposure is continuous, as is the case with an indoor pet bird at home, the presentation can be with breathlessness without systemic symptoms, and if the cause is not recognised this may result in the formation of irreversible pulmonary fibrosis. For reasons that remain uncertain, there is a lower incidence of EAA in smokers compared to non-smokers.
In the acute stage of the disease widespread end-inspiratory crepitations are the rule and the chest radiograph shows diffuse micronodular shadowing, often more pronounced in the upper zones. High-resolution CT in patients with acute EAA shows bilateral areas of consolidation superimposed on small centrilobar nodular opacities and air-trapping on expiration. In more chronic disease, features of fibrosis with linear opacities and architectural distortion predominate. Pulmonary function studies reveal a restrictive ventilatory defect with preservation of (or an increase in) the FEV1/FVC ratio. The PaO2 is reduced and the PaCO2 is often below normal because of over-ventilation. Diffusion capacity is impaired.
The diagnosis of EAA is usually based on the characteristic clinical and radiological features, together with the identification of a potential source of antigen at the patient's home or place of work. Reduction in the carbon monoxide transfer factor is the most sensitive functional abnormality. The diagnosis may be supported by a positive precipitin test or by more sensitive serological tests based on the enzyme-linked immunosorbent assay (ELISA) technique. However, it is also important to recognise that the great majority of farmers with positive precipitins do not have farmer's lung, and up to 15% of pigeon breeders may have positive serum precipitins and yet remain healthy. Where the diagnosis is suspected but the cause is not readily apparent, it may be helpful to visit the patient's home or workplace. Occasionally, such as when a new agent is suspected, it may be necessary to prove the diagnosis by a provocation test; if positive, the inhalation of the relevant antigen is followed after 3-6 hours by pyrexia and a reduction in VC and gas transfer factor. Open lung biopsy may be necessary to establish a diagnosis.
Mild forms of extrinsic allergic alveolitis rapidly subside when exposure to the antigen ceases. In acute cases prednisolone should be given for 3-4 weeks, starting with an oral dose of 40 mg per day. Severely hypoxaemic patients may require high-concentration oxygen therapy initially. Most patients recover completely, but the development of interstitial fibrosis causes permanent disability when there has been prolonged exposure to antigen.
Not all inhaled organic dusts cause interstitial infiltration. In byssinosis the initial lesion caused by cotton dust inhalation is acute bronchiolitis associated with symptoms and signs of generalised airflow obstruction, more in keeping with asthma. Initially, symptoms tend to recur after the weekend break ('Monday fever') but eventually become continuous. There is usually no radiological abnormality. Recovery usually follows removal from the dust hazard. Smokers have a greater incidence of byssinosis than non-smokers.
INHALATION ('HUMIDIFIER') FEVER
Inhalation fever is characterised by self-limiting fever and breathlessness following exposure to organism-contaminated water from humidifiers or air-conditioning systems. An identical syndrome can also develop after disturbing an accumulation of mouldy hay, compost or mulch.
LUNG DISEASES DUE TO INORGANIC DUSTS
13.79 SOME LUNG DISEASES CAUSED BY EXPOSURE TO INORGANIC DUSTS
Cause Occupation Description Characteristic pathological features
Coal dust Silica Coal mining Mining, quarrying, stone dressing, metal grinding, pottery, boiler scaling Coal worker's pneumoconiosis Silicosis Focal and interstitial fibrosis, centrilobular emphysema, progressive massive fibrosis
Asbestos Demolition, ship breaking, manufacture of fireproof insulating materials and brake-pads, pipe and boiler lagging Asbestos-related disease Interstitial fibrosis, pleural disease, carcinoma of larynx and bronchus
Iron oxide Arc welding Siderosis Mineral deposition only
Tin oxide Tin mining Stannosis
Beryllium Aircraft, atomic energy and electronics industries Berylliosis Granulomata, interstitial fibrosis
13.80 SOME LUNG DISEASES CAUSED BY INORGANIC GASES AND FUMES
Cause Occupation Disease
Irritant gases (chlorine, ammonia, phosgene, nitrogen dioxide) Various (industrial accidents) Acute lung injury ARDS
Cadmium Welding and electroplating COPD
Isocyanates (e.g. epoxy resins, paints) Plastic, paints; manufacture of epoxy resins and adhesives Bronchial asthma Eosinophilic pneumonia
In certain occupations, the inhalation of inorganic dusts, fumes or other noxious substances may give rise to specific pathological changes in the lungs. The risk of these forms of occupational lung disease is highest in spray painters, shipyard and dock workers, miners and quarrymen, welders, electronic assembly workers and those that work in the construction industry or in chemical processing. Generally, prolonged exposure to inorganic dusts (see Box 13.79) leads to diffuse pulmonary fibrosis (the pneumoconioses), although berylliosis causes an interstitial granulomatous disease similar to sarcoidosis. The dusts themselves cause little direct damage to the lung parenchyma and the pathological result depends largely on the inflammatory and fibrotic responses to the particular dust. The fibrogenic properties of mineral dusts vary, silica being markedly fibrogenic whereas iron and tin are almost inert. The most important types of pneumoconiosis are coal worker's pneumoconiosis, silicosis and asbestosis.
Industrial inorganic gases and fumes can cause other, often more acute, respiratory diseases including pulmonary oedema and asthma (see Box 13.80).
Clearly, it is essential to elicit a detailed occupational history, both present and past, since a diagnosis of occupational lung disease can easily be overlooked and the patient may be eligible for compensation. It must also be emphasised that in many types of pneumoconiosis a long period of dust exposure is required before radiological changes appear, and these may precede clinical symptoms.
Notes on diagnosis and claims for benefits in pneumoconiosis, occupational asthma and other related occupational disease in Britain are contained in government pamphlets. New industrial processes are constantly being introduced and it is necessary to remain alert to the possibility that they may be associated with occupational lung disease.
COAL WORKER'S PNEUMOCONIOSIS
This disease follows prolonged inhalation of coal dust. The condition is subdivided into simple pneumoconiosis and progressive massive fibrosis for both clinical purposes and certification. It must be emphasised that for certification purposes in Britain the diagnosis rests at present on radiological and not clinical features.
Simple coal worker's pneumoconiosis
This is categorised radiologically into three grades, depending on the size and extent of the nodulation present. It does not progress if the miner leaves the industry.
Progressive massive fibrosis
In this form of the disease, large dense masses, single or multiple, occur mainly in the upper lobes. These may be irregular in shape and may cavitate. Tuberculosis may be a complication. The disease can be disabling, may shorten life expectancy and may progress even after the miner leaves the industry.
Cough and sputum from associated chronic bronchitis are frequently present. The sputum may be black (melanoptysis). Progressive breathlessness on exertion occurs in the later stages, and respiratory and right ventricular failure supervene as terminal events. There may be no abnormal physical signs in the chest but when present they are those of chronic obstructive airways disease.
Antinuclear factor is present in the serum of about 15% of patients with coal worker's pneumoconiosis. Rheumatoid factor is present in some patients in whom rheumatoid arthritis coexists, with rounded fibrotic nodules 0.5-5 cm in diameter. These are mainly in the periphery of the lung fields and the association is known as Caplan's syndrome. This syndrome may also occur in other types of pneumoconiosis.
This disease is becoming rare as the standards of industrial hygiene improve. It is caused by the inhalation of fine free crystalline silicon dioxide (silica) dust or quartz particles.
Silica is a most fibrogenic dust and causes the development of hard nodules which coalesce as the disease progresses. Tuberculosis may modify the silicotic process with ensuing caseation and calcification. The radiological features are similar to those seen in coal worker's pneumoconiosis, though the changes tend to be more marked in the upper zones. The hilar shadows may be enlarged; 'egg-shell' calcification in the hilar lymph nodes is a distinctive feature but does not occur in all patients. The disease progresses even when exposure to dust ceases. The patient should, therefore, be removed from the offending environment as soon as possible. Clinical features are also similar to those of coal worker's pneumoconiosis.
Intense exposure to very fine crystalline silica dust can cause a more acute disease similar to alveolar proteinosis (see p. 562) with over-production of surfactant by type II alveolar pneumocytes.
The main types of the fibrous mineral, asbestos, are chrysotile (white asbestos), which accounts for 90% of the world's production, crocidolite (blue asbestos) and amosite (brown asbestos). Exposure occurs in the mining and milling of the mineral and in a variety of occupations (see Box 13.79).
Asbestos exposure is a recognised risk factor for the development of a number of respiratory diseases (see Fig. 13.49), including carcinoma of the lung and larynx. Asbestos-related pleural disease is covered on page 572. Asbestosis itself is defined as diffuse fibrosis of the lungs caused by inhalation of asbestos particles. This condition may or may not be associated with fibrosis of the parietal or visceral layer of the pleura. Together with asbestos-related diffuse pleural fibrosis and mesothelioma, it qualifies an individual in the UK for industrial injury benefit. In contrast to the other forms of asbestos-related respiratory disease, asbestosis tends to develop in individuals exposed to significant levels of asbestos dust over a number of years.
Figure 13.49 Asbestos: the range of possible effects on the respiratory tract.
Asbestosis usually has an indolent course and may be present subclinically for many years before becoming symptomatic in late middle age with dyspnoea, digital clubbing and inspiratory crepitations audible over the lower zones of both lungs. The chest radiograph shows bi-basal reticular nodular shadowing and occasionally 'honeycombing'. Other features of asbestos exposure may also be present (e.g. pleural plaques). Pulmonary function abnormalities are a restrictive defect with decreased lung volumes and reduced gas transfer factor. The risk of bronchial carcinoma is extremely high, especially in patients who also smoke.
The diagnosis is usually easy to establish from the history of exposure to asbestos and the above clinical, radiological and pulmonary function abnormalities. Lung biopsy may be required to confirm the diagnosis (and exclude other treatable causes of interstitial lung disease) but should not be undertaken solely for the purpose of allowing patients to claim benefit.
No specific treatment is available. Corticosteroids are of no value in the management of asbestosis. Respiratory failure and cor pulmonale should be treated appropriately.
Improvements in standards of industrial hygiene are now enforced by law in many countries; such measures as wearing respirators, damping dust and efficient ventilation systems are already proving effective in a number of industries.
LUNG DISEASES DUE TO SYSTEMIC INFLAMMATORY DISEASE
THE ACUTE RESPIRATORY DISTRESS SYNDROME
See page 198.
RESPIRATORY INVOLVEMENT IN CONNECTIVE TISSUE DISORDERS
Fibrosing alveolitis is a recognised complication of most connective tissue diseases. The clinical features are usually indistinguishable from cryptogenic fibrosing alveolitis (see p. 555) and the response to immunosuppressive drugs is similarly unpredictable. Connective tissue disorders may also cause disease of the pleura, diaphragm and chest wall muscles (see Box 13.81 and Ch. 20). Pulmonary hypertension and cor pulmonale may result from advanced fibrosing alveolitis associated with connective tissue disorders and is particularly common in patients with systemic sclerosis.
Indirect associations between connective tissue disorders and respiratory complications include those due to disease in other organs, e.g. thrombocytopenia causing haemoptysis; pulmonary toxic effects of drugs used to treat the connective tissue disorder (e.g. gold and methotrexate); and secondary infection due to the disease itself, neutropenia or immunosuppressive drug regimens.
Fibrosing alveolitis is the most common pulmonary manifestation (rheumatoid lung). The clinical features, investigations, treatment and prognosis are similar to those of cryptogenic fibrosing alveolitis, although a rare variant of localised upper lobe fibrosis and cavitation has been described.
Pleural effusion is common, especially in men with seropositive disease. Effusions are usually small and unilateral but can be large and bilateral. Most resolve spontaneously. Biochemical testing shows an exudative effusion (see p. 501) with markedly reduced glucose levels and raised protein lactate dehydrogenase (LDH). Effusions that fail to resolve spontaneously may respond to a short course of oral prednisolone (30-40 mg daily) but some become chronic.
13.81 RESPIRATORY COMPLICATIONS OF CONNECTIVE TISSUE DISORDERS
Disorder Airways Parenchyma Pleura Diaphragm and chest wall
Rheumatoid arthritis Bronchitis, obliterative bronchiolitis, bronchiectasis, crico-arytenoid arthritis, stridor Fibrosing alveolitis, nodules, upper lobe fibrosis, infections Pleurisy, effusion, pneumothorax Poor healing of intercostal drain sites
Systemic lupus erythematosus - Fibrosing alveolitis, 'vasculitic' infarcts Pleurisy, effusion 'Shrinking lungs'
Systemic sclerosis Bronchiectasis Pulmonary fibrosis, aspiration pneumonia - 'Hidebound chest'
Dermatomyositis/polymyositis Bronchial carcinoma Fibrosing alveolitis - Intercostal and diaphragmatic myopathy
Rheumatic fever - Pneumonia Pleurisy, effusion -
Figure 13.50 Rheumatoid (necrobiotic) nodules. Thoracic CT just below the level of the main carina showing the typical appearance of peripheral, pleural-based nodules. The nodule in the left lower lobe shows characteristic cavitation.
Rheumatoid pulmonary nodules do not usually cause symptoms and are detected on chest radiographs performed for other reasons. They are usually multiple and subpleural in site (see Fig. 13.50). Solitary nodules can mimic primary bronchial carcinoma and when multiple the differential diagnosis includes pulmonary metastatic disease. Cavitation of nodules can raise the possibility of tuberculosis and cause pneumothorax. The combination of rheumatoid nodules and pneumoconiosis is known as Caplan's syndrome (see p. 558).
Bronchitis and bronchiectasis are both more common in rheumatoid patients. Rarely, the potentially fatal condition, obliterative bronchiolitis, may develop.
Systemic lupus erythematosus
Fibrosing alveolitis is a relatively uncommon manifestation of systemic lupus erythematosus (SLE). Pleuropulmonary involvement is more common in lupus than in any other connective tissue disorder. Up to two-thirds of patients have repeated episodes of pleurisy, with or without effusions. Effusions may be bilateral and involve the pericardium.
Some patients with SLE present with exertional dyspnoea and orthopnoea but without overt signs of fibrosing alveolitis. The chest radiograph reveals elevated diaphragms, and pulmonary function testing shows reduced lung volumes. This condition has been described as 'shrinking lungs' and is thought to be caused by diaphragmatic myopathy.
Most patients with systemic sclerosis eventually develop diffuse pulmonary fibrosis; at necropsy more than 90% have evidence of lung fibrosis. In some patients it is indolent, but when progressive, like cryptogenic fibrosing alveolitis, the median survival time is around 4 years. Pulmonary fibrosis is rare in the CREST variant of progressive systemic sclerosis but isolated pulmonary hypertension may develop.
Other pulmonary complications include recurrent aspiration pneumonias secondary to oesophageal disease. Rarely, sclerosis of the skin of the chest wall may be so extensive and cicatrising as to restrict chest wall movement seriously-the so-called 'hidebound chest'.
PULMONARY EOSINOPHILIA AND VASCULITIDES
This term is applied to a group of disorders of different aetiology in which lesions in the lungs produce a chest radiograph abnormality associated with an increase in the number of the eosinophil leucocytes in the peripheral blood. There is no satisfactory classification of this disparate group of disorders, but they can be divided into two main categories (see Box 13.82).
Some causes of extrinsic pulmonary eosinophilia are also given in the box. The most common disorder of this type in developed countries is allergic bronchopulmonary aspergillosis (see p. 540); in tropical countries the presence of microfilariae in the pulmonary capillaries (see p. 73) has to be considered.
CRYPTOGENIC EOSINOPHILIC PNEUMONIA
13.82 PULMONARY EOSINOPHILIA
Extrinsic (cause known)
e.g. Ascaris, Toxocara, Filaria
Nitrofurantoin, para-aminosalicylic acid (PAS), sulfasalazine, imipramine, chlorpropamide, phenylbutazone
e.g. Aspergillus fumigatus causing allergic bronchopulmonary aspergillosis (see p. 540)
Intrinsic (cause unknown)
Cryptogenic eosinophilic pneumonia
Churg-Strauss syndrome (diagnosed on the basis of four or more of the following features: asthma, peripheral blood eosinophilia of > 10%, mononeuropathy or polyneuropathy, pulmonary infiltrates, paranasal sinus disease or eosinophilic vasculitis on biopsy of an affected site)
Polyarteritis nodosa (see p. 1042; rare)
Cryptogenic eosinophilic pneumonia is more common in middle-aged females, and usually presents with malaise, fever, breathlessness and unproductive cough. The chest radiograph can show abnormal parenchymal shadowing which tends to be bilateral, peripheral and upper lobe in distribution. Unless corticosteroids have been given, the peripheral blood eosinophil count is almost always very high, and the ESR and total serum IgE are elevated. Bronchoalveolar lavage reveals a high proportion of eosinophils in the lavage fluid. Response to prednisolone (20-40 mg daily) is usually dramatic. Prednisolone treatment can usually be withdrawn after a few weeks without relapse, but long-term low-dose therapy is occasionally necessary to control the disease.
LUNG DISEASES DUE TO IRRADIATION AND DRUGS
The lungs are exposed during radiotherapy treatment of lung tumours and also tumours of the breast, spine and oesophagus. The pulmonary effects of radiation (see p. 219) are exacerbated by treatment with cytotoxic drugs, oxygen delivery and previous radiotherapy. Radiotherapy may cause acute damage to the lung, and also a chronic insidious scarring disease.
After pulmonary irradiation, acute radiation pneumonitis may present with cough and dyspnoea within 6-12 weeks. This acute form of lung damage may resolve spontaneously or respond to corticosteroid treatment. Chronic interstitial fibrosis presents later, usually with symptoms of exertional dyspnoea and cough. Established post-irradiation fibrosis does not usually respond to corticosteroid treatment.
13.83 DRUG-INDUCED RESPIRATORY DISEASE
Non-cardiogenic pulmonary oedema (ARDS)
I.v. ß-adrenoceptor agonists (e.g. treatment of premature labour)
Aspirin and opiates (in overdose)
Amiodarone, flecainide, gold, nitrofurantoin, cytotoxic agents-especially bleomycin, busulfan, mitomycin C, methotrexate
Antimicrobials (nitrofurantoin, penicillin, tetracyclines, sulphonamides, nalidixic acid)
Antirheumatic agents (gold, aspirin, penicillamine, naproxen)
Cytotoxic drugs (bleomycin, methotrexate, procarbazine)
Psychiatric drugs (chlorpromazine, dosulepin (dothiepin), imipramine)
Anticonvulsants (carbamazepine, phenytoin)
Others (sulfasalazine, nadolol)
Bromocriptine, amiodarone, methotrexate, methysergide
Via induction of SLE-phenytoin, hydralazine, isoniazid
Via pharmacological mechanism (ß-blockers, cholinergic agonists, aspirin and NSAIDs)
Idiosyncratic reaction (tamoxifen, dipyridamole)
Drugs may cause a number of parenchymal reactions, including ARDS (see Box 13.83), eosinophilic reactions and diffuse interstitial inflammation/scarring. Drugs can also cause other lung disorders including asthma (see p. 514), haemorrhage (e.g. anticoagulants, penicillamine) and occasionally pleural effusions and pleural thickening (e.g. hydralazine, isoniazid, methysergide). An ARDS-like syndrome of acute non-cardiogenic pulmonary oedema may present with dramatic onset of breathlessness, severe hypoxaemia and signs of alveolar oedema on the chest radiograph. This syndrome has been reported most frequently in cases of opiate overdose in drug addicts (see p. 176) but also after salicylate overdose, and there are occasional reports of its occurrence after therapeutic doses of drugs including hydrochlorothiazides and some cytotoxic drugs.
ISSUES IN OLDER PEOPLE
INTERSTITIAL LUNG DISEASE
Cryptogenic fibrosing alveolitis is the most common interstitial lung disease in old people and has a worse prognosis.
Chronic aspiration pneumonitis must always be considered in elderly patients presenting with bilateral basal shadowing on a chest radiograph.
Wegener's granulomatosis is a rare condition but is more common in old age. Renal involvement is more common at presentation and upper respiratory problems are fewer in older people.
The symptoms of asbestosis may appear for the first time in old age because of the prolonged latent period between exposure and the development of disease.
Drug-induced interstitial lung disease is more common in old age, presumably because of the increased chance of exposure to multiple drugs.
Sarcoidosis, idiopathic pulmonary haemosiderosis, alveolar proteinosis and eosinophilic pneumonia rarely present in old age.
Coexistent muscle weakness, chest wall deformity (e.g. thoracic kyphosis) and deconditioning may all exacerbate the extent of dyspnoea associated with interstitial lung disease.
Open lung biopsy is often inappropriate in the very frail and a diagnosis therefore frequently depends on clinical and high-resolution CT findings alone.
13.84 RARE INTERSTITIAL LUNG DISEASES
Disease Presentation Chest radiograph Course
Idiopathic pulmonary haemosiderosis Haemoptysis, breathlessness, anaemia Bilateral infiltrates often perihilar Diffuse pulmonary fibrosis Rapidly progressive in children Slow progression or remission in adults Death from massive pulmonary haemorrhage or cor pulmonale and respiratory failure
Alveolar proteinosis Breathlessness and cough Occasionally fever, chest pain and haemoptysis Diffuse bilateral shadowing, often more pronounced in the hilar regions Air bronchogram Spontaneous remission in one-third Whole lung lavage or granulocyte macrophage-colony stimulating factor (GM-CSF) therapy may be effective
Langerhans cell histiocytosis (histiocytosis X) Breathlessness, cough, pneumothorax Diffuse interstitial shadowing progressing to honeycombing Progressive leading to respiratory failure Poor response to immunosuppressive therapy Smoking cessation is important and may result in significant improvement
Neurofibromatosis Breathlessness and cough in a patient with multiple organ involvement with neurofibromas including skin Bilateral reticular nodular shadowing of diffuse interstitial fibrosis Slow progression to death from respiratory failure Poor response to corticosteroid therapy
Alveolar microlithiasis No symptoms Breathlessness and cough Diffuse calcified micronodular shadowing more pronounced in the lower zones Slowly progressive to cor pulmonale and respiratory failure May stabilise in some Disodium etidronate may be effective
Lymphangioleiomyomatosis Haemoptysis, breathlessness, pneumothorax and chylous effusion in females Diffuse bilateral shadowing CT shows characteristic thin-walled cysts with well-defined walls throughout both lungs Progressive to death within 10 years Oestrogen ablation and progesterone therapy of doubtful value Lung transplantation
Pulmonary tuberous sclerosis Very similar to lymphangioleiomyomatosis except occasionally occurs in men
Pulmonary fibrosis may occur in response to a variety of drugs, but is seen most frequently with bleomycin, methotrexate, amiodarone and nitrofurantoin. Eosinophilic pulmonary reactions can also be caused by drugs. The pathogenesis may be an immune reaction similar to that in extrinsic allergic alveolitis, which specifically attracts large numbers of eosinophils into the lungs. This type of reaction is well described as a rare reaction to a variety of antineoplastic agents (e.g. bleomycin), antibiotics (e.g. sulphonamides), sulfasalazine and the anticonvulsants phenytoin and carbamazepine. Patients usually present with breathlessness, cough and fever. The chest radiograph characteristically shows patchy shadowing. Most cases resolve completely on withdrawal of the drug, but if the reaction is severe, rapid resolution can be obtained with corticosteroids.
RARE INTERSTITIAL LUNG DISEASES
See Box 13.84.
pages 550 - 562
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > PULMONARY VASCULAR DISEASE
PULMONARY VASCULAR DISEASE
Deep venous thrombosis (DVT, see pp. 953-956) and pulmonary embolism (PE) can be usefully considered under the heading venous thromboembolism (VTE); 75% of pulmonary emboli derive from DVT in the lower limb and 60% of patients with DVT will have evidence of PE on scanning even in the absence of symptoms. Rarely, PE may occur due to amniotic fluid, placenta, air, fat, tumour (especially choriocarcinoma) and septic emboli from endocarditis affecting tricuspid or pulmonary valves. Pulmonary emboli occur in 1% of patients admitted to hospital and are responsible for about 5% of all hospital deaths. The prophylaxis of VTE is the same as DVT (see p. 956). Clinical presentation, physical signs and treatment of PE are best understood when classified on the basis of size, site and speed of onset (see Box 13.85).
Acute massive pulmonary embolism
The clinical features are of acute haemodynamic collapse with central chest pain, apprehension, a low cardiac output and syncope. The pathophysiology is due to acute obstruction of more than 50% of either the main or the proximal pulmonary artery, leading to an acute reduction of cardiac output and right ventricular dilatation. On examination there is a sinus tachycardia, hypotension and peripheral vasoconstriction. Tachypnoea is typically present with cyanosis and an elevated JVP. A right ventricular gallop may be heard with wide-splitting of the second heart sound. Other signs of pulmonary hypertension are not expected in acute massive pulmonary embolism.
13.85 CATEGORISATION OF PULMONARY THROMBOEMBOLI
Acute massive PE Acute small/medium PE Chronic PE
Pathophysiology Major haemodynamic effects: ? cardiac output; acute right heart failure; disordered ventilation-perfusion ratio Occlusion of segmental pulmonary artery ? infarction ± effusion Chronic occlusion of pulmonary microvasculature; pulmonary hypertension, right heart failure
Symptoms Sudden syncope, faintness, central chest pain, apprehension, severe dyspnoea Pleurisy, restricted breathing, haemoptysis Exertional dyspnoea Late-exertional syncope, symptoms of right ventricular (RV) failure
Cardiovascular Major circulatory collapse; tachycardia; hypotension; ? jugular venous pressure; gallop rhythm; P2 widely split (late) Tachycardia May be minimal early in disease Late-RV heave, loud, split P2 Terminal-signs of RV failure
Respiratory Severe cyanosis, otherwise no local signs Pleural rub, raised hemidiaphragm, crepitations, effusion (usually blood-stained)
Other ? Urine output Low-grade fever
Chest radiograph Often subtle; oligaemic lung fields, slight ? hilar shadows Pleuropulmonary opacities; pleural effusion; linear shadows; raised hemidiaphragm Enlarged pulmonary artery trunk; enlarged heart, prominent RV
ECG S1Q3T3 (see Fig. 13.52) T wave ? V1-V4 Right bundle-branch block Sinus tachycardia Signs of RV hypertrophy and 'strain'
Blood gases ? PaO2; ? PaCO2 (? PaCO2) Exertional ? PaO2 or desaturation (on formal exercise testing)
[Vdot]/[Qdot] scan Major areas of ? perfusion Perfusion defect(s) not matched on the ventilation scan May be no abnormality
Pulmonary angiography Definitive diagnosis Definitive diagnosis Usually diagnostic; may need lung biopsy to confirm diagnosis
Acute minor pulmonary embolism
Figure 13.51 Features of pulmonary thromboembolism/infarction on chest radiograph.
The majority of patients will present with so-called 'pulmonary infarction syndrome' with pleurisy, shortness of breath and haemoptysis. Clinically, there may be a pleural rub and signs of a pleural effusion. The chest radiograph (see Fig. 13.51) may show wedge-shaped opacity due to haemorrhage, pleural effusion or an elevated diaphragm. Some cases present with isolated breathlessness and these patients tend to have more extensive central thrombus if pulmonary angiography is performed.
Acute embolism in patients with chronic cardiopulmonary disease
Patients with a small degree of cardiopulmonary reserve may demonstrate a major and sudden deterioration in their clinical state even with small pulmonary emboli. The clinical features of PE may be obscured by the clinical features of the underlying disease and diagnosis can be difficult in this important situation. A high index of suspicion is required if successful investigation and management in this group of patients are to be achieved.
Chronic venous thromboembolism leading to thromboembolic pulmonary hypertension
This is a relatively rare but important condition which arises without a history of previous acute PE in over 50% of cases. Patients typically present with a history of exertional breathlessness, syncope and chest pain developing over months or years. On examination there are signs of pulmonary hypertension with a loud pulmonary component to the second heart sound and a right ventricular heave. The JVP is raised and there may be v waves indicating tricuspid regurgitation (see p. 462). Patients with severe pulmonary hypertension secondary to chronic pulmonary emboli should be considered for thromboendarterectomy, an operation that involves removal of the organised obstructing thrombus via an endarterectomy. The operation should be carried out in specialist centres; despite a significant operative mortality (10-20%), it has a high degree of success.
All patients presenting with suspected pulmonary embolism should undergo basic investigations including chest radiography, electrocardiography and arterial blood gases.
Although the chest radiograph may be normal or show non-specific changes, it is extremely valuable in excluding other diagnoses such as heart failure, pneumonia, pneumothorax or tumour. The common findings in PE include focal infiltrates, segmental collapse, raised hemidiaphragm and pleural effusion (see Fig. 13.51). A wedge-shaped pleural-based opacity, though well described, is rare. Hypovascularity as described in a large embolism is often difficult to detect. A normal chest radiograph in an acutely breathless and hypoxaemic patient increases the likelihood of PE.
ECG abnormalities in PE are common but usually comprise non-specific changes in the ST segment and/or T wave. The classic S1Q3T3 pattern (see Fig. 13.52) is rare and again not specific for PE. ECG is also useful in excluding other diagnoses such as acute myocardial infarction and pericarditis.
Arterial blood gases
Pulmonary embolism is characterised by ventilation-perfusion mismatch and reduced cardiac output with a low mixed venous oxygen saturation and hyperventilation. Arterial blood gases typically show reduced PaO2 and a normal or low PaCO2. Normal PaO2 and PaCO2 values may be found, particularly in small emboli. In acute massive PE, cardiovascular collapse typically results in a metabolic acidosis.
Figure 13.52 ECG from a patient with pulmonary embolism showing 'S1Q3T3' pattern. S wave in lead I, Q wave and inverted T wave in lead III.
D-dimer is a specific degradation product released into the circulation when cross-linked fibrin undergoes endogenous fibrinolysis (see p. 900). In patients with suspected PE a low plasma D-dimer (< 500 mg/ml measured by ELISA) has a 95% predictive power for excluding PE and hence the D-dimer can be used as an initial screening investigation (see Fig. 13.53). A positive D-dimer, however, does not positively diagnose PE since raised levels may be seen in a whole range of inflammatory conditions including pneumonia.
Figure 13.53 Algorithm for the investigation of patients with suspected pulmonary thromboembolism. Clinical risk is based on the presence of risk factors for VTE and the probability of another diagnosis.
Ventilation-perfusion ([Vdot]/[Qdot]) lung scanning (see p. 490) has been the most popular method of attempting to confirm the presence of PE by demonstrating the presence of 'non-matched' defects of perfusion. In practice, however, many patients presenting with a suspected PE have pre-existing chronic cardiopulmonary disease (such as COPD) which can seriously impair the diagnostic efficacy of ventilation-perfusion scanning and lead to indeterminate reports. The recognition of an over-reliance on ventilation-perfusion scanning and the recent acquisition of spiral CT imaging in most UK hospitals has led to increased use of CT pulmonary angiography. Ventilation-perfusion scanning remains useful in patients with no previous lung disease and should be carried out within 24 hours of presentation since some scans revert to normal very quickly and 50% do so by 1 week. Spiral CT angiography has good sensitivity and specificity for central or segmental thrombi and this is now considered the investigation of choice in patients presenting with isolated dyspnoea. Colour Doppler ultrasound of the leg veins remains the investigation of choice in patients with clinical DVT but may also be applied to patients presenting with features of PE alone since many will have identifiable proximal thrombus in the lower limbs. It is important to note that the sensitivity and specificity of ventilation-perfusion scanning in ruling pulmonary embolism in or out can be increased by the use of a simple clinical probability score indicating high or low clinical risk.
Echocardiography can be used to diagnose a major central PE and is valuable for excluding other conditions such as myocardial infarction, aortic dissection and pericardial tamponade. Changes only occur when there has been significant obstruction to the pulmonary circulation and this investigation should therefore be carried out only in patients with systemic hypotension. Accuracy can be increased by using the transoesophageal route, which is much more likely to show clot in either the right heart or the main pulmonary arteries.
Although conventional pulmonary angiography is said to be the 'gold standard' for the diagnosis of PE, there may be difficulties in interpretation, even with an experienced radiologist. While there are no absolute contraindications, particular care should be exercised in patients with known sensitivity to contrast media.
Opiates may be necessary to relieve pain and distress but should be used with great caution in the hypotensive patient. Resuscitation by external cardiac massage may be successful in the moribund patient by dislodging and breaking up a large central embolus. Oxygen should be given to all hypoxaemic patients in a concentration necessary to restore arterial oxygen saturation to over 90%. Diuretics and vasodilators should be avoided in the acute setting. Likewise, in the shocked patient inotropic agents are of limited value since in massive PE the hypoxic dilated right ventricle is near maximally stimulated by endogenous catecholamines.
Heparin should be given to all patients with a high clinical suspicion of PE whilst confirmatory test results are awaited. Low molecular weight heparin given subcutaneously has been demonstrated to be as effective as intravenous unfractionated heparin and it is much easier to administer (see p. 955). The dose is standardised for the weight of the patient and does not require monitoring by tests of coagulation. Heparin is effective in reducing mortality in PE by reducing the potential of further emboli. It should be administered for at least 5 days and anticoagulation continued using oral warfarin. Heparin should not be discontinued until the INR is over 2. The duration of warfarin therapy is under considerable discussion but should be continued for a minimum of 6 weeks for patients who have an identifiable and reversible cause for their DVT such as hip surgery, and for 3 months in patients with no identified cause. Patients with an underlying prothrombotic risk or a history of previous emboli should be anticoagulated for life. (For all anticoagulation control, see p. 955.)
ACUTE VENOUS THROMBOEMBOLISM (VTE)-use of subcutaneous low molecular weight heparins
'Low molecular weight heparins given subcutaneously in a weight-adjusted dosage are the treatment of choice for acute VTE.'
Columbus Investigations. Low molecular weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337:657-662.
Simonneau G, Sors H, Charbonnier B, et al. A comparison of low molecular weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337:663-669.
Further information: www.acponline.org/journals/annals/15jun98/Imwhepar.htm
Patients with an acute massive PE and evidence of right ventricular dysfunction on echocardiography or of hypotension should be considered for urgent thrombolytic therapy when the diagnosis is confirmed. Streptokinase or alteplase (human tissue plasminogen activator or tPA) can be used. The latter is more expensive but less likely to lead to systemic side-effects and hypotension. A dose of 60 mg i.v. administered over 15 minutes is sufficient. Heparin should be given subsequently.
Patients with recurrent PE despite adequate anticoagulation control benefit from the insertion of a filter placed in the inferior vena cava below the origin of the renal vessels. Such filters may also be placed in patients with PE in whom anticoagulation is contraindicated (e.g. immediately following neurosurgery).
ACUTE MASSIVE VENOUS THROMBOEMBOLISM-role of thrombolysis
'In patients presenting with acute massive venous thromboembolism, thrombolytic therapy has been shown to cause more rapid restoration of haemodynamic instability and reduce the risk of recurrent emboli compared with the use of heparin.'
Thomas MD, Chauhan A, More RS. Pulmonary embolism-an update on thrombolytic therapy. QJM 2000; 93:261-267.
Konstantinides ST, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and the prognosis of haemodynamically stable patients with major pulmonary embolism. Results of a Multi-centre Registry. Circulation 1997; 96:882-888.
Further information: www.icsi.org/guide/VTE.pdf
SEVERE PULMONARY HYPERTENSION
Although respiratory failure due to intrinsic pulmonary disease is the most common cause of pulmonary hypertension (see p. 505), severe pulmonary hypertension may occur as a primary disorder or as a result of chronic repeated thromboembolic events. The primary disorder may be familial, sporadic or associated with an underlying cause such as previous ingestion of appetite suppressant drugs, HIV infection or underlying connective tissue disease, particularly limited cutaneous systemic sclerosis (see p. 1036).
The pathological features include hypertrophy of both the media and intima of the vessel wall, and the so-called plexiform lesion which represents a clonal expansion of endothelial cells. There is marked narrowing of the vessel lumen and this, together with the frequently observed in situ thrombosis, leads to an increase in pulmonary vascular resistance and pulmonary hypertension. The gene responsible for familial pulmonary hypertension has recently been identified as a member of the TGF-ß superfamily, BMPR2. Up to 30% of patients with sporadic pulmonary hypertension have also been found to have mutations in this gene.
PRIMARY PULMONARY HYPERTENSION-role of continuous epoprostenol (prostacyclin) infusion
'RCTs have demonstrated that continuous intravenous epoprostenol (prostacyclin) therapy produces sustained symptomatic and haemodynamic benefit and improved survival in patients with severe primary pulmonary hypertension.'
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334:296-301.
McLaughlin W, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338:273-277.
Further information: www.atsqol.org/pulmhyp.asp
Patients usually present with an insidious history of breathlessness on exertion and commonly the diagnosis is delayed for up to 2 years until the presence of severe pulmonary hypertension and right heart failure is evident. The prognosis of primary pulmonary hypertension was, until recently, very poor, with the majority of patients dying within 3 years of diagnosis unless they underwent heart-lung transplantation. The introduction of epoprostenol (prostacyclin) or iloprost therapy, given either as a continuous intravenous infusion through a central venous catheter or via the nebulised route, has dramatically improved exercise performance, symptoms and prognosis. All patients should undergo a trial of this therapy prior to consideration of heart-lung transplantation. Anticoagulation with warfarin has also been demonstrated to improve prognosis in severe pulmonary hypertension.
For issues in older people relating to haemostasis and thrombosis, see page 956.
ISSUES IN OLDER PEOPLE
The risk of thromboembolic disease rises by a factor of 2.5 over the age of 60 years.
In women aged over 60 years hormone replacement therapy increases the risk of thromboembolism by a factor of 2-4.
Prophylaxis for venous thromboembolism should be considered in all older patients who are immobile as a result of acute illness, except when this is due to acute stroke, as heparin increases the risk of haemorrhagic complications.
The prevalence of cancer among those with DVT increases with age, but the relative risk of malignancy with DVT falls with age; therefore intensive investigation is not justified if initial assessment reveals no evidence of an underlying neoplasm.
Older patients are more sensitive to the anticoagulant effects of warfarin, partly due to the concurrent use of other drugs and the presence of other pathology. Life-threatening or fatal bleeds on warfarin are significantly more common in those aged over 80 years.
Long-term anticoagulant therapy should not be given prophylactically to older people with chronic immobility, as there is no evidence that the latter increases the risk of thromboembolism.
pages 562 - 566
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > DISEASES OF THE NASOPHARYNX, LARYNX AND TRACHEA
DISEASES OF THE NASOPHARYNX, LARYNX AND TRACHEA
DISEASES OF THE NASOPHARYNX
This is a disorder in which there are episodes of nasal congestion, watery nasal discharge and sneezing. It may be seasonal or perennial.
Allergic rhinitis is due to an immediate hypersensitivity reaction in the nasal mucosa. The antigens concerned in the seasonal form of the disorder are pollens from grasses, flowers, weeds or trees. Grass pollen is responsible for hay fever (pollenosis), the most common type of seasonal allergic rhinitis in northern Europe; in the UK this disorder is at its peak between May and July.
Perennial allergic rhinitis may be a specific reaction to antigens derived from house dust, fungal spores or animal dander but similar symptoms can be caused by physical or chemical irritants-for example, pungent odours or fumes, including strong perfumes, cold air and dry atmospheres. The term 'vasomotor rhinitis' is often used for this type of nasal problem because in this context the term 'allergic' is a misnomer.
In the seasonal type there are frequent sudden attacks of sneezing, with profuse watery nasal discharge and nasal obstruction. These attacks last for a few hours and are often accompanied by smarting and watering of the eyes and conjunctival infection. In the perennial variety the symptoms are similar but more continuous and generally less severe. Skin hypersensitivity tests with the relevant antigen are usually positive in seasonal allergic rhinitis and are thus of diagnostic value, but these tests are less useful in perennial rhinitis.
The following symptomatic measures, singly or in combination, are usually effective in both seasonal and perennial allergic rhinitis:
an antihistamine drug such as loratadine 10 mg daily by mouth
sodium cromoglicate nasal spray, one metered dose of a 2% solution into each nostril 4-6-hourly
beclometasone dipropionate or budesonide aqueous nasal spray, one or two doses of 50 µg into each nostril 12-hourly.
Patients failing to respond to these measures may obtain symptomatic relief from intramuscular injection of a long-acting corticosteroid preparation; this form of treatment should be reserved for occasional use in patients whose symptoms are very severe and seriously interfere with school, business or social activities. Vasomotor rhinitis is often difficult to treat, but may respond to ipratropium bromide, administered into each nostril 6-8-hourly.
In the seasonal type an attempt should be made to reduce exposure to pollen-for example, by avoiding country districts and keeping indoors as much as possible with windows closed during the pollen season, especially when pollen counts are reported to be high. The prevention of perennial rhinitis consists of avoiding, as far as possible, exposure to any identifiable aetiological factors but this is often difficult or impossible.
Acute infections have already been described (see Box 13.38, p. 525). Other disorders of the larynx include chronic laryngitis, laryngeal tuberculosis, laryngeal paralysis and laryngeal obstruction. Tumours of the larynx are relatively common. For detailed information on these conditions, the reader should refer to a textbook of diseases of the ear, nose and throat.
The common causes of this condition are listed in Box 13.86.
13.86 SOME CAUSES OF CHRONIC LARYNGITIS
Repeated attacks of acute laryngitis
Excessive use of the voice, especially in dusty atmospheres
Heavy tobacco smoking
Mouth-breathing from nasal obstruction
Chronic infection of nasal sinuses
The chief symptom is hoarseness and the voice may be lost completely (aphonia). There is irritation of the throat and a spasmodic cough. The disease pursues a chronic course frequently uninfluenced by treatment, and in long-standing cases the voice is often permanently impaired.
The causes of chronic hoarseness are listed in Box 13.87.
These conditions must be considered in the differential diagnosis if hoarseness does not improve within a few weeks. In some patients a chest radiograph may bring to light an unsuspected bronchial carcinoma or pulmonary tuberculosis. If no such abnormality is found, laryngoscopy should be performed, usually by a specialist in otolaryngology.
13.87 CAUSES OF CHRONIC HOARSENESS
If hoarseness persists for more than a few days, consider:
Tumour of the larynx
Inhaled corticosteroid treatment
The voice must be rested completely. This is particularly important in public speakers. Smoking should be prohibited. Some benefit may be obtained from frequent inhalations of medicated steam.
Paralysis is due to interference with the motor nerve supply of the larynx. It is nearly always unilateral and, by reason of the intrathoracic course of the left recurrent laryngeal nerve, usually left-sided. One or both recurrent laryngeal nerves may be damaged at thyroidectomy or by carcinoma of the thyroid. Rarely, the vagal trunk itself is involved by tumour, aneurysm or trauma.
This always accompanies laryngeal paralysis, whatever its cause. Paralysis of organic origin is seldom reversible but when only one vocal cord is affected hoarseness may improve or even disappear after a few weeks, following a compensatory adjustment whereby the unparalysed cord crosses the midline and approximates with the paralysed cord on phonation.
A characteristic feature of organic laryngeal paralysis is a cow-like cough which results from the loss of the explosive phase of normal coughing consequent upon the failure of the cords to close the glottis. Difficulty in bringing up sputum, which some patients experience, is also explained on the same basis. A normal cough in patients with partial loss of voice or aphonia virtually excludes laryngeal paralysis.
Stridor is occasionally present but is seldom severe, except when laryngeal paralysis is bilateral.
Laryngoscopy is necessary to establish the diagnosis of laryngeal paralysis with certainty. The paralysed cord lies in the so-called 'cadaveric' position, midway between abduction and adduction.
The cause of laryngeal paralysis should be treated if that is possible. In unilateral paralysis the voice may be improved by the injection of Teflon into the affected vocal cord. In bilateral organic paralysis, tracheal intubation, tracheostomy or a plastic operation on the larynx may be necessary.
PSYCHOGENIC HOARSENESS AND APHONIA
Psychogenic causes of hoarseness or complete loss of voice may be suggested by associated symptoms in the history (see p. 254). However, laryngoscopy may be necessary to exclude a physical cause of the voice abnormality. In psychogenic aphonia only the voluntary movement of adduction of the vocal cords is seen to be impaired.
Laryngeal obstruction is more liable to occur in children than in adults because of the smaller size of the glottis. Some important causes are given in Box 13.88.
13.88 CAUSES OF LARYNGEAL OBSTRUCTION
Inflammatory or allergic oedema, or exudate
Spasm of laryngeal muscles
Inhaled foreign body
Inhaled blood clot or vomitus in an unconscious patient
Tumours of the larynx
Bilateral vocal cord paralysis
Fixation of both cords in rheumatoid disease
Sudden complete laryngeal obstruction by a foreign body produces the clinical picture of acute asphyxia-violent but ineffective inspiratory efforts with indrawing of the intercostal spaces and the unsupported lower ribs, accompanied by cyanosis. Unrelieved, the condition progresses rapidly to coma and death within a few minutes. When, as in most cases, the obstruction is incomplete at first, the main clinical features are progressive breathlessness accompanied by stridor and cyanosis. There is indrawing of the intercostal spaces and lower ribs on both sides with each inspiratory effort. In such cases the great danger is that complete laryngeal obstruction may occur at any time and result in sudden death.
Transient attacks of laryngeal obstruction due to exudate and spasm, which may occur with acute laryngitis in children (see p. 525) and with whooping cough, are potentially dangerous but can usually be relieved by the inhalation of steam.
Laryngeal obstruction from all other causes carries a high mortality and demands prompt treatment. The following measures may have to be employed.
Relief of obstruction by mechanical measures
When a foreign body is known to be the cause of the obstruction in children it can often be dislodged by turning the patient head downwards and squeezing the chest vigorously. In adults this is often impossible, but a sudden forceful compression of the upper abdomen (Heimlich manoeuvre) may be effective. In other circumstances the cause of the obstruction should be investigated by direct laryngoscopy which may also permit the removal of an unsuspected foreign body, or the insertion of a tube past the obstruction into the trachea. Tracheostomy must be performed without delay if these procedures fail to relieve laryngeal obstruction, but except in dire emergencies this operation should be performed in an operating theatre by a surgeon.
Treatment of the cause
In cases of diphtheria, antitoxin should be administered, and for other infections the appropriate antibiotic should be given. In angio-oedema complete laryngeal occlusion can usually be prevented by treatment with adrenaline (epinephrine) 0.5-1 mg (0.5-1 ml of 1:1000) intramuscularly, chlorphenamine maleate 10-20 mg by slow intravenous injection and intravenous hydrocortisone sodium succinate 200 mg.
See Box 13.38, page 525.
External compression by enlarged mediastinal lymph nodes containing metastatic deposits, usually from a bronchial carcinoma, is a more frequent cause of tracheal obstruction than the uncommon primary benign or malignant tumours. Rarely, the trachea may be compressed by an aneurysm of the aortic arch, or in children by tuberculous mediastinal lymph nodes. Tracheal stenosis is an occasional complication of tracheostomy, prolonged intubation, Wegener's granulomatosis or trauma.
Stridor can be detected in every patient with severe tracheal narrowing. Endoscopic examination of the trachea should be undertaken without delay to determine the site, degree and nature of the obstruction.
Localised tumours of the trachea can be resected, but reconstruction after resection may present complex technical problems. Endobronchial laser therapy, tracheal stents and radiotherapy are alternatives to surgery. The choice of treatment depends upon the nature of the tumour and the general health of the patient. Radiotherapy or chemotherapy may temporarily relieve compression by malignant lymph nodes, and tracheal stents introduced bronchoscopically may be of temporary value. Benign tracheal strictures can sometimes be dilated but may have to be resected.
This may be present in newborn infants as a congenital abnormality. In adults it is usually due to malignant lesions in the mediastinum, such as carcinoma or lymphoma, eroding both the trachea and oesophagus to produce a communication between them. Swallowed liquids enter the trachea and bronchi through the fistula and provoke coughing.
Surgical closure of a congenital fistula, if undertaken promptly, is usually successful. There is usually no curative treatment for malignant fistulae and death from over-whelming pulmonary infection rapidly supervenes.
pages 566 - 569
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Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > DISEASES OF THE PLEURA, DIAPHRAGM AND CHEST WALL
DISEASES OF THE PLEURA, DIAPHRAGM AND CHEST WALL
DISEASES OF THE PLEURA
Pleurisy is not a diagnosis but simply a term used to describe the result of any disease process involving the pleura and giving rise to pleuritic pain or evidence of pleural friction. Pleurisy is a common feature of pulmonary infarction and may be an early manifestation of pleural invasion by pulmonary tuberculosis or a bronchogenic carcinoma.
Pleural pain is the characteristic symptom. On examination rib movement is restricted and a pleural rub is present. This may only be heard in deep inspiration or near the pericardium, where a so-called pleuro-pericardial rub may be present. The other clinical features depend upon the nature of the disease causing the pleurisy. Loss of the pleural rub and diminution in the chest pain may indicate recovery or herald the development of a pleural effusion.
Every patient must have a chest radiograph but a normal radiograph does not exclude a pulmonary cause for the pleurisy. A preceding history of cough, purulent sputum and pyrexia is presumptive evidence of a pulmonary infection which may not have been severe enough to produce a radiographic abnormality or which may have resolved before the chest radiograph was taken.
The primary cause of pleurisy must be treated. The symptomatic treatment of pleural pain is described on page 530.
See page 501.
This term describes the presence of pus in the pleural space. The pus may be as thin as serous fluid or so thick that it is impossible to aspirate even through a wide-bore needle. Microscopically, neutrophil leucocytes are present in large numbers. The causative organism may or may not be isolated from the pus. An empyema may involve the whole pleural space or only part of it ('loculated' or 'encysted' empyema) and is almost invariably unilateral.
Empyema is always secondary to infection in a neighbouring structure, usually the lung. The principal infections liable to produce empyema are the bacterial pneumonias and tuberculosis. Over 40% of patients with community-acquired pneumonia develop an associated pleural effusion ('para-pneumonic' effusion) and about 15% of these become secondarily infected. Other causes are infection of a haemothorax and rupture of a subphrenic abscess through the diaphragm. Despite the widespread availability of effective antibacterial therapy for patients with pneumonia, empyema continues to be a significant cause of morbidity and mortality even in developed countries. All too often, this reflects a delay in the diagnosis or instigation of appropriate therapy.
Both layers of pleura are covered with a thick, shaggy inflammatory exudate. The pus in the pleural space is often under considerable pressure and if the condition is not adequately treated pus may rupture into a bronchus causing a bronchopleural fistula and pyopneumothorax, or track through the chest wall with the formation of a subcutaneous abscess or sinus.
The only way in which an empyema can heal is by eradication of the infection, obliteration of the empyema space and apposition of the visceral and parietal pleural layers. This cannot occur unless re-expansion of the compressed lung is secured at an early stage by removal of all the pus from the pleural space. This cannot take place if:
the visceral pleura becomes grossly thickened and rigid due to delayed treatment or inadequate drainage of the infected pleural fluid
the pleural layers are kept apart by air entering the pleura through a bronchopleural fistula
there is underlying disease in the lung, such as bronchiectasis, bronchial carcinoma or pulmonary tuberculosis preventing re-expansion.
In all these circumstances an empyema tends to become chronic, and healing may not take place without surgical intervention.
An empyema should be suspected in patients with pulmonary infection if there is persistence or recurrence of pyrexia despite the administration of a suitable antibiotic. In other cases the illness produced by the primary infective lesion may be so slight that it passes unrecognised and the first definite clinical features are due to the empyema itself.
Once an empyema has developed, two separate groups of clinical features are found. These are shown in Box 13.89.
13.89 CLINICAL FEATURES OF EMPYEMA
Pyrexia, usually high and remittent
Rigors, sweating, malaise and weight loss
Polymorphonuclear leucocytosis, high CRP
Pleural pain; breathlessness; cough and sputum usually because of underlying lung disease; copious purulent sputum if empyema ruptures into a bronchus (bronchopleural fistula)
Clinical signs of fluid in the pleural space
The appearances are often indistinguishable from those of pleural effusion. When air is present in addition to pus (pyopneumothorax), a horizontal 'fluid level' marks the interface between the liquid and air. Ultrasound and CT are extremely valuable in defining the extent of pleural thickening and location of the fluid, and in the case of CT assessing the underlying lung parenchyma and patency of the major bronchi.
Aspiration of pus
This confirms the presence of an empyema. Ultrasound or CT is recommended to identify the optimal place to undertake pleuracentesis, which is best performed using a wide-bore needle. The pus is frequently sterile when antibiotics have already been given; the distinction between tuberculous and non-tuberculous disease can be difficult and often requires pleural histology and culture.
Treatment of non-tuberculous empyema
When the patient is acutely ill and the pus is thin an intercostal tube should be inserted under ultrasound CT guidance into the most dependent part of the empyema space and connected to a water-seal drain system. If the initial aspirate reveals turbid fluid or frank pus, or if loculations are seen on ultrasound, the tube should be put on suction (5-10 cm water) and flushed regularly with 20 ml normal saline. Although intrapleural fibrinolytic therapy is widely used in such situations there is currently insufficient evidence to support its routine use (see EBM panel). Finally, an antibiotic directed against the organism causing the empyema should be given for 2-4 weeks.
PARA-PNEUMONIC EFFUSIONS AND EMPYEMA-role of intrapleural fibrinolytic therapy
'There is currently insufficient evidence to support the routine use of intrapleural fibrinolytic therapy in the treatment of para-pneumonic effusions or empyema.'
Cameron R. Intra-pleural fibrinolytic therapy for parapneumonic effusions and empyema (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Chin NK, Lim TK. Controlled trial of intrapleural streptokinase in the treatment of empyema and complicated parapneumonic effusions. Chest 1997; 111:275-279.
An empyema can often be aborted if these measures are started early. If, however, the intercostal tube is not providing adequate drainage, which can happen when the pus is thick or loculated, surgical intervention is required. The empyema cavity is cleared of pus and adhesions, and a wide-bore tube inserted to allow optimal drainage. Surgical 'decortication' of the lung may also be required if gross thickening of the visceral pleura has developed and is preventing re-expansion of the lung.
Treatment of tuberculous empyema
Antituberculosis chemotherapy must be started immediately (see p. 538) and the pus in the pleural space aspirated through a wide-bore needle until it ceases to reaccumulate. Intercostal tube drainage is often required. In many patients no other treatment is necessary but surgery is occasionally required to ablate a residual empyema space.
Pneumothorax is the presence of air in the pleural space; it can either occur spontaneously, or result from iatrogenic injury or trauma to the lung or chest wall (see Box 13.90). The incidence of pneumothorax is highest in males aged 15-30 (see Fig. 13.54) where smoking, height and the presence of apical subpleural blebs appear to be the most important aetiological factors. Secondary pneumothorax is most common in older patients and those living in urban areas, and is associated with the highest mortality rates.
13.90 CLASSIFICATION OF PNEUMOTHORAX
Without evidence of overt lung disease. Air is usually introduced into the pleural space through rupture of a small subpleural emphysematous bulla or pleural bleb, or the pulmonary end of a pleural adhesion
Underlying lung disease, most commonly COPD and tuberculosis; also seen in asthma, lung abscess, pulmonary infarcts, bronchogenic carcinoma, all forms of fibrotic and cystic lung disease
Iatrogenic (e.g. following thoracic surgery or biopsy) or non-iatrogenic
Figure 13.54 Bimodal age distribution for hospital admissions for pneumothorax in England. The incidence of primary spontaneous pneumothorax peaks in males aged 15-30. Secondary spontaneous pneumothorax occurs mainly in males > 55 years.
Most episodes of primary spontaneous pneumothorax occur while the individual is at rest. Virtually all patients experience sudden-onset unilateral chest pain or breathlessness. In those with underlying chest disease, breathlessness can be severe and does not resolve spontaneously. In patients with a small pneumothorax the physical examination may be normal except for a tachycardia. A larger pneumothorax (> 15% of the hemithorax) results in decreased movement of the chest wall, a hyper-resonant percussion note and decreased or absent breath sounds.
A tension pneumothorax may develop if the communication between the pleura and lung persists but is small, and if it acts as a one-way valve which allows air to enter the pleural space during inspiration and coughing but prevents it from escaping. Very large amounts of air may be trapped in the pleural space and the intrapleural pressure may rise to well above atmospheric levels. This causes not only compression of the underlying deflated lung but also mediastinal displacement towards the opposite side, with consequent compression of the opposite lung and cardiovascular compromise (see Fig. 13.55C). Clinically, this results in rapidly progressive breathlessness associated with a marked tachycardia, hypotension and cyanosis.
Figure 13.55 Types of spontaneous pneumothorax. A Closed type. B Open type. C Tension (valvular) type.
Where the communication between the lung and pleural space seals off as the lung deflates and does not reopen, the pneumothorax is referred to as 'closed' (see Fig. 13.55A). In such circumstances the mean pleural pressure remains negative, spontaneous reabsorption of air and re-expansion of the lung occur over a few days or weeks, and infection is uncommon. This contrasts with an 'open' pneumothorax, where the communication fails to seal and air continues to transfer freely between the lung and pleural space (see Fig. 13.55B). An example of the latter is a bronchopleural fistula which, if large, can also facilitate the transmission of infection from the air passages into the pleural space, and empyema is a common complication. An open pneumothorax is most commonly seen following rupture of an emphysematous bulla, tuberculous cavity or lung abscess into the pleural space.
Figure 13.56 Haemopneumothorax. Chest radiograph of a patient with a right traumatic haemopneumothorax showing the characteristic visceral pleural line displaced from the chest wall (arrows), together with free fluid within the pleural cavity (not seen in patients with uncomplicated spontaneous pneumothorax).
The chest radiograph usually shows the sharply defined edge of the deflated lung with complete translucency between this and the chest wall and no lung markings (see Fig. 13.56). The practice of obtaining films in both inspiration and expiration has been abandoned as the latter do not improve the diagnostic yield. Care must be taken to differentiate between a large pre-existing emphysematous bulla and a pneumothorax; where any doubt exists, an emergency thoracic CT is indicated. Radiographs also show the extent of any mediastinal displacement and give information regarding the presence or absence of pleural fluid and underlying pulmonary disease. It is important to note that the absence of mediastinal shift on a chest radiograph does not exclude the presence of a tension pneumothorax, the diagnosis of which is largely clinical.
Figure 13.57 Management of spontaneous pneumothorax. (1) Immediate decompression is required prior to insertion of intercostal drain. (2) Aspirate in the 2nd intercostal space anteriorly in the mid-clavicular line using a 16 F cannula; discontinue if either resistance is felt, the patient coughs excessively, or > 2.5 litres of air are removed. (3) Beware: the post-aspiration chest radiograph is not a reliable indicator of whether a pleural leak remains and hence all patients should be told to attend again immediately in the event of noticeable deterioration.
It is now recognised that percutaneous needle aspiration of air is a simple, effective and well-tolerated alternative to intercostal tube drainage in young patients presenting with a moderate or large spontaneous pneumothorax (see Fig. 13.57). However, even a small pneumothorax may cause severe respiratory failure in patients with underlying chronic lung disease, and hence all such patients require intercostal tube drainage and inpatient observation. If required, an intercostal drain should be inserted in the 4th, 5th or 6th intercostal space in the mid-axillary line following blunt dissection through to the parietal pleura. The tube should be advanced in an apical direction, connected to an underwater seal or one-way Heimlich valve, and secured firmly to the chest wall. Clamping of the drain is potentially dangerous and never indicated. The drain should be removed 24 hours after the lung has fully reinflated and bubbling stopped. If bubbling in the underwater bottle stops prior to full reinflation, the tube is either blocked, kinked or displaced. All patients should receive supplemental oxygen as this accelerates the rate at which air is reabsorbed by the pleura.
Patients presenting with a spontaneous pneumothorax should not fly or dive for 3 months following full reinflation of the lung. They should also be advised to stop smoking and be informed about the risks of a further attack.
Recurrent spontaneous pneumothorax
Due to the seriousness of this condition surgical pleurodesis is recommended in all presenting with a secondary pneumothorax. This can be achieved by pleural abrasion or parietal pleurectomy at thoracotomy or thoracoscopy. In patients with their first primary spontaneous pneumothorax the risk of recurrence is high (approximately 30-50%), particularly in women and those who continue to smoke. Currently, chemical or surgical pleurodesis is recommended in all such patients following a second pneumothorax (even if ipsilateral) or in patients following their first pneumothorax where there is a persistent air leak (> 7 days). Patients who plan to continue activities that increase the risk of complications developing following a pneumothorax (e.g. flying or diving) should also undergo preventative treatment after the first episode of a primary spontaneous pneumothorax.
ASBESTOS-RELATED PLEURAL DISEASE
Benign pleural plaques
These areas of pleural thickening do not produce clinical symptoms and are usually identified on routine chest radiograph. They are often calcified and in the early stage are best seen on oblique films. They are most commonly observed on the diaphragm and anterolateral pleural surfaces (see Fig. 13.58).
Benign pleural effusion
This is considered to be a specific asbestos-related entity and may be associated with pleural pain, fever and leucocytosis. The pleural liquid may be blood-stained, and differentiation of this benign condition from a malignant effusion caused by mesothelioma can be difficult. The disease is self-limiting but may cause considerable pleural fibrosis which sometimes leads to breathlessness.
Diffuse pleural fibrosis
Diffuse pleural fibrosis is an important pleural manifestation of asbestos fibre inhalation and can restrict chest expansion and cause breathlessness. The restrictive defect caused by diffuse pleural fibrosis tends to progress and, like asbestosis and mesothelioma, qualifies a patient for industrial injury benefit in the UK.
Figure 13.58 Asbestos-related benign pleural plaques. Chest radiograph showing extensive calcified pleural plaques ('candle wax' appearance), particularly marked on the diaphragm and lateral pleural surfaces.
Mesothelioma of the pleura
Mesothelioma is a malignant tumour affecting the pleura (pleural mesothelioma) or, less commonly, the peritoneum (peritoneal mesothelioma). Blue asbestos (crocidolite) is thought to be the most potent cause of mesothelioma. A time lag of 20 years or more between asbestos exposure and the development of mesothelioma is typical. The incidence of this tumour has increased markedly over the past 20 years and this trend is predicted to continue until 2010. Asbestos exposure is also a recognised risk factor for the development of bronchogenic carcinoma.
Clinical presentation is frequently with chest pain. A pleural effusion, often blood-stained, may develop and cause breathlessness. Diagnosis rests on percutaneous or surgical biopsy of the pleura. Surgical resection is rarely indicated and most tumours are resistant to chemotherapy. Radiotherapy is, however, effective in preventing tumour growth through previous chest drain or biopsy sites. There is no curative treatment and chest wall pain is often difficult to control.
ISSUES IN OLDER PEOPLE
Spontaneous pneumothorax in the elderly is invariably associated with underlying lung disease and has a significant mortality. Surgical or chemical pleurodesis is advised in all such patients.
Rib fracture is a common cause of pleural-type pain in the elderly and underlying osteomalacia may contribute to poor healing, especially in the housebound with no exposure to sunlight.
Tuberculosis should always be considered and actively excluded in any elderly patient presenting with a unilateral pleural effusion.
Mesothelioma is more common in older than younger people due to a long latency between asbestos exposure (often > 40 years) and the development of disease.
Frail older people are particularly sensitive to the respiratory depressant effects of opiate-based analgesia and careful monitoring is required when using these agents for pleural pain.
DISEASES OF THE DIAPHRAGM
Abnormalities of the diaphragm are common and may be congenital or acquired. Both hemidiaphragms are displaced downwards and functionally impaired by diseases which cause pulmonary hyperinflation, notably emphysema. Diaphragmatic function can also be impaired in a variety of neuromuscular and connective tissue diseases (e.g. Guillain-Barré syndrome and polymyositis-see pp. 1180 and 1038) and with skeletal deformities such as thoracic scoliosis (see Box 13.91). Unilateral diaphragmatic palsy results from injury or damage to the phrenic nerve and should always alert the clinician to the possibility of intrathoracic malignancy (see below).
13.91 CAUSES OF ELEVATION OF A HEMIDIAPHRAGM
Phrenic nerve paralysis
Eventration of the diaphragm
Decrease in volume of one lung (e.g. lobectomy, unilateral pulmonary fibrosis)
Severe pleuritic pain
Large volume of gas in the stomach or colon
Large tumours or cysts of the liver
Congenital defects of the diaphragm can allow herniation of abdominal viscera. Posteriorly situated hernias through the foramen of Bochdalek are more common than anterior hernias through the foramen of Morgagni.
Eventration of the diaphragm
Abnormal elevation or bulging of one hemidiaphragm, more often the left, results from total or partial absence of muscular development of the septum transversum. Most eventrations are asymptomatic and are detected by chance on radiograph in adult life, but severe respiratory distress can be caused in infancy if the diaphragmatic muscular defect is extensive.
Other diaphragmatic abnormalities
These include defects of the oesophageal hiatus, congenital absence and duplication. The diaphragm may be involved in most primary muscle disorders.
Phrenic nerve damage leading to paralysis of a hemidiaphragm is most often produced by bronchial carcinoma but can also be idiopathic or the result of a number of neurological disorders, injury or disease of cervical vertebrae and tumours of the cervical cord. Trauma to the chest and neck, including road traffic and birth injuries, surgery and stretching of the phrenic nerve by mediastinal masses and aortic aneurysms may also lead to diaphragmatic paralysis.
Paralysis of one hemidiaphragm results in loss of approximately 20% of ventilatory capacity, but this is not usually noticed by otherwise healthy individuals.
Diagnosis is suggested by elevation of the hemidiaphragm on chest radiograph and is confirmed by screening or ultrasound examination, which show paradoxical movement of the paralysed hemidiaphragm on sniffing.
Other acquired diaphragmatic disorders
Hiatus hernia is common (see p. 775). Diaphragmatic rupture is usually caused by a crush injury and may not be detected until years later. Peripheral neuropathies of any type can involve the diaphragm, as can disorders affecting the anterior horn cells, e.g. poliomyelitis (see p. 1198). Connective tissue disorders such as systemic lupus erythematosus, and hypothyroidism and hyperthyroidism, may cause diaphragmatic weakness. Respiratory disorders which cause pulmonary hyperinflation, e.g. emphysema, and those which result in small stiff lungs, e.g. diffuse pulmonary fibrosis, decrease diaphragmatic efficiency and predispose to fatigue. Severe skeletal deformity, such as kyphosis, causes gross distortion of diaphragmatic muscle configuration and gross mechanical disadvantage.
DEFORMITIES OF THE CHEST WALL
Abnormalities of alignment of the dorsal spine and their consequent effects on thoracic shape may be caused by:
vertebral disease, including tuberculosis, osteoporosis and ankylosing spondylitis
neuromuscular disease such as poliomyelitis.
Simple kyphosis causes less pulmonary embarrassment than kyphoscoliosis.
Kyphoscoliosis, if severe, restricts and distorts expansion of the chest wall, causing maldistribution of the ventilation and blood flow in the lungs and impaired diaphragmatic function. Patients with severe deformity may develop type II respiratory failure (initially manifest during sleep), pulmonary hypertension and right ventricular failure; such patients can often be successfully treated with nocturnal and, if necessary, day-time, non-invasive ventilatory support (see p. 508).
In pectus excavatum (funnel chest) the body of the sternum, usually only the lower end, is curved backwards. The heart is displaced to the left and may be compressed between the sternum and the vertebral column; only rarely is there associated disturbance of cardiac function. The deformity may restrict chest expansion and reduce vital capacity. Operative correction is usually only indicated for cosmetic reasons.
Pectus carinatum (pigeon chest) is frequently caused by severe asthma during childhood. Very occasionally, this deformity can be produced by rickets or be idiopathic.
Beckett WS. Occupational respiratory diseases. N Engl J Med 2000; 342:406-413. Medline Similar articles Full article
Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345:1465-1472. Medline Similar articles Full article
Global Initiative for Chronic Obstructive Lung Disease (GOLD guidelines). National Institutes of Health, April 2001. Full article
Lim WS, Macfarlane JT. Hospital-acquired pneumonia. Clin Med 2001; 1:180-184. Medline Similar articles
Peppard PE, Young PT, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384. Medline Similar articles Full article
Smoking cessation guidelines and their cost-effectiveness. Thorax 1998; 53(suppl). Full article
Tattersfield AE, Harrison TW. Inhaled steroids for COPD? Thorax 2001; 56(suppl 11):ii2-6.
www.brit-thoracic.org.uk British Thoracic Society website; has access to guidelines from recent years including community-acquired pneumonia, COPD, asthma, selection of patients with cancer for operation, pulmonary embolism etc.
www.cancerlinks.usa.com/lung.htm An American site which provides a good synopsis of thoracic oncology.
www.cancernews.com/lung/htm An American site which provides very good links to other relevant sites and is constantly updated.
www.lunguk.org British Lung Foundation site.
www.sign.ac.uk/guidelines/published/index.htm/#cancer Royal College site outlining the guidelines for the management of lung cancer, asthma, sleep etc.
www.thoracic.org Contains useful information and guidelines for management.
www.thoraxjnl.com Journal of the British Thoracic Society on-line Full article
pages 569 - 574
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013363
For problems or suggestions concerning this service, please contact: [email protected] |
<urn:uuid:3f0f4919-de63-458a-95f6-e3ecaa721b83> | seed | Suture selection is dependent on the anatomic site, surgeon’s preference, and the required suture characteristics. No standardized sizing system or nomenclature is available for needles or needle holders; the main consideration in needle selection is to minimize trauma. The length, diameter, and curvature of the needle influence the surgeon’s ability to place a suture.
• Half-curved ski
• Compound curved
Characteristics of the ideal surgical needle and needle performance are reviewed in this section.
Ideal surgical needle characteristics
The ideal surgical needle has the following characteristics:
• High-quality stainless steel
• Smallest diameter possible
• Stable in the grasp of the needle holder (see the following image)
Interaction between the needle holder and suture needle. A: A needle holder of appropriate size for the needle; B: a needle holder that is too large for the needle—pressure applied by the needle holder leads to inadvertent straightening of the suture needle; C: a needle holder that is too small for the needle—the needle rotates around the long axis of the needle holder.
• Capable of implanting suture material through tissue with minimal trauma
• Sharp enough to penetrate tissue with minimal resistance
• Sterile and corrosion-resistant to prevent introduction of microorganisms or foreign materials into the wound
Needle performance characteristics and definitions
The following terms describe various characteristics related to needle performance:
• Strength – Resistance to deformation during repeated passes through tissue (ie, increased needle strength results in decreased tissue trauma); ultimate moment is the measure of maximum strength determined by bending the needle to 90°, and surgical-yield moment is the amount of angular deformation that can occur before permanent needle deformation occurs
• Ductility – Resistance (of a needle) to breakage under a given amount of deformation/bending
• Sharpness – Measure of the ability of the needle to penetrate tissue; factors affecting sharpness include the angle of the point and the taper ratio (ie, ratio of taper length to needle diameter)
• Clamping moment – Stability of a needle in a needle holder, determined by measuring the interaction of the needle body with the jaws of the needle holder
Anatomy of a needle
The anatomy of a needle includes the point, body, and swage (see the following image).
The point portion of the needle extends from the tip to the maximum cross-section of the body. Point types include the following (see the image below):
• Cutting needles (conventional, reverse, or side [spatula])
• Taper-point (round) needles
• Beveled, conventional cutting edge needles
• Blunt-point needles
Commonly used suture needles, with cross-sections of the needles shown at the point, body, and swage. A: A taper needle; B: a conventional cutting needle; C: a reverse cutting needle.
The cutting needle has at least 2 opposing cutting edges (the point is usually triangular). This type is designed for penetration through dense, irregular, and relatively thick tissues. The point cuts a pathway through tissue and is ideal for skin sutures. Sharpness is due to the cutting edges.
Conventional cutting needles have 3 cutting edges (triangular cross-section that changes to a flattened body). The third cutting edge is on the inner, concave curvature (surface-seeking).
In reverse-cutting needles, the third cutting edge is on the outer convex curvature of the needle (depth-seeking). These needles are stronger than conventional cutting needles and have a reduced risk of cutting out tissue. The needles are designed for tissue that is tough to penetrate (eg, skin, tendon sheaths, oral mucosa). Reverse-cutting needles are also beneficial in cosmetic and ophthalmic surgery, causing minimal trauma.
Side-cutting (spatula) needles are flat on the top and bottom surfaces to reduce tissue injury. These needles allow maximum ease of penetration and control as they pass between and through tissue layers. Side-cutting needles were designed initially for ophthalmic procedures.
Taper-point (round) needles penetrate and pass through tissues by stretching without cutting. A sharp tip at the point flattens to an oval/rectangular shape. The sharpness is determined by taper ratio (8-12:1) and tip angle (20-35°). The needle is sharper if it has a higher taper ratio and lower tip angle. The taper-point needle is used for easily penetrated tissues (eg, subcutaneous layers, dura, peritoneum, abdominal viscera) and minimizes the potential tearing of fascia.
Beveled, conventional cutting edge needles
A beveled, conventional cutting edge needle was developed with superior performance characteristics over those of other conventional cutting edge needles. It is composed of a unique stainless steel, ASTM 45500, that has been heat-treated after the curving process to enhance the resistance to bending. The angle of presentation of its cutting edge has been decreased to enhance needle sharpness. On the basis of the results of experimental and clinical studies done by Kaulbach et al, this needle is recommended for closure of lacerations. |
<urn:uuid:acbff6a4-d4b4-4105-a9b4-310a50c2ee28> | seed | Amniocentesis is a test that can be done during pregnancy to look for birth defects and genetic problems in the developing baby.
Culture - amniotic fluid; Culture - amniotic cells; Alpha-fetoprotein - amniocentesis
How the test is performed
Amniocentesis removes a small amount of fluid from the sac around the baby in the womb (uterus). It is most often done in a doctor's office or medical center. You do not need to stay in the hospital.
You will have a pregnancy ultrasound
first. This helps your health care provider see where the baby is in your womb.
Numbing medicine is then rubbed onto part of your belly. Sometimes, the medicine is given through a shot in the skin on the belly area.
The health care provider inserts a long, thin needle through your belly and into the womb. A small amount of fluid (about 4 teaspoons) is removed from the sac surrounding the baby.
The fluid is sent to a laboratory. Testing may include:
- Genetic studies
- Measurement of alpha-fetoprotein (AFP) levels
Results come back in about 2 weeks.
Amniocentesis is also used at times later in pregnancy to diagnose infection, to check to see if the baby’s lungs are developed and ready for delivery, and to remove excess fluid from around the baby when an abnormally high amount of fluid is made (polyhydramnios).
How to prepare for the test
Your bladder must be full for the ultrasound.
Before the test, blood may be taken to find out your blood type
and Rh factor. You may get a shot of medicine called RhoGAM if you are Rh negative.
Why the test is performed
Amniocentesis is most often offered to women who are at increased risk for bearing a child with birth defects. This includes women who:
- Will be 35 or older when they give birth
- Had a screening test result that shows there may be a birth defect or other problem
- Have had babies with birth defects in other pregnancies
- Have a family history of genetic disorders
You may choose genetic counseling before the procedure. This will allow you to:
- Learn about other prenatal tests
- Make an informed decision regarding options for prenatal diagnosis
- Is a diagnostic test, not a screening test
- Is 99% accurate for diagnosing Down syndrome
- Is usually done between 14 and 20 weeks
Amniocentesis can be used to diagnose many different gene and chromosome problems in the baby, including:
- Down syndrome
- Rare, metabolic disorders that are passed down through families
- Other genetic abnormalities, like trisomy 18
A normal result means:
- No genetic or chromosome problems were seen in your baby
- Bilirubin and alpha fetoprotein levels appear normal
Note: Even with normal results after an amniocentesis, a baby may still have other types of birth defects.
What abnormal results mean
An abnormal result may mean your baby has:
- A gene or chromosome problem, such as Down syndrome or other abnormalities
- Birth defects that involve the spine or brain, such as spina bifida
Talk to your doctor about the meaning of your specific test results.
- How the condition or defect may be treated during or after the pregnancy
- Special needs your child may have after birth
- What other options you have regarding maintaining your pregnancy
What the risks are
Risks are minimal, but may include:
Simpson JL, Holzgreve W, Driscoll DA. Genetic counseling and genetic screening. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: Normal and Problem Pregnancies. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2012:chap 10.
Simpson JL, Richards DA, Otao L, Driscoll DA. Prenatal genetic diagnosis. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: Normal and Problem Pregnancies. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone;2012:chap 11.
Susan Storck, MD, FACOG, Chief, Eastside Department of Obstetrics and Gynecology, Group Health Cooperative of Puget Sound, Bellevue, Washington; Clinical Teaching Faculty, Department of Obstetrics and Gynecology, University of Washington School of Medicine. Also reviewed by David Zieve, MD, MHA, Bethanne Black, and the A.D.A.M. Editorial team. |
<urn:uuid:2faa675a-fc86-4a07-88a2-5d192789ce87> | seed | Kidney Disease Biomarkers
Kidney Disease Biomarkers
Summary: This study will identify biomarkers (proteins and other molecules in the blood or urine) that may help scientists predict what kidney disease a patient has and whether a given patient would respond to particular therapies. The study will look for biomarkers in the blood and urine of patients with various kidney diseases and study of the effects of angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARB) on biomarkers. Blood and urine from healthy volunteers will be studied for comparison.
Healthy people and the following patients may be eligible for this study: adults with diabetic nephropathy 18 years of age and older; children with newly diagnosed clinical idiopathic nephrotic syndrome between 2 and 18 year of age; children and adults with glomerular disease (minimal change disease, focal segmental glomerulosclerosis, or collapsing glomerulopathy).
Participants undergo tests and procedures as follows:
Glomerular Disease: Adults with glomerular disease provide about four to six blood and urine samples over the course of 6 to 12 months. The samples are collected at the time of regularly scheduled visits for the NIH treatment protocol in which they are participating. Children provide only blood samples.
Chronic Kidney Disease: Patients with chronic kidney disease provide a blood and urine sample every 6 months for 3 years or more.
Angiotensin Antagonism: Patients with chronic kidney disease who are taking ACE inhibitors or ARBs stop their medicines for 4 weeks, while those who are not taking ACE inhibitors or ARBs begin one of the medicines. In general, patients just starting on the medications continue them after the study is completed, since they are beneficial for chronic kidney disease.
- Medication withdrawal group: Patients come to NIH for 2 successive days at the beginning of the study for blood and urine tests (including one 24-hour urine collection) and to receive iothalamate (a chemical used to measure kidney function). Iothalamate is delivered over 24 hours through a needle placed in the abdomen (or elsewhere) via a pump similar to pumps that some diabetics use to deliver insulin. Patients then stop taking their ACE inhibitor or ARB medication. They monitor their blood pressure every day and return to NIH after 1, 2 and 4 weeks for blood tests. During week 4, the iothalamate infusion is repeated, and blood and urine samples are collected as at the beginning of the study. Patients then resume taking their ACE inhibitor or ARB once a day with the dose being increased at 2-week intervals. They come to NIH weekly after 1 week and then every other week for blood tests. Four weeks after reaching the highest FDA-recommended dose of medication tolerated, the iothalamate infusion and blood and urine collections are repeated.
- Medication induction group: At the beginning of the study, patients have the iothalamate infusion and blood and urine collections described above and then begin to take either an ACE inhibitor or ARB. The dose is increased after 2 weeks. Patients monitor their blood pressure every day. After being on the highest dose for 4 weeks, patients repeat the iothalamate infusion and blood and urine collections. The study is then complete and they are provided a 2-month supply of medicine to take home.
Information is gathered on symptoms, treatments, and results of past laboratory tests of all patients. Healthy volunteers provide blood and urine sample collections every month or every other month for up to four collections to be used for biomarker studies and the screen for common chronic diseases.
Idiopathic Nephrotic Syndrome
Focal Segmental Glomerulosclerosis
|Study Design:||Time Perspective: Prospective|
|Official Title:||Kidney Disease Biomarkers|
|Study Start Date:||November 2005|
|Estimated Study Completion Date:||December 2014|
There is a pressing need to develop biomarkers for renal disease, which might assist in diagnosis and prognosis and might provide endpoints for clinical trials of drugs designed to slow progression of renal insufficiency. We propose to study potential biomarkers in five populations. First, we will study remittive therapy for glomerular disease (sample size up to 40), enrolling children with idiopathic nephrotic syndrome (N=20) and adults with minimal change, focal segmental glomerulosclerosis, and collapsing glomerulopathy (N=20). We will collect periodic urine samples as these patients receive remittive therapy with glucocorticoids or other agents. We will also study up to 10 healthy adult volunteers. We will carry out targeted urine proteomic studies, measuring levels of glomerular cell markers and cytokines, and we will profile urine proteins using mass spectrometry. Our goals are to identify markers of particular disease entities and of steroid responsiveness and to explore whether biomarkers contribute to the histologic sub-classification of these diseases. Second, we will study up to 40 adults with progressive chronic kidney disease of various etiologies and glomerular filtration rate < 60 ml/min/1.73m2. We will study blood and urine samples, using both targeted and profiling approaches. Our goal is to identify biomarkers that correlate with progressive loss of glomerular filtration function, which is a functional correlate of progressive renal fibrosis. Third, we will study up to 40 adults, primarily with diabetic nephropathy, who start or stop angiotensin antagonist therapy (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) and compare urine proteomic profiles on therapy and off therapy (4 week interval). Our goal is to identify potential biomarkers that correlate with the beneficial anti-fibrotic effects of these agents. Fourth, we wish to define possible sex differences in urine exosome proteins, obtained from healthy volunteers, who are hospitalized for six days for administration of a standard diet and collection of research urine samples. Fifth, we wish to determine whether salt intake influences urine exosome proteins, obtained from healthy volunteers. These subjects will be hospitalized for 12 days during which time they will be placed sequentially on a high salt diet and a low salt diet, with collection of research urine samples and blood pressure monitoring. Proteomic analysis in these studies will take several approaches, including mass spectrometry of urinary peptides, analysis of urinary exosomes, and immunologic detection and quantification of candidate proteins in urine and blood.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00255398
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Jeffrey B Kopp, M.D.||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)| |
<urn:uuid:545abf52-070c-4741-83a3-da45b893c9ba> | seed | Why albumin may not workBMJ 1998; 317 doi: http://dx.doi.org/10.1136/bmj.317.7153.240 (Published 25 July 1998) Cite this as: BMJ 1998;317:240
Starling's principle is often represented as the leakage of fluids from the arterial end of capillaries, where the hydrostatic pressure is greater than the oncotic pressure (derived from the plasma proteins), and the reabsorption of fluid into the venous end, where the oncotic pressure exceeds the hydrostatic pressure. A small excess of fluid in the interstitial space—when filtration from the capillaries is greater than reabsorption—is dealt with by lymphatic drainage from the interstitial space. The rationale for giving albumin solutions rather than crystalloid solutions in cases of hypovolaemic shock is that fluid reabsorption from the interstitial space is enhanced, and fluid therefore remains in the vascular system for longer.
But in recent years the assumed reabsorption of fluid at the venous end of capillaries has been challenged. There is now good evidence to show that, except in the gut and the renal circulation, there is no sustained reabsorption of fluid at the venous end of capillaries. Instead, there is a small constant level of filtration from the capillaries, restrained by the osmotic pressure of the plasma proteins. In some rare circumstances—for example, in hypovolaemic shock—there is a transient reabsorption of fluid, but this lasts for only a few minutes and it amounts to an “internal transfusion” of about 500 ml of fluid over 15 minutes.
The production of life threatening pulmonary oedema begins when the loss of protein and fluid from the blood vessels exceeds the volume of fluid that can be drained from the interstitial space by the lymphatics. In some disease states or when tissue is damaged, as in severe burns, the capillary walls become very much more permeable under the influence of direct cellular damage and from inflammatory mediators. The filtration of fluids, together with proteins, out into the interstitial space is greatly increased and cannot be matched by lymphatic drainage. The filtration rate may be further increased by a fall in the hydrostatic pressure in the interstitial space as a result of tissue damage, so that even more fluid is sucked out of the capillaries.
Conventionally, colloids such as albumin are administered to these patients in an attempt to maintain their intravascular volume, but because of the increased permeability of the vessels, the albumin solution becomes much less effective in maintaining plasma volume than in healthy individuals who have normal vessel permeability. Thus the rationale for administering albumin solutions becomes much less clear. In disease states such as the nephrotic syndrome, for example, there is new evidence to show that protein is lost not only from the renal circulation owing to greater permeability of the renal vessels, but also from the rest of the systemic circulation. This being the case, it is difficult to see how the administration of albumin could ever replace the deficit without causing further problems. |
<urn:uuid:34a5d629-5384-40bb-93ca-b45f0eafb3f8> | seed | Lapatinib is a clinically relevant receptor tyrosine kinase inhibitor that binds to the kinase domains of ERBB1 and ERBB2. ERBB1 and ERBB2 have previously been shown to act upstream of RAS proteins in radiation-induced signal transduction pathways and to play a role in protecting tumor cells from the toxic effects of ionizing radiation. Lapatinib blocked radiation-induced tyrosine phosphorylation of ERBB1, ERBB2 and ERBB3 in parental HCT116 cells and in HCT116 cells expressing H-RAS V12 () (Caron et al, 2005a
; Caron et al, 2005b
). Inhibition of ERBB family receptor function correlated with Lapatinib inhibiting radiation-induced activation of ERK1/2 and AKT (). Lapatinib radiosensitized parental HCT116 cells expressing K-RAS D13 and HCT116 cells expressing H-RAS V12 (). These findings demonstrate that in the presence of expressed mutated active K-RAS and H-RAS proteins, the pan-ERBB receptor inhibitor Lapatinib can act as a radiosensitizer in HCT116 cells.
Lapatinib blocks radiation-induced activation of ERBB1, ERBB2, ERBB3 and activation of ERK1/2 and AKT in HCT116 cells
The development of resistance to ERBB receptor inhibitors has been observed clinically. In many of these studies, resistance to the ERBB tyrosine kinase inhibitor has been due to mutation of the receptor within its catalytic domain so that the inhibitor no-longer can bind and inhibit receptor tyrosine kinase activity. We initially cultured parental HCT116 cells in 10 µM Lapatinib, a concentration which is below the Cmax for this drug in patients although the average plasma profile of a 1500 mg QD dose peaks at ~2.5 µM; within 72h, many cells (> 95%) became detached and died from this drug exposure (data not shown). Cells were cultured in the presence of Lapatinib for a further ~ 3 months until an essentially homogeneous population of cells grew out from the survivors that were adapted to Lapatinib.
In assays to determine cell survival in the absence of serum with a Lapatinib challenge; Lapatinib adapted cells survived to a significantly greater extent than parental cells (; Figure S1
in the presence of serum). Lapatinib adapted cells grew more quickly than parental cells in the presence or absence of Lapatinib (Figure S2
). In general agreement with these findings, Lapatinib resistant cells had a greater level of survival than parental cells in colony formation assays (). When Lapatinib adapted cells were cultured in the absence of Lapatinib for > 10 flask passages (~2 months), no reversion of the resistant phenotype was observed back to the parental phenotype (). Lapatinib adapted cells were cross resistant to multiple chemotherapeutic agents including VP-16, UCN-01, Taxotere, Oxaliplatin and Doxorubicin (Figures S3–S5
). Resistance to Taxotere appeared to be somewhat less than to the other agents. As drug efflux could represent a mechanism of Lapatinib adaptation, particularly as we observed cross-resistance to multiple cytotoxic therapeutic drugs, we performed flow cytometric and immunoblotting analyses to determine the expression of ABC and MDR plasma membrane drug transporters. Little change in the protein levels of any membrane drug transporter was observed, however, comparing wild type and Lapatinib adapted HCT116 cells, arguing that changes in drug efflux was unlikely to be a major component of Lapatinib resistance mechanism under investigation (Fisher and Dent, Unpublished observations).
The generation of Lapatinib resistant HCT116 cells
Based on the above findings, we examined in molecular detail the role of ERBB receptors in Lapatinib resistance. Co-expression of dominant negative ERBB1 (CD533) and dominant negative ERBB2 (CD572) proteins suppressed basal and EGF-stimulated tyrosine phosphorylation of ERBB1 and ERBB2 in immunoprecipitates from parental HCT116 cells (). Co-expression of dominant negative ERBB1 (CD533) and dominant negative ERBB2 (CD572) suppressed basal and EGF-stimulated tyrosine phosphorylation of ERBB1 and ERBB2 in immunoprecipitates from parental HCT116 cells (). To our surprise, however, while co-expression of ERBB1 (CD533) and ERBB2 (CD572) acted in a very similar manner as Lapatinib to inhibit ERBB receptor tyrosine phosphorylation, the dominant negative receptors did not recapitulate the toxic effects of Lapatinib in serum-starved parental or adapted cells (). Further analyses revealed that although parental and Lapatinib adapted cells expressed similar total cellular amounts of ERBB1 as judged by immunoblotting of whole cell lysate, and that stimulated ERBB1 phosphorylation in response to EGF was inhibited equally well by Lapatinib in both parental and adapted cells, the plasma membrane associated levels of ERBB1 in adapted cells were considerably lower in adapted than those in parental cells. These findings were reflected also in a reduced ability of EGF to stimulate ERK1/2 signaling in adapted cells compared to parental cells () Collectively, these findings strongly argue that an ERBB1 receptor mutation has not occurred in Lapatinib adapted HCT116 cells to make these cells resistant to Lapatinib toxicity.
Molecular inhibition of ERBB1 and ERBB2 does not recapitulate the effects of Lapatinib in HCT116 cells: Lapatinib resistant cells express less cell surface ERBB1 than parental cells
We then examined the activities of known signaling pathways whose activities could become altered in the adapted HCT116 cell line. However, almost no difference in basal activities of any pathway, or in the basal activity of any pathway in the presence of Lapatinib, could be observed between parental and adapted cells (data not shown). In HCT116 cells expressing H-RAS V12 and effector mutants of H-RAS V12 that had been characterized to specifically activate: the Raf-MEK-ERK pathway (S35); the RAL-GDS pathway (G37); the PI3K-AKT pathway (C40), only H-RAS V12 expression, but not expression of any H-RAS V12 single point mutant that activated a single signaling pathway, suppressed Lapatinib toxicity (). In contrast to our findings with Lapatinib, for example, expression of H-RAS V12, H-RAS V12 S35 and H-RAS V12 C40, but not H-RAS V12 G37, acted to protect HCT116 cells from the toxic effects of radiation in colony formation assays (). After a 1 Gy radiation exposure, approximating to the shoulder of the survival curve, no statistically significant difference between cell survival for cells expressing H-RAS V12 and H-RAS V12 C40 was observed. Cells expressing H-RAS V12 S35 had a greater level of survival than vector control transfected cells however these cells had significantly less survival than cells expressing H-RAS V12 C40 (After a 1 Gy exposure: vector survival 0.70 ± 0.04; H-RAS V12 S35 survival 0.82 ± 0.04; H-RAS V12 C40 survival 0.90 ± 0.03, p < 0.05 difference between each value). The survival of cells expressing H-RAS V12 S35 was not significantly different from wild type HCT116 cells expressing K-RAS D13.
Lapatinib resistance requires multiple pathways downstream of RAS: lack of involvement of “classical” effectors of resistance
In general agreement with our short-term cell killing data using Lapatinib exposure and serum starvation, expression of constitutively active MEK1 EE and constitutively active AKT, to a greater extent than the individual activated kinases, suppressed Lapatinib toxicity in parental cells (). In contrast to the use of activated proteins, expression of dominant negative AKT and/or dominant negative MEK1 did not restore Lapatinib sensitivity in adapted cells (Figure S6
). As inhibition of ERK1/2 and AKT did not restore Lapatinib sensitivity, we explored whether other mechanisms of Lapatinib resistance were present in HCT116 cells.
Lapatinib resistance has been linked to re-activation of the estrogen receptor in breast cancer cells and the estrogen receptor is known to be expressed in colon cancer cells (Xia et al, 2006
; Cho et al, 2007
). However, incubation of adapted cells with the ER inhibitor Tamoxifen did not restore Lapatinib sensitivity (). Similarly, inhibition of NFκB function by over-expression of the IκB super repressor (dominant negative IκB) or inhibition of STAT1 and STAT3 function by expression of a dominant negative STAT3 protein did not restore Lapatinib sensitivity in adapted cells. In some cell types, including colon cancer cells, Src family nonreceptor tyrosine kinases and the insulin like growth factor receptor tyrosine kinase have been linked to the transformed phenotype. However, inhibition of neither Src family kinases using the inhibitor PP2 nor IGF1 receptor function using the inhibitor PPP restored Lapatinib sensitivity (). Of note, inhibition of the IGF1 receptor with PPP caused significant toxicity in parental cells that was abolished in Lapatinib adapted cells arguing that adapted cells were also cross resistant to agents that inhibit the function of other receptor tyrosine kinases that are known to compensate for ERBB1 survival signaling.
Based on our relative lack of success at precisely defining the signaling pathways downstream of ERBB1 and ERBB2 that could be mediating Lapatinib adaptation, we next determined the proximal downstream molecular mechanisms by which serum starved and Lapatinib treated cells die, and the mechanisms by which adaptation was gained. Adapted HCT116 cells expressed higher levels of MCL-1, BCL-XL and p53 than parental cells; these cells expressed lower levels of BAX and BAK than parental cells (, upper blotting section). No obvious changes in the protein expression of CD95, FAS ligand, pro-caspase 8, pro-caspase 9, pro-caspase 3, Apaf-1, A10, Smac/DIABLO, c-FLIP-s, XIAP, BCL-2, BID, BIM, NOXA or PUMA were noted based on immunoblotting analyses (data not shown). Based on the established concept of the so called “apoptotic rheostat,” in which BCL-2 family proteins act in a dynamic balance to suppress the pro-apoptotic signals generated by BH3 domain proteins such as BAX and BAK, our data suggest that adapted cells could be more resistant to Lapatinib than parental cells because they express more of the mitochondrial protective proteins BCL-XL and MCL-1 and that they express less of the mitochondrial toxic proteins BAX and BAK.
Lapatinib resistance is mediated by increased expression of MCL-1, decreased activation of BAK and mutation of p53
As we observed changes in the expression of proteins who act at the mitochondrion to modulate mitochondrial stability, we next determined whether activation of caspase proteases, and specifically pro-caspase 9, played a role in Lapatinib toxicity. To our surprise, inhibition of caspase function only modestly suppressed Lapatinib toxicity in parental cells treated with Lapatinib (, lower graphical section). In contrast, inhibition of caspases significantly reduced serum-withdrawal –induced cell killing (Figure S7
). Inhibition of cathepsin, calpain and serine protease function also caused similar very modest effects on promoting cell survival in Lapatinib treated cells (data not shown). Over-expression of BCL-XL abolished Lapatinib toxicity in parental cells (). Finally, we tested whether apoptosis inducing factor (AIF) played a role in Lapatinib toxicity. Knock down of AIF expression reduced Lapatinib toxicity in parental HCT116 cells, and knock down of AIF expression combined with pan-caspase inhibition almost eliminated Lapatinib toxicity ().
Knock down of MCL-1 expression, to a greater extent than that of BCL-XL, reverted Lapatinib sensitivity in adapted cells (). In we noted that the expression levels of pro- and anti-apoptotic proteins were altered comparing parental and adapted HCT116 cells. In parental cells, Lapatinib treatment caused release of AIF into the cytosol whereas in adapted cells, no AIF release was observed (). Thus the induction of cell killing by Lapatinib in parental cells correlated with activation of BAK and BAX. Knock down of BAK activation in adapted cells significantly reduced the reversion of their resistant phenotype by reduced MCL-1 expression ().
Knock down of BAK re-reverts Lapatinib adapted cells after siMCL-1 exposure
In , we noted that the expression of p53 was elevated, even though the protein levels of a p53 target protein, BAX, were reduced. In cells that express a mutated p53 protein, the expression of total p53 within a cell is often noted to be elevated. Thus, parental HCT116 cells which express a wild type p53 protein may have in part survived and adapted to Lapatinib exposure by mutating one of their p53 alleles.
Native p53 proteins were immunoprecipitated from parental and Lapatinib resistant HCT116 cells using an antibody that specifically recognizes mutated forms of p53, as judged by recognition of mutant p53 tertiary structure within the DNA binding domain of p53. The p53 proteins were then separated on denaturing SDS PAGE and immunoblotted; Lapatinib resistant cells, but not parental cells, immunoprecipitated a greater amount of “mutant” p53 (). Total poly A mRNA was isolated from adapted HCT116 cells and amplified and sequenced using primers specific for the DNA binding domain of p53. We noted, however, that adapted HCT116 cells did not contain a mutation in p53, suggesting that either our antibody was recognizing an alteration in p53 tertiary conformation in adapted cells unrelated to p53 mutation or that p53 mutation had occurred in a domain unrelated to the DNA binding domain of p53 but that was affecting the tertiary conformation of the DNA binding domain. These findings argue that Lapatinib adaptation in HCT116 cells is mediated by changes in the expression of multiple mitochondrial protective proteins, rather than mutation of ERBB receptors. |
<urn:uuid:c1beed1e-788b-4a32-a66f-3d180a4adb6d> | seed | Disorders of the vestibular system are common. Dizziness is a symptom that frequently results from vestibular disorders and affects up to 36% of the population (Gopinath et al., 2009). More specifically, up to 7% of people experience vertigo related to a vestibular disorder within their lifetime (Neuhauser and Lempert, 2009). Bilateral partial or complete vestibular loss, sometimes referred to as bilateral vestibular hypofunction (BVH) or Dandy’s (1941) syndrome, is less often identified than unilateral vestibular loss as a cause of dizziness; however, it remains a significant clinical problem. In a review of the office records of over 6000 patients from an academic dizziness practice, 4% of patients were diagnosed with BVH (Zingler et al., 2009).
A variety of conditions can produce BVH, and in many cases the cause of the disease is unknown. Table 1 lists causes of BVH; the three most common etiologies that have been documented are exposure to ototoxic antibiotics, Menière’s disease, and encephalitis (Rinne et al., 1998; Gillespie and Minor, 1999; Zingler et al., 2009). It is also likely that a variety of autoimmune disorders cumulatively result in an appreciable fraction of cases of BVH (Rinne et al., 1998; Gillespie and Minor, 1999; Zingler et al., 2009). While BVH resulting from autoimmune disorders (Hughes et al., 1984), ototoxic antibiotics (Reiter et al., 2011), and traumatic injury such as blast exposure (Akin and Murnane, 2011) can develop quickly, that resulting from Menière’s disease usually develops slowly over time, as the disease typically first manifests on one side, with involvement of the contralateral ear in a subset of patients after a number of years (Sumi et al., 2011). The occurrence of BVH is sometimes associated with cerebellar ataxia, which may be a distinct syndrome that is associated with an impaired visually enhanced vestibulo-ocular reflex (Szmulewicz et al., 2011).
Even following complete loss of labyrinthine inputs, some of the signs and symptoms resulting from BVH diminish over time. Other clinical problems, however, are permanent. This review describes and contrasts the short- and long-term consequences of BVH, as well as the possible neural mechanisms that mediate the process of compensation. Although a large number of reviews have addressed compensation following a unilateral labyrinthectomy (e.g., Dieringer, 1995; Vidal et al., 1998; Curthoys, 2000; Gliddon et al., 2005; Cullen et al., 2009; Dutia, 2010), far less is known about recovery following the complete loss of vestibular inputs. Nonetheless, some existing information does provide insights into the mechanisms underlying this process, which will be discussed along with the shortfalls in the data. In addition, this review evaluates new clinical tools and strategies that may aid patients with BVH.
Compensation Following Bilateral Vestibular Dysfunction: Studies in Animals
Effects of Removal of Vestibular Inputs on Animal Behavior and Physiological Responses
Research on animals has provided a better opportunity than clinical studies to understand compensation following the bilateral loss of vestibular inputs, as lesions can be created at a prescribed time and the effects on behavior or physiological responses can be studied systematically. Macpherson and colleagues documented the effects of a bilateral labyrinthectomy on postural stability in cats (Thomson et al., 1991; Inglis and Macpherson, 1995; Stapley et al., 2006; Macpherson et al., 2007). The animals were severely impaired for the first 2 days after lesions, after which they could stand unsupported on a tilt platform and walk in a staggering fashion (Thomson et al., 1991). Within a week, animals could jump to and from a chair, ataxia was profoundly reduced, and locomotion speeds were much faster (Thomson et al., 1991). Although limb muscle responses to linear translations had normal patterning after the loss of vestibular inputs, hypermetria was present for the first 10 days (Inglis and Macpherson, 1995). These observations show that a rapid compensation process occurs during the first 7–10 days following the removal of labyrinthine signals, which then slows considerably. However, some postural deficits were enduring. For example, balance was permanently destabilized when the head was turned (Thomson et al., 1991; Stapley et al., 2006), due to the fact that at peak yaw head velocity the lesioned cats produced an unexpected burst in extensors of the contralateral limbs that thrust the body to the ipsilateral side (Stapley et al., 2006). The magnitude of the counterproductive limb extension was largest during the first few days after lesions, but the response remained present when the experiment was discontinued ∼40 days after the removal of vestibular inputs.
Other groups have also examined the effects of a bilateral labyrinthectomy on postural responses. It was demonstrated that limb extension during falling, which is critical for normal landing, is permanently lost following a bilateral labyrinthectomy (Watt, 1976). However, righting responses did recover over time (Igarashi and Guitierrez, 1983). In addition, there were permanent impairments in the ability to keep to a straight course in darkness, although veering was minimal when visual cues were present (Marchand and Amblard, 1990). In another study, tonic activity of some trunk muscles, including the abdominal musculature, remained elevated for the entire 30-day recording period following a bilateral labyrinthectomy (Cotter et al., 2001), although muscle activity was highest during the first week following lesions.
Postural alterations that place the long axis of the body below the heart, such as head-up tilts in quadrupeds or standing in man, tend to produce a reduction in venous return to the heart (Yavorcik et al., 2009) that requires rapid responses of the autonomic nervous system to avoid an alteration in blood pressure (Rushmer, 1976; Hall, 2011). The responses include vasoconstriction in the portion of the body below the heart to prevent peripheral blood pooling (Wilson et al., 2006; Yavorcik et al., 2009). The top panel of Figure 1B illustrates that in a vestibular-intact animal, blood flow to the hindlimb decreased below basal levels within 10 s of a sudden 60° head-up tilt. However at the onset of the tilt, blood flow to the hindlimb increased because of the effects of gravity; this increased blood flow would have persisted if vasoconstriction did not occur (Wilson et al., 2006; Yavorcik et al., 2009). As a consequence of the autonomic nervous system responses during large head-up rotations, blood pressure remains relatively stable during the postural alteration (see Figure 1A; Jian et al., 1999).
Figure 1. Arterial blood pressure (A) and femoral artery blood flow (B) recorded in a conscious cat during a 60° head-up tilt before (top) and a few days subsequent (bottom) to a combined bilateral labyrinthectomy and vestibular neurectomy. When the labyrinth was intact (top), blood pressure remained relatively stable during the head-up rotation. Although femoral artery blood flow initially increased during the movement due to the effects of gravity, flow quickly dropped due to peripheral vasoconstriction. However, following the removal of vestibular inputs (bottom), a drop in blood pressure occurred at the onset of the head-up rotation. In addition, the gravity-induced increase in blood flow in the femoral artery was larger and more prolonged, because peripheral vasoconstriction was delayed. Data in (A) from Jian et al. (1999); data in (B) from Wilson et al. (2006).
Following a bilateral labyrinthectomy, the attenuation in hindlimb blood flow that ordinarily occurs during 60° head-up rotations was delayed and diminished (Wilson et al., 2006; Yavorcik et al., 2009), as shown in the bottom panel of Figure 1B. In addition, blood pressure became unstable at the onset of head-up tilts (Jian et al., 1999), as illustrated in the bottom panel of Figure 1A. However, these deficits were only prominent for a week after the loss of vestibular inputs, at which time blood pressure was stable during postural alterations (Jian et al., 1999). A caveat is that the animals could have expected to be tilted quite often when restrained in the rotating device, such that they were particularly vigilant during the experimental sessions. Animals may not always maintain such a high level of attention to environmental cues regarding body position in space outside of laboratory conditions. Thus, BVH could result in a long lasting deficit in correcting blood pressure, but this deficit only becomes apparent when the level of alertness diminishes.
Eye movements in response to head rotations performed in the dark are permanently abolished in animals following a bilateral labyrinthectomy (Baarsma and Collewijn, 1974; Barmack et al., 1980; Waespe and Wolfensberger, 1985; Waespe et al., 1992). The rapid component of eye movements during head rotations in a lighted environment is also lost, but the slow component driven by visual inputs persists (Baarsma and Collewijn, 1974; Barmack et al., 1980; Waespe and Wolfensberger, 1985). Although eye movements triggered by a slowly moving visual field (optokinetic responses) were retained following the loss of labyrinthine inputs (Baarsma and Collewijn, 1974; Barmack et al., 1980), optokinetic after nystagmus was eliminated (Cohen et al., 1973; Waespe and Wolfensberger, 1985). These observations show that unlike postural and autonomic responses that recover rapidly following the loss of labyrinthine inputs, vestibular-related eye movements are permanently affected.
Following chemical damage of both labyrinths, rodents have impaired navigational abilities and diminished spatial memory (Blair and Sharp, 1995; Stackman and Herbert, 2002; Wallace et al., 2002; Russell et al., 2003a; Smith et al., 2005; Baek et al., 2010). Furthermore, the spatially related modulation of activity of neurons believed to be critical for spatial cognition, including place cells in the hippocampus (Russell et al., 2003b) and head direction cells in the lateral mammillary nucleus, postsubiculum, and anterior thalamic nuclei (Stackman and Taube, 1997; Taube, 1998; Muir et al., 2009; Shinder and Taube, 2010), is lost following bilateral vestibular lesions. The effects of removal of labyrinthine inputs on navigational abilities showed little recovery even when animals were tested 14 months after injury (Baek et al., 2010). Thus, the cognitive deficits produced by BVH do not appear to dissipate over time.
Effects of Removal of Vestibular Inputs on Activity of Vestibular Nucleus Neurons
Although an initial report indicated that the firing rate of vestibular nucleus neurons is depressed for a prolonged period following a bilateral labyrinthectomy (Ryu and McCabe, 1976), more recent studies showed that spontaneous activity of vestibular nucleus units returns within hours following bilateral elimination of labyrinthine inputs, and is nearly identical to prelesion levels within less than a week (Waespe et al., 1992; Ris and Godaux, 1998; Miller et al., 2008). For example, Figure 2 compares the spontaneous activity and firing regularity (coefficient of variation, the SD of interval between spikes divided by mean interval between spikes) of neurons in the inferior and caudal medial vestibular nuclei of a conscious cat before and in the first week after a combined labyrinthectomy and vestibular neurectomy (Miller et al., 2008). The firing rates before and after elimination of vestibular inputs [30 ± 2 (SEM) vs. 32 ± 2 spikes/s, respectively], as well as the coefficient of variation of firing rates (0.78 ± 0.05 vs. 0.76 ± 0.05), were virtually identical in the two populations. Ris and Godaux (1998) conducted a longitudinal study of firing rates of vestibular nucleus neurons in conscious guinea pigs before and at 1 h, 1 day, and 1 week after a bilateral vestibular neurectomy. In control animals, no silent vestibular nucleus units could be detected; 53% of the cells were inactive at 1–5 h after a bilateral labyrinthectomy, and ∼35% were inactive at 1 day after lesions. By a week after elimination of labyrinthine signals, no silent neurons could be observed in the vestibular nuclei (Ris and Godaux, 1998).
Figure 2. The rate and coefficient of variation (CV) of spontaneous activity of vestibular nucleus neurons before (prelesion) and in the first week following (postlesion) removal of vestibular inputs through a bilateral vestibular neurectomy in one animal. Data from Miller et al. (2008).
Although vestibular nucleus neurons are insensitive to horizontal rotations following the removal of labyrinthine inputs (Ris and Godaux, 1998), the firing rates of some cells can be modulated by 15° tilts in vertical planes (Yates et al., 2000; Miller et al., 2008). In conscious cats, such response modulation was uncommon (7/168 neurons recorded in three animals; Miller et al., 2008); however, 18/67 neurons recorded from the vestibular nuclei of decerebrate cats that had undergone a combined bilateral labyrinthectomy and vestibular neurectomy over a month previously responded to vertical rotations (Yates et al., 2000). The response properties of vestibular nucleus neurons to vertical rotations in animals lacking labyrinthine inputs are illustrated in Figure 3. Figure 3A compares the vector orientations for responses to vertical tilts in animals lacking vestibular inputs to those observed in labyrinth-intact decerebrate and conscious animals tested using the same tilt table. In both decerebrate and conscious cats lacking vestibular inputs, the response vector orientations of most neurons were near the pitch plane (mean deviation from the pitch axis of 15°). In contrast, in labyrinth-intact cats, the response vector orientations were much nearer the roll axis; the mean vector deviation from the pitch axis was 50° in conscious animals (Miller et al., 2008) and 57° in decerebrate animals (Jian et al., 2002). The differences in response vector orientations between labyrinth-intact and labyrinthectomized animals were shown to be significantly different (p < 0.01) using a non-parametric one-way ANOVA (Kruskal–Wallis test). Figure 3B illustrates the dynamic properties of the responses of vestibular nucleus neurons to vertical tilts in labyrinthectomized animals. The response gain for units was relatively constant across stimulus frequencies, whereas the response phase was near stimulus position at low frequencies, and lagged position slightly at higher frequencies. Such properties are consistent with the responses being elicited by graviceptive inputs. In contrast, a large fraction of neurons in the vestibular nuclei of labyrinth-intact cats have responses to vertical tilts that are similar to those of semicircular canals: the response gain increases with advancing stimulus position and the response phase is near stimulus velocity (Jian et al., 2002; Miller et al., 2008). The marked differences in the responses to tilt of vestibular nucleus neurons in labyrinth-intact and labyrinthectomized animals show that the activity recorded in the latter group is not due to failure to eliminate inputs from the inner ear. Responses to vertical rotations were also recordable in bilaterally labyrinthectomized animals from additional regions of the central nervous system that receive vestibular inputs, particularly the cerebellar fastigial nucleus (Yates and Miller, 2009).
Figure 3. (A) The difference from the pitch axis in the response vector orientations for vestibular nucleus neurons determined using rotations in vertical planes. Response vector orientations aligned with the pitch axis have a vector difference of 0°, whereas those aligned with the roll axis have a vector difference of 90°. Left column: response vector orientations determined for neurons recorded in animals with a bilateral vestibular labyrinthectomy (LABX). Blue symbols represent data from decerebrate animals, and red symbols indicate findings from conscious cats. Middle column: response vector orientations determined in labyrinth-intact conscious animals. Right column: response vector orientations determined in labyrinth-intact decerebrate animals. Horizontal lines indicate mean values, and error bars designate one SEM. The response vector orientations for most neurons in animals lacking vestibular inputs were aligned near the pitch axis, whereas those in decerebrate and conscious labyrinth-intact animals were nearer the roll axis. (B) Bode plots indicating the response dynamics of neurons in animals lacking labyrinthine inputs. Response gain and phase are plotted with respect to stimulus position. Blue lines represent data from decerebrate animals, and red lines indicate findings from conscious cats. Data from Yates et al. (2000); Miller et al. (2008).
Mechanisms Responsible for Activity in the Central Vestibular System Following the Loss of Labyrinthine Inputs
The rapid restoration of vestibular nucleus neuronal activity following a bilateral labyrinthectomy is likely due to an increase in the relative influence of non-labyrinthine excitatory inputs to the vestibular nuclei. The injection of retrogradely transported tracers into the inferior and caudal medial vestibular nuclei showed that this area receives direct inputs from several areas of the nervous system that process non-labyrinthine inputs, including the spinal gray matter, prepositus hypoglossi, pontomedullary reticular formation, inferior olivary nucleus, lateral reticular nucleus, medullary raphe nuclei, the spinal and principal trigeminal nuclei, and the facial nucleus (Jian et al., 2005). Other anatomical studies showed that the caudal regions of the inferior and medial vestibular nuclei receive direct inputs from primary afferent fibers entering the cervical spinal cord (Bankoul et al., 1995). In addition, neurons throughout the vestibular nucleus complex receive direct and polysynaptic inputs from cerebral cortex (Wilson et al., 1999). The firing rate of a majority of neurons in the medial, inferior, and lateral vestibular nuclei is affected by stimulation of somatosensory afferents from the limbs (Fredrickson et al., 1966; Wilson et al., 1966; Rubin et al., 1977; Jian et al., 2002); most neurons were excited by limb inputs. The excitability of some cells was also altered by activation of visceral afferents (Jian et al., 2002). However, the influences of limb afferents on vestibular nucleus neuronal activity are not ubiquitous. For example, few neurons that mediate vestibulo-ocular reflexes respond to stimulation of limb nerves (Rubin et al., 1978). Vestibulo-ocular neurons are concentrated in the rostral portion of the vestibular nucleus complex, in the superior and rostral medial and lateral nuclei (Graybiel and Hartwieg, 1974; Gacek, 1977, 1979a,b). Since afferents from the spinal cord only provide heavy inputs to the caudal regions of the vestibular nuclei (Rubertone and Haines, 1982; McKelvey-Briggs et al., 1989; Bankoul et al., 1995), the paucity of somatosensory influences on vestibulo-ocular units is not surprising. Thus, the non-labyrinthine inputs that are responsible for restoration of vestibular nucleus neuronal activity following bilateral damage to the inner ear may differ along a rostral–caudal gradient. For the caudal portions of the vestibular nuclei (caudal medial, inferior, and lateral nuclei), ascending inputs from the spinal cord could play a major role in regulating neuronal excitability. In contrast, descending inputs from cerebral cortex and thalamus could play a larger role in regulating the excitability of neurons in the rostral vestibular nuclei (superior and rostral medial nuclei).
As noted in Section “Eye Movements and Oscillopsia,” body rotations in the sagittal plane modulate the activity of some vestibular nucleus neurons in animals lacking labyrinthine inputs. Caudal vestibular nucleus neurons become more sensitive to somatosensory and visceral stimulation subsequent to a bilateral labyrinthectomy, suggesting that their postural-related responses after removal of vestibular inputs could be due to these inputs (Jian et al., 2002). This notion is supported by the observation that the responses were abolished by spinalization (Cotter et al., 2004). These findings suggest that non-labyrinthine sensory inputs generated by body movement, such as those related to stretch of muscles, brushing of the skin, or movement of the viscera, can elicit responses of vestibular nucleus neurons that reflect body position in space. As such, these findings raise the prospect that recovery of behavioral and physiological responses after BVH is due to substitution of non-labyrinthine for labyrinthine inputs in the central vestibular system.
Mechanisms Responsible for the Recovery of Physiological and Behavioral Responses Following BVH
Some deficits produced by bilateral damage to the inner ear in animals, such as loss of reflexive eye movements during head rotations (Baarsma and Collewijn, 1974; Barmack et al., 1980; Waespe and Wolfensberger, 1985; Waespe et al., 1992) and reduced navigational abilities (Baek et al., 2010), do not diminish over time. However, rapid recovery occurs for other consequences of bilateral loss of vestibular inputs, particularly impaired postural stability (Thomson et al., 1991) and inability to maintain stable blood pressure during postural alterations (Jian et al., 1999). It thus is useful to consider the similarities and differences between these responses to gain insights into the process of compensation. As illustrated in Figure 4, one difference between the deficits that dissipate and those that do not is the region of the vestibular nucleus complex where they are mediated. Vestibulo-ocular reflexes are mainly elicited by neurons in the rostral portion of the vestibular nucleus complex (Graybiel and Hartwieg, 1974; Gacek, 1977, 1979a,b), as are cognitive responses that are dependent on labyrinthine inputs (Brown et al., 2005; Shinder and Taube, 2010). In contrast, many of the neurons that control balance (Nyberg-Hansen and Mascitti, 1964; Petras, 1967; Peterson et al., 1978; Carleton and Carpenter, 1983; Carpenter, 1988) and influence blood pressure (Uchino et al., 1970; Yates et al., 1993; Kerman and Yates, 1998) are located caudally in the vestibular nucleus complex. In addition, the major components of vestibulo-ocular reflexes are dependent on inputs from semicircular canals (Money and Scott, 1962; Suzuki and Cohen, 1964, 1966; Baker et al., 1982; Hess et al., 2000; Sadeghi et al., 2009; Yakushin et al., 2011). Although data are limited, at least some cognitive responses related to vestibular inputs also appear to require inputs from semicircular canals (Muir et al., 2009). In contrast, while the properties of vestibulo-spinal reflexes are altered by canal plugging, which inactivates the semicircular canals but not the otolith organs, postural stability mainly requires otolithic inputs (Money and Scott, 1962; Watt, 1976; Schor and Miller, 1981). Similarly, vestibular system influences on the sympathetic nervous system are mainly related to signals from the otolith organs (Yates and Miller, 1994). Thus, following a bilateral labyrinthectomy, compensation occurs for responses that are elicited by otolith organ inputs processed by the caudal portion of the vestibular nucleus complex, but not for responses elicited predominantly by semicircular canal inputs that are processed by the superior and rostral medial vestibular nuclei. This dichotomy is at least partly related to the fact that otolithic inputs tend to target more caudal regions of the vestibular nuclear complex (Dickman and Angelaki, 2002; Newlands and Perachio, 2003; Newlands et al., 2003).
Figure 4. A horizontal section through the vestibular nucleus complex in the cat, showing the locations of the majority of neurons that mediate vestibulo-ocular reflexes (red shading), spatial cognition (black shading), balance (blue shading), and autonomic responses (green shading). Neurons that elicit eye movements and participate in spatial cognition are located rostrally in the vestibular nucleus complex, mainly in the superior vestibular nucleus (SVN) and rostral portion of the medial vestibular nucleus (MVN). In contrast, neurons responsible for vestibulo-spinal and vestibulo-autonomic responses are located more caudally, in the lateral vestibular nucleus (LVN), inferior vestibular nucleus (IVN), and caudal portion of the medial vestibular nucleus (MVN).
Since a variety of sensory systems provide graviceptive signals to the central nervous system (Mittelstaedt, 1992, 1995, 1996; Mittelstaedt and Mittelstaedt, 1996; Balaban and Yates, 2004), it is not surprising that these inputs can be substituted at least partially for those from the otolith organs. Some of these graviceptive inputs are conveyed to the vestibular nuclei (see “Cognitive deficits”), and are likely responsible for the modulation of vestibular nucleus neuronal activity that can be detected during body rotations in the pitch plane conducted following a bilateral vestibular neurectomy (Yates et al., 2000; Miller et al., 2008). Bilateral lesions placed in the caudal region of the vestibular nuclei result in a permanent deficit in cardiovascular system responses during postural alterations (Mori et al., 2005), as well as deficits in postural control that are more severe and long lasting than those resulting from a bilateral labyrinthectomy (unpublished observations). These findings suggest that the vestibular nuclei participate in the “sensory substation” that facilitates recovery of postural stability and movement-related cardiovascular adjustments following the loss of labyrinthine inputs. However, the specific role that the central vestibular system plays in the compensation process is yet to be determined.
Compensation Following BVH in Human Subjects
Analysis of longitudinal compensation in humans with BVH, in contrast to animals with experimentally generated damage to the inner ear, has been limited by a lack of access to BVH patients early in the compensation process. Most studies investigating the effects of BVH describe findings years after the vestibular loss occurred and presumably the dynamic compensatory process had long been completed. The postural effects of BVH therefore have just been studied in humans who previously underwent the dominant period of vestibular compensation; consequently, the literature only describes the end result of BVH on posture (see “Postural stability”). Studies on eye movements (see “Eye Movements and Oscillopsia”) and cognition (see “Cognitive deficits”) are limited by the same constraint.
Humans with BVH are able to maintain normal stance in the light, although when the support surface they stand upon moves, falls are much more likely to occur (Nashner et al., 1982; Mergner et al., 2009). When the support surface is systematically tilted in the eyes closed condition, BVH subjects either sway with the platform movement (at lower peak tilt angular velocity) or fall (at higher peak tilt angular velocity; Maurer et al., 2006). Tandem Romberg stance (one foot in front of the other) is a challenging posture to maintain: control subjects without assistance are able to maintain the posture in light or dark, but subjects with BVH fall in both conditions (Lackner et al., 1999). The elevated fall risk presented by unstable support surfaces and challenging postural positions translates to increased risk of fall and injury in the daily lives of BVH patients.
Patterning of postural muscular responses following perturbations is altered in BVH patients, but the origin and organization of the muscular responses that occur in this patient population is debatable. It has been proposed that balance-correcting responses are elicited by somatosensory signals from the trunk or about the hip joint, which are then modulated by inputs from the ankles, knees, and the vestibular system (Horstmann and Dietz, 1990; Allum and Honegger, 1998). Other investigators have proposed that somatosensory signals originating about the ankle may be the primary drivers of postural responses (Nashner et al., 1982; Horak and Nashner, 1986; Horak et al., 1990). To add to the complexity of deciphering muscular control of posture, direction of perturbation is an important factor in maintenance of posture. Humans are more unstable when subjected to perturbations in the roll plane then when they are tilted in the pitch plane (Carpenter et al., 2001). Hip and trunk muscles are activated during roll motion, while pitch perturbations mainly involve an activation of leg muscles (Henry et al., 1998; Gruneberg et al., 2005; Allum et al., 2008). BVH subjects have been shown to demonstrate increased paraspinal muscular activity in response to toes up pitch rotations (Allum et al., 2001). The normal lower body response to roll tilt of a support surface also involves uphill leg flexion and downhill leg extension; BVL subjects have a reduction of this compensatory leg motion (Allum et al., 2008). Quasi-static roll perturbations, which are believed to be detected mainly via proprioceptors rather than otolithic graviceptors, are perceived at low thresholds in both normal subjects and BVH patients suggesting that proprioceptive inputs are satisfactory for maintenance up upright posture in relatively adynamic conditions (Teasdale et al., 1999; Bringoux et al., 2002). The relative role such proprioceptive inputs play in more dynamic conditions, such as during ambulation, remains undefined.
Dependence on other sensory systems, namely proprioceptive and visual, is widely regarded as the means that permits BVH patients to maintain upright posture. Some data suggest that a transition occurs months to years following the onset of BVH from a visually dominant postural control paradigm to a more proprioceptive guided paradigm, although longitudinal studies within individuals are lacking (Bles et al., 1983). Modeling of human posture indicates that normal subjects are able to reweigh sensory data from visual, proprioceptive, and vestibular inputs in response to changes in stimulus amplitude (i.e., non-linear changes in gain and phase occur in response to changes in amplitude of stimuli; Peterka, 2002). Subjects with BVH are not able to reweigh sensory information in this fashion. Some BVH subjects utilize a balance strategy dependent upon an increase in stiffness, which results in decreased sensory error, but necessitates a higher energy expenditure to maintain (Peterka, 2002). Subjective visual vertical (SVV) estimates during rotation of the visual field or placement of the body in the lateral position are more deviated in BVH patients compared with normal subjects, suggesting that vestibular inputs normally serve to influence or supersede less accurate proprioceptive or visual postural information (Bronstein et al., 1996). Alternatively, exaggeration of error in SVV when BVH subjects are tilted onto their sides could suggest that signals from proprioceptive pathways are enhanced following vestibular loss. As balance control strategies are not nearly as critical for preventing falls in the supine position, errors in estimated verticality in this position are less clinically relevant than if such errors were to occur with upright stance. Enhancement or disinhibition of proprioceptive pathways may be important to maintenance of upright posture in BVH. For example, the enhanced pattern of paraspinal muscular activity in toes up pitch rotations is opposite to that seen in patients with proprioceptive loss, suggesting that proprioceptive responses may be enhanced in BVH (Allum et al., 2001). Alternative sensory input in the form of putative trunk graviceptors may be another important factor in postural control following loss of vestibular input (Mittelstaedt, 1998).
Eye Movements and Oscillopsia
Humans with BVH exhibit eye movement abnormalities. BVH results in markedly diminished or absent vestibulo-ocular reflexes (VOR) bilaterally, such that measurement of the VOR during clinical vestibular testing is used to diagnose BVH (Brown et al., 2001; Goebel et al., 2009; Jen, 2009). Responses to head thrust testing, which assesses the high-frequency VOR, are also abnormal in BVH (Halmagyi and Curthoys, 1988; Jorns-Haderli et al., 2007; Zingler et al., 2008). Over time, there does not appear to be recovery of VOR function regardless of the etiology of BVH (Baloh et al., 2001; Zingler et al., 2008). Optokinetic after nystagmus is also severely reduced or abolished in BVH (Zee et al., 1976; Ireland and Jell, 1982; Bles et al., 1984; Hain and Zee, 1991). Most groups have found smooth pursuit to be undisturbed in BVH (Kasai and Zee, 1978; Leigh et al., 1987; Waterston et al., 1992), although a slight potentiation of smooth pursuit in BVH has been reported (Bockisch et al., 2004).
Since the VOR is believed to stabilize vision during head motion, its absence in BVH requires compensatory mechanisms to optimize visual input. Mechanisms postulated to participate in this compensatory process include enhancement of the cervico-ocular reflex, central preprogramming of eye movements, and increase in the optokinetic response (Kasai and Zee, 1978; Bronstein and Hood, 1986; Huygen et al., 1989, 1991; Waterston et al., 1992). The cervico-ocular reflex, which is triggered by inputs from neck muscles, is normally of small magnitude in humans, but its gain increases following bilateral vestibular loss particularly when the head is moved at low frequency (∼0.1 Hz; Bronstein and Hood, 1986; Huygen et al., 1991). Central preprogramming of eye movements necessitates that the subject is aware of where the next target will be located or what head movement will take place; in this situation, subjects with BVH more accurately identify the visual target (Herdman et al., 2001). However, many head movements and choices for gaze direction in daily life are not predictable and this strategy would not be useful in many circumstances. Efference copy of motor commands may also facilitate accurate targeting during gaze shifts (Maurer et al., 1998), but it is unclear whether this mechanism provides for compensation in BVH patients. In some low frequency head movement circumstances, optokinetic responses can also contribute to compensatory eye movements in BVH patients (Leigh et al., 1992).
It is known that the generation of compensatory eye movements in patients with BVH requires a functioning cerebellum (Bronstein et al., 1991; Waterston et al., 1992). In the converse situation, individuals with cerebellar deficiency and intact vestibular systems have an elevated VOR gain, show an inappropriate direction of the slow phase of eye movements orthogonal to the axis of rotation, and display abnormalities during cervical vestibulo-ocular myogenic potential testing thought to be analogous to an increase in vestibulocollic reflex gain (Shaikh et al., 2011). Therefore, the cerebellum may be responsible for potentiating a number of pathways for compensation in BVH.
Oscillopsia is the perception of blurring or movement of the environment when the head is placed in motion during activities such as turning the head to the side or ambulating (Schubert et al., 2004). Oscillopsia is a common symptom in BVH, but it is not ubiquitous (McGath et al., 1989; Sargent et al., 1997). Oscillopsia is thought to occur in BVH because slip of visual targets across the retina occurs in the absence of a functioning corrective VOR. Dynamic visual acuity during ambulation is reduced in BVH, which is likely related to retinal slip (Lambert et al., 2010). Tolerance to retinal slip, rather than corrective eye movements, appears to be important for adaptation to oscillopsia. Subjective reporting of the degree of oscillopsia is negatively correlated with the amount of retinal slip (Grunfeld et al., 2000). Similarly, visual motion detection thresholds are reduced in BVH patients compared with controls (Shallo-Hoffmann and Bronstein, 2003). It is likely that adaptive compensatory mechanisms are responsible for the reduced sensitivity to visual field motion, although the pathways involved remain to be elucidated.
Patients with vestibular loss are often noted to suffer cognitive deficits such as difficulty concentrating or being in a “brain fog,” and patients with BVH are likely not an exception (Hanes and McCollum, 2006). Although cognitive deficits of this nature are sometimes difficult to study, several important cognitive effects have been demonstrated in humans with BVH, chiefly impaired spatial learning and memory and, less directly, impairment in dual tasking.
Humans with bilateral vestibular loss have impaired spatial learning and spatial memory deficits. BVH subjects had poor performance on the virtual Morris water task, which tests spatial learning and memory in the absence of somatosensory or vestibular cues (Schautzer et al., 2003). Anatomic and physiologic data support these findings and indicate that the hippocampus, a brain region known to be involved in spatial learning and memory, is responsible for the deficiencies (Brandt et al., 2005; Jahn et al., 2009; Smith et al., 2010b; Viard et al., 2011). MRI testing showed that BVH subjects have a 17% reduction in hippocampal volume (Brandt et al., 2005), and functional MRI studies demonstrated that these patients also have decreased activity within the anterior hippocampus (Jahn et al., 2009). Memory and navigation deficits in BVH patients were limited to spatial problems; general memory was found to be intact (Brandt et al., 2005). Although there is some suggestion that the right cerebral cortex is dominant for spatial orientation, right unilateral vestibular loss subjects only displayed subtle differences in task performance compared with subjects with left unilateral loss, and there is no hippocampal atrophy in unilateral vestibular loss subjects (Hufner et al., 2007; Jahn et al., 2009). Taken together, these data suggest that spatial learning and memory are dependent upon the presence of function of at least one labyrinth; without any functional labyrinthine input, deficits of spatial learning and memory arise.
Patients with vestibular loss have also been shown to have difficulty with dual mental tasks, such as performing arithmetic along with orienting or balance tasks (Yardley et al., 2001, 2002). These dual task studies mostly included patients with unilateral vestibular loss; a few patients with BVH were also studied but were not segregated, such that drawing specific conclusions on dual tasking in BVH is not currently possible. As such, further study of multitask performance is warranted in BVH patients.
Strategies and Therapies to Aid Patients with BVH
Vestibular Physical Therapy
Spontaneous recovery of vestibular function rarely occurs in BVH patients (Brandt et al., 2010); treatment strategies therefore necessarily rely upon coping with existing vestibular function (in the case of partial loss) or providing alternative means to present information normally sensed by the vestibular system to the brain (Minor, 1998). The mainstay of treatment for BVH is vestibular physical therapy. Treatment in an active vestibular rehabilitation program was shown in a double blind placebo-controlled study to improve dynamic gait stability considerably among patients with BVH (Krebs et al., 1993). Similarly, dynamic visual acuity has been shown to improve with vestibular physical therapy in BVH (Herdman et al., 2007). Such improvements should translate readily to improvements in quality of life amongst treatment responders.
Improvement with vestibular physical therapy has been shown to occur in approximately 50% of patients with BVH; however, this leaves a substantial population that does not benefit (Shepard and Telian, 1995; Gillespie and Minor, 1999; Brown et al., 2001). Risk factors for poor response to vestibular physical therapy include multiple medical comorbidities, slowly progressive bilateral vestibular loss, and increased severity of BVH (Gillespie and Minor, 1999). A further understanding of the compensatory process in BVH may lead to explanations about the variability of recovery in BVH and suggest new treatment strategies.
Investigators continue to search for new ways to refine balance function in patients suffering from BVH. Sensory substitution, converting information normally encoded by one system (in this case, the vestibular system) into information that can be detected with another sensory modality (such as visual cues or sensory tactile information), has been one approach taken to improve stance and gait in BVH patients. Sensory substitution in BVH is a pragmatic approach because evidence suggests that patients with BVH already may use a form of it – visual sensory substitution. While undergoing optokinetic stimulation, fMRI data from BVH patients demonstrates increased activity within visual and oculomotor areas in comparison with normal subjects, suggesting that BVH individuals use visual flow to assist with balance (Dieterich et al., 2007). Furthermore, BVH subjects have been shown to have better postural stability when permitted to use visual cues (Buchanan and Horak, 2002; Horak, 2010). Non-supportive light touch can also substitute as an earth vertical reference point and stabilize posture (Creath et al., 2002, 2008). Auditory biofeedback has also been used as a form of vestibular sensory substitution by notifying patients about the degree of postural sway through auditory cues (Dozza et al., 2007, 2011).
Several devices are under investigation to assist in sensory substitution for BVH. The most studied sensory substitution device delivers body tilt information through a vibrotactile somatosensory feedback system attached to the torso that has been shown to reduce postural sway and decrease falls (Kentala et al., 2003; Wall and Kentala, 2005). Another sensory substitution system involves wearing a head mounted vibrotactile device. This system has undergone phase 1 clinical testing and was shown to significantly reduce instability in BVH patients as measured by dynamic posturography (Goebel et al., 2009). Another device provides electrotactile feedback to the tongue based upon head position relative to gravity (Barros et al., 2010).
Vestibular Prosthesis/Vestibular Stimulation
An alternative approach to sensory substitution based prosthetics involves direct electrical stimulation of vestibular sensory nerves with an implanted vestibular prosthetic device. Single channel and multichannel head mounted devices are currently under study in animals (Della Santina et al., 2005, 2007; Merfeld et al., 2007; Lewis et al., 2010; Dai et al., 2011). The foundation of modern vestibular prosthesis work comes from experiments in which precise eye movements were elicited through electrical stimulation of branches of the vestibular nerve (Suzuki et al., 1964, 1969). Current vestibular prostheses typically include electrodes within the semicircular canals that deliver electrical stimulation to individual ampullary nerves. The electrical stimuli are controlled by measurements from accelerometers that detect head rotation. An underlying premise for this therapy is that the animal or human with the implant will adapt to the firing rate of ampullary nerves induced by the device, and use this information to elicit appropriate compensatory eye movements. In guinea pigs, this acclimation process was shown to occur rapidly. Importantly, acclimation to chronic baseline stimulation did not interfere with generation of eye movements when electrical stimulation was used to modify the activity of particular vestibular nerves (Merfeld et al., 2006). Longer-term adaptation studies in the squirrel monkey showed that an electrically evoked VOR is synchronized with head motion after 3 months of chronic stimulation (Merfeld et al., 2007). One important concern regarding electrical stimulation is the problem of current spread from the intended ampullary nerve to other nearby ampullary nerves, resulting in cross stimulation. VOR adaptation studies have shown that over the first week following prosthesis activation in chinchillas, erroneous VOR eye movements caused by current spread rapidly diminish, such that eye movements more closely approximate those expected based upon head motion (Dai et al., 2011). To date, one human has been implanted with an electrically based vestibular prosthesis. The surgery involved placing a single electrode from a modified cochlear implant adjacent to the posterior ampullary nerve in a patient with BVH and bilateral deafness. Experiments using the device demonstrated that nystagmus diminished over time, and that eye movements were elicited in accordance with the amplitude and frequency of stimulation (Guyot et al., 2011).
Since we are at the forefront of investigation of vestibular prostheses in humans, many questions remain. It is unclear whether such prostheses will stabilize oscillopsia by accurately encoding head motion in space. Similarly, it remains to be reported whether electrical stimulation of ampullary nerves improves balance control in patients or animal subjects with BVH. Galvanic or caloric stimulation of the vestibular system of normal humans has been shown to improve memory (spatial, verbal, and facial recall; Bachtold et al., 2001; Wilkinson et al., 2008; Smith et al., 2010a). Whether electrical vestibular stimulation will affect cognitive processing in BVH patients remains unknown. It is also unclear whether vestibular prostheses will alter the sensory substitution that ordinarily occurs in BVH patients, and whether sensory substitution and electrical stimulation devices can be effectively used in combination in particular subjects.
Summary and Future Research Directions
Very little is known about the compensatory process in humans with BVH because virtually all studies of the effects of this condition on posture, visual stability, and cognition have been conducted in patients long into the disease process. Longitudinal studies in humans that commence upon the acute bilateral loss of vestibular function would be particularly enlightening, but are inherently challenging or impossible to perform, since access to patients with acute onset BVH is rare. To understand the compensatory processes that have occurred, we can only make conclusions based upon the end functional result. Although it is clear that the effects of BVH on posture, eye movements, and spatial learning and memory are long lasting, it is unknown how much improvement in signs and symptoms occurs over time. Another important open question is, what neural systems contribute to recovery of these responses? It is tempting to infer about compensation for BVH from what is known about recovery following unilateral vestibular lesions, but such thinking may be spurious. As an example, patients with unilateral vestibular loss performed better on balance measures when they relied on their remaining vestibular information rather than on visual or somatosensory information. In contrast, subjects with BVH would necessarily have to depend on visual and somatosensory signals (Horak, 2010). A more pragmatic approach is to draw conclusions from compensation studies in experimental animals, learn how they compensate from the onset of BVH, and determine where we may intervene to improve compensation. As noted above, the consequences of elimination of vestibular inputs are similar in animal subjects and human patients, such that studies in animals will likely provide insights that can be translated to clinical medicine.
Experiments on animal subjects with induced BVH have shown that non-labyrinthine inputs rapidly restore resting activity in the vestibular nuclei (Waespe et al., 1992; Ris and Godaux, 1998; Miller et al., 2008) and can modulate this neural activity during some changes in body position (Yates et al., 2000; Miller et al., 2008). An important line of investigation is to determine whether non-labyrinthine effects on activity in the vestibular system can be strengthened following BVH, and whether the information can be effectively utilized to compensate for deficits. Experiments in animals could also be used to determine whether a combination of prosthetic devices, such as combined stimulation of ampullary nerves and somatosensory receptors, may be more effective in facilitating recovery following bilateral damage to the inner ear than a therapy that activates one sensory modality. A promising finding is that some strategies thought to be compensatory for BVH are plastic and modifiable over time. COR gain and phase readily and appropriately change in BVH subjects wearing magnifying or reducing lenses (Heimbrand et al., 1996). If we are able to identify other compensatory strategies in humans, whether they utilize proprioceptive, visual, or other inputs, we may ultimately be able to modify these signals for therapeutic use.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors’ work related to this manuscript is supported by National Institutes of Health grant R01-DC00693 to Bill J. Yates.
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<urn:uuid:f1facd5a-8dfd-4b25-bdac-b5f88c7b2c5d> | seed | APPENDIX C: Statistical and Epidemiologic Approaches
A suspected cancer cluster investigation attempts to answer two questions: 1) is there an actual "excess" (that meets statistical and biological plausibility criteria) and 2) is this excess associated with an environmental contaminant? Addressing these questions begins by defining the study population and locating relevant cases and then determining the appropriate geographic boundaries and time period.
This section provides an outline of the basic epidemiological and statistical analysis methods that are recommended for investigating a cancer cluster. This section focuses on the methods most relevant and most commonly used in cancer cluster investigations: the SIR and confidence interval, mapping, and descriptive and spatial statistical and epidemiologic methods.
Standardized Incidence Ratio and Confidence Interval
The measure typically used to assess whether there is an excess number of cancer cases is the SIR. This measure is explained in many epidemiologic textbooks (sometimes under standardized mortality ratio, which uses the same method but measures mortality instead of incidence rates) (1–5). Simply stated, the SIR is a ratio of the number of observed cancer cases in the study population to the number that would be observed (often called "expected") if the study population experienced the same cancer rates as an underlying population (often called the "reference" population). The reference population could be the surrounding census tracts, other counties in the state, or the state as a whole (not including the community under study).
The SIR can be adjusted for factors such as sex, race, and/or ethnicity, but it is most commonly used to adjust for differences in age between two populations. Various techniques can be used to account for these factors. For example, stratification, which is calculating an SIR by groups (e.g., by calendar year), is a commonly employed technique. (6)
A confidence interval is calculated to determine the precision of the SIR estimate and the statistical significance. If the confidence interval includes 1.0, the SIR is not statistically significant. The narrower the confidence interval, the more confidence one has in the precision of the SIR estimate. One difficulty in cancer cluster investigations is that the population under study is generally a community or part of a community, typically resulting in a small denominator, and such small denominators frequently yield wide confidence intervals, meaning that the SIR is therefore not as precise as desired (1).
Considering Alpha and Beta Level Values
The alpha is the probability of rejecting the null hypothesis when the null hypothesis is true (no difference in cancer rates between the study population and reference population). Although there are no absolute cut-points, responders often use an alpha value of 0.05 (or equivalently a 95% confidence interval).
Selection of an alpha value larger than 0.05 (e.g., 0.10: 90% confidence interval) will increase the risk of false positive results. Selection of a smaller alpha value (e.g., 0.01: 99% confidence interval) may be considered when many SIRs are computed because the number of SIRs that will be statistically significant by chance alone increases (in other words, with a 95% confidence interval, one expects to see five statistically significant results in a group of 100 results).
Beta and power are related to each other. Both are related to the sample size of the study—the larger the sample size, the larger the power. Power, or 1- β (beta), is the probability of rejecting the null hypothesis when the null hypothesis is actually false. Like alpha, the beta has no absolute cut-points; however, responders often use a beta value of 0.20 or less (or equivalently a power of 0.8 or more) (1).
Power analysis is useful in determining the minimum number of people (sample size) needed in a study in order to test the hypothesis and detect a possible association. In most suspected cancer cluster investigations, the cases and study population are defined prior to the analysis. Therefore, a power analysis can be used to determine if the number of cases in the investigation is sufficient, usually a power of 0.8 or greater (3).
Mapping the Cancer Cluster
When considering the geographic distribution of cases, responders have various methods they can use. For example, they might develop a visual representation showing the location of each case superimposed on the underlying population density to get an approximation of the distribution of the relative rates of cancer.
It also can be useful to plot the location of suspected environmental risk factors on the map for the purpose of making a crude assessment of their proximity to the cases. However, to avoid the "Texas Sharpshooter fallacy" (i.e., a situation in which cases are noticed first and then the "affected" area is selected around them, thus making there appear to be a geographical relationship, similar to an instance in which the sharpshooter shoots the side of the barn first and then draws the bull's-eye around the bullet holes), responders must first outline their definitions, assumptions, and methods (7). Often, a few different spatial (e.g., spatial: census block, census tract, zip code, municipality, or county) or temporal scales (e.g., week, month, year, or several years) can be mapped to look for possible patterns related to specific space and/or time units that merit more careful investigation. This process is systematic, and procedures are outlined a priori. The patterns in such maps often differ dramatically, and they might suggest specific exposures that warrant further consideration. This practice is more useful when longer periods of time are under study, as well as larger numbers of cases (e.g., >10 cases).
Cancer registries and state health agencies typically have criteria related to release of data for small geographic areas. Because of privacy concerns, some data cannot be released to the public, unless the privacy concerns are addressed. For example, a pin-point map of a small geographic area that identifies the residence of a cancer patient should not be made public (8). Similarly, many health agencies are prohibited from publicly releasing a table for a small geographic area with a small population, for each table cell might have only a few cases.
Descriptive and Spatial Statistical and Epidemiologic Methods
Frequencies, rates, and descriptive statistics are useful first steps in evaluating the suspected cancer cluster. Confidence intervals can also be calculated for rates. Epidemiologic references can explain these methods (9). Other statistical approaches include Poisson regression. Often, the number of cases is limited, therefore limiting the type of analysis. If an investigation progresses to a case-control study, the odds ratio can be calculated. These study designs have been discussed in detail elsewhere (1,3,4).
Since the publication of the 1990 Guidelines, the field of spatial epidemiology has grown, especially in environmental health. This growth is influenced by the increased availability of geocoded data and statistical software. Space/time cluster analysis methods are often used to provide evidence about the existence of a suspected cluster and to define more precisely the extent of the suspected cluster in space and time.
As with any other epidemiologic analysis, there might be methodological issues with the use of clustering tools. Many of these concerns (e.g., limitations associated with small populations, environmental data quality, disease latency periods, and population migration) have been described in this report. Census data can provide the denominators for this type of analysis, and all the limitations associated with rapidly changing populations and intercensal year estimates also apply to these spatial/time cluster methods. In addition, when exposure or outcome analysis uses aggregate data and not data collected on an individual level, responders must use caution when interpreting this type of analysis, because the association with a particular environmental contaminant might not be true for individual cases, especially if there is heterogeneous distribution of the exposure over the geographic area. The related bias is known as ecological inference fallacy. Detailed information regarding methodological issues has been published previously (10).
Many methods have been developed to facilitate what is termed "space/time cluster analysis." These methods assess whether cases are closer to one another than would be observed if the cases had been distributed at random. The concept of "close" might mean closer geographically, closer in time, or closer both geographically and in time. The numeric value of "close" is determined by the responder. For a responder to make a determination of clustering, the space-time distances have to be summarized and then evaluated with any of a variety of statistical techniques. This task can be performed by summarizing where and when each case occurred, typically using the individuals' residence and the reported date of incidence. Some of the simplest methods merely compare the average distances between nearby cases to the average distances between cases and nearby noncases (or controls). If, on average, the cases are sufficiently closer to other cases (in space, time, or both space and time) than they are to noncases, the situation may be described as a cluster. Clusters can be detected by use of spatial autocorrelation techniques. Global clustering statistics, such as Geary's C (11), detect spatial clustering that occurs anywhere in a study area. They do not identify where the cluster(s) occur, nor do they identify differences in spatial patterns within the area. Local clustering statistics, such as Local Indicators of Spatial Autocorrelation (LISA) (12), identify potential clustering within smaller areas inside a study area. Often, global techniques are used first to identify potential clustering; then, local methods are used to pinpoint the clusters in the sample area. Many global statistics have local counterparts. For example, global Moran's I is the summation of local Moran's I statistics (13). Clusters reported to health agencies most often are local. It is beyond the scope of this report to describe more than a few of the most commonly used methods, and even then, these methods are described only briefly.
A useful summary of these techniques has been published recently (14). One of the most popular techniques for detecting clusters is called the spatial scan statistic. Its most commonly used implementation is the SaTScan software (15) (available at http://www.satscan.org). The underlying concept for this approach is the scan statistic, which considers both spatial areas and time intervals (16). Other implementations include the nearest neighbor test (17) and the Small Area Health Statistical Unit (SAHSU)'s "Rapid Inquiry Facility" (RIF) (18). Additional, statistical cluster methods have been discussed elsewhere (19). All of these methods have strengths and weaknesses. In a choice of a statistical cluster method, it might be useful to consider several criteria, such as ease of use and availability, the clarity and transparency of the method, its statistical power to detect the cluster of interest, and the method's ability to produce the desired output (20). Comparisons and reviews have been published (21). In addition, the Appendix of the 1990 Guidelines describes additional spatial statistical methods.
- Kelsey JL. Methods in observational epidemiology. New York, NY: Oxford University Press; 1996.
- Khurshid A. Statistics in epidemiology: methods, techniques, and applications: CRC; 1996.
- Selvin S. Statistical analysis of epidemiologic data. New York, NY: Oxford University Press; 1996.
- Breslow NE, Day NE. Statistical methods in cancer research. In: International Agency for Research on Cancer. The design and analysis of cohort studies. Lyon, France: International Agency for Research on Cancer Scientific Publications; 1980.
- Rothman KJ, Greenland S, Lash TL. Modern epidemiology. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
- New Jersey Department of Health & Senior Services Cancer Epidemiology Services. Fact sheet: explanation of standardized incidence ratios. Available at http://www.state.nj.us/health/eohs/passaic/pompton_lakes/pompton_lakes_fs_sir.pdf.
- Gawande A. The cancer-cluster myth. The New Yorker 1999;8:34–7.
- CDC. National Programs of Cancer Registry United States Cancer Statistics technical notes: statistical methods: suppression of rates and counts. Available at http://www.cdc.gov/cancer/npcr/uscs/technical_notes/stat_methods/suppression.htm.
- Gordis L. Epidemiology. Philadelphia, PA: Saunders Elsevier; 2009.
- Beale L, Abellan JJ, Hodgson S, Jarup L. Methodologic issues and approaches to spatial epidemiology. Environ Health Perspect 2008;116:1105–10.
- Geary RC. The contiguity ratio and statistical mapping. The Incorporated Statistician 1954;5:115–46.
- Anselin L. Local indicators of spatial association: LISA. Geographical Analysis 1995;27:93–115.
- Moran P. Notes on continuous stochastic phenomena. Biometrika 1950;37:17–23.
- Tango T. Statistical methods for disease clustering. New York, NY: Springer; 2010.
- Kulldorff M. A spatial scan statistic. Commun Stat-Theor M 1997;26:1481–96.
- Naus J. The distribution of the size of maximum cluster of points on the line. J Am Stat Assoc 1965;60:532–8.
- Cuzick J, Edwards R. Spatial clustering for inhomogeneous populations. J Roy Stat Soc B Met 1990;52:73–104.
- Aylin P, Maheswaran R, Wakefield J, et al. A national facility for small area disease mapping and rapid initial assessment of apparent disease clusters around a point source: the UK Small Area Health Statistics Unit. J Public Health Med 1999;21:289–98.
- Rogerson PA. Statistical methods for geography: a student's guide. Thousand Oaks, CA: Sage Publications Ltd; 2010.
- Robertson C, Nelson TA, MacNab YC, Lawson AB. Review of methods for space-time disease surveillance. Spatial and Spatio-temporal Epidemiology 2010;1:105–16.
- Waller LA, Gotway CA. Applied spatial statistics for public health data. New York: John Wiley and Sons; 2004.
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<urn:uuid:5a27333c-9d8b-4145-a971-40550b388707> | seed | Approximately ten percent of children suffering from cerebral palsy have a combination of two or more types. Mixed cerebral palsy and it is the result of an injury to both the extrapyramidal and pyramidal areas of the brain.
The most common form of Mixed CP is a combination of spastic and athetoid movements (accounting for 10% of all mixed cases, but other combinations are also possible. Although by no means common, there are patients who have a combination of ataxic, athetoid and spastic CP.
Since spastic CP causes one or more muscle groups to become tight, patience experience severe movement limitations. As a result, children with this disability have stiff and jerky movements often having trouble changing positions and find it difficult to hold and let go of objects.
Due to the injury they experienced to both the pyramidal and extra pyramidal areas of the brain, patients suffering from mixed CP often exhibit the involuntary movements of athetoid CP as well as the tight muscle tone of spastic CP. The spasticity is often more dominant, while the involuntary athetoid movements increase as the child begins to grow, usually between nine months and three years. It can take years until the symptoms of mixed CP are noticed.
Other combinations (beside the joint affects of spastic and athetoid CP) are prevalent. While any mix of types can occur (including all three types), the rarest combination is athetoid and ataxic.
Mixed CP involving athetoid movements result from damage to either the basal ganglia part of the brain or the cerebellum because these areas are process the signals which facilitate coordinated movements and correct body posture. Injury to either of these areas will often cause a child to exhibit involuntary movements, in the face, arms, and trunk.
This type of involuntary movement is not controlled by the brain. A “twitch” which is a common example of involuntary movement in healthy people is caused by electrical stimulation of the muscle. In individuals suffering from mixed CP, the frequency of the involuntary movement interferes with their ability to perform otherwise “simple” activities like grasping, reaching, eating and speaking, and similar skills.
Uncontrolled sticking their tongue out and grimacing often result in drooling, slurred speech and swallowing problems which will disappear while they are sleeping and increase during periods of emotional stress. Mixed CP children often have low muscle tone and can not maintain posture for either sitting or walking. |
<urn:uuid:f4f75dd2-c29f-47a7-8e6f-3dd1b0b1174f> | seed | Exposure treatment is a technique that is widely used in cognitive-behavioral therapy (CBT). Exposure treatment is used for a variety of anxiety disorders, and it has also recently been extended to the treatment of substance-related disorders. Generally speaking, exposure treatment involves presenting a patient with anxiety-producing material for a long enough time to decrease the intensity of their emotional reaction. As a result, the feared situation or thing no longer makes the patient anxious. Exposure treatment can be carried out in real situations, which is called in vivo exposure; or it can be done through imagination, which is called imaginal exposure. The category of imaginal exposure includes systematic desensitization, which asks the patient to imagine certain aspects of the feared object or situation combined with relaxation. Graded or graduated exposure refers to exposing the patient to the feared situation in a gradual manner. Flooding refers to exposing the patient to the anxiety-provoking or feared situation all at once and kept in it until the anxiety and fear subside. There are several variations in the delivery of exposure treatment: patient-directed exposure instructions or self-exposure; therapist-assisted exposure; group exposure; and exposure with response prevention.
The basic purpose of exposure treatment is to decrease a person's anxious and fearful reactions (emotions, thoughts, or physical sensations) through repeated exposures to anxiety-producing material. This reduction of the patient's anxiety response is known as habituation. A related purpose of exposure treatment is to eliminate the anxious or fearful response altogether so that the patient can face the feared situation repeatedly without
Exposure treatment is generally a safe treatment method; however, some patients may find that the level of anxiety that occurs during treatment sessions is higher than they can handle. Some studies of exposure treatment have reported a high dropout rate, perhaps because the method itself produces anxiety. In addition, exposure treatment is not effective for all patients; after treatment, some continue to experience anxiety symptoms.
Exposure treatment usually begins with making a list or hierarchy of situations that make the patient anxious or fearful. The situations are ranked on a scale of zero (representing the situation producing the least anxiety) to ten (representing the situation of highest anxiety). In addition, patients are usually asked to rate their level of anxiety in each situation on a scale from zero (no anxiety or discomfort) to 100 (extreme anxiety and discomfort). This scale is called the subjective units of distress scale, or SUDS. Patients may be asked to provide SUDS ratings at regular intervals during exposure treatment, for example every five minutes.
Methods of delivering exposure treatment
PATIENT-DIRECTED EXPOSURE. Patient-directed exposure is the simplest variation of exposure treatment. After the patient makes his or her hierarchy list with the therapist, he or she is instructed to move through the situations on the hierarchy at his or her own rate. The patient starts with the lowest anxiety situation on the list, and keeps a journal of his or her experiences. Patient-directed exposure is done on a daily basis until the patient's fears and anxiety have decreased. For example, if a patient is afraid of leaving the house, the first item on the hierarchy might be to stand outside the front door for a certain period of time. After the patient is able to perform this action without feeling anxious, he or she would move to the next item on the hierarchy, which might be walking to the end of the driveway. Treatment would proceed in this way until the patient has completed all the items on the hierarchy. During therapy sessions, the therapist reviews the patient's journal; gives the patient positive feedback for any progress that he or she has made; and discusses any obstacles that the patient encountered during exposures to the feared situation.
THERAPIST-ASSISTED EXPOSURE. In this form of exposure treatment, the therapist goes with the patient to the feared location or situation and provides on-the-spot coaching to help the patient manage his or her anxiety. The therapist may challenge the patient to experience the maximum amount of anxiety. In prolonged in vivo exposure, the therapist and patient stay in the situation as long as it takes for the anxiety to decrease. For example, they might remain in a crowded shopping mall for four or more hours. The therapist also explores the patient's thoughts during this exposure so that any irrational ways of thinking can be confronted.
GROUP EXPOSURE. In group exposure, self-exposure and practice are combined with group education and discussion of experiences during exposure to feared situations. These sessions may last as long as three hours and include 30 minutes of education, time for individual exposure practice, and 45 minutes of discussion. Group sessions may be scheduled on a daily basis for 10–14 days.
Exposure treatment for specific anxiety disorders
AGORAPHOBIA. Many research studies have shown that graded exposure treatment is effective for agoraphobia. Long-term studies have shown that improvement can be maintained for as long as seven years. Exposure treatment for agoraphobia is best done in vivo, in the actual feared situation, for example entering a packed subway car. Exposure treatment for agoraphobia is likely to be more effective when the patient's spouse or friend is involved, perhaps because of the support a companion can offer the patient during practice sessions.
PANIC DISORDER. Exposure treatment is the central component of cognitive-behavioral treatment for panic disorder. Treatment for this disorder involves identifying specific fears within the patient's experience of panic, such as fears of being sick, fears of losing control, and fears of embarrassment. Once these fears are identified, the patient is instructed to expose himself or herself to situations in which the fearful thoughts arise (walking away from a safe person or place, for example). The rationale behind this instruction is that enduring the anxiety associated with the situation will accustom the patient to the situation itself, so that over time the anxiety will diminish or disappear. In this way, the patient discovers that the feared consequences do not happen in real life.
In some patients, physical symptoms of panic lead to fears about the experience of panic itself. Fears related to the physical symptoms associated with panic can be targeted for treatment by inducing the bodily sensations that mimic those experienced during a panic attack. This technique is called interoceptive exposure. The patient is asked to induce the feared sensations in a number of ways. For example, the patient may spin in a revolving chair to induce dizziness or run up the stairs to induce increased heart rate and shortness of breath. The patient
Interoceptive exposure treatment for panic usually begins with practice sessions in the therapist's office. The patient may be instructed to practice at home and then practice in a less "safe" environment, such as the patient's work setting or a nearby park. The next step is the addition of the physical activities that naturally produce the feared symptoms. Situational or in vivo exposure would then be introduced for patients with agoraphobia combined with panic disorder. The patient would be instructed to go back into a situation that he or she has been avoiding, such as an elevator or busy railroad terminal. If the patient develops symptoms of anxiety, he or she is instructed to use the techniques for controlling anxiety that were previously learned.
The effectiveness of exposure treatment for decreasing panic attacks and avoidance has been well demonstrated. In research studies, 50%–90% of patients experience relief from symptoms.
SPECIFIC PHOBIA AND SOCIAL PHOBIA. Graded exposure is used most often to treat specific phobia or simple phobia. In graded exposure, the patient approaches the feared object or situation by degrees. For example, someone afraid of swimming in the ocean might begin with looking at photographs of the ocean, then watch movies of people swimming, then go to the beach and walk along the water's edge, and then work up to a full swim in the ocean. Graded exposure can be done through patient-directed instruction or therapist-assisted exposure. Research studies indicate that most patients respond quickly to graded exposure treatment, and that the benefits of treatment are well maintained.
Treatment for social phobia usually combines exposure treatment with cognitive restructuring. This combination seems to help prevent a recurrence of symptoms. In general, studies of exposure treatment for social phobia have shown that it leads to a reduction of symptoms. Since cognitive restructuring is usually combined with exposure, it is unclear which component is responsible for the patients' improvement, but there is some indication that exposure alone may be sufficient.
Exposure treatment can be more difficult to arrange for treating social phobia, however, because the patient has less control over social situations, which are unpredictable by their nature and can unexpectedly become more intense and anxiety-provoking. Furthermore, social exchanges usually last only a short time; therefore, they may not provide the length of exposure that the patient needs.
OBSESSIVE-COMPULSIVE DISORDER. The most common non-medication treatment for obsessive-compulsive disorder (OCD) is exposure to the feared or anxiety-producing situation plus response prevention (preventing the patient from performing a compulsive behavior, such as hand washing after exposure to something thought to be contaminated). This form of treatment also uses a hierarchy, and begins with the easiest situation and gradually moves to more difficult situations. Research has shown that exposure to contamination situations leads to a decrease in fears of contamination, but does not lead to changes in the compulsive behavior. In a similar fashion, the response prevention component leads to a decrease in compulsive behavior, but does not affect the patient's fears of contamination. Since each form of treatment affects different OCD symptoms, a combination of exposure and response prevention is more effective than either modality by itself. Exposure combined with response prevention also appears to be effective for treating OCD in children and adolescents.
Prolonged continuous exposure is better than short, interrupted periods of exposure in treating OCD. On average, exposure treatment of OCD requires 90-minute sessions, although the frequency of sessions varies. Some studies have shown good results with 15 daily treatments spread over a period of three weeks. This intensive treatment format may be best suited for cases that are more severe and complex, as in patients suffering from depression as well as OCD. Patients who are less severely affected and are highly motivated may benefit from sessions once or twice a week. Treatment may include both therapist-assisted exposure and self-exposure as homework between sessions. Imaginal exposure may be useful for addressing fears that are hard to include in vivo exposure, such as fears of a loved one's death. Patients usually prefer gradual exposure to the most distressing situation in their hierarchy; however, gradual exposure does not appear to be more effective than flooding or immediate exposure to the situation.
POST-TRAUMATIC STRESS DISORDER. Exposure treatment has been used successfully in the therapy of post-traumatic stress disorder (PTSD) resulting from such traumatic experiences as combat, sexual assault, and motor vehicle accidents. Research studies have reported encouraging results for exposure treatment in reducing PTSD or PTSD symptoms in children, adolescents, and adults. Such intrusive symptoms of PTSD as nightmares and flashbacks may be reduced by having the patient relive the emotional aspects of the trauma in a safe therapeutic environment. It may take 10–15 exposure sessions to decrease the negative physical sensations associated with PTSD. These sessions
A recent study showed that imaginal exposure and cognitive treatment are equally effective in reducing symptoms associated with chronic or severe PTSD, but that neither brought about complete improvement. In addition, more patients treated with exposure worsened over the course of treatment than patients treated with cognitive approaches. This finding may have been related to the fact that the patients receiving exposure treatment had less frequent sessions with long periods of time between sessions. Some patients diagnosed with PTSD, however, do not seem to benefit from exposure therapy. They may have difficulty tolerating exposure, or have difficulty imagining, visualizing, or describing their traumatic experiences. The use of cognitive therapy to help the patient focus on thoughts may be a useful adjunctive treatment, or serve as an alternative to exposure treatment.
Many persons who have undergone sexual assault or rape meet DSM-IV-TR criteria for PTSD. They may re-experience the traumatic event, avoid items or places associated with the trauma, and have increased levels of physical arousal. Exposure treatment in these cases involves using either imaginal or in vivo exposure to reduce anxiety and any tendencies to avoid aspects of the situation that produce anxiety (also known as avoidance behavior). Verbal description of the event (imaginal exposure) is critical for recovery, although it usually feels painful and threatening to patients. It is important that the patient's verbal description of the traumatic event, along with the expression of thoughts and feelings related to it, occur as early in the treatment process as possible. It is in the patient's "best long-term interest to experience more discomfort temporarily in order to suffer less in the long run."
Prolonged exposure is the most effective non-medical treatment for reducing traumatic memories related to PTSD. It combines flooding with systematic desensitization. The goal is to expose patients using both imaginal and in vivo exposure techniques in order to reduce avoidance behavior and decrease fears. Prolonged exposure may occur over nine to 12 ninety-minute sessions. During the imaginal exposure phase of treatment, the patient is asked to describe the details of the traumatic experience repeatedly, in the present tense. The patient uses the SUDS scale to monitor levels of fear and anxiety. The in vivo component occurs outside the therapist's office; it involves the client exposing himself or herself to cues in the environment that he or she has been avoiding— for example, the place where the motor vehicle accident or rape occurred. The patient is instructed to stay in the fear-producing situation for at least 45 minutes, or until their anxiety levels have gone down significantly on the SUDS rating scale. Often patients will use a coach or someone who will stay with them at the beginning of in vivo practice. The coach's role gradually decreases over time as the patient experiences less anxiety.
Recent innovations in exposure treatment
VIRTUAL REALITY EXPOSURE TREATMENT. Virtual reality is a technique that allows a person to participate actively in a computer-generated (or virtual) scenario or environment. The participant has the sense of being present in the virtual environment. Virtual reality uses a device mounted on the participant's head that shows computer graphics and visual displays in real time, and tracks the person's body movements. Some forms of virtual reality also allow participants to hold a second device in their hands that enables them to interact more fully with the virtual environment, such as opening a car door.
Virtual reality has been proposed as a new way of conducting exposure therapy because it can provide a sense of being present in a feared situation. Virtual reality exposure may be useful for treating such phobias as fear of heights, flying, or driving, as well as for treating PTSD. This method appears to have several advantages over standard exposure therapy. First, virtual reality may offer patients a greater sense of control because they can instantly turn the device on and off or change its level of intensity. Second, virtual reality would protect patients from harm or social embarrassment during their practice sessions. Third, it could be implemented regardless of the patient's ability to imagine or to remain with prolonged imaginal exposure. These proposed advantages of virtual reality over standard exposure therapy have yet to be tested, however.
Some studies have been conducted using virtual reality in the treatment of patients with fear of heights and fear of flying, and in a sample of Vietnam veterans diagnosed with PTSD. These studies of virtual reality exposure therapy have limitations in terms of study design and small sample size, but their positive results suggest that virtual reality exposure therapy deserves further investigation.
CUE EXPOSURE TREATMENT FOR ALCOHOL DEPENDENCE. Cue exposure is a relatively new approach to treating substance-related disorders. It is designed to recreate real-life situations in a safe therapeutic environment that expose patients repeatedly to alcohol-related cues, such as the sight or smell of alcohol. It is thought that this repeated exposure to cues, plus prevention of the usual response (drinking alcohol) will reduce and possibly eliminate urges experienced in reaction to the cues.
Persons diagnosed with alcohol dependence face a number of alcohol-related cues in their environment, including moods associated with previous drinking patterns;
There are various approaches to cue exposure. The choice of cues is usually based on treatment philosophy and goals, which may require abstinence from alcohol or permit moderate drinking. In abstinence-only programs, patients may be exposed to actual alcohol cues and/or imagined high-risk situations. This imaginal exposure is useful for dealing with cues and circumstances that cannot be reproduced in treatment settings, such as fights. Patients learn and practice urge-specific coping skills. While a patient may learn to cope successfully with one cue (such as the smell of alcohol), the urge to drink may reappear in response to another cue, such as seeing a friend with whom they used to go to bars. The patient would then learn how to manage this particular cue. This program may take six to eight individual or group sessions and may occur on an inpatient or outpatient basis. Often patients remain in the treatment setting for several hours after the exposure to ensure that any lasting urges are safely managed with the therapist's help.
More specifically, cue exposure focuses on the aspect of alcohol consumption that produces the strongest urge. The patient would report each change in their level of urgency, using a scale of zero to ten that resembles the SUDS scale. The urge to drink usually peaks after one to five minutes. When the desire for a drink arises, the patient is instructed to focus on the cue to see what happens to their desire. In most cases the urge subsides within 15 minutes, which is often different from what the patient expected. In later sessions, the patient is instructed when the urge peaks to imagine using the coping skills that he or she was recently taught. The patient may also be instructed to imagine being in high-risk situations and using the coping skills. Some examples of these coping skills include telling oneself that the urge will go away; picturing the negative consequences of drinking alcohol; and thinking of the positive consequences of staying sober.
Although there has been little research on cue exposure, available studies show positive outcomes in terms of decreasing the patients' consumption of alcohol. There have been, however, few outcome studies comparing cue exposure treatment to other treatment approaches. It may be hard to separate the benefits due to exposure from the benefits due to coping skills training. In any event, cue exposure treatment is a promising approach that deserves further study to determine if either component alone is sufficient or if a combination of the two is more effective.
Progress in exposure therapy is often slow in the beginning, and occasional setbacks are to be expected. As the patient gains experience with various anxiety-producing situations, his or her rate of progress may increase. While flooding can produce positive results more quickly than graded exposure, it is rarely used because of the high level of discomfort associated with it.
See also Agoraphobia; Alcohol and related disorders; Anxiety and anxiety disorders; Anxiety-reduction techniques; Cognitive-behavioral therapy; Obsessive-compulsive disorder; Panic attack; Panic disorder; Systematic desensitization
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Joneis Thomas, Ph.D. |
<urn:uuid:fc130b53-d16e-4e61-9dec-43882eeb5639> | seed | The report by scientists in New York offers more good news for the burgeoning field of cancer immunotherapy, which uses what some describe as a "living drug" that was hailed by Science magazine as the breakthrough of 2013.
The latest trial, published in the journal Science Translational Medicine, involved 16 people with a kind of blood cancer known as adult B cell acute lymphoblastic leukemia (ALL).
Some 1,400 people die of ALL in the United States each year, and while it is among the most treatable cancers, patients often become resistant to chemotherapy and eventually relapse.
For this study, 14 of 16 adult patients achieved complete remission after their T cells were genetically engineered so that they could focus on eradicating cancer.
The patients' median age was 50, and they were all on the brink of death when they entered the trial, having relapsed or discovered that chemotherapy was no longer working.
The longest remission among them so far is about two years, and that patient is still going strong, said lead author Renier Brentjens, director of cellular therapeutics at Memorial Sloan Kettering Cancer Center.
Without this therapy, just 30 percent of relapsed patients would be expected to respond to salvage chemotherapy.
- 'Re-educating' T cells -
The process involves removing some of the patient's T-cells and altering them with a gene to make them recognize a protein, known as CD19, on the cancer cells, so that they can attack them.
Left to their own devices, T cells can attack other harmful invaders in the body but will allow cancer to grow uninterrupted.
"Basically, what we do is re-educate the T cell in the laboratory with gene therapy to recognize and now kill tumor cells," Brentjens said.
After 15 years of work on the technology, known as tumor-targeted chimeric antigen receptor–modified T cells, "it seems to really work in patients with this particular type of cancer," Brentjens told AFP.
Last year, his team reported the first promising results in five adult patients who achieved remission after the therapy.
He estimated that between 60 and 80 people in the United States have since entered experimental trials of the new treatment, which is also being studied in Europe.
- 'Not a fluke' -
In December 2013, experts from multiple US centers where trials are ongoing presented their findings at the American Society of Hematology (ASH) annual meeting, including the University of Pennsylvania, which is also studying the approach in adults with chronic lymphocytic leukemia (CLL).
The Children's Hospital of Philadelphia is enrolling pediatric patients in trials of T-cell therapy.
Brentjens said other US centers have shown similar remission rates in their studies so far, "demonstrating that this isn't a fluke."
"This is a real phenomenon," he told AFP. "This could be a paradigm shift in the way we approach cancer therapy."
Kanti Rai, chief of the CLL Research and Treatment Program at North Shore-LIJ Health System in New York, described the latest study as "a major service to all of us."
Rai, who was not involved in the research, noted that it has been a few years since scientists first reported on their initial success against CLL.
"In the present report, we are told that equally dramatic and excellent results were obtained when a more frightening and fatal disease, such as adult ALL was the enemy," said Rai.
Researchers are still trying to figure out why it does not work in all patients.
Efforts are also ongoing to identify cancer-specific receptor cells that could allow the technique to tackle other types of tumors.
"The expansion to other kinds of cancers is next on the to-do list," said Brentjens.
In the meantime, the therapy remains expensive, costing around $100,000 per patient, a price tag experts believe will come down once pharmaceutical companies get more involved and the technique becomes more widespread. |
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Am Fam Physician. 2003 Dec 1;68(11):2277-2280.
AHRQ Criteria on Disability in Infants and Children
The Agency for Healthcare Research and Quality (AHRQ) has issued three guidelines to assist the Social Security Administration in determining disability in infants and children with low birth weights, failure to thrive, and short stature. The full evidence reports are available online at http://www.ahrq.gov.
Low Birth Weight. The AHRQ investigated the presence of developmental disability in former premature infants and risk for long-term developmental disabilities. Among the 4 million infants born in the United States in 2000, about 58,000 (1.5 percent) weighed less than 1,500 g (3.3 lb). This category of infants has the highest neonatal mortality and morbidity. The AHRQ found evidence that infants who weigh less than 1,500 g at birth are at increased risk for cerebral palsy, major neurologic disability, cognitive abnormality in early childhood, mental retardation, blindness, hearing loss, and growth impairment. Infants with very low birth weights and bronchopulmonary dysplasia also are at increased risk for long-term pulmonary disability.
Failure to Thrive. The underlying cause of failure to thrive is insufficient nutrition. This may occur when sufficient nutrients are not available to the child as a result of social or environmental causes that prevent parents from obtaining, preparing, or offering age-appropriate food. This growth failure often includes concurrent and potentially persistent disability.
Almost any serious childhood illness also can result in failure to thrive through the following mechanisms:
Insufficient nutrition because of the child's inability to feed properly (e.g., severe neurologic dysfunction, gastroesophageal reflux, cleft palate).
Nutrition is adequate but inadequately absorbed (e.g., malabsorption syndromes).
The disease process creates added metabolic requirements (e.g., asthma, cardiac failure, thyroiditis).
Failure to thrive may be the first clue to an active disease process that has not yet manifested with specific symptoms.
Severe malnutrition has been shown to cause permanent damage to various parts of the brain and central nervous system, leading to a range of disabilities manifested by aberrant behavior, cognitive, language, and motor development. Failure to thrive also is closely linked with infectious disease.
Children who are undernourished consistently have been found to have significant and profound changes in cell-mediated immunity, complement levels, and opsonization that lead to susceptibility to various infections. Failure to thrive also is associated with disabilities in cardiac function, gastrointestinal conditions, persistently small stature, and other physiologic problems.
The AHRQ found evidence that in developed countries, failure to thrive is associated with growth retardation that persists despite adequate correction of malnutrition.
Short Stature. Medically determinable causes of short stature include abnormalities in the growth hormone axis (e.g., decreased growth hormone production, diminished response to growth hormone). Other endocrine abnormalities such as hypothyroidism and Cushing's disease may lead to short stature, as can a variety of genetic disorders, including chromosomal, metabolic, and single gene disorders.
Skeletal dysplasias are genetic disorders that result in abnormal formation of part or all of the skeleton. The skeletal dysplasias most likely to lead to short stature are those that involve formation and growth of the long bones or the spine. The AHRQ found that children with skeletal dysplasias are not at increased risk for severe impairments in intelligence, academic achievement, or psychologic outcomes. There was an increased risk for delay in achievement of motor skills in children with achondroplasia and osteogenesis imperfecta, and decreased ambulation, range of motion, and mobility in children with more severe forms of osteogenesis imperfecta.
The presence of a chronic disease in a child is known to be a risk factor for decreased growth to a varying degree. However, the underlying cause of the decreased growth has not been determined in all chronic diseases.
The AHRQ found that children with short stature do not have enough difficulties with academic achievement to qualify as a disability.
CDC Guidelines for Infection Control
The Centers for Disease Control and Prevention (CDC) has issued guidelines for controlling environmental infection in health care facilities. The full report is available online at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5210a1.htm.
Although health care facilities rarely are implicated in disease transmission, inadvertent exposures to environmental or airborne pathogens can result in adverse patient outcomes and cause illness among health care workers. Environmental infection-control strategies and engineering controls can effectively prevent these infections.
Included in the recommendations are standards for the following:
Design and maintenance of air-handling systems.
Demolition, construction, repair, and renovation projects.
Ventilation requirements for protective environment, airborne infection isolation, and operating rooms.
Control of waterborne microorganisms in distribution systems, ice machines, and hydrotherapy tanks.
Cleaning and disinfecting surfaces in patient-care areas.
Cleaning blood and body substance spills.
Allowing flowers and plants in patient-care areas.
Handling of laundry and bedding.
Sampling of air, water, and environmental surfaces.
Handling of animals in health care facilities.
Handling, transporting, storing, and disposal of medical waste.
The CDC concludes that the incidence of infections and pseudo-outbreaks can be minimized by appropriate use of cleaners and disinfectants, appropriate maintenance of medical equipment, adherence to water-quality standards for hemodialysis and ventilation standards for specialized care environments, and prompt management of water intrusion into the health care facility.
New Web Site on Hormone Therapy
The U.S. Food and Drug Administration (FDA) has launched a Web site containing information about hormone therapy for women. Recent clinical trial data regarding the usage of hormone therapy through menopause and beyond has created confusion and concern for many women. The Web site is available at http://www.fda.gov/womens/menopause.
The Web site contains information for women about hormones, hormone therapy, and a pocket guide that women can carry to their physician's office when discussing therapy options. The guide explains how to weigh the risks and benefits of both estrogen-progestin combination and estrogen alone.
Print versions of the resources can be ordered online or by calling 800-994-9662.
The U.S. Food and Drug Administration has approved lamotrigine (Lamictal) for the long-term maintenance treatment of adults with bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.
The FDA has noted that the findings for lamotrigine maintenance treatment were more robust in bipolar depression. The effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.
According to the manufacturer, the most common side effects are nausea, insomnia, somnolence, back pain, fatigue, rhinitis, nonserious rash, abdominal pain, dry mouth, constipation, vomiting, exacerbation of cough, and pharyngitis. Serious rashes requiring hospitalization and discontinuation of therapy, such as Stevens-Johnson syndrome, have been reported in association with the use of lamotrigine. The safety and effectiveness of lamotrigine have not been established as initial monotherapy, for conversion to monotherapy from nonenzyme-inducing antiepileptic drugs, or for simultaneous conversion to monotherapy from two or more concomitant antiepileptic drugs.
Lamotrigine has been available since 1994 and is indicated as adjunctive therapy for partial seizures in adults and children.
Copyright © 2003 by the American Academy of Family Physicians.
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<urn:uuid:c0cf48dc-e934-4169-8998-de14310edf1c> | seed | What would you do with a 15-year window between the diagnosis and the onset of a terminal illness? Most likely, everything possible to slow the progress of the disease.
With Alzheimer’s disease (AD), there is on average a 15-year gap between the development of amyloid plaques in the brain and the presentation of symptoms. But researchers at the University of Pennsylvania believe they may have found a drug treatment that prevents amyloid formation, which could slow AD onset.
Amyloid plaques are caused by a build-up of the amyloid-beta (Aβ) peptide in the brain and are thought to be a trigger for AD. All of us, even the young and healthy, have Aβ in their brain along with spinal fluid. We get into trouble when there is too much build up over too long a period of time.
Amyloid plaques and neurofibrillary tangles are characteristic of AD, an illness that affects more than five million Americans, according to the Alzheimer’s Association. AD is the most common form of dementia, and is associated with the loss of brain function, memory, and motor skills.
Antidepressant medications are used to boost levels of the neurotransmitter serotonin. In a report published in Science Translational Medicine, researchers say they have found that the chemical can also reduce Aβ concentration by limiting its production. For preventing AD, the next step may be an antidepressant.
The formula is simple: more serotonin means less Aβ. Researchers focused on selective serotonin reuptake inhibitor (SSRI) drugs, which block the absorption of serotonin that the brain releases naturally, increasing the amount of serotonin that's available. Specifically, researchers focused on the effects of the drug citalopram in mouse studies.
In these mouse models of AD, citalopram stopped the growth of amyloid plaques and reduced the formation of new plaques by 78 percent. “We used citalopram because it is one of the most selective SSRIs—but all the SSRIs we've tested so far in mouse models work to lower amyloid concentrations,” says study co-author Dr. Yvette Sheline, a professor of psychiatry at the University of Pennsylvania’s Perelman School of Medicine.
In addition to mouse studies, Sheline and her team found that citalopram lowered levels of Aβ in the cerebrospinal fluid (CSF) of young and healthy humans by 37 percent, compared to a group of healthy human volunteers who took a placebo pill.
While moving from mouse models to human testing will require clearing some high hurdles, it’s possible that antidepressants or another form of SSRI drugs will be used to slow AD onset in the future.
“We still have more work to do before prevention trials could be undertaken,” Sheline says. “The next step we will take—we are starting this study momentarily—is to enroll older cognitively normal volunteers to have their CSF tested for amyloid concentration before and after taking [an] SSRI or placebo for two weeks. This will enable us to determine if the drug effect is sustained.”
“If that trial is successful then we will plan a prevention trial where we use [an] SSRI to treat cognitively normal elderly [people] at risk for AD and where we hope to show that giving [an] SSRI for several years prevents brain plaque growth,” Sheline adds.
Stopping AD before it starts? Suffice it to say that using an already approved SSRI to prevent AD in elderly patients would be tremendous step forward. |
<urn:uuid:7dcea3a0-836c-43d1-a95b-7fc70ded2b1e> | seed | Clostridium perfringens bacterium is a normal bacteria found in the environment, commonly inhabiting decaying vegetation and marine sediment, as well as raw or improperly cooked meats and poultry. However, when abnormally high levels of this bacteria is found in the intestine, it can lead to Clostridial enterotoxicosis.
Generally, the implications of the intestinal syndrome are limited to infections of the intestinal tract and do not progress to systemic disease conditions. Symptoms typically last a week in acute cases and include diarrhea, abdominal pain, and nausea. Long-term (chronic) cases of clostridial enterotoxicosis, meanwhile, involve recurrences of diarrhea, which may repeat every two to four weeks, and may continue for months to years.
When compared to its incidence in dogs, this is an uncommon condition in cats. Most animals have antibodies that will effectively fight the bacteria and clear it from the body.
Clostridial enterotoxicosis is caused by an overgrowth of the bacteria Clostridium perfringens in the intestine. Often, the bacteria is acquired from the environment (e.g., flora) or as the result of eating raw, undercooked, or old meat. Other risk factors include:
You will need to give a thorough history of your cat's health, onset of symptoms, and possible incidents that might have precipitated/preceded this condition, such as time spent outdoors, rummaging through garbage or getting hold of old or uncooked meat, or being boarded at a kennel.
Your veterinarian will conduct a thorough physical exam on your cat as well as standard blood work, including a complete blood count, chemical blood profile, and urinalysis. Most of these tests will return normal. Because this infection has obvious intestinal symptoms, a fecal sample will need to be taken for microscopic analysis.
This intestinal disease is sometimes difficult to identify because there is no one good test for it. Often, false positive results will return as the result of interfering substances in the feces. Your veterinarian may also want to use an endoscope to visualize the interior of your cat's intestines, and possibly take a tissue sample.
The organisms and bacteria that are found inside the gastrointestinal system
A type of slime that is made up of certain salts, cells, or leukocytes
An in-depth examination of the properties of urine; used to determine the presence or absence of illness
The digestive tract containing the stomach and intestine
Something that is related to the whole body and not just one particular part or organ
A medical condition in which the small intestine and stomach become inflamed
The singular form of the word bacteria; a tiny, microscopic organism only made up of one cell.
The exiting of excrement from the body; bowel movements.
A type of instrument that is used to look inside the body
Term used to imply that a situation or condition is more severe than usual; also used to refer to a disease having run a short course or come on suddenly. |
<urn:uuid:35f65bb5-a63c-4161-9cf0-6b145395e78d> | seed | Polymeric Nanoparticles for Tumor Vaccines
The quest for an effective antitumor vaccine has received a boost from the results of work aimed at developing a nanoparticle that delivers tumor antigens to the immune system cells that trigger antibody production. The results of this effort, led by Shinsaku Nakagawa, Ph.D., and Naoki Okada, Ph.D., of Osaka University in Japan, were published in the journal Biochemical and Biophysical Research Communications.
Vaccines are complex preparations of proteins and other materials designed to produce maximal immune response to those proteins. One factor that determines a vaccine’s potency is the ability of this mixture to trigger a recognition event between the protein antigen and immune system cells known as antigen-presenting cells (APCs). Using the biocompatible polymer poly(y-glutamic acid), the investigators were able to create self-assembling nanoparticles that entrap proteins as they form. The resulting nanoparticles were relatively stable, releasing their protein content over the course of a month. The investigators also demonstrated that they could freeze-dry these nanoparticles and reconstitute them without altering the functionality of the entrapped protein, a desirable property for any vaccine vehicle designed for use outside of major medical centers.
To determine whether these nanoparticles would trigger a useful immune response, the investigators entrapped the protein ovalbumin in the nanoparticles and then immunized three sets of mice with a metastatic ovalbumin-producing mouse melanoma. One set of mice received the nanoparticle, and the other two were immunized with either ovalbumin or a saline solution. Immunization consisted of three injections over the course of 1 week. Eighteen days after the last injection, the investigators examined the lungs of the treated mice, finding that there were virtually no metastatic lesions in the lungs of the nanoparticle-immunized mice. In contrast, mice immunized with either ovalbumin or saline had large numbers of metastatic nodules in their lungs.
Further experiments showed that the nanoparticles were taken up efficiently by APCs. In addition, the nanoparticles were able to traffic out of endosomes and release their protein antigens into the cytoplasm of the APCs, boosting the immune response to the antigen.
This work is detailed in the paper “Development of amphiphilic gamma-PGA-nanoparticle based tumor vaccine: potential of the nanoparticulate cytosolic protein delivery carrier.” An abstract of this paper is available through PubMed.View abstract |
<urn:uuid:83cf0d3e-cb82-48c6-99c4-6a8d59ffaad0> | seed | A new, easy-to-perform method for detecting both seasonal influenza A virus and the emerging H1N1 swine-derived influenza A virus in human clinical samples offers a fast, sensitive, and cost-effective diagnostic test that runs on standard laboratory equipment. This timely and broadly applicable molecular technique is described in a new article.
The recent emergence and global spread of a new swine flu virus highlights the urgent need for a reliable diagnostic test that can discriminate the H1N1 influenza virus from other strains and can be readily implemented in clinical testing laboratories. The molecular strategy described in the article in Vector-Borne and Zoonotic Diseases is based on proven and widely used Real-Time, Polymerase Chain Reaction (RT-PCR) technology.
The authors of the report describe the development of a new molecular probe that improves on the existing PCR assay used to diagnose seasonal influenza and enables detection of both the seasonal and H1N1 influenza A viruses in the same patient sample using a simple test protocol. Laetitia Ninove and colleagues from Université de la Méditerranée and Institut de Recherche pour le Développement (Marseille, France), Hôpitaux de Marseille, CEH Oxford (UK), and EHESP School of Public Health (Rennes, France) provide data to support the sensitivity and effectiveness of the SYBR Green RT-PCR one-step assay used for screening clinical samples to detect the presence of influenza A virus. In positive samples this is followed by the addition of two probes that are able to discriminate between the seasonal and swine H1N1 viruses to yield a definitive diagnosis.
Early, accurate identification of infected individuals will expedite appropriate antiviral therapy and enhance control and containment efforts. Furthermore, this new molecular test specifically amplifies and characterizes the viral genetic material, enabling rapid detection of new viral strains as they evolve. Using these genetic sequence data and making minor alterations to the PCR primers used in the assay, the test could be easily modified to detect newly emerging viral variants, including avian influenza strains.
"Early recognition of new influenza strains is vitally important for implementing effective control measures to limit spread. This cost-effective, comprehensive, and rapid test is a highly significant contribution to diagnostics that will greatly enhance our capacity to deal with future influenza outbreaks," says Stephen Higgs BSc, PhD, FRES, Editor-in-Chief of Vector-Borne and Zoonotic Diseases, and Associate Professor, Department of Pathology, Center for Biodefense & Emerging Infectious Diseases, Sealy Center for Vaccine Development and WHO Collaborating Center for Tropical Diseases, University of Texas Medical Branch, Galveston.
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<urn:uuid:e17fdb9d-4100-439c-becf-b54196ffc606> | seed | I’ve been playing phone tag with a friend recently. I guess it’s not too surprising considering that we’re all especially busy this time of year and she has a newborn (and four older children) in the house. I am hoping we get in touch with each other soon, though. She wants advice about coming up with a deworming protocol for her puppy and cats. She’s worried (and so am I) about the possibility that her pets could pass parasites on to her kids.
My two biggest concerns are hookworms (Ancylostoma spp.) and roundworms (Toxocara spp.). Here’s what the Centers for Disease Control (CDC) has to say about the zoonotic potential (the ability of animal diseases to spread to people) of these two parasites.
Puppies and kittens are especially likely to have hookworm infections. Animals that are infected pass hookworm eggs in their stools. The eggs can hatch into larvae, and both eggs and larvae may be found in dirt where animals have been. People may become infected while walking barefoot or when exposed skin comes in contact with contaminated soil or sand. The larvae in the contaminated soil or sand will burrow into the skin and cause the skin to become irritated in that area. For example, this can happen if a child is walking barefoot or playing in an area where dogs or cats have been (especially puppies or kittens).
Most animal hookworm infections result in a skin condition called cutaneous larva migrans. People are infected when animal hookworm larvae penetrate the skin, causing a local reaction that is red and itchy. Raised, red tracks appear in the skin where the larvae have been and these tracks may move in the skin day to day, following the larvae’s movements. The symptoms of itching and pain can last several weeks before the larvae die and the reaction to the larvae resolves. In rare cases, certain types of animal hookworm may infect the intestine and cause abdominal pain, discomfort, and diarrhea.
The most common Toxocara parasite of concern to humans is T. canis, which puppies usually contract from the mother before birth or from her milk. The larvae mature rapidly in the puppy’s intestine; when the pup is 3 or 4 weeks old, they begin to produce large numbers of eggs that contaminate the environment through the animal’s stool. [People] can become infected after accidentally ingesting (swallowing) infective Toxocara eggs in soil or other contaminated surfaces. There are two major forms of toxocariasis:
- Ocular toxocariasis: Toxocara infections can cause ocular toxocariasis, an eye disease that can cause blindness. Ocular toxocariasis occurs when a microscopic worm enters the eye; it may cause inflammation and formation of a scar on the retina.
- Visceral toxocariasis: Heavier, or repeated Toxocara infections, while rare, can cause visceral toxocariasis, a disease that causes abnormalities in the body’s organs or central nervous system. Symptoms of visceral toxocariasis, which are caused by the movement of the worms through the body, include fever, coughing, asthma, or pneumonia.
The best way to protect people from hookworms and roundworms is for all of us to pick up pet feces immediately when in a public environment and on a daily basis in our own yards, and to follow a veterinarian’s recommendation regarding fecal examinations and deworming. Hopefully I’ll get a chance to talk to my friend about this soon.
Dr. Jennifer Coates
Healthy Pets Healthy People. National Center for Infectious Diseases. Centers for Disease Control. Accessed 12/17/2012
Last reviewed on August 14, 2015 |
<urn:uuid:5889c777-faa0-49fa-9b2b-972771a415be> | seed | Regulation of Gene Expression: Building Transcriptional Regulatory Complexes
INTRODUCTION. More than thirty years ago Francois Jacob and Jacques Monod described the first paradigm for differential gene expression. They proposed that regulation of the switching on and off of genes involved in sugar (lactose) metabolism in bacterial cells is accomplished by the binding of regulatory proteins to regulatory DNA sequences. Looking back it is amazing how prescient they were because we now know that, in general, eukaryotic genes also contain regulatory sequences in their DNA called enhancers and promoters. Gene expression in eukaryotic cells occurs when: (i) genes encoded by the cell's DNA are copied into mRNAs by transcription (much of the regulation of differential gene expression takes place at the level of transcription) and (ii) specific mRNAs are used as templates to make specific proteins in translation. But every gene is not expressed in every cell type (differential gene regulation). Thus, regulation of gene expression can be described as follows: A human cell contains about 100,000 genes, but each specific cell type expresses only about 10,000 genes. The production of a specific collection of proteins by a specific cell type is the result of differential gene expression.
PROMOTERS AND ENHANCERS. Promoters constitute binding sites for RNA polymerase and the general transcription factors. In eukaryotic cells, RNA Polymerase II (RNAPII; a large complex of proteins whose enzymatic activity does the actual copying of DNA into RNA during transcription) is responsible for the transcription of protein-encoding genes. RNAP's helper proteins are the so-called general transcription factors. Together, RNAPII and the general transcription factors are involved in the transcription of nearly every protein-encoding gene. Enhancers are DNA binding sites for gene-specific trancriptional regulatory proteins (proteins that regulate the transcription of one or a subset of genes). In bacteria, generally one protein binds to a single regulatory sequence in the DNA and turns transcription on or off. In eukaryotes, gene transcription is regulated by enhancer DNA sequences that contain not one but multiple regulatory DNA sequence elements that represent binding sites for multiple transcription factors. DNA-bound transcriptional regulatory proteins come together [through protein-protein interactions] to form gene-specific transcriptional regulatory complexes. So it is not a single factor and binding site, but, rather, the specific combination of DNA sequence elements and regulatory proteins that determines which genes will be transcribed in which cell types, a concept known as combinatorial regulation of gene expression. These gene-specific trancription complexes relay trancriptional regulatory information to RNAPII and help to determine whether a gene is transcriptionally active or silent under specific conditions (for example, at a specific time in development; in a particular cell type).
ANIMAL VIRUSES AS MODEL SYSTEMS FOR STUDIES ON TRANSCRIPTIONAL REGULATORY COMPLEXES. What general principles have emerged from studies of transcriptional regulation? In many cases, viruses that infect mammalian cells have served as model systems for studies of eukaryotic gene regulation. Because the virus uses some of the host cell machinery to carry out its own processes, the virus provides us with a window through which to observe regulatory mechanisms operating in animal cells. A model system that has been intensively studied is the Herpes simplex virus (HSV) immediate early (IE) enhancer. Soon after entry of a host cell by HSV, a lytic infection is initiated by activation of transcription of the five IE genes in the HSV genome. Induction of IE gene transcription relies on cellular proteins that interact with the viral transcriptional activating protein VP16. These host cell proteins along with VP16 form multicomponent regulatory complexes on the IE enhancer that activate IE transcription. The IE enhancer contains one or more copies of two distinct regulatory DNA elements, one with the sequence TAATGARAT and the other consisting of repeats of the sequence CGGAAR (A=adenine, T=thymine, C=cytosine, G=guanine, and R = any of the four bases found in DNA, i.e., A, C, T, or G). Investigators were surprised to discover that VP16 does not itself bind to either of these DNA sequences. Rather, the TAATGARAT and CGGAAR elements in the HSV genome constitute binding sites for cellular proteins that bind to DNA in a sequence specific manner.
THE CGGAAR ELEMENT. In order to understand the mechanisms of regulation of IE gene transcription, it was necessary to identify all of the proteins that interact with the IE enhancer and then decipher how they fit together to form transcriptional regulatory complexes. It was shown that one DNA binding activity, called GABP for GA binding protein, was composed of two distinct polypeptides, GABP[alpha] and GABP[beta]. These two proteins, which bind to the CGGAAR element, were first detected in rat liver, and later shown to exist in human tissues. The next step was to unravel the molecular contacts between the proteins and DNA elements that establish the GABP trancriptional regulatory complex. The GABP[alpha] protein contains a domain similar to the DNA binding domain of the ETS family of transcription factors. The so-called ETS domain of GABP[alpha] allows weak binding to DNA, thus providing the first molecular interface of the regulatory complex. GABP[beta] cannot interact with DNA on its own, but in the presence of GABP[alpha], a stable protein-DNA binding complex is formed. What additional contacts are required to build a stable protein-DNA complex at the CGGAAR DNA element? GABP[beta] also interacts with the ETS domain of GABP[alpha] via a series of four tandem 33--amino acid repeats (the ankyrin repeats) found in [beta]. It is interesting that this protein-protein contact surface is also used by other proteins like the red blood cell membrane protein ankyrin, the transcriptional repressor protein IkB, and the developmental regulatory protein Notch from fruit flies. The GABP[beta] protein also contains a domain that facilitates the formation of a tetrameric (four-component) complex consisting of two copies of GABP[alpha] and two copies of GABP[beta]. Other experiments revealed that in the presence of GABP[alpha], GABP[beta], too, makes contact with DNA. Recently, the three-dimensional crystal structure of the GABP complex was determined (see references below).
THE TAATGARAT ELEMENT. Although the HSV transcriptional activator protein VP16, like GABP[beta], cannot interact with DNA on its own, VP16 can participate in the formation of a stable trancriptional regulatory complex at the TAATGARAT element when VP16 is in the presence of certain cellular proteins. The first step in identifying these cellular proteins came when researchers noticed a similarity in the DNA sequence of the TAATGARAT element and the so-called octamer element, an eight-nucleotide DNA sequence that is recognized by a family of cellular octamer binding proteins. Members of the octamer protein family have been shown to regulate transcription of the immunoglobulin genes in immune (B) cells and to participate in cell type specific transcription in neurons (brain cells). Octamer binding (Oct) proteins interact with DNA with the use of a specific type of protein domain called a homeodomain. Association of the Oct-1 with VP16 also occurs via the homeodomain. Oct-1 is very similar to another family member called Oct-2; both proteins bind on their own to the octamer sequence (ATGCTAAT). However, despite the similarities, Oct-1 and Oct-2 have been implicated in the trancriptional regulation of distinct sets of genes. Two related proteins that recognize identical DNA sequences likely regulate different genes by interacting with different proteins to build unique transcriptional regulatory complexes. For example, although the homeodomains of Oct-1 and Oct-2 differ at just seven out of 60 amino acid positions, only Oct-1 is capable of interacting with VP16.
So far, then, we have the following interaction surfaces: Oct-1 to DNA and VP16 to Oct-1. Further experimentation (including DNA-protein crosslinking studies) revealed that in the presence of Oct-1 and the TAATGARAT DNA sequence, VP16, too, makes contact with DNA (specifically with the GARAT part of the sequence). This sounds very much like the story with GABP[beta]. Like GABP[beta], VP16 must interact with another protein to contact DNA. However unlike GABP[beta], entry of Oct-1 into a stable transcriptional regulatory complex with VP16 and TAATGARAT requires at least one additional cellular protein, HCF (host cell factor). HCF interects with VP16 to aid in the building of a stable transcription complex at the TAATGARAT element. What general principles can we extract from these studies on the HSV IE enhancer: that regulation of transcription involves the precise assembly of specific proteins and DNA elements into unique transcriptional regulatory complexes, and that the stability of the complex is determined by a collection of specific protein-DNA and protein-protein contacts. To summarize, the molecular contacts necessary to build stable transcriptional regulatory complexes on the IE enhancer consist of the following: GABP[alpha] contacts DNA and GABP[beta]; one copy of GABP[beta] contacts DNA and another copy of GABP[beta]d; Oct-1 contacts DNA and VP16; and VP16 contacts DNA and HCF. It is through these additional molecular contacts that proteins that bind DNA weakly on their own (GABP[alpha] and Oct-1) can assemble into a stable transcriptional regulatory complex. These protein-DNA complexes can then regulate transcription of the associated gene.
WHY ARE DIFFERENT GENES EXPRESSED IN DIFFERENT CELL TYPES? Now that we have an idea of how transcriptional regulatory complexes are built, let us return to the problem of cell-type specific gene expression. If every cell in the body contains the same DNA, why do only brain cells produce neurotransmitter proteins and only liver cells produce albumin? Through studies conducted over the past ten to 15 years, transcriptional regulation has emerged as a major control point in cell-type specific gene expression. As an example of cell-type specific transcription, we will consider trancriptional regulatory processes that take place in the fat cell.
ORPHAN RECEPTORS. The so-called orphan receptors constitute an intriguing and ever-growing class of transcriptinal regulatory proteins. Orphan receptor proteins are similar to the steroid hormone receptor class of transcription factors. Steroid hormone receptors are ligand-activated proteins that modulate the transcription of selected genes under specific developmental and metabolic conditions. Steroid hormones (the ligand) enter the cell and exert their effects via the steroid hormone receptor proteins which, upon hormone binding, recognize specific DNA binding sequences (hormone response elements, HRE). The HRE-bound receptor modulates the rate of transcription of the adjacent gene, thereby effecting a change in the cellular phenotype. For the orphan receptors, the physiological regulatory ligands have not yet been identified. The discovery of physiologically relevant ligands is a priority in this field, as their identity may provide clues as to how aspects of physiology and development are regulated and integrated. Orphan receptors participate in a wide variety of biological processes, including liver development, neurogenesis, and modulation of pain. Here, our discussion is limited to a fat cell--specific orphan receptor protein that illustrates seminal concepts in transcriptional regulation.
ADIPOCYTE (FAT CELL) DIFFERENTIATION. In vertebrate organisms like humans, fat cells (adipocytes) serve as a nutritional energy repository. An increase in the number of fat cells in the body, through cellular differentiation, can occur at any point in the life of the organism in response to increased food intake. Cellular differentiation, the process by which a precursor cell becomes a specialized cell, usually involves changes in gene expression. Adipocyte differentiation is characterized by alterations in gene expression and cellular morphology. The metabolic changes that occur in cells during adipocyte development can be mimicked in cell culture. Because the "model" system exists, fat cell development is a widely studied process. Adipocyte P2 (aP2) is an adipocyte-specific intracellular lipid binding protein expressed exclusively in differentiated fat cells. Differentiation-dependent, tissue-specific transcription is directed by an adipocyte-specific enhancer, which is composed of several regulatory DNA elements. One DNA element, termed ARE6, is necessary and sufficient for adipocyte-specific transcription. ARE6 specifies a binding site for specific transcriptional regulatory proteins and exhibits sequence similarity with the HREs. The particular DNA sequence motif found in ARE6 is a preferred binding site for two classes of transcriptional regulatory proteins: the retinoid X receptors (RXRs) and the peroxisome proliferator-activated receptors (PPARs). The RXRs constitute a class of transcription factors that bind to and are activated by physiological compounds called retinoids. The PPARs belong to the steroid hormone receptor superfamily and were discovered as proteins that are activated by agents (hypolipidemic drugs, plasticizers, herbicides) that cause proliferation of peroxisomes in rat liver. Scientists went on to discover a PPAR family member (mPPAR[gamma]2) that is present only in fat cells and showed that a distinct RXR protein and mPPAR[gamma]2 form a protein-protein-DNA complex on the ARE6 element of the aP2 enhancer. Also, introduction of mPPAR[gamma]2 and RXR into cultured cells results in transcriptional activation of the aP2 gene via the aP2 enhancer. This aP2 enhancer activity is stimulated by peroxisome proliferators, fatty acids, and certain retinoids. Although the physiological ligand for mPPAR[gamma]2 is unknown, transcriptional activation by the PPARs is stimulated by various complex fats or lipids, including unsaturated fatty acids and arachidonic acid. However, these naturally occuring lipids have not been shown to bind directly to mPPAR[gamma]2. Because fatty acids can induce transcription of the aP2 gene as well as activate the transcription factor mPPAR[gamma]2, it is likely that mPPAR[gamma]2 facilitates the activation of aP2 transcription by fatty acids in differentiating fat cells.
mPPAR[gamma]2 CAN INDUCE ADIPOCYTE DIFFERENTIATION. If one function of mPPAR[gamma]2 is to induce fat cell differentiation in response to physiological lipid activators like fatty acids, this orphan receptor might provide a molecular means of communication between fat cell differentiation and fat metabolism. In a direct test of this possibility, mPPAR[gamma]2 was introduced into cultured precursor cells and was shown to induce differentiation of these cells into fat cells. Differentiation of these cells into fat cells was potentiated by the addition of known PPAR activators to the cells. When mPPAR[gamma]2 and another protein, C/EBP (which belongs to a different class of transcription factors), were introduced into cultured cells at the same time, the cells differentiated into fat cells even more efficiently. Thus several levels of transcriptional regulation participate to achieve tissue-specific transcription and fat cell differentiation: stimulation by lipid and lipid-like compounds (and potentially by an appropriate physiological ligand), the tissue-specific expression of distinct transcription factors, and the establishment of appropriate molecular contacts among multiple types of transcription factors.
TRANSCRIPTIONAL REGULATION AND CHROMATIN. No article on transcription regulation would be complete without mentioning the concept of chromatin. I introduce the topic briefly here; however, this is an extremely active area of research, and one can find numerous articles on chromatin structure and function in the scientific literature. In eukaryotes, transcription occurs in the context of chromatin, where DNA is wound around a complex of eight histone proteins (this octamer complex contains two of each of four types of histone proteins) to form a structure called a nucleosome. One important consideration is how transcriptional regulatory proteins contend with the inherently repressive effects of chromatin. In general, when promoter and enhancer DNA sequences are reconstituted into nucleosomes in vitro, protein binding to DNA and initiation of transcription is inhibited. However, a number of transcripton factors have the ability to recognize their cognate DNA elements in the context of nucleosomal DNA. Binding of these transcription factors causes a disruption of the nucleosomal structure, such that an adjacent regulatory site becomes available for binding to other gene-specific and general transcriptional regulatory proteins. Scientists are in the process of deciphering fully the mechanisms by which trancriptional regulatory proteins enhance transcription in the context of chromatin.
RNAPII - RNA polymerase II
HSV - Herpes simplex virus
IE genes - HSV immediate early genes
GABP - GA binding protein
Oct-1 - Octamer binding protein 1
HRE - Hormone response element
aP2 - adipocyte-specific lipid binding protein 2
RXR - Retinoid X receptor
PPAR - Peroxisome proliferator-activated receptor.
Post your question for Dr. LaMarco. |
<urn:uuid:ffbaa8e2-8c20-4bf6-8cd7-a21013eb6355> | seed | Cocaine and Crack Abuse
Cocaine is a powerfully addictive stimulant drug. The powdered hydrochloride salt form of cocaine can be snorted or dissolved in water and injected. Crack is cocaine base that has not been neutralized by an acid to make the hydrochloride salt. This form of cocaine comes in a rock crystal that is heated to produce vapors, which are smoked. The term "crack" refers to the crackling sound produced by the rock as it is heated.
How is Cocaine Abused?
Three routes of administration are commonly used for cocaine: snorting, injecting, and smoking. Snorting is the process of inhaling cocaine powder through the nose, where it is absorbed into the bloodstream through the nasal tissues. Injecting is the use of a needle to release the drug directly into the bloodstream. Smoking involves inhaling cocaine vapor or smoke into the lungs, where absorption into the bloodstream is as rapid as by injection. All three methods of cocaine abuse can lead to addiction and other severe health problems, including increasing the risk of contracting HIV and infectious diseases.
The intensity and duration of cocaine's effects, which include increased
energy, reduced fatigue, and mental alertness, depend on the route of drug
administration. The faster cocaine is absorbed into the bloodstream and
delivered to the brain, the more intense the high. Injecting or smoking cocaine
produces a quicker, stronger high than snorting. On the other hand, faster
absorption usually means shorter duration of action. The high from snorting
cocaine may last 15 to 30 minutes, but the high from smoking may last only 5 to
10 minutes. In order to sustain the high, a cocaine abuser has to administer the
drug again. For this reason, cocaine is sometimes abused in
How Does Cocaine Affect the Brain?
Cocaine is a strong central nervous system stimulant that increases levels of dopamine, a brain chemical associated with pleasure and movement, in the brain's reward circuit. Certain brain cells, or neurons, use dopamine to communicate. Normally, dopamine is released by a neuron in response to a pleasurable signal (e.g., the smell of good food), and then recycled back into the cell that released it, shutting off the signal between neurons. Cocaine acts by preventing the dopamine from being recycled, causing excessive amounts of dopamine to build up, amplifying the message, and ultimately disrupting normal communication. It is this excess of dopamine that is responsible for cocaine's euphoric effects. With repeated use, cocaine can cause long-term changes in the brain's reward system and in other brain systems as well, which may eventually lead to addiction. With repeated use, tolerance to the cocaine high also often develops. Many cocaine abusers report that they seek but fail to achieve as much pleasure as they did from their first exposure. Some users will increase their dose in an attempt to intensify and prolong the euphoria, but this can also increase the risk of adverse psychological or physiological effects. |
<urn:uuid:63a81399-87c9-4ab6-9d63-174027476b8c> | seed | Newly discovered role for heart response enzyme may yield better heart failure therapy
Durham, N.C. – Duke University Medical Center researchers have identified a new protein that plays a critical role in enabling the heart to respond to such external stimuli as exercise or stress, as well as in the progressive loss of heart function that is heart failure, the researchers said.
Their findings, they said, suggest new approaches to prevent or reverse heart failure, which affects two to three million people in the U.S. The team reports its findings in the August 2005 issue of Nature Cell Biology. The study is now available as an advance online publication.
"We've uncovered new details of the first step of heart failure, in which heart receptors that normally allow the heart to adapt in the face of changing conditions are lost, rendering the heart unable to pump enough blood to meet the needs of the body's other organs," said cardiologist and geneticist Howard Rockman, M.D., of Duke. "If we could prevent this loss of heart receptors, we might improve heart function in patients with heart failure."
The enzyme the researchers studied, called phosphoinositide 3-kinase (PI(3)K), governs the function of beta-adrenergic receptors on the surface of heart cells. Such receptors are protein switches that nestle in the cell membrane and that are activated by the hormone adrenaline to enhance the heart's pumping action in response to exercise or stress.
In heart failure patients, chronic stress leads to an excess of adrenaline, over-stimulating beta-adrenergic receptors, a process that results in receptor desensitization and loss, Rockman said.
Earlier work by Rockman's team identified PI(3)K as being required for beta-adrenergic receptors to be drawn back into the cell for recycling once they have been activated. Those studies showed that increases in PI(3)K underlie the loss of beta-adrenergic receptors in animals and patients with heart failure, Rockman said.
The researchers' earlier experiments showed that disrupting the function of PI(3)K preserves beta-adrenergic receptors on heart cells when they are chronically exposed to adrenaline and thus preserves heart function. However, it has remained unclear exactly how the heart enzyme exerts its effects on the heart receptors, Rockman added.
The researchers' experiments revealed that PI(3)K plays multiple roles as an enzyme that affect heart responses. It manufactures signaling molecules called phospholipids in the cell. And it activates other molecules, among them one called "non-muscle tropomyosin," which plays an important role in maintaining cell structure. In both cases, PI(3)K functions by attaching a phosphate group to the molecule to be activated, a process called phosphorylation.
By preventing activation of tropomyosin by PI(3)K in cells, the researchers prevented heart receptors from leaving the cell surface, thereby blocking the initial step that occurs during heart failure. Also, the researchers reported, when they eliminated tropomyosin activity altogether, they also maintained heart receptors.
"These studies demonstrate a previously unknown role for the protein phosphorylation activity of PI(3)K in receptor internalization and identify non-muscle tropomyosin as an important substrate of the enzyme's activity," Rockman said. "The findings may offer a new approach to the treatment of heart failure."
Drugs that selectively prevent PI(3)K from activating tropomyosin -- either by modifying tropomyosin or inhibiting PI(3)K's enzymatic activity -- might effectively block heart receptor loss to maintain or restore normal heart function in those at risk or suffering from heart failure, he added.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved. |
<urn:uuid:c8661c94-05a5-42ab-908f-09f9915d7a92> | seed | An individual's race or ethnic background could be a determining factor when it comes to risk of atrial fibrillation, the most frequently diagnosed type of irregular heart rhythm, according to researchers at UC San Francisco.
In a study to be published online October 8 and in the November 12 issue of Circulation, researchers discovered that self-described non-Hispanic whites are more likely to develop atrial fibrillation than people from other race or ethnic groups.
"We found that consistently, every other race had a statistically significant lower risk of atrial fibrillation compared to whites," said senior author Gregory Marcus, MD, MAS, FHRS, an associate professor of medicine who specializes in electrophysiology in the UCSF Division of Cardiology. "So this suggests that white race is itself a risk factor for atrial fibrillation."
The researchers studied the records of 14 million California patients who visited the emergency room, had outpatient services, or were hospitalized between 2005 and 2009. The patient sample included Caucasians, African Americans, Hispanics and Asian Americans. Previous research that established African Americans at lower risk for atrial fibrillation than whites, despite having more risk factors for atrial fibrillation, studied only Caucasians and African Americans. This raised the question as to whether African Americans were protected or whites were at increased risk, forming the foundation for the current study.
"We were surprised to find that Asian Americans and Hispanics have similar relative decreases in atrial fibrillation risk as African Americans, suggesting there is some characteristic unique to whites that increases the likelihood of this abnormal heart rhythm," said first author Thomas A. Dewland, MD, a cardiac electrophysiology fellow in the UCSF Division of Cardiology.
Atrial fibrillation is the most common cardiac arrhythmia. People over 40 years of age have a 26 percent lifetime risk of developing this abnormality, according to the Framingham Heart Study.
"Presumably there may be a gene, or a set of genes, in European ancestry or some important behavior or environmental exposure in whites that increases the risk for atrial fibrillation," Marcus said. "Based on several analyses performed in the study, the risk is not related to existing cardiac conditions like high blood pressure or existing heart disease."
In comparison to Caucasians, African Americans had 16 percent lower risk, Hispanics had 22 percent lower risk, and Asian Americans also had 22 percent lower risk for atrial fibrillation.
"Despite the frequency with which we see this disorder in our clinical practice, our understanding of why certain patients are affected remains incomplete," Dewland said. "Continued research into how atrial fibrillation develops will allow us to better predict, treat, and ultimately prevent this rhythm abnormality."
Co-authors are Eric Vittinghoff, PhD, MPH, from the UCSF Department of Epidemiology and Biostatistics, and Jeffrey E. Olgin, MD, from the UCSF Department of Medicine, Division of Cardiology, Electrophysiology Section.
This study was supported by grant numbers 12POST11810036 and 12GRNT11780061 from the American Heart Association and by the Joseph Drown Foundation. The funding sources played no role in the study design, data collection, data management, data analysis, data interpretation, manuscript preparation, manuscript review, or manuscript approval.
The authors have reported that they have no conflicts of interest relevant to the contents of this paper to disclose.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospital. |
<urn:uuid:9652c8b8-a3b5-4f09-b411-01988224df55> | seed | Optical Coherence Tomography (OCT) allows for real time in vivo tissue imaging analogous to ultrasound, except that it uses light rather than sound waves and has a much greater resolution. It operates at 1300nm (near infrared). Michelson Diagnostics’ Vivosight OCT scanner produces images with a resolution of 7.5 microns to a depth of slightly greater than 1mm. The resolution is equal to the size of a melanocyte. The image extends to about 2mm in depth with progressive degradation of resolution.
Imalux OCT technology is an endoluminal application with a fiberoptic probe that has resolution of 10-20 microns and penetration of 2.5mm. The company at this time does not have products with dermatologic applications in the market. This technology is well represented in research and development for endoluminal applications. It can be followed by an industry website http://www.octnews.org/.
Although Optical Coherence Tomography is an attractive technology, its clinical utility is limited by the relatively shallow imaging. Its high cost (>$100,000) places it as a research tool given lack of meaningful ROI.
Final technology worth mentioning is photoacoustic imaging. It requires intravascular contrast agent, hemoglobin, or melanin for visualization, relying on laser pulses to create thermoelastic expansion and subsequent ultrasonic emission. It produces a remarkable 3-D image with significant depth of penetration up to 7cm enabling full body imaging, also named photoacoustic tomography. Its resolution extends from micro scale of organelle detection to macro scale of tumor imaging. One of its potential applications is identifying methylene blue in lymph nodes for sentinel lymph node biopsy. No commercial application is available at this time. |
<urn:uuid:2bf9cfab-3130-41d8-81e7-eee0bfd8da07> | seed | male and female condoms (Femidoms)
are highly effective at preventing pregnancy, the transmission of HIV and most
sexually transmitted infections. However, they need to be used properly and
consistently in order for them to be effective. You can find out more about how
to use both male and female condoms in NAM’s factsheet on condoms at (see www.aidsmap.com/factsheets).
can also ask for help from your healthcare team or from a range of
community-based organisations; for example, you may be able to attend one of
the sexual health and relationship workshops run by the organisation Positively
UK to get more information and support around this topic.
HIV treatment centres and sexual health (GUM) clinics offer both male and
female condoms free of charge.
of the need for condoms to be used properly every time you have sex to prevent
pregnancy, women often want to use a back-up form of contraception as well.
anti-HIV drugs interfere with the way some hormonal contraceptives work, and
the contraceptive may not be as effective as usual. You can use the HIV & contraception tool to find out
if that’s the case with any anti-HIV drugs you take.
other medications, such as some antibiotics, can also affect hormonal
contraceptives and make them less effective. It is important to let your doctor
know about any other drug you are taking, including any contraceptives. Getting
advice on possible drug interactions from your HIV doctor or pharmacist is
hormonal contraceptives are less effective if you’re taking HIV treatment:
- the combined pill
- the progestogen-only pill, also known as the mini-pill
- patches – a small beige patch applied to the skin like a sticky plaster
that is changed once a week
- implants – a small flexible rod that is inserted under the skin on the
upper part of the arm, and works for up to three years
- vaginal rings – a small flexible ring that is inserted in the vagina for
three weeks of the month.
types of hormonal contraceptives are not affected by anti-HIV drugs. They are
the intrauterine device (IUD or coil), the Mirena
intrauterine system (IUS) and the Depo-Provera
IUD is a small, T-shaped contraceptive device made from plastic and copper that
fits inside the womb (uterus), sometimes called a coil. It releases copper into
the body, causing changes that prevent sperm from fertilising eggs. You will be
offered a sexual health screen, and any sexually transmitted infection (STI)
will be treated before the coil is fitted by a doctor or nurse. It can be
easily removed if it doesn't suit you.
Mirena IUS is a small plastic device also
fitted in the womb, which contains hormones that reduce the risk of heavy
periods (sometimes stopping them altogether). It is also used by women with
heavy, painful periods as an alternative to hysterectomy. It must be fitted by
a doctor or nurse, after a sexual health check and treatment of any STI. Once
it’s fitted, it works for five years.
most common type of contraceptive injection is called Depo-Provera; it contains the hormone progestogen and each
injection lasts for 12 weeks.
and caps are flexible rubber or silicone dome-shaped devices which are placed
in the vagina each time you have sex. They are not recommended for women with
HIV, as they should be used with a substance called a spermicide that can
irritate the vagina and increase the chances of passing on HIV to an
of these methods prevent the transmission of HIV or other STIs.
National Health Service (NHS) provides free access to contraception; that is,
you do not need to pay a prescription charge. Contraception is available from
general practitioners (GPs), and from sexual health or contraception clinics.
Details of local clinics are available on local NHS websites or at www.nhs.uk
or from the FPA (www.fpa.org.uk). |
<urn:uuid:8601a285-cf42-405e-9b9e-d6c8fef04c8e> | seed | Mouse study yields clue to why liver is less prone to rejection, say Pitt researchers
BOSTON, May 17 – Researchers from the University of Pittsburgh's Thomas E. Starzl Transplantation Institute believe they have identified a mechanism that may help to explain why the liver enjoys privileged immunological status over other organs, making it the least vulnerable to rejection when transplanted.
Playing a central role in this mechanism is the dendritic cell, known for its ability to identify and present antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen. When mature, dendritic cells signal T cells, the soldiers of the immune system, to attack a transplanted organ, for example. But dendritic cells that reside in the liver are relatively docile in nature. Why this is, according to the Pitt study, may be due to the fact that they express lower amounts of a certain molecule that serves as a switch for the maturation process.
Reporting in a plenary session at the American Transplant Congress, the joint scientific meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, An de Creus, Ph.D., identified the key molecule as a Toll-like receptor known as TLR-4. Toll-like receptors are like night watchmen that look for suspicious activity characterized by unusual patterns of other molecules. TLR-4 is known to react to lipopolysaccharide (LPS), a component found in the cell wall of bacteria. Reacting to LPS sets in motion a cascade of immune events that begins with the rapid maturation of dendritic cells.
Because of the liver's position downstream from the intestines, dendritic cells there encounter large amounts of LPS as remnants of bacteria from the gut are carried by blood flowing through the liver's portal vein. But unlike dendritic cells found elsewhere, such as in the spleen, dendritic cells that reside in the liver express less TLR-4, making them more apathetic toward LPS, the researchers found in their studies of mice.
"With the liver constantly being exposed to LPS it must have a mechanism that prevents its immune cells from being activated all the time, and we believe the low expression of TLR-4 is in part responsible. The same thing is probably happening in the setting of transplantation," explained Dr. de Creus, a research associate working in the laboratory of Angus Thomson, Ph.D., D.Sc., professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute and University of Pittsburgh School of Medicine.
"In humans, perhaps it would be possible to manipulate dendritic cells of the donor organ so that they express little or no TLR-4. In this way, we might be able to induce complete immune tolerance of the liver," she added.
According to the researchers, their data are the first to show how TLRs are expressed by liver dendritic cells.
"This work has important implications for understanding the liver's inherent tolerogenic potential. But we still don't have enough information to understand why it is easier to get liver transplant patients off anti-rejection drugs compared to recipients of other organs," said Dr. Thomson.
In a mouse model, researchers compared the expression of TLR-4 and other Toll-like receptors by liver dendritic cells to dendritic cells found in the spleen, an organ more immune active than the liver. Liver dendritic cells expressed more TLR-3 and lower amounts of TLR-4 and TLR-9 than those in the spleen. However, the lower expression of TLR-4 by the liver dendritic cells correlated with their reduced capacity to be stimulated by LPS and activate T cells to induce secretion of interferons, which signal other immune system cells. The liver dendritic cells were not entirely incapable of reacting to LPS, they just required higher concentrations of LPS to mature, reported Dr. de Creus.
For her work, ATC recognized Dr. de Creus with a Young Investigator's Award. Such an award is given to those under the age of 40 who submit a scientific abstract judged to be among the very best. The award provides the recipient with $1,000 to help defray the costs of attending the meeting.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved. |
<urn:uuid:9c752572-f540-48a8-9ec9-fea5761dbe9b> | seed | Learn something new every day
More Info... by email
Systemic circulation is a part of the cardiovascular system in many complex organisms, including humans; it is responsible for carrying oxygenated blood from the heart to the rest of the body and the deoxygenated blood from the rest of the body back to the heart. In pulmonary circulation, this deoxygenated blood is moved from the heart to the lungs, where it is oxygenated before being returned to the heart. These two main components of the cardiovascular system are responsible for providing the entire body with oxygen and important nutrients that are carried through the blood. Blood from the systemic circulatory system also passes through the kidneys, where waste is filtered from the blood.
A variety of different types of blood vessels known as arteries, arterioles, capillaries, veins, and coronary vessels are all involved in the process of systemic circulation. Blood is first pumped from the left ventricle of the heart into a large artery called the aorta. The aorta then branches into many other major arteries that supply blood to the cells in the parts of both the upper and lower body. Major arteries continue to branch into smaller arteries called arterioles. These many branching arterioles eventually terminate into capillaries.
Capillaries are the smallest and most numerous of the blood vessels in systemic circulation and are the most directly involved in the process of actually supplying blood to the cells that need it. Capillaries form a branched, web-like structure known as a "capillary bed" in any given area of tissue. These capillary beds are responsible both for keeping organs well supplied with oxygen and nutrients and for collecting waste from the nearby tissues. The broad, dispersed capillary beds eventually combine at their ends and widen into venules, thereby allowing the blood to flow from the capillaries to the veins.
The blood from the veins is oxygen-depleted, and it carries a variety of cellular waste products. This blood is carried back to the heart, concluding systemic circulation. The blood is then moved to the lungs for oxygenation through pulmonary circulation so it can again be used for systemic circulation.
The heart itself also needs to receive a constant supply of oxygen and nutrients from the systemic circulatory system in order to function. It does not receive these through the process of supplying the rest of the body with blood, however. A distinct part of the systemic circulatory system known as coronary circulation is responsible for providing the heart with a steady supply of blood. Coronary circulation appears as a small loop in systemic circulation that only carries blood from the heart back to the heart. |
<urn:uuid:e178d500-993a-4389-8f75-bba394518943> | seed | Osteoporosis is a disease in which bones become fragile and more likely to break. If not prevented or if left untreated, osteoporosis can progress painlessly until a bone breaks. These broken bones, also known as fractures, occur typically in the hip, spine, and wrist.
Osteoporosis is a major public health concern for an estimated 44 million Americans. In the U.S. today, 10 million individuals are estimated to already have the disease and almost 34 million more are estimated to have low bone mass, placing them at increased risk for Osteoporosis.
The Osteoporosis Facts *
* Source: National Osteoporosis Foundation
- Each year, about one-third of individuals 65 years of age or older will fall, and some will be disabled by the broken bones that can follow.
- Eighty percent of those affected by Osteoporosis are women.
- One in two women and one in four men over age 50 will have an Osteoporosis-related fracture in their lifetime.
- Osteoporosis is responsible for more than 1.5 million fractures annually.
- Twenty percent of those affected by Osteoporosis are men.
- The estimated national direct expenditures (hospitals and nursing homes) for Osteoporotic and associated fractures was $17 billion in 2001 ($47 million each day)
- The rate of hip fractures is two to three times higher in women than men; however the one year mortality following a hip fracture is nearly twice as high for men as for women.
- A woman's risk of hip fracture is equal to her combined risk of breast, uterine and ovarian cancer.
- At six months after a hip fracture, only 15% of hip fracture patients can walk across a room unaided.
Although there is no cure for Osteoporosis, there are steps you can take to prevent, slow, or stop its progress.
- A balanced diet rich in calcium and vitamin D.
- Weight-bearing exercise.
- A healthy lifestyle with no smoking or excessive alcohol intake.
- Appropriate testing and prescription medication.
While your doctor plays a key role in diagnosis, bone density testing, and prescribing medications, a physical therapy program helps provide you with a complete treatment solution.
Physical Therapy is Important
With physical therapy you will experience the following:
- A personalized posture program, weight-bearing and resistance exercise program.
- Education regarding Osteoporosis, proper nutrition, and calcium and Vitamin D intake recommendations
- Risk factors and fall prevention information. |
<urn:uuid:426473b4-f7d3-4801-8086-e3cbceec884d> | seed | Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.
Prion diseases, also known as transmissible spongiform encephalopathies, are infectious fatal neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated form which may contribute to brain damage. In uninfected individuals, normal PrP is anchored to the outer cell membrane by a sugar-phosphate-lipid linker molecule. In the present report we show that prion infection of mice expressing PrP lacking the anchor can result in a new type of fatal neurodegenerative disease. This disease displays mechanisms of damage to brain cells and brain blood vessels found in Alzheimer's disease and in familial amyloid brain diseases. In contrast, the typical sponge-like brain damage seen in prion diseases was not observed. These results suggest that presence or absence of PrP membrane anchoring can influence the type of neurodegeneration seen after prion infection.
Citation: Chesebro B, Race B, Meade-White K, LaCasse R, Race R, et al. (2010) Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring. PLoS Pathog 6(3): e1000800. doi:10.1371/journal.ppat.1000800
Editor: David Westaway, University of Alberta, Canada
Received: September 25, 2009; Accepted: January 29, 2010; Published: March 5, 2010
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: Funded by the Intramural program of NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Transmissible spongiform encephalopathies (TSE diseases) or prion diseases are fatal neurodegenerative diseases of humans and animals. These diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in cervids, as well as several human diseases including kuru, Gerstmann-Sträussler-Scheinker syndrome(GSS), and sporadic, familial and variant forms of Creutzfeldt-Jakob disease (CJD) (see for review). TSE diseases are transmissible within a species, but can also cross to new species in some cases. For example, variant CJD appears to be a form of BSE transmitted to humans. In addition, experimental transmission to rodents such as mice, hamsters and, more recently, bank voles ,, has provided numerous models for laboratory research.
In prion diseases brain pathology is characterized by spongiform degeneration of the gray matter together with neuronal loss and gliosis. During disease there is an accumulation in brain of an abnormal partially protease-resistant form of prion protein (PrPres) derived from host-encoded protease-sensitive prion protein (PrPsen). PrPres can be detected by immunoblot or immunohistochemistry, and this detection is often used as an important diagnostic feature of prion disease. PrPres can be deposited in brain either as large fibrillar amyloid plaques and/or as small diffuse punctate deposits of non-amyloid aggregated protein. The diffuse non-amyloid PrPres form is prevalent in many human sCJD cases and most prion disease animal models –. However, both amyloid and non-amyloid forms of PrPres coexist in some human and animal prion diseases –, and both forms may contribute to prion disease pathogenesis.
A variety of proteins are capable of forming amyloid deposits in nervous system tissues as well as other organs. Amyloid deposits often displace organ structure resulting in dysfunction and cell death. In cerebral amyloid angiopathy (CAA), associated with Alzheimer's disease (AD) and several genetic CNS amyloid diseases, vascular amyloid deposits can damage the structure of blood vessel walls leading to hemorrhage or thrombosis ,. However, in AD, oligomeric pre-amyloid Aß aggregates are also thought to have important neuropathogenic effects. For therapy of diseases such as AD and prion diseases, where both amyloid and non-amyloid may be pathogenic, it will be important to understand the contribution of both types of abnormal protein aggregates to the various pathogenic processes present in these complex diseases. Therefore, we focused on the pathogenic effects of PrPres amyloid versus non-amyloid induced by prion infection in mice.
In uninfected animals PrPsen is anchored to the plasma membrane by a glycosylphosphatidylinositol (GPI) moiety . In prion disease PrPres is found on plasma membranes of neurons and other brain cells, where it is associated with morphological membrane changes that are common to different animal TSEs ,. Membrane attachment of PrP may have an important influence on the prion disease process. To study the role of PrP membrane linkage on pathogenesis of prion disease we previously generated 2 lines of transgenic mice (tg44+/− and tg23+/−), which express PrP lacking the GPI anchor at similar levels and do not express GPI membrane–anchored PrP. Anchorless PrP in these mice is secreted by cells and is not attached to the plasma membrane . After scrapie infection, both lines of transgenic mice developed high titers of prion infectivity and extensive PrPres amyloid deposits in brain at late times after infection; however, typical scrapie clinical signs and gray matter spongiosis characteristic of prion diseases were not seen .
In the present paper we studied homozygous anchorless PrP transgenic mice, which expressed two-fold more anchorless PrPsen than the above mentioned heterozygous transgenic mice. In these experiments scrapie infection of homozygous mice produced a fatal clinical disease. However, this disease differed in incubation period, clinical signs, and neuropathology from typical prion disease seen in non-transgenic mice, which express anchored PrP, and thus appeared to be a distinct pathogenic process. Therefore, depending on the presence or absence of anchored PrP, scrapie infection could induce two different fatal brain diseases: PrPres amyloidosis without gray matter spongiosis in anchorless PrP transgenic mice, and diffuse non-amyloid PrPres with gray matter spongiosis in mice with anchored PrP.
Brain PrPsen levels in anchorless PrP transgenic mice and non-transgenic mice
Since PrPsen expression is known to influence scrapie incubation period , it is possible that low PrP expression might account in part for the lack of clinical scrapie disease in previous experiments using heterozygous tg44+/− and tg23+/− mice . Therefore, in the present study we generated homozygous anchorless PrP transgenic mice from both lines 44 and 23. These mice each expressed two anchorless PrP transgene alleles and no normal mouse PrP alleles.
PrPsen levels were analyzed by immunoblotting in brain homogenates of uninfected transgenic and non-transgenic mice. Homozygous tg44+/+ mice expressed 2-fold higher levels compared to tg44+/− mice (Figure 1A). Non-transgenic C57BL/10SnJ mice homozygous for the PrP gene (Prnp+/+) were used as controls, and these mice expressed 2-fold higher PrP levels than did Prnp+/− mice (generated by crossing Prnp+/+ mice to Prnp-null mice also on the C57BL/10SnJ background (see methods)) (Figure 1A). Quantitative comparisons between transgenic and non-transgenic mice were difficult due to PrP glycosylation differences (Figure 1A). Therefore we compared these mice using PrPsen deglycosylated with PNGase F (Figure 1B). In these experiments Prnp+/− mice had approximately four-fold higher PrPsen levels than tg44+/+ mice (compare lanes 2 vs. 4 and lanes 7 vs. 10). Given the 2-fold difference between Prnp+/+ and +/− mice, tg44+/+ expressed 8-fold lower levels of brain PrPsen than did Prnp+/+ mice. Brain PrPsen levels in tg44+/+ and tg23+/+ mice were indistinguishable (data not shown).
Figure 1. Brain PrPsen expression levels.
C57BL/10 (Prnp+/+), Prnp+/−, expressing normal anchored mouse PrP, and transgenic mice (tg44+/+ and tg44+/−), expressing only anchorless mouse PrP were compared. Immunoblots were done using brain homogenates made as described in methods, and samples were serially diluted two-fold in sample buffer to give the mg brain equivalents shown on the figure. Bands were detected with monoclonal antibody D13. (A) No PNGase digestion. Lanes 1–3: Prnp+/+, Lanes 4–6: Prnp+/−, Lanes 7–9: tg44+/+ and Lanes 10–12: tg44+/−. (B) After PNGase F treatment. Lanes 1–3: Prnp+/−, Lanes 4–5: tg44+/+, Lanes 6–8: Prnp+/− and 9–11: tg44+/+ mice. Lanes 1–5 were from one experiment and 6–11 were from a separate experiment and results shown are for 4 different mice. Lower apparent molecular weight in PrP of transgenic mice is due to lack of the GPI anchor. Prnp+/− mice appeared to have 4-fold more brain PrPsen than tg44+/+ mice (compare lanes 2 and 4, also lanes 7 and 10). Data shown are for tg44+/+ and tg44+/− mice. By immunoblot PrPsen expression levels in tg23 mice were indistinguishable from those in tg44 mice (data not shown).doi:10.1371/journal.ppat.1000800.g001
Scrapie-induced clinical disease in transgenic and non-transgenic mice
Scrapie-induced clinical disease was analyzed in transgenic and non-transgenic mice using two different scrapie strains, RML and 22L. After intracerebral (IC) inoculation of scrapie strain 22L, Prnp+/+ and +/− mice developed clinical scrapie at 150–165 dpi and 245–260 dpi respectively (Figure 2A). Similar results were also seen using the RML scrapie strain in Prnp+/+ mice (Figure 2B). Prnp+/− mice were not tested with the RML strain. In contrast to experiments with non-transgenic mice, all tg44+/+ and tg23+/+ mice infected with strains 22L or RML developed neurological signs and required euthanasia from 300 to 480 dpi (Figure 2). Homozygous transgenic mice differed from non-transgenic mice in incubation period, duration and progression of clinical signs, as well as gait and postural abnormalities (Table 1). The most obvious signs in homozygous transgenic mice were the presence of a wide-based gait, rear extremity weakness with low posture, and lack of kyphosis. The signs seen in homozygous transgenic mice differed from the narrow-based tippy-toed gait and frequent kyphosis seen in infected Prnp+/+ and +/− mice (Table 1). The gait and postural differences probably reflected different patterns of neurological damage. Overall the differences between non-transgenic mice and homozygous transgenic mice suggested that there might be different pathogenic mechanisms operating in these two scrapie-induced disease models.
Figure 2. Survival curves for scrapie-infected mice.
Transgenic mice (tg44+/+ and tg23+/+) expressing only anchorless PrP, C57BL/10 (Prnp+/+) and Prnp+/− mice, expressing normal anchored mouse PrP were compared. Mice were inoculated intracerebrally with 22L scrapie (panel A) and RML scrapie (panel B) and observed weekly for development of disease (see Table 1). Mice were euthanized when clinical signs were severe as described in Table 1. N values for each group are as follows: Panel A (22L): Prnp+/+, 11; Prnp+/−, 17; tg44+/+, 23; tg23+/+, 10. Panel B (RML): Prnp+/+, 8; tg44+/+, 21; tg23+/+, 9.doi:10.1371/journal.ppat.1000800.g002
Table 1. Clinical aspects of disease in 22L or RML scrapie-infected C57BL/10 and tg44+/+ mice.doi:10.1371/journal.ppat.1000800.t001
In our earlier studies, heterozygous tg44+/− and tg23+/− mice did not manifest the usual clinical signs of scrapie during 600 days of observation after infection with scrapie strains 22L or RML (Table 1) . However, in the present experiments with the experience of observing the clinical signs described above in homozygous transgenic mice, we noted similar clinical signs in the infected heterozygous transgenic mice starting around 480 dpi. Clinical diagnosis in these mice was difficult due the erratic presence of signs in the initial stages, the longer duration of signs, and the possibility of confusion with signs of old age. These mice were euthanized between 480 and 700 dpi, but the indication for euthanasia was primarily debilitation (weight loss, dermatitis, bladder distention, cancer and infections), rather than neuromuscular dysfunction.
PrPres deposition in brain is a major hallmark of prion diseases, and PrPres is often associated with areas of brain degeneration. Therefore brain PrPres levels in scrapie-infected mice were analyzed by immunoblot. As shown in Figure 3, tg44+/+ mice with clinical neurological disease had higher amounts of PrPres at 348–408 dpi than tg44+/− mice had at 567–594 dpi, which was when these mice had to be euthanized due to debilitating signs as described in Table 1. A similar difference was seen between tg23+/+ and tg23+/− mice (data not shown). The difference between tg44+/+ and tg44+/− mice in timing and levels of PrPres correlated with the higher PrPsen expression level seen in homozygous mice (Figure 1A), and appeared to explain the earlier onset and more prominent clinical signs seen in homozygous transgenic mice.
Figure 3. Detection of PrPres by immunoblot using monoclonal antibody D13.
Comparison of PrPres in brain of 22L scrapie-infected tg44+/+ and tg44+/− mice at the time of clinical disease. All lanes were loaded with 0.25 mg brain tissue equivalents. A clinical Prnp+/− mouse is shown for comparison. Lane 1: Prnp+/− (251 dpi), PrPres bands are seen at 21, 28, and 31 kD; lanes 2–5: tg44+/− mice (567, 589, 594, 594 dpi) and lanes 6–9 tg44+/+ (348, 365, 384, 408 dpi). PrPres bands are at 18 and 23 kD. The sizes are lower in these mice due to lack most carbohydrates and lack of GPI . PrPres levels in tg44+/− mice were approximately 50% lower than in tg44+/+ mice.doi:10.1371/journal.ppat.1000800.g003
The PrPres detected in these immunoblots had a molecular weight of 19 kD. In our earlier study this band was found to react with an anti-PrP peptide antibody (R20) directed at the C-terminal region of PrP (residues 218–232) . Therefore, there was no evidence for loss of these C-terminal residues as often occurs in human GSS ,.
Interestingly tg44+/+ and tg44+/− mice had higher PrPres levels than did non-transgenic Prnp+/+ or +/− mice, but the non-transgenic mice died earlier than the tg44+/+ mice (Figure 2). This suggested either that amyloid PrPres in tg44+/+ mice might be less pathogenic than the non-amyloid PrPres in non-transgenic mice, or that transgenic mice might be less susceptible to the pathogenic effects of PrPres amyloid due to the absence of membrane-anchored PrP.
Infectivity levels in tg44 mice
Previously we showed that scrapie-infected tg44+/− mice lacked signs of clinical scrapie but had infectivity titers in brain as high as 4.6×108 ID50/gram brain at 120–286 dpi as measured by end-point titration in C57BL/10 mice . In the present experiments we passaged brain from infected tg44+/− (passage 1) mice into other tg44+/− mice (passage 2), and at 512 and 531 dpi we found brain infectivity titers of 1.1–1.3×1010 ID50/gram brain (Table 2). These mice also had brain PrPres levels similar to those shown in other tg44+/− mice (Figure 3). Similar high titers were detected in passage 1 homozygous tg44+/+ mice at 384 dpi (Table 2). Thus in the transgenic anchorless PrP model, scrapie infectivity was present in brain at very high titers. Furthermore, the agent did not appear to develop new strain-like properties selective for tg44+/− mice as it could passage easily from tg44+/− mice to either C57BL/10 or tg44+/− mice.
Table 2. Infectivity titers of 22L scrapie from brains of Tg44 mice after 1 or 2 passages.doi:10.1371/journal.ppat.1000800.t002
Histopathology and PrPres distribution detected by IHC
We compared the PrPres deposition and neuropathology after scrapie infection in transgenic tg44+/+ mice and non-transgenic C57BL/10 control mice (Table 3). Following scrapie infection in C57BL/10 mice typical TSE-specific diffuse deposits of PrPres were found in many brain areas (Figure 4A, 4B). This PrPres did not stain with the amyloid stain, Thioflavin S . In many brain regions by H&E staining we observed gray matter spongiosis (Figure 4C), which is an important feature of TSE/prion diseases.
Figure 4. Light microscopic histopathology of scrapie-infected C57BL/10 and tg44+/+ transgenic mice.
(A) Whole brain sagittal section of C57BL/10 mouse infected IV with RML scrapie at 180 dpi showing wide distribution of diffuse PrPres stained with monoclonal antibody D13. (B) High power view of C57BL/10 mouse infected IC with RML scrapie at 157 dpi showing diffuse punctuate pattern of PrPres in hippocampus. (C) H&E stain of forebrain of C57BL/10 mouse infected IP with 22L scrapie at 375 dpi. Anterior commissure white matter (WM) is seen in lower right. Numerous scrapie vacuoles (arrows) are visible in surrounding gray matter(GM). (D) Whole brain saggital section of tg44+/+ mouse D554 infected IC with RML scrapie showing dense plaque-like PrPres stained with monoclonal antibody D13 at 341 dpi. PrPres was found in most CNS areas including cerebral cortex, corpus callosum, forebrain, hippocampus, thalamus, hypothalamus, midbrain, colliculi, brainstem, and spinal cord. Cerebellar involvement was minimal after RML infection, as shown in panel 4D, but was strong in cerebellar molecular layer, granular layer and meninges after 22L infection (not shown). (E) Higher power of panel D shows large dense PrP plaques surrounding dentate gyrus of hippocampus often in a perivascular distribution (arrows). Note difference compared to diffuse PrPres staining in panel B. (F) H&E stain of mouse D554 showing vacuoles in the white matter (WM) near the anterior commissure and no vacuoles in surrounding gray matter, i.e. opposite distribution of vacuoles compared to C57BL/10 mouse in panel C. (G) Astrogliosis seen by staining with anti-GFAP in dentate gyrus of mouse D554. (H) H&E stain of dentate gyrus of mouse D554 shows marked neuronal loss in lower arm of gyrus (box and arrow). Boxed outlines region shown in panel I. (I) High power view of lower arm of dentate gyrus outlined in panel H, shows multiple areas of neuronal loss (arrows). Plaques surround this area and one plaque is indicated with the arrowhead at the left. (J) High power view of area shown in panel I shows D13 staining of PrPres plaques impinging on damaged neurons of the dentate gyrus (arrow). Arrowhead shows plaque around blood vessel in upper left corner. (K) Deposition of amyloid precursor protein, APP, (red-brown stain) adjacent to area of neuronal loss (arrows) in dentate gyrus of same area shown in panels I and J. (L) Abnormal axonal proliferation shown by staining with anti-neurofilament protein in area of neuronal loss (arrows) in dentate gyrus of mouse D554. (M) Anti- neurofilament protein staining of dentate gyrus of uninfected control mouse shows no neuronal damage or abnormal axonal staining within the gyrus. Scale bars in panels B, E, G, and H are 100 microns; all other scale bars are 50 microns. Similar pathological changes were seen at the time of clinical disease in both tg44+/+ and tg23+/+ mice infected with either 22L or RML strains of scrapie. D13 staining of PrPres in panels E and J was similar to results described previously in tg44+/− and tg23+/− mice at ≥498 dpi .doi:10.1371/journal.ppat.1000800.g004
Table 3. Comparison of histopathological features in scrapie-infected C57BL/10 mice and homozygous anchorless PrP transgenic mice (tg44+/+).doi:10.1371/journal.ppat.1000800.t003
In scrapie-infected tg44+/+ mice PrPres accumulated as large dense plaque-like deposits, usually in a perivascular location around capillaries, veins and arteries in numerous brain regions, including leptomeninges, cerebral cortex, corpus callosum, forebrain, hippocampus, thalamus, hypothalamus, midbrain, colliculi, brainstem, and spinal cord (Figure 4D, 4E, 5A, 5B) After infection with the 22L scrapie strain, the cerebellar molecular layer and granular layer were also involved , but this was not seen after infection with the RML strain (Figure 4D). These deposits were Thioflavin S-positive , and no areas of diffuse non-amyloid PrPres were observed. The most distinguishing histopathological feature in tg44+/+ mice at the time of clinical signs was distortion of brain structures adjacent to large amyloid plaques in many areas (Figures 4D, E, H–L). These areas had intense micro- and astrogliosis (Figures 4G). Small blood vessels showed occasional micro-hemorrhages, or perivascular haemosiderin accumulation, but no lymphocyte infiltration of blood vessel walls was detected. Marked neuronal loss was seen around edges of some gray matter plaques (Figure 4H, I); however, no gray matter spongiosis typical of prion diseases was seen (Figure 4C vs 4F). In addition, tg44+/+ mice had focal areas of abnormal staining of amyloid precursor protein (APP) (Figure 4K), non-phosphorylated neurofilament protein (NFP) (Figure 4L), and phosphorylated NFP (not shown), all of which indicated a process of severe axonal dystrophy. These latter effects were rarely seen in scrapie-infected C57BL/10 mice (Table 3). These results suggested that scrapie-infected anchorless PrP transgenic mice had a different pathogenic process compared to non-transgenic C57BL/10 mice.
Ultrastructural analysis of brain from infected tg44+/+ mice
For higher resolution of details, scrapie-infected tg44+/+ mice were also studied using immunohistochemistry on 1 micron thick plastic-embedded sections as well as immunogold labeling at the ultrastructural level. Light microscopy on thin sections showed both perivascular and vascular PrPres labeling (Figure 5A), as well as occlusion of vessels in some cases (Figure 5B). By electron microscopy abundant PrPres labeling of blood vessels was seen most predominantly at basement membranes. In some larger vessels smooth muscle cells of the media were atrophied and replaced by extensive PrPres accumulation (Figure 5C). Vascular and plaque PrPres accumulation could be seen to be of a fibrillar amyloid nature at high magnification (Figure 5D). In smaller vessels PrPres was seen at both endothelial and pericyte basement membranes (Figure 5E). PrPres was also observed within the extracellular space along the borders of swollen astroglial and neurite processes in the absence of visible fibrillar amyloid (Figure 5F and G). No PrPres labeling was seen in uninfected control mice.
Figure 5. Immunological detection of PrPres in brain at both light and electron microscopic levels.
The 22L scrapie-infected anchorless PrP tg44+/+ mouse shown was clinically positive at 377 dpi. (A–B) Light microscopy of 1 µm thick plastic-embedded tissue labelled with monoclonal antibody 1A8. (A) shows intravascular and perivascular PrPres. In (B), the marked vascular amyloid infiltration is associated with occlusion of the vascular lumen (boxes indicate occluded lumens of two vessels). When these vessels were visualised in the electron microscope the smooth muscle of the vascular media was totally replaced by amyloid and an amorphous electron dense material filled the lumen (not shown). (C–F) Electron microscopy. (C) Low power view of large PrPres amyloid plaque adjacent to a small artery. Vessel lumen is in upper left corner and an endothelial cell with a prominent nucleus is to the right of the lumen. Silver enhanced gold-labeled PrPres is seen within the basement membrane (BM) and within the heavy amyloid accumulation which partially replaces the smooth muscle media layer. Amyloid bundles radiate away from the vessel and through the neuropil at the bottom right. (D) A high magnification illustration of (C) showing PrPres labelling on small bundles of amyloid fibrils at the periphery of the plaque. (E) Marked PrPres accumulation at the endothelial and pericyte basement membranes (arrows) and extending into narrow extracellular spces between nearby neurites and perivascular glial processes. Asterix (*) shows area of astrocytic cytoplasmic swelling. Lu; lumen. (F) Neuropil of cerebrum showing immunogold label for PrPres present over the extracellular spaces between neurites bounded by pairs of adjacent plasmalemmae. No visible amyloid fibrils were visible and the spaces between cellular processes were regular and even. This non-fibrillar PrPres labelling which dissects between neurite and glial cell profiles may extend over large area of neuropil as shown in (G). Asterix (*) on left side shows enlarged glial process with loss of normal cytoplasmic organelles. Similar findings were observed in tg44+/+, tg44+/− and tg23+/− mice. Tg23+/+ mice were not examined by electron microscopy. Scale bars: A and B, 20 µm; C and D, 1 µm; E and G, 2 µm; F, 500 nm.doi:10.1371/journal.ppat.1000800.g005
Using staining with uranyl acetate/lead citrate large areas of distended swollen processes could be seen (Figure 6A), which were similar to the areas of immunogold-labeled PrPres shown above (Figure 5G). At higher magnification swollen perivascular glial processes were often seen (Figure 6B), and fibrils were visible in the endothelial basement membrane (Figure 6C) and/or pericyte basement membrane (Figure 6D). The initial site of aggregation into fibrils was in the ablumenal basement membranes (Figure 5D). Dystrophic neurites were also frequently noted in gray matter (Figure 6E). These were most conspicuous surrounding perivascular amyloid plaques and corresponded to sites of APP labeling. In white matter we observed degeneration of axons, including empty distended myelin sheaths (Figure 6F) (Table 3) which could be seen as white matter vacuoles by light microscopy (Figure 4F).
Figure 6. Ultrastructure of cerebral cortex and cerebellum of a 22L scrapie-infected tg44+/+ mouse.
Sections were from same mouse as shown in Figure 5, and were stained with uranyl acetate/lead citrate. (A) Area of neuropil with severe vacuolation where most vacuoles originate within processes and are separated from each other by intact membranes. (B) Several distended astrocytic processes (asterisks) of the perivascular glial limitans are present around a blood vessel Lu: lumen. (C) On higher magnification of boxed area from (B), the endothelial basement is shown to be filled with irregularly orientated amyloid fibrils (arrows). (D) The earliest stage of vascular amyloid is shown. Here the endothelial basement membrane (black arrowheads) is intact, but the pericyte basement membrane (black arrows) is thickened and heavily infiltrated with short amyloid fibrils (white arrowheads). (E) Severe neuritic dystrophy in which several processes show an excessive accumulation of organelles and abnormal electron dense bodies. (F) White matter of the cerebellum showing an empty myelin sheath (seen as vacuoles by light microscopy) and also a dark degenerate axon (asterisk) within an intact myelin sheath. Similar findings were observed in RML scrapie-infected tg44+/+ mice. Scale bars: A, 2 µm; B, E, F, 1 µm; C, 500 nm; D, 500 nm.doi:10.1371/journal.ppat.1000800.g006
In contrast to transgenic mice, infected C57BL/10 mice at the time of clinical disease had numerous TSE vacuoles with broken or “hanging” membranes (not shown) . Such vacuoles were never seen in infected transgenic mice (Table 3). In C57BL/10 mice other ultrastructural hallmarks specific for classical prion diseases including membrane accumulation of disease-specific PrPres and TSE-specific membrane alterations were also seen, as reported previously in other prion disease models ,, (Table 3). However, none of these prion disease-specific features was seen in infected tg44+/+ mice. The ultrastructural differences between scrapie-infected C57BL/10 and tg44+/+ mice supported the conclusion that the pathogenesis of disease in these transgenic mice was not typical TSE/prion disease.
Brain graft experiments
The reasons for the different types of scrapie-induced pathogenesis in C57BL/10 mice and anchorless PrP transgenic mice are not known. Two possibilities include: first, PrPres amyloid and diffuse non-amyloid PrPres might have different neurotoxic effects; second, PrPsen anchoring might influence neurotoxicity induced by infection.
To test whether PrPres derived from GPI-anchored PrPsen could induce gray matter vacuoles in tissue expressing anchorless PrPsen, brain tissue from C57BL/6 mice at embryonic day E12–E14, which expressed green fluorescent protein constitutively in all tissues , was grafted into the brain of adult tg44+/− mice or PrP null mice as controls . One month after grafting, mice were infected IC with scrapie, and at 132–511 dpi the brain tissue was examined by histopathology. Recipients had from 1–6 detectable grafts per mouse (Table 4). Representative grafts are shown in Figure 7.
Figure 7. Detection of PrPres and vacuolation in brain tissue of PrPnull and tg44+/− mice with C57BL/6 brain grafts.
Grafts expressed green fluorescent protein (GFP), and mice were infected IC with 22L scrapie approximately 5 weeks after grafting. Panels A–C, PrPnull recipient at 261 dpi; Panels D–F, tg44+/− recipient at 261 dpi; Panels G–I, tg44+/− recipient at 200 dpi. Panels A, D, G show staining with anti- GFP which detects constitutive GFP expression in the C57BL/6 donor tissue. Panels B, E, H show D13 staining of PrPres. Panels C, F, I show H&E staining to detect scrapie-induced vacuoles indicated by arrows.doi:10.1371/journal.ppat.1000800.g007
Table 4. Studies of PrPres and gray matter vacuolation in scrapie-infected anchorless PrP tg44+/− mice with C57BL/6 embryonic brain grafts.doi:10.1371/journal.ppat.1000800.t004
At 261 dpi in the control PrPnull recipient, C57BL/6 graft tissue, identified by presence of green fluorescent protein (GFP) (Figure 7A), had easily detectable PrPres (Figure 7B) present both within the graft and at the interface between the graft and the host tissue, but PrPres did not appear to spread extensively into the PrPnull tissue. TSE gray matter vacuolation was seen only within the graft tissue (Figure 7B and 7C). This was similar to a previous report .
In tg44+/− recipient mice receiving C57BL/6 grafts, PrPres and gray matter vacuolation was also seen in the graft (Figure 7F and 7I). In the adjacent host tissue expressing anchorless PrP, amyloid PrPres and white matter vacuoles were noted; however, the C57BL/6 PrPres present at the edges of the graft appeared to be unable to induce gray matter vacuoles in the adjacent transgenic tissue (Figure 7F). In some cases the graft cells were not well-demarcated from the host (Figure 7G), and it was not clear whether the PrPres and vacuoles were in the graft or the host (Figure 7H and 7I). These results were representative of observations in 25 grafts in tg44+/− recipients where PrPres was detected in the graft (Table 4). In summary, we found no grafts where expression of anchored PrPres from the C57BL/6 graft could be associated with gray matter spongiosis in adjacent transgenic host tissue. This result suggested that expression of anchored PrPsen in gray matter might be a fundamental requirement for the induction of the typical TSE/prion disease pathogenic process.
In the present experiments scrapie infection of transgenic mice expressing anchorless PrP resulted in a slow fatal brain disease. These results demonstrated new mechanisms of prion-induced pathogenesis associated with the presence of PrPres amyloid and the absence of GPI-anchored PrP. This disease lacked gray matter spongiosis and differed in this respect from scrapie infection in non-transgenic mice, where the disease is characterized by extensive gray matter spongiosis and non-amyloid PrPres deposition.
The current results raised the question of how lack of GPI-linked membrane anchoring of PrP might facilitate formation of PrPres amyloid. GPI anchorless PrP has a longer biological half-life and is secreted by the cell. Both of these attributes might allow more effective and extensive interactions between soluble PrP molecules. In addition, the minimal amount of carbohydrates and the absence of the GPI group on anchorless PrP might favor amyloidogenic hydrophobic protein-protein interactions, particularly at a time of partial protein unfolding during PrP conversion. These features of anchorless PrP are likely to contribute to its enhanced tendency to form amyloid during conversion to PrPres. Anchorless protease-resistant PrP, cleaved at residue 228, comprises 15% of the PrPres in hamster scrapie brain extracts , but it is unclear whether this material contributes to the amyloid PrP seen in this model.
Our results differed from those of two interesting mouse prion disease models where PrPres was also found almost entirely in an amyloid form. In the GSS PrP-8kd model and the G3-ME7 model , which both used PrP mutant mice, PrP amyloid was seen primarily in the corpus callosum, but did not spread significantly to other brain regions. There was no clinical disease in these models, and transmission experiments suggested very low infectivity titers in the GSS PrP-8kd model. Compared to these two models, the three main distinguishing features of the anchorless PrP model are the ability of the PrPres amyloid to accumulate widely throughout the brain (Figure 4), the resulting fatal brain disease (Figure 2), and the high titer of transmissible agent (Table 2) .
The association of amyloid deposition without gray matter spongiosis in our system is reminiscent of the neuropathology seen in certain human familial prion diseases. For example, GSS patients with PrP mutations Y145Stop and Y163Stop had both CAA and parenchymal perivascular amyloid without gray matter spongiosis . Both these mutations result in C-terminally truncated PrP lacking the GPI anchor. Parenchymal amyloid deposition without gray matter spongiosis has also been seen in GSS patients with several other PrP mutations including P102L, P105L, A117V and F198S . Recently two human GSS patients with new PrP mutations producing nonsense codons at positions 226 and 227 were described . Both patients had widespread PrPres amyloid deposition in the absence of gray matter spongiosis, and one had CAA. These patients expressed a nearly full-length form of PrP lacking 6–7 C-terminal residues and the GPI anchor, which was quite similar to the PrP expressed in our anchorless PrP tg mice.
In many GSS patients, amyloid PrPres purified from brain was truncated resulting in a 7–11 kDa protease-resistant fragment from the central region of PrP (approximately residues 81–150),,. Interestingly, presence of this truncation has been correlated with the lack of gray matter spongiosis ,. In contrast, based on previous immunoblot studies, the proteinase K-resistant PrPres amyloid in our model appeared to contain residues 88–231 , which was similar to the PrPres found in human and animal prion diseases with extensive gray matter spongiosis. Furthermore, PrPres in tissue sections could be stained with anti-PrP serum R24, specific to residues 23–37 (data not shown) suggesting that there was no significant truncation at the N-terminus beyond the signal peptide. Thus, lack of spongiosis in our model appeared dependent on the absence of GPI-anchoring rather than truncation of the PrPres.
Two possibilities might explain the correlation between lack of GPI- anchored PrP and lack of gray matter spongiosis in our infected transgenic mice: (1) anchorless amyloid PrPres might be less neurotoxic than diffuse PrPres, and/or (2) anchored PrPsen might be required for PrPres-mediated neurotoxic membrane interactions. The former explanation could not be proven or excluded by our results. However, the latter interpretation was supported by data from brain graft experiments. After scrapie infection of tg44+/− mice grafted with C57BL/6 brain expressing normal anchored PrPsen, we observed gray matter spongiosis and non-amyloid PrPres deposition in C57BL/6 grafts, but not in adjacent host tissue expressing only anchorless PrPsen. Tissue expressing only anchorless PrPsen appeared to be unable to respond to the presence of GPI-anchored PrPres produced in the nearby grafts, and no gray matter spongiosis was produced. Therefore, lack of anchored PrPsen might by itself explain the lack of gray matter spongiosis in transgenic mice.
However, even in the absence of anchored PrPsen, the amyloid PrPres was able to induce additional pathogenic processes capable of causing fatal neurological disease. By both light and electron microscopy we observed evidence for three distinct pathogenic processes not seen in typical prion disease in C57BL/10 mice (Box 1):
(1) Brain damage caused by tissue distortion by large amyloid plaques. These plaques were associated with neuronal loss, axonal pathology and gliosis (Figure 4E, H–L Figure 6A,E,F). The more rapid accumulation of PrPres in tg44+/+ mice compared to tg44+/− mice (Figure 3) suggested a faster growth of large space-occupying plaques which might explain in part the clinical neurological signs leading to death of tg44+/+ and tg23+/+ mice (Figure 2).
(2) A second pathogenic process in scrapie-infected transgenic mice was suggested by ultrastructural studies finding that the early aggregation of PrPres into fibrillar amyloid was located at or within vascular basement membranes (Figures 5C, 5D, 6C, 6D). This was associated with vascular damage including occlusion (Figure 5B), amyloid replacement of basement membrane and tunica media, and occasional micro-hemorrhages. This pathology was similar to that observed in CAA seen in Alzheimer's disease and several familial amyloid diseases including two prion diseases ,,,.
(3) Evidence of a third pathogenic process in the transgenic mice was suggested by finding of small deposits of immunogold-labeled PrPres at the ultrastructural level in the extracellular spaces between glial and neuritic processes in gray matter (Figures 5D, 5E, 5F). These PrPres deposits were small, and there was no distortion of the extracellular space or visible aggregation into amyloid fibrils. However, the adjacent processes were often highly dystrophic (Figure 6E) or swollen and devoid of organelles, and they appeared to coalesce to form empty spaces larger than the original processes (Figures 5G, 6A, 6B). These abnormal areas, which were also noted in heterozygous tg44+/− and tg23+/− mice, appeared to represent a form of damage related to small, rather than large, PrPres deposits, and they did not require the presence of anchored PrPsen for their formation.
Box 1. Three neuropathogenic processes found in scrapie-infected homozygous anchorless PrP transgenic mice (tg44+/+ and tg23+/+)
- Displacement of brain structure by rapidly expanding amyloid plaques
- Associated with neuronal dropout and adjacent axonal and neurite damage
- Early PrPres amyloid on or within basement membranes of endothelial cells, smooth muscle cells and pericytes
- Possible damage to basement membrane and obstruction of the flow of interstitial brain fluid by PrPres amyloid
- Possible role of basement membrane components in assisting PrPres formation, e.g. glucosaminoglycans, collagen, laminin, etc.
- Vascular occlusion and occasional micro-hemorrhages
- Accumulation of PrPres in the interstitial space between neurite and glial processes
- Neuronal and glial toxicity with formation of swollen neurites and glial processes with fewer organelles
The early localization of PrPres at basement membranes (Figures 5A, C, D), suggested that the PrP conversion process might initiate at these sites, and implied that basement membrane molecules might facilitate PrP conversion. For example, basement membrane might filter or trap soluble PrPsen molecules or small PrPres oligomers from the extracellular interstitial fluid of brain increasing their local concentration, thus favoring conversion to larger PrPres amyloid aggregates. Serum amyloid P-component which binds to all amyloids and is a constituent of basement membranes might also contribute to local PrP conversion . In addition, collagen, laminin and heparin sulfate-containing proteoglycans are major components of basement membranes, and PrP can bind to both the laminin receptor and heparan sulfate which can associate directly or indirectly with PrP –. Heparan sulfate and other glycosaminoglycan (GAG) moieties can delay scrapie disease in vivo – ,, and some GAG molecules can alter PrP conversion in vitro . A scaffolding mechanism might account for this effect. For example, soluble anchorless PrPsen monomers might be held in place by GAG polymers to increase local concentration and facilitate conversion by PrPres, analogous to the tethering of anchored PrPsen on cell membranes ,. In addition, attachment of small mobile PrPres oligomers to GAG polymers might assist conversion at the basement membrane. Subsequently newly formed larger less mobile PrPres could serve as an efficient scaffold for further conversion allowing the process to extend out into the brain parenchyma. Eventually this process might form very large PrPres amyloid plaques with blood vessels at the center as we observed (Figure 4E and 5A).
The vascular amyloid pathology seen in our scrapie-infected transgenic mice (Figures 4E, 5A–D, 6B–D) was similar to CAA seen in Alzheimer's disease as well as several familial amyloid diseases , including two forms of familial prion disease . In Alzheimer's disease, amyloid fibrils within vascular basement membranes are thought to impede interstitial fluid drainage leading to an increase in Aβ concentrations within the extracellular space. Such increased soluble Aβ and oligomeric proto-amyloid fragments are considered a likely contributory factor in the cognitive decline of Alzheimer's disease patients . Similar processes might contribute to the clinical disease seen in the anchorless PrP scrapie model. Since all these diseases with CAA show amyloid localization with basement membranes, drugs capable of blocking amyloid-basement membrane interactions might be effective treatments for some of these diseases. In the case of prion diseases, one such compound, pentosan polysulfate, a small GAG oligomer, was effective in blocking PrPres generation in an infected cell line and delayed onset of clinical scrapie in vivo . Similarly a decoy molecule preventing PrP interaction with the laminin receptor (LRP/LR) reduced PrPres levels and delayed disease in vivo . Determining the precise glycans and proteins involved in the protein interactions leading to amyloid deposition in all the CAA diseases might be important in designing new therapeutic approaches.
Ethics statement: All mice were housed at the Rocky Mountain Laboratories (RML) in an AAALAC-accredited facility, and research protocols and experimentation were approved by the NIH RML Animal Care and Use Committee.
C57BL/10SnJ mice (Prnp+/+) were obtained from Jackson Laboratories (Bar Harbor, Maine). C57BL/10SnJ PrP−/− mice were created at RML by crossing 129/Ola PrP−/− mice with C57BL/10SnJ mice, followed by nine serial backcrosses to C57BL/10SnJ with selection for the Prnp+/− genotype using previously described PCR reactions to detect both the Prnp+ and Prnp null alleles . One intercross was then done, and C57BL/10SnJ Prnp−/− (PrP−/−) mice were selected and interbred. Heterozygous Prnp+/− mice were obtained by intercrossing C57BL/10 (Prnp+/+) mice with C57BL/10 Prnp−/− mice.
Transgenic GPI anchorless PrP mice (tg44+/− and tg23+/−) were made as described previously and then backcrossed to C57BL/10SnJ-Prnp−/− mice for six to nine generations with selection for the Prnp−/− genotype and the tg44 or 23+/− genotype. Thus these mice contained one anchorless PrP transgene allele and did not express any normal anchored mouse PrP allele. Heterozygous transgene lines tg23+/− and tg44+/− were each interbred to create homozygous lines (tg44+/+ and tg23+/+). Offspring were tested for transgene zygosity using real-time DNA PCR on an ABI Prism 7900 HT Sequence detection system and SDS 2.2.2 software. The following probes and primers were designed to amplify the mouse Prnp sequence: probe (moPrPlower418T): (5′-CGGTCCTCCCAGTCGTTGCCAAA), forward primer (moPrP-396F): (5′-CGTGAGCAGGCCCATGATC), reverse primer (moPrP-465R): (5′GCGGTACATGTTTTCACGGTAGT). Individual mice identified by rtPCR as transgene homozygous were then bred to Prnp−/− mice to confirm homozygosity. Homozygous mice were then interbred to create additional mice for experimentation. Both tg44 and tg23 lines were used in the present experiments to demonstrate that the observed findings were consistent with transgene expression rather than a result of an integration site artifact.
Four to six week old mice were inoculated intracerebrally with 50 µl of a 1% brain homogenate of 22L or RML scrapie containing 0.7–1.0×106 ID50. One ID50 is the dose causing infection in 50% of C57BL/10 mice. Animals were observed daily for onset and progression of scrapie. Mice were euthanized when clinical signs were consistent and progressive. Signs differed somewhat in C57BL/10 and tg44+/+ and tg23+/+ mice (Table 1). In heterozygous tg44+/− and tg23+/− mice many mice developed signs of debilitation such as weight loss, dermatitis and infections requiring euthanasia prior to severe neurological signs.
For detection of PrPsen from uninfected brains, tissues were homogenized (20% w/v) using a bead beater in ice-cold 0.01 M Tris-HCl pH 7.6 containing protease inhibitors (10 µM leupeptin, 1 µM pepstatin, and 1 µM aprotinin). Each sample was vortexed for 1 minute followed by sonication for 1 minute. Insoluble debris was removed by centrifugation at 2700 g for 10 minutes at 4°C. Samples were mixed 1:1 with 2X SDS-PAGE sample buffer and boiled for 3–5 minutes. PNGase F reactions were done using 4.4 mg tissue equivalents in a total volume of 20 µl SDS-PAGE sample buffer . Samples were serially diluted two-fold in sample buffer to give the amount of brain tissue (mg brain equivalents) indicated for each lane. Immunoblots were probed by using monoclonal anti-PrP D13 at a dilution of 1:5000 (InPro Biotechnology, South San Francisco, CA), followed by secondary antibody sheep anti-human Ig (dilution 1:5000) (GE Healthcare, formerly Amersham Biosciences, Piscataway, NJ) and enhanced chemiluminescence according to the manufacturers instructions (Amersham-Pharmacia, Uppsala, Sweden).
For detection of PrPres either with or without PNGase F, samples were prepared as described . Blots were probed as described above.
Embryonic brain tissue was obtained from E12–E14 C57BL/6 embryos which expressed green fluorescent protein (GFP) in all tissues . Mice were purchased originally from Jackson laboratories and were bred at Rocky Mountain Laboratories by Dr. Kim Hasenkrug. Pregnant mothers were euthanized and embryos dissected with forceps in media under a dissecting microscope to obtain the mesencephalon and telencephalon. Tissue was partially disrupted by pipetting to generate small fragments. This suspension (30 µl) was inoculated intracerebrally through the skull into the parietal brain region of 3–4 week old PrPnull mice or tg44+/− mice. One month later recipient mice were infected intracerebrally with 22L scrapie as described above. At various times thereafter mice were euthanized and brain tissue was examined histologically for GFP and PrPres by specific immunohistochemistry and for typical scrapie-induced gray matter spongiosis by H&E staining.
Histopathology and immunohistochemistry
Mice were euthanized and brains were placed in 3.7% phosphate-buffered formalin for 3 to 5 days before dehydration and embedding in paraffin. Serial 4 µm sections were cut using a standard Leica microtome, placed on positively charged glass slides and dried overnight at 56°C. Slides were stained with a standard protocol of hematoxylin and eosin (H&E) for observation of overall pathology. For PrPres detection, slides were rehydrated in 0.1 M citrate buffer, pH 6.0 and then heated at 120°C, 20 psi for 20 minutes in a decloaking chamber (Biocare, Walnut Creek, CA). Immunohistochemical staining was performed using the Ventana automated Nexus stainer (Ventana, Tucson, AZ). Staining for PrP used a standard avidin-biotin complex immunoperoxidase protocol using anti-PrP antibody D13 (In-Pro Biotechnology, South San Francisco, CA) at a dilution of 1:500 and incubated at 4°C for 16 hours. Biotinylated goat anti-human IgG (Jackson Immuno Research, West Grove, PA) was used at a 1:500 dilution as the secondary antibody. Detection was performed with Ventana streptavidin-alkaline phosphatase with Fast Red chromogen. Tissue sections for microglia staining were pretreated and stained with anti-Iba1 as described except that detection was done using the Ventana Fast Red chromagen as above. Astroglia were stained with anti-GFAP as described , and detection was completed with Ventana streptavidin-alkaline phosphatase using Fast Red. Tissue sections for staining with anti-amyloid precursor protein (APP) were pretreated as described for anti-PrP antibody D13. Anti-APP (Zymed Laboratories, San Francisco, CA) was used at a 1:500 dilution followed by a 1:250 dilution of biotinylated-goat anti-rabbit IgG (Vector Laboratories, Burlington, CA), and detection with Ventana streptavidin-horseradish peroxidase plus amino ethyl carbazol (AEC) chromagen. Staining of phosphorylated neurofilament proteins was performed using a monoclonal antibody cocktail pan-axonal neurofilament marker SMI-312 (Covance, Princeton, NJ) at a 1:250 dilution. Monoclonal antibody to nonphosphorylated neurofilament proteins was also used (SMI-311). Primary antibodies were followed by biotinylated horse anti-mouse IgG secondary antibody at a 1:250 dilution. Ventana AEC reagent was used for detection. Green fluorescent protein (GFP) was detected using a mixture of two mouse anti-GFP monoclonal antibodies (clones 7.1 and 13.1) at dilution of 1:200 (Roche Applied Science, Indianapolis, IN), followed by biotinylated horse anti-mouse IgG (Vector Laboratories, Burlington, CA) at a dilution of 1:250 and detected with AEC chromogen (Ventana) as described above. All histopathology slides were read using an Olympus BX51 microscope and images were obtained using Microsuite FIVE software.
Perfusion/Processing for electron microscopy
Mice were perfused with fixative containing 3% paraformaldehyde and 1% glutaraldehyde in PBS. Excised tissues were then immersed in this fixative and held overnight at 4 degrees C. Tissue pieces were processed further using a Lynx® automated tissue processor with agitation as follows: one wash in PBS for 3 hr at 20 degrees, one wash in 0.1 M sodium phosphate buffer pH 7.2 at 20 degrees for 4 hr, post-fix in 2% osmium tetroxide in phosphate buffer at 20 degrees for 6 hr, one wash in phosphate buffer at 20 degrees for 3 hr, three washes in water at 20 degrees for 3 hr each, in-block staining with 1% uranyl acetate in water at 20 degrees for 6 hr, 3 washes in water at 20 degrees for 3 hr each, dehydration in 70%, 100%, and 100% acetone at 10 degrees for 3 hr each, and infiltration at 20 degrees in Araldite resin (Structure Probe, Inc., West Chester, PA) at 50% for 8 hr, 75% for 12 hr, and two changes of 100% for 20 hr each. Further tissue blocks were processed using a Leica EM TP processor using the procedure above with the omission of the uranyl acetate. Tissue blocks were then transferred to fresh resin in molds and polymerized at 65 degrees for 24 to 48 hr.
Immunolabelling of resin block sections for light microscopy
Thick (1 µm) sections were stained by toluidine blue or were immunolabelled using the avidin-biotin technique. Sections were deplasticized with saturated sodium ethoxide for up to 30 minutes. Endogenous peroxidase was blocked and sections were de-osmicated with 6% hydrogen peroxide for 10 minutes, followed by pre-treatment with neat formic acid for 5 minutes. Normal serum was then applied for 1 hour to block non-specific labeling. 1A8 anti-PrP serum at a dilution of 1:6000, or pre-immune serum were then applied for 15 hours and reaction product developed using 3-3′ diaminobenzidine.
Immunolabeling for electron microscopy
For routine electron microscopy areas were selected from 1 µm thick toluidine blue stained sections and counterstained with uranyl acetate and lead citrate. For ultrastructural immunohistochemistry, serial 65 nm sections were taken from blocks previously identified from immuno-labeled 1 µm thick sections as described above. The 65 nm sections were placed on 600 mesh gold grids and etched in sodium periodate for 60 minutes. Endogenous peroxidase was blocked and sections de-osmicated with 6% hydrogen peroxide in water for 10 minutes followed by enhancement of antigen expression with formic acid for 10 minutes. Residual aldehyde groups were quenched with 0.2 M glycine in PBS, pH 7.4 for 3 minutes. Preimmune serum or anti-PrP primary antibody 1A8 or R30 at a 1:500 or 1:1500 dilution respectively in incubation buffer were then applied for 15 hours. After rinsing extensively, sections were incubated with Auroprobe 1 nm colloidal gold diluted 1:50 in incubation buffer for 2 hours. Sections were then post-fixed with 2.5% glutaraldehyde in PBS and labeling enhanced with Goldenhance (Universal Biologicals, Cambridge, UK) for 10 minutes. Grids were counterstained with uranyl acetate and lead citrate.
The authors thank Drs. Karin Peterson, Suzette Priola and Byron Caughey for helpful suggestions concerning the manuscript, Lynne Raymond for assistance in breeding the transgenic mice, and Ed Schreckengust for animal husbandry.
Conceived and designed the experiments: BC BR KMW RR MJ. Performed the experiments: BR KMW RL RR DD GM MJ. Analyzed the data: BC BR KMW MK JS MJ. Wrote the paper: BC BR KMW MK MJ.
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<urn:uuid:5dff084f-b427-4468-8aac-620f7d582630> | seed | Campylobacter jejuni is a non-sporeforming, Gram-negative rod with a curved- to S- shaped morphology. Many strains display motility, which is associated with the presence of a flagellum at one or both of the polar ends of this bacterium.
Members of the Campylobacter genus are microaerophilic; i.e., they grow at lower-than- atmospheric oxygen concentrations. Most grow optimally at oxygen concentrations from 3% to 5%. Thus, these bacteria generally are fairly fragile in the ambient environment and somewhat difficult to culture in the laboratory. Additional conditions to which C. jejuni are susceptible include drying, heating, freezing, disinfectants, and acidic conditions.
Other Campylobacter species, such as C. coli and C. fetus, also cause foodborne diseases in humans; however, more than 80% of Campylobacter infections are caused by C. jejuni. C. coli and C. jejuni cause similar disease symptoms. C. fetus infections often are associated with animal contact or consumption of contaminated foods and beverages and are especially problematic for fetuses and neonates, in whom the mortality rate may be up to 70%.
Campylobacter genomes are relatively unstable; several mechanisms that may lead to this genetic instability have been proposed, including bacteriophage activity, DNA recombination and transformation. There are several typing methods, such as pulsed-field gel electrophoresis, PCR-based typing, ribotyping and genomotyping, for assessing the genetic diversity of C. jejuni. A list of Campylobacter genomes that have been sequenced is available under the National Center for Biotechnology Information web link.
• Mortality: Approximately 99 deaths in the United States, per year, are estimated to be due to campylobacteriosis.
• Infective dose: In general, the minimum number of ingested Campylobacter cells that can cause infection is thought to be about 10,000. However, in trials, as few as 500 ingested Campylobacter cells led to disease in volunteers. Differences in infectious dose likely can be attributed to several factors, such as the type of contaminated food consumed and the general health of the exposed person.
• Onset: The incubation period, from time of exposure to onset of symptoms, generally is 2 to 5 days.
• Disease / complications: The disease caused by C. jejuni infections is called campylobacteriosis. The most common manifestation of campylobacteriosis is self- limiting gastroenteritis, termed “Campylobacter enteritis,” without need for antimicrobial therapy. When antimicrobial therapy is indicated, erythromycin or ciprofloxacin are most commonly prescribed. A small percentage of patients develop complications that may be severe. These include bacteremia and infection of various organ systems, such as meningitis, hepatitis, cholecystitis, and pancreatitis. An estimated 1.5 cases of bacteremia occur for every 1,000 case of gastroenteritis. Infections also may lead, although rarely, to miscarriage or neonatal sepsis. Autoimmune disorders are another potential long-term complication associated with campylobacteriosis; for example, Guillain-Barré syndrome (GBS). One case of GBS is estimated to develop per 2,000 C. jejuni infections, typically 2 to 3 weeks post infection. Not all cases of GBS appear to be associated with campylobacteriosis, but it is the factor most commonly identified prior to development of GBS. Various studies have shown that up to 40% of GBS patients first had Campylobacter infection. It is believed that antigens present on C. jejuni are similar to those in certain nervous tissues in humans, leading to the autoimmune reaction. Reactive arthritis is another potential long-term autoimmune complication. It can be triggered by various kinds of infections and occurs in about 2% of C. jejuni gastroenteritis cases. Hemolytic uremic syndrome and recurrent colitis following C. jejuni infection also have been documented.
• Symptoms: Fever, diarrhea, abdominal cramps, and vomiting are the major symptoms. The stool may be watery or sticky and may contain blood (sometimes occult – not discernible to the naked eye) and fecal leukocytes (white cells). Other symptoms often present include abdominal pain, nausea, headache, and muscle pain.
• Duration: Most cases of campylobacteriosis are self-limiting. The disease typically lasts from 2 to 10 days.
• Route of entry: Oral.
• Pathway: The mechanisms of pathogenesis by C. jejuni are not well understood and usually vary based on the virulence genes present in a particular strain. In general, C. jejuni cause infections by invading and colonizing the human gastrointestinal tract.
Motility appears to be an important factor in C. jejuni pathogenesis, enabling the bacterium to invade the human intestinal mucosa. The mechanisms by which cellular invasion by C. jejuni cause the observed symptoms remain a mystery. In genome- sequencing studies, researchers were not able to identify the presence of toxin genes that likely contribute to diarrhea and other common symptoms.
Campylobacter species are believed to be the third leading cause of domestically acquired bacterial foodborne illness in the United States, with an estimated 845,024 cases occurring annually, according to the Centers for Disease Control and Prevention (CDC). According to data from FoodNet, the incidence of cases of campylobacteriosis reported to the CDC in 2008 was 12.68 per 100,000 individuals, which is a decrease of 32% over the last decade. For each reported case of campylobacteriosis, it is estimated that 30 cases are unreported.
Major food sources linked to C. jejuni infections include improperly handled or undercooked poultry products, unpasteurized (“raw”) milk and cheeses made from unpasteurized milk, and contaminated water. Campylobacter infection in humans has been linked to handling and eating raw or undercooked meat and poultry, whether fresh or frozen. Avoiding cross contamination of uncooked items from raw meat and poultry products, thorough cooking, pasteurization of milk and dairy products, and water disinfection are effective ways to limit food- and water-borne exposure to Campylobacter. Reduction of risk from contaminated poultry products can be achieved through good hygienic practices by manufacturers and consumers.
Campylobacter is part of the natural gut microflora of most food-producing animals, such as chickens, turkeys, swine, cattle, and sheep. Typically, each contaminated poultry carcass can carry 100 to 100,000 Campylobacter cells. Given the fact that up to 500 Campylobacter cells can cause infection, poultry products pose a significant risk for consumers who mishandle fresh or processed poultry during preparation or who undercook it.
C. jejuni has been found in a variety of other foods, such as vegetables and seafood, and in non- food animal species. C. jejuni also occurs in nonchlorinated water, such as that found in ponds and streams.
Special incubation conditions are required for isolation and growth of C. jejuni cells, since the organism is microaerophilic. Samples from stool or rectal swabs are inoculated directly onto selective media, or they can be enriched to increase recovery. To limit growth of competing organisms, media used for cultivation usually are supplemented with blood and antimicrobial agents. The cultures are incubated at 42oC, under microaerophilic conditions (5% oxygen and 5% to 10% carbon dioxide), for optimal recovery.
6. Target Populations
Children younger than 5 years old and young adults 15 to 29 years old are the populations in whom C. jejuni gastroenteritis most commonly is detected. The highest incidence of infection is among infants 6 to 12 months old. C. jejuni bacteremia may also affect pregnant women, leading to infection of the fetus, which can lead to miscarriage or stillbirth. The incidence of infection is estimated to be 40-fold greater in people with HIV/AIDS, compared with others in the same age group.
7. Food Analysis
Isolation of C. jejuni from food is difficult, because the bacteria are usually present in very low numbers. For isolation from most food products, samples are rinsed and the rinsate is collected and subjected to pre-enrichment and enrichment steps, followed by isolation of C. jejuni from the agar medium. For more information about isolation of Campylobacter from food and water, see FDA’s Bacteriological Analytical Manual.
8. Examples of Outbreaks
For an update on recent outbreaks related to Campylobacter, please visit the CDC’s Morbidity and Mortality Weekly Report and enter Campylobacter in the search field.
The following reports are available on the surveillance of foodborne outbreaks in the U.S.: CDC annual report, CDC report #1, CDC report #2, and FoodNet report.
9. Other Resources
The following web links provide more information about Campylobacter and its prevention and control:
• U.S. Department of Agriculture – Q&A from Food Safety and Inspection Services
• CDC – Disease Listing
• CDC – Emerging Infectious Diseases review
• Several federal surveillance and monitoring programs in the U.S. report the incidences of Campylobacter infections and their resistance to antimicrobial drugs; for example, FoodNet, PulseNet, and National Antimicrobial Resistance Monitoring System. Additional resources include:
- National Center for Biotechnology Information (taxonomy)
- World Health Organization
- FDA report on risk assessment |
<urn:uuid:3466b99d-dfb0-49d9-8840-92921f0a7a50> | seed | Volume 4, Number 4—December 1998
An Outbreak of Hantavirus Pulmonary Syndrome, Chile, 1997
An outbreak of 25 cases of Andes virus-associated hantavirus pulmonary syndrome (HPS) was recognized in southern Chile from July 1997 through January 1998. In addition to the HPS patients, three persons with mild hantaviral disease and one person with asymptomatic acute infection were identified. Epidemiologic studies suggested person-to-person transmission in two of three family clusters. Ecologic studies showed very high densities of several species of sigmodontine rodents in the area.
Hantavirus pulmonary syndrome (HPS), first recognized in 1993 after a cluster of acute respiratory distress syndrome deaths in the southwestern United States, is now considered a pan-American zoonosis (1,2). HPS is characterized by fever, myalgia, gastrointestinal symptoms, and headache, with subsequent characteristic cardiopulmonary dysfunction and a 40% to 60% case-fatality rate (3). Although the etiologic agent, Sin Nombre virus (SNV), causes clinical symptoms that appear different from those that Eurasian hantaviruses cause in hemorrhagic fever with renal syndrome, SNV shares many features with these Old World hantaviruses (4,5), including an association with a single primary rodent host (Peromyscus maniculatus [deer mouse] in the case of SNV), which acts as the natural reservoir (6).
After SNV was identified, numerous other New World hantaviruses were rapidly identified throughout the Americas by reverse transcription-polymerase chain reaction (RT-PCR) amplification of viral RNA from captured antibody-positive rodents and, occasionally, from infected patients (2). HPS was first identified in Chile in 1995 in the Cochamo, Los Lagos region. Genetic sequencing of RT-PCR products from the autopsy tissues of another patient presumptively infected in this region in 1996 confirmed infection with Andes virus (7), which had previously been identified in southern Argentina as a cause of HPS, with Oligoryzomys longicaudatus postulated as the reservoir host (8). Sporadic cases were reported in Chile until an outbreak that included two family clusters was recognized in the Coyhaique Health District, Aysen region, in August 1997; a third cluster was reported in January 1998. This outbreak prompted a joint investigation by the National Administration of Laboratories and Institutes of Health (Argentina), Pan American Health Organization, Centers for Disease Control and Prevention (CDC, USA), in collaboration with the Ministry of Health of Chile, to define the epidemiology and ecology of the syndrome in Chile.
Epidemiologic Surveillance and Case Identification
National and local surveillance for HPS was reinforced with explicit case definitions for HPS, asymptomatic hantavirus infection, and mild hantaviral disease. HPS was defined as an acute febrile illness (temperature >38.3°C) characterized by unexplained acute respiratory distress syndrome or bilateral interstitial pulmonary infiltrates, with respiratory compromise requiring supplemental oxygen, or an unexplained illness resulting in death, with autopsy results showing noncardiogenic pulmonary edema without an identifiable specific cause of death. In addition to a compatible clinical illness, the following laboratory evidence of infection was required: 1) hantavirus-specific immunoglobulin M (IgM) or a fourfold rise in IgG titer, or 2) positive RT-PCR results for hantavirus RNA, or 3) positive immunohistochemical results for hantavirus antigen.
Asymptomatic hantavirus infection was defined as laboratory evidence of acute hantavirus infection (presence of IgM antibodies) in persons with no documented concurrent illness. Mild hantaviral disease was defined as IgM-positive results and a febrile illness without objective pulmonary dysfunction (i.e., hypoxemia and radiographic abnormalities). All other persons with isolated detectable hantavirus-specific IgG antibodies were classified as "other seropositives."
All available clinical charts and case reports from the Aysen region were reviewed in conjunction with interviews of family members from the two described clusters and survivors. A third cluster was identified in January 1998 and was also reviewed.
Rodents were trapped at two principal sites near the residence sites of the first two reported family clusters, as well as in several areas of less disturbed native vegetation in Lago Atravesado. Traps were placed at each of the two case-households, as well as at two neighboring controls for each case-household (one within 500 m and the other 500 m to 1,000 m). Each evening, 150 to 200 live-capture traps were placed within and around residences, outbuildings, gardens, and woodpiles, along fence lines, and within remnant patches of native vegetation. Traps were checked in the early morning, and samples of blood and organ tissues were collected according to standardized protocols (9). For comparison, we used similar trapping techniques at additional sites near Valdivia (700 km north of the outbreak area) and the capital city of Santiago (1,400 km north). Rodent taxonomy is as described by Musser and Carleton, 1993 (10).
Human serum specimens were tested for IgG antibodies reactive with SNV and Andes antigens by an enzyme-linked immunosorbent assay (ELISA) (11). Rodent whole-blood specimens were similarly tested for IgG antibodies to SNV. An IgM-capture ELISA was performed on human sera by using inactivated Laguna Negra virus at CDC and an IgM-capture ELISA with recombinant Andes nucleocapsid antigen at the National Institute for Infectious Disease, Buenos Aires, Argentina (P. Padula, unpub. data). Immunohistochemical analysis for hantaviral antigens was performed by using a cross-reactive monoclonal antibody directed against conserved hantaviral nucleocapsid epitopes (12). Specimens from HPS patients were also examined for viral genetic materials (M and S segment) by nested and heminested RT-PCR from either autopsied tissues or blood clot samples (13,14). Genetic sequencing of RT-PCR products derived from patient samples was also performed.
From October 1995 when HPS was first recognized in Chile through June 1997, seven additional cases were identified (Figure 1). Between July 1, 1997, and January 22, 1998, 25 HPS patients and three family clusters were identified in Chile. By RT-PCR we confirmed that 16 of these patients had been infected with Andes virus. Except for six cases, the recent outbreak was centered in Regions X (Llanchipal) and XI (Aysen) (combined population = 1.1 million) (Figure 2). The areas where these patients lived are sparsely populated, with numerous lakes, in a Nothofagus (southern beech) forest ecosystem. From October 4, 1995, to January 22, 1998, a total of 33 cases were identified in Chile, with a case-fatality rate of 54%. The mean age was 31.4 years (range: 1 year 11 months to 60 years); five (15.2%) of the patients were children under 17 years of age; and 76% of the patients were male. No cases were reported among health-care workers.
No significant difference in mean age, case-fatality rate, or proportion of male patients was evident between the July to January outbreak and previous cases; however, all the pediatric cases occurred during the July to January outbreak.
The first family cluster (Cluster 1) of HPS cases was reported from Cisne Medio, Lago Verde community, Aysen region. The 39-year-old male head of the family became ill with an acute febrile illness on July 15 and died in transit to the regional hospital on July 21; HPS was subsequently confirmed by immunohistochemistry and RT-PCR (M and S segment), with a genetic sequence consistent with Andes virus. The family moved to the village of Villa Amengual, 7 km away, on July 22 and remained there except for a brief visit to Cisne Medio on July 27 to retrieve personal belongings. The wife of the index patient became ill with HPS on August 2 and died on August 8. Her 2-year-old and 12-year-old sons became ill 1 week and 16 days, respectively, after she became ill. HPS was confirmed in both children by serologic testing; both children survived. The brother-in-law of the index patient, who continued to reside intermittently in the original household, became ill 33 days after his sister became ill and died (Figure 3). Thus, the immediate family members became ill 12, 19, and 28 days after leaving the family homestead, and the intervals between the onset of the index and later cases were 18, 25, and 34 days.
In contrast, the second family cluster (Cluster 2) included all four members of a household in Lago Atravesado, Coyhaique community, Aysen region, who became ill within 5 days of each other; one of them, a 2-year-old child with no respiratory symptoms, was classified as having a mild hantaviral infection. The third family cluster (Cluster 3) included a husband, who worked in a rural area, and his wife, who remained in the family home in urban Coyhaique, a city of 60,000 inhabitants. The husband became ill with symptoms suggestive of HPS 12 days after returning to his family home. He was hospitalized and died on December 19. His wife became ill 22 days after the onset of the husband's symptoms. She had not traveled outside the town of Coyhaique during the previous 12 months and reported no exposure to rodents or their excreta. The only known exposures for the wife were washing her husband's clothing and caring for him while he was ill. She survived and was discharged from the hospital on January 28.
Genetic sequencing of viral RNA from cases of immediate family members from Clusters 1 and 2 demonstrated 3.6% divergence in a 167-nucleotide G2 fragment between the clusters. However, the genetic sequence was identical within each of the two clusters. Genetic sequencing of viral RNA from an additional patient from Cisne Medio not related to the family members in Cluster 1, and the brother-in-law in Cluster 1, demonstrated a distinct G2 sequence, with 1%-4% sequence divergence between them (P. Padula, unpub. data).
Clinical and Histopathologic Features
In general, the clinical description of HPS cases in Aysen was similar to that of the cases in North America. However, included in the Aysen cases were three children with petechiae; one of them died rapidly with hemorrhagic pulmonary secretions and bleeding from puncture sites. Six of the seven patients on whom urinanalysis was performed had microscopic hematuria and casts; three had proteinuria of >100 mg/dl. In addition, one child in the Llanchipal region had concurrent acute rubella infection. One of the most recent cases occurred in Maule, Region VII, in a 23-week pregnant woman who had typical HPS symptoms and fetal death. Subsequently, disseminated intravascular coagulopathy developed and the woman died of multisystem failure.
The histopathologic features in the lung of HPS case-patients included an interstitial mononuclear infiltrate and intraalveolar edema. Immunohistochemical staining showed hantaviral antigens in the microvascular endothelial cells of the lung and other tissues—typical SNV-associated HPS cases. Prominent immunostaining of pulmonary macrophages was also noted in some cases. A unique feature in the series was fine granular immunostaining in the hepatic cells in some cases, a pattern not observed in a large series of North American HPS cases previously examined (Figure 4) (12).
Laboratory Test Results
Serologic testing was conducted for all patients and contacts of patients with confirmed HPS cases in Aysen. Among 53 contacts of 14 patients, two (3.8%) had serologic evidence of an acute infection (one had no illness, and another [described previously in cluster 2] had a mild febrile illness without pulmonary disease that did not meet the HPS case definition), and one was IgG positive. In addition, two hospitalized patients had mild hantaviral disease (M. Tapia, unpub. data). Test results of specimens (SNV and Andes antigens were used) were 100% concordant. Nested and heminested RT-PCR assays were conducted for 20 (71.4%) of 28 HPS cases; all 20 were positive. Sixteen (57.1%) were sequenced and characterized as Andes virus.
A total of 253 rodents were captured during 3 nights of trapping (574 trap nights) in the vicinity of Coyhaique. Overall trap success (captures per 100 trap nights) at case and control home sites was 37% at Cisne Medio and 50% at Lago Atravesado. Trap success at Cisne Medio within and adjacent to the case-household was 66%, compared with only 18% at control homes; this difference may reflect the use of rodenticides in and around the control households. Trap success at distances greater than 100 m from the households was more similar between case and controls (63% versus 43%). The most frequently captured rodent species was O. longicaudatus, which comprised 47% of the captured rodents in the area; 13 (12.7%) of 102 tested were hantavirus-antibody–positive. Akodon olivaceus comprised a further 33% of the captures (6 [7.5%] of 80 were antibody-positive), and 16% were Akodon longipilis (1 [2.7%] of 36 antibody-positive). Eight of 10 rodents captured inside the case-home at Cisne Medio were O. longicaudatus, and one was hantavirus-antibody–positive. High trap success in a forested area near Lago Atravesado (22 captures in 40 trap nights, or 55%) indicated that high rodent population densities were not restricted to peridomestic areas.
Trap success was moderate near Valdivia (52 captures from 660 trap nights, or 8% trap success) and very low near Santiago (8 captures from 453 trap nights, or <2%). The species composition was also very different from that encountered in the Coyhaique area: despite trapping in rural areas, 31% of rodents captured near Valdivia and Santiago were the murine species, Rattus rattus, R. norvegicus, and Mus musculus. No hantavirus-antibodypositive rodents were found from Valdivia or Santiago.
This outbreak of HPS and the presence of endemic disease in Chile support the assumption that HPS will continue to occur throughout the Americas (range of the sigmodontine rodents that host the genetic group of HPS-causing hantaviruses). In Latin America, endemic HPS and epidemics have been reported in Argentina, Brazil, and Paraguay (15-19). Sporadic cases and SNV-like viral sequences have been reported in these countries and in Bolivia and Uruguay (P. Padula, pers. comm.,7,20). Retrospective studies have verified that HPS cases occurred in the United States as early as 1959 (21). The factors responsible for the outbreaks in the Americas have not been well defined and may not be the same in all regions. However, periodic climatic and ecologic events cause dramatic local increases in rodent reservoir populations, known as "irruptions" or "ratadas" (22) and may lead to an increase in the number of rodent-human contacts.
Small-mammal trap success in the Coyhaique area was 5 to 30 times higher than in rural areas 700 km to 1,400 km further north. These extremely high trap success values indicate a rodent irruption in southern Chile whose causes may be related to the flowering of a species of bamboo and a relatively benign preceding winter (22). Regardless of causes, however, the extremely high rodent densities and evidence of hantavirus infection in the two most common species strongly implicate contact with rodents as the primary mode of disease transmission to humans. The rodent species with the highest antibody prevalence, O. longicaudatus, is the reservoir for Andes virus in Argentina and Chile (8,23). No hantavirus has been associated with A. olivaceus. RT-PCR conducted on tissue samples from seropositive animals yielded amplifiable viral RNA from seven of seven O. longicaudatus, two of four A. olivaceus, and one of one A. longipilis. Sequencing showed that all PCR products represented Andes virus, and sequences were nearly identical among all three species (S. Morzunov, unpub. data). The near identity between sequences from all three species and the fact that two of four samples from A. olivaceus were PCR negative suggest that hantavirus infection in A. olivaceus and A. longipilis represents spillover of virus from the primary reservoir, O. longicaudatus. The absence of viral RNA in two of the four samples from A. olivaceus also suggests that the infection is of shorter duration in this presumably nonhost species.
A number of features may eventually differentiate HPS caused by Andes virus from that caused by other New World viruses. Several mild and asymptomatic hantavirus infections have been reported in Argentina and Chile, whereas in North America the case-to-infection ratio is approximately 1:1 (24,25). In this investigation, four (11%) of the patients with serologic evidence of acute infection did not have HPS. More mild and asymptomatic disease in some South American hantavirus infections, in addition to infection with nonpathogenic hantaviruses, may be among the factors explaining antibody prevalence as high as 40% among indigenous persons of Argentina (C. Johnson, unpub. data). Similar case-to-infection ratios may explain the high prevalence (35% to 57%) of hantavirus antibodies in some regions of Paraguay (16,26).
Disease in Chile has also been characterized by an increased propensity toward bleeding, with petechiae in 50% of the pediatric cases and increased renal involvement with microscopic hematuria and cellular casts in the three patients whose urinanalysis results were available. Flushing of the head and upper thorax is indicative of vascular dysregulation and is a well-described sign in hemorrhagic fever with renal syndrome. It has also been described in Andes virus-infected patients from the adjacent areas of Argentina (17,27), but not in Chile.
The relatively large proportion of children with HPS reported in Chile is unexplained. Infection in children is relatively rare in the United States, where only 8 (4.5%) of 179 reported cases were in children 16 years old or younger. Moreover, this dearth of pediatric cases has also been reported for hemorrhagic fever with renal syndrome (28). It is unclear if this greater incidence of pediatric cases is Andes virus- or outbreak-specific. However, Argentina has also seen a larger proportion of pediatric HPS cases than the United States, caused by three different genotypes: Andes, Oran, and Lechiguanas.
Immunostaining showed hantaviral antigens in the microvascular endothelial cells of the lung and other tissues with prominent staining of pulmonary macrophages in some cases. A unique feature not previously described in SNV-associated HPS cases was fine, granular immunostaining in the hepatic cells of three patients. The specificity of this hepatic staining is being investigated. In Argentina, person-to-person transmission has been demonstrated in at least one epidemic of Andes virus infection (17). Although the mechanism of that transmission is unknown, the increased staining of intraalveolar pulmonary macrophages suggests the presence of virus within the alveolar space with the potential for small-particle aerosolization. A comparison of disease variants that may be hantavirus-strain–specific will be required to address this hypothesis.
No discrepancies were observed in serologic results from testing with SNV or Andes antigens, which underlines the current recommendation that diagnosis be based on serologic testing, especially given the difficulties in handling and transporting fresh tissues for RT-PCR and the possibility of cross-contamination. Formalin-fixed tissues from case-patients who died should be used for immunohistochemical tests, particularly if no serum or blood was obtained. However, even in fatal cases, an attempt should be made to obtain heart blood for serologic tests.
Person-to-person transmission cannot be excluded in the first or third family cluster. We did not trap rodents within the town limits at Villa Amengual or in the city of Coyhaique. However, although large numbers of rodents were seen in rural areas, rodent infestation in Villa Amengual or Coyhaique had not been reported. Further, since O. longicaudatus is a sylvatic species not generally associated with urban habitats, subsequent exposure to infected O. longicaudatus was likely not responsible for the wife's illness in family cluster 3. However, as in Cluster 2, Andes and other associated hantaviruses can cause clustering attributable to a single point–source contact with infected rodents.
Person-to-person transmission of Andes virus-associated HPS has been documented (17,29), although this type of transmission has not been observed with SNV-associated HPS (24,30). The lack of cases among health-care workers suggests that current protective methods are adequate; however, standard precautions should be reinforced. Until the propensity of Andes virus to be transmitted from person to person is clarified, patients with suspect cases should be isolated in separate rooms, contact and droplet precautions should be used, and respiratory precautions should be considered.
Dr. Toro is an epidemiologist with the Chilean Ministry of Health, professor of public health at the Universidad de Chile in Santiago, and director of the Chilean Society of Epidemiology.
We thank Drs. Alex Figueroa, Roberto Belmar, Hugo Salinas, and J. Montecinos for their support to complete these studies, and John O'Connor for editorial review of this manuscript. Dr. Roberto Murua provided valuable support of rodent trapping efforts, and Dr. Milton Gallardo confirmed the rodent species identifications.
- Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki SR, Hantavirus pulmonary syndrome: a clinical description of 17 persons with a newly recognized disease. N Engl J Med. 1994;330:949–55.
- Khan AS, Ksiazek TG, Peters CJ. Hantavirus pulmonary syndrome. Lancet. 1996;347:739–41.
- Khan AS, Khabbaz RF, Armstrong LR, Holman RC, Bauer SP, Graber J, Hantavirus pulmonary syndrome: the first 100 U.S. cases. J Infect Dis. 1996;173:1297–303.
- Ksiazek TG, Peters CJ, Rollin PE, Zaki S, Nichol S, Spiropoulou C, Identification of a new North American hantavirus that causes acute pulmonary insufficiency. Am J Trop Med Hyg. 1995;52:117–23.
- Nichol S, Spiropoulou C, Morzunov S, Rollin P, Ksiazek T, Feldmann H, Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science. 1993;262:914–7.
- Childs JE, Ksiazek TG, Spiropoulou CF, Krebs JW, Morzunov S, Maupin GO, Serologic and genetic characterization of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. J Infect Dis. 1994;169:1271–80.
- Espinoza R, Vial P, Noriega LM, Johnson A, Nichol ST, Rollin PE, Hantavirus pulmonary syndrome in a Chilean patient with recent travel in Bolivia. Emerg Infect Dis. 1998;4:93–4.
- Levis SC, Morzunov SP, Rowe JE, Enria D, Pini N, Calderon G, Genetic diversity and epidemiology of hantaviruses in Argentina. J Infect Dis. 1998;177:529–38.
- Mills JN, Childs JE, Ksiazek TG, Peters CJ, Velleca WM. Methods for trapping and sampling small mammals for virologic testing. Atlanta (GA): U.S. Department of Health and Human Services; 1995. p. 61.
- Musser GG, Carleton MD. Family Muridae. In: Wilson DE, Reeder DM, editors. Mammal species of the world, a taxonomic and geographic reference. Washington: Smithsonian Institute; 1993. p. 501-755.
- Feldmann H, Sanchez A, Morzunov S, Spiropoulou CF, Rollin PE, Ksiazek TG, Utilization of autopsy RNA for the synthesis of the nucleocapsid antigen of a newly recognized virus associated with hantavirus pulmonary syndrome. Virus Res. 1993;30:351–67.
- Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, Hantavirus pulmonary syndrome: pathogenesis of an emerging infectious disease. Am J Pathol. 1995;146:552–79.
- Lopez N, Padula P, Rossi C, Lazaro ME, Franze-Fernandez MT. Genetic identification of a new hantavirus causing severe pulmonary syndrome in Argentina. Virology. 1996;220:223–6.
- Hjelle B, Jenison S, Torrez-Martinez N, Yamada T, Nolte K, Zumwalt R, A novel hantavirus associated with an outbreak of fatal respiratory disease in the southwestern United States: evolutionary relationships to known hantaviruses. J Virol. 1994;68:592–6.
- Da Silva MV, Vasconcelos MJ, Hidalgo NTR, Veiga APR, Canzian M, Marotto PCF, Hantavirus pulmonary syndrome: report of the first three cases in São Paulo, Brazil. Rev Inst Med Trop Sao Paulo. 1997;39:231–4.
- Joachini L, Thompson M, Rojas de Arias A, Iwasaki E, Torrez-Martinez N, Von Bredow C, Prevalence of hantavirus antibodies in select populations of Eastern and Western Paraguay. In: Abstracts of the Fourth International Conference on HFRS and Hantaviruses; 1998 Mar 5-7; Atlanta, Georgia.
- Wells RM, Sosa ES, Yadon ZE, Enria D, Padula P, Pini N, An unusual hantavirus outbreak in southern Argentina: person-to-person transmission? Emerg Infect Dis. 1997;3:171–4.
- Levis SC, Briggiler AM, Cacase M, Peters CJ, Ksiazek TG, Cortes J, Emergence of hantavirus pulmonary syndrome in Argentina [abstract]. Am J Trop Med Hyg. 1995;54(Suppl):441.
- Williams RJ, Bryan RT, Mills JN, Palma RE, Vera I, Velasquez F, An outbreak of hantavirus pulmonary syndrome in Western Paraguay. Am J Trop Med Hyg. 1997;57:274–82.
- Hjelle B, Torrez-Martinez N, Koster FT. Hantavirus pulmonary syndrome-related virus from Bolivia [letter]. Lancet. 1996;347:57.
- Frampton JW, Lanser S, Nichols CR, Ettestad PJ. Sin Nombre virus infection in 1959 [letter]. Lancet. 1995;346:781–2.
- Murua R, Gonzales LE, Gonzales M, Jofre YC. Efectos del florecimiento del arbusto Chusquea quila Kunth (Poaceae) sobre la demografía de poblaciones de roedores de los bosques templados frios del sur Chileno. Boletín de la Sociedad de Biología. Concepción, Chile. 1996;67:37–42.
- López N, Padula P, Rossi C, Miguel S, Edelstein A, Ramirez E, Genetic characterization and phylogeny of Andes virus and variants from Argentina and Chile. Virus Res. 1997;50:77–84.
- Wells RM, Young J, Williams RJ, Armstrong LR, Busico K, Khan AS, Hantavirus transmission in the United States. Emerg Infect Dis. 1997;3:361–5.
- Levis S, Rowe JE, Morzunov S, Enria DA, St Jeor S. New hantaviruses causing hantavirus pulmonary syndrome in Central Argentina [letter]. Lancet. 1997;349:998–9.
- Ferrer JF, Jonsson CB, Esteban E, Calligan D, Basombrio MA, Peralta-Ramos M, High prevalence of hantavirus antibodies in Indian communities of the Paraguayan and Argentinean Gran Chaco. Am J Trop Med Hyg. 1998;59:438–44.
- Parisi MDN, Enria DA, Pini NC, Sabattini MS. Retrospective detection of clinical infections caused by hantavirus in Argentina. Medicina (B Aires). 1996;56:1–13.
- Khan AS, Ksiazek TG, Peters CJ. Viral hemorrhagic fevers among children. Semin Pediatr Infect Dis. 1997;8:64–73.
- Padula PJ, Edelstein A, Miguel SDL, López NM, Rossi CM, Rabinovich RD. Hantavirus pulmonary syndrome (HPS) outbreak in Argentina: molecular evidences for person-to-person transmission of Andes virus. Virology. 1998;241:323–30.
- Vitek CR, Breiman RF, Ksiazek TG, Rollin PE, McLaughlin JC, Umland ET, Evidence against person-to-person transmission of hantavirus to health care workers. Clin Infect Dis. 1996;22:824–6.
Suggested citation: Toro J, Vega JD, Khan AS, Mills JN, Padula P, Terry W, et al. An Outbreak of Hantavirus Pulmonary Syndrome, Chile, 1997. Emerg Infect Dis [serial on the Internet]. 1998, Dec [date cited]. Available from http://wwwnc.cdc.gov/eid/article/4/4/98-0425
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- Page last updated: December 16, 2010
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<urn:uuid:9becc766-6188-48d6-99d2-75db6eeabbf3> | seed | Although controversial, chemotherapy is one of the most common mainstream medical answers in the treatment of cancer. Not only is its effectiveness questionable — makers claim an extension of life as a “success” — but there is a whole slew of unpleasant and even debilitating side effects. A new analysis from researchers at the Moffitt Cancer Center have substantiated one more, long term side effect to add to that list — cognitive deficit, known as chemo brain — and this one doesn’t go away when the treatment is over.
According to the study published in the Journal of Clinical Oncology, breast cancer patients who underwent chemo treatment showed mild impairments in verbal abilities and visuospatial abilities. This means the women studied had a harder time finding the words they needed to communicate and were more likely to get lost. The meta-analysis looked at numerous previously published studies and was funded in part by the National Cancer Institute and the National Institutes of Health.
“Chemo brain” is an incidence that cancer patients have long experienced, though were sometimes met with disbelief and frustration from their doctors. Now, more and more research is showing that the poison that kills cancer cells may also affect the brain.
“The objective of our analysis was to clarify existing research on cognitive functioning in patients who had received standard dose chemotherapy for breast cancer at least six months previously,” said lead author Heather S.L. Jim, Ph.D., lead author of the study and an assistant member at Moffitt. “Earlier studies had reported conflicting evidence on the severity of cognitive deficits, especially over the long term.”
The analysis found that those patients treated with chemo performed worse on tests of verbal ability and tests of visuospatial ability than those patients who either didn’t have cancer or weren’t treated with chemo.
There was a time when if a doctor recommended chemotherapy for your cancer treatment, you complied. Now, more and more people are weighing the pros and cons of this medication and finding they might be better without.
Common side effects include the well-known: nausea, hair loss, diarrhea, vomiting, fever, pain and fatigue. More long term and later developing side effects, however, can be far more serious, and include: lung damage, heart problems, nerve damage, kidney problems, infertility, risk of more incidents of cancer and chemo brain.
The reason chemotherapy is so damaging is because it is a poison, plain and simple. It attacks cancer cells and kills them. Unfortunately, it doesn’t recognize the differences between healthy and unhealthy cells. In other words — it attacks them all.
Cancer prevention is the key to avoiding the tough treatment decisions. And cancer prevention is accomplished through the diet.
The World Cancer Research Fund has determined fruits and vegetables can reduce the incidents of cancer. There is no magic bullet, so to speak, but the combination of a variety of fresh produce every day can have significant effects on your health overall and your risk of developing cancer. Cruciferous vegetables, like cabbage and broccoli, are particularly potent in cancer prevention and even cancer treatment. Study after study has shown compounds in these vegetables to stop cancer cell growth in its tracks.
Modern medicine is a marvel — and in some cases it can extend the life of people diagnosed with a tragic disease like cancer. But all of modern medicine, including chemotherapy, comes at a cost. As conscientious consumers and health-conscious individuals, it’s our responsibility to prevent these diseases and illnesses through proper nutrition and whole-body health, and when we are presented with the tough decisions on treatment — to make those decisions with as much unbiased information as possible. |
<urn:uuid:87385a39-62af-439d-b909-b434766c2b4a> | seed | Rare infection may have caused death of Chicago scientist
September 19, 2009
A University of Chicago researcher died Sun., Sept. 13, at the Medical Center's Bernard Mitchell Hospital from an infection which may be attributable to a weakened laboratory strain of Yersinia pestis, the bacteria that causes the plague.
The researcher studied the genetics of harmful bacteria, including a weakened strain of Yersinia pestis that lacks the bacteria's harmful components. This strain is not known to cause illness in healthy adults and has been used in some countries as a live-attenuated vaccine to protect against plague. It has been approved by the Centers for Disease Control and Prevention (CDC) for routine laboratory studies. The weakened strain does not require the special safety precautions required for work with virulent strains.
Though there does not appear to be a threat to the public, and no other illness related to this case has been reported, the Medical Center infection control team is working with the Chicago Department of Public Health (CDPH), the Illinois Department of Public Health (IDPH) and the CDC to investigate the case and take all appropriate precautions.
"This death is a tragic loss to our community," said James L. Madara, MD, Dean of the Biological Sciences Division and Pritzker School of Medicine, and CEO of the Medical Center. "We are all saddened to lose a valued colleague."
The patient's initial autopsy showed no obvious cause of death except for the presence of bacteria. Routine cultures of the patient's blood grew the weakened strain of Y. pestis. Whether the attenuated strain caused the fatal illness in this researcher remains uncertain. Additional studies to assess the connection are underway.
Nevertheless, once the attenuated strain of Y. pestis was identified on Sept. 18, Medical Center officials immediately notified the CDPH. As a precautionary measure and in cooperation with the CDPH, Medical Center personnel began notification of family, friends, colleagues and health care personnel who may have had contact with the patient.
People exposed to Y. pestis typically develop symptoms within 2 to 10 days. None of the potential contacts has reported illness. The weakened strain is not believed to be dangerous to healthy individuals, but underlying health conditions could potentially increase susceptibility. Anyone who might have been exposed will be offered antibiotics as a precaution.
While rare in the United States, plague remains a significant problem in the developing world, where up to 3,000 cases are reported every year. U.S. cases still occur in parts of California, Colorado, Utah, Arizona, Nevada and New Mexico. The last known case of person-to-person transmission of plague in the United States occurred in 1924.
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<urn:uuid:6adf4e68-e695-44c2-8eef-0b2d5e9bc054> | seed | (From the Brochure)
- WHAT IS CYSTINOSIS?
- Cystinosis is a metabolic disease characterized by an abnormal
accumulation of the amino acid cystine in various organs of the body such as
the kidney, eye, muscle, pancreas, and brain. Different organs are affected at
- IS IT INHERITED?
- The disease is inherited in an autosomal recessive fashion,
meaning that each parent of a child with cystinosis carries one defective gene
and one normal gene. The parents never have any signs of the disease.
- WHAT CAUSES CYSTINOSIS?
- The cystine content of cystinotic cells averages 50-100 times the
normal value. The cause is a defect in the transport of cystine out of a cell
compartment called the lysososme, in which cystine accumulates. Because of
cystine's low solubility, this amino acid forms crystals within the lysosomes
of cells, and this is probably what destroys the cells.
- WHAT ARE THE SYMPTOMS?
- There are three clinical forms of cystinosis. Infantile (or
nephropathic) cystinosis; late-onset cystinosis; and benign cystinosis. The
latter form does not produce kidney damage. Infantile and late-onset cystinosis
differ in the age of appearance of the first symptoms and in the rapidity of
the clinical course. Infantile cystinosis is usually diagnosed between 6 and 18
months of age with symptoms of excessive thirst and urination, failure to
thrive, rickets, and episodes of dehydration. These findings are caused by a
disorder called renal tubular reabsorb nutrients and minerals. As a
consequence, these important molecules are lost in the urine. Children with
cystinosis also have crystals in their eyes (after one year of age) and an
increased level of cystine in their white blood cells. Without specific
treatment, children with cystinosis develop end-stage renal failure, i.e., lose
their kidney function, at approximately 9 years of age.
- If cystinosis patients receive a kidney transplant and reach
adulthood, their new kidney will not be affected by the disease. However,
without cysteamine treatment (see below), they can develop complications in
other organs due to the continued accumulation of cystine throughout the body.
These complications can include muscle wasting, difficulty swallowing,
diabetes, heypthroidism, and blindness. Not all older patients develop these
- CAN CYSTINOSIS BE TREATED?
- The symptomatic treatment of the Fanconi syndrome
is essential. The urinary losses of water, salts, bicarbonate, and minerals
must be replaced. Most children receive a solution of sodium and potassium
citrate, as well as phosphate. Some also receive extra vitamin D.
- The aim of specific treatment for cystinosis is to
reduce cystine accumulation within the cells. This goal is achieved by
cysteamine treatment, which has proven effective in delaying or preventing
renal failure. Cysteamine also improves growth of cystinosis children. The Food
and Drug Administration (FDA) has approved a capsule form of cysteamine called
CYSTAGON . .
- Kidney transplantation has proven very helpful in patients with
cystinosis, and cysteamine therapy should be considered to try to prevent the
late complications of the disease (see above)..
- For both young children with cystinosis and older patients with a
kidney transplant, cysteamine eyedrops may be available to remove the corneal
cystine crystals. However, these are not yet approved by the FDA.
- IS PRENATAL DETECTION POSSIBLE?
- Today, prenatal diagnosis is available for families known to be at
risk for having a child with cystinosis. Chorionic villus sampling is performed
at 8-9 weeks of gestation; amniocentesis can be performed at 14-16 weeks of |
<urn:uuid:8d70e955-92ff-4209-8414-c2852563bcb1> | seed | The increasing racial disparity in infant mortality rates: Composition and contributors to recent US trends
ABSTRACT We examined trends in birthweight-gestational age distributions and related infant mortality for African American and white women and calculated the estimated excess annual number of African American infant deaths.
Live births to US-resident mothers with a maternal race of white or African American were selected from the National Center for Health Statistics' linked live birth-infant death cohort files (1985-1988 and 1995-2000).
The racial disparity in infant mortality widened despite an increasing rate of white low-birthweight infants. White preterm infants had relatively greater gains in survival and the white advantage in survival at term increased. Annually, African American women experience approximately 3300 more infant deaths than would be expected.
The increasing US racial disparity in infant mortality is largely influenced by changes in birthweight-gestational age-specific mortality, rather than the birthweight-gestational age distribution. Improvement in the survival of white preterm and low-birthweight infants, probably reflecting advances in and changing access to medical technology, contributed appreciably to this trend.
- SourceAvailable from: Emily Harville
[Show abstract] [Hide abstract]
- "Decades of policy and public health intervention targeting reproductive health have done little to reduce the disproportionately high rates of adverse perinatal outcomes experienced by African American women compared to women of other racial and ethnic groups in the United States (Alexander et al., 2008; Lu et al., 2010). Moving beyond individual and interpersonal-level risk factors, a growing body of research has examined social and structural determinants of reproductive health in an effort to explain the persistence of racial disparities (Kramer and Hogue, 2009). "
ABSTRACT: Large disparities in adverse birth outcomes persist between African American and white women in the US despite decades of research, policy, and public health intervention. Allostatic load is an index of dysregulation across multiple physiologic systems that results from chronic exposure to stress in the physical and socio-cultural environment which may lead to earlier health deterioration among racially or socio-economically disadvantaged groups. The purpose of this investigation was to examine relationships between maternal biomarkers of allostatic load prior to conception and the occurrence of preterm birth and small for gestational age infants among a cohort of white and African American women participants in the Bogalusa Heart Study. Data from women participants were linked to the birth record of their first-born infant. Principal components analysis was used to construct an index of allostatic load as a summary of the weighted contribution of nine biomarkers representing three physiologic domains: cardiovascular, metabolic, and immune systems. A series of Poisson regression models based on samples ranging from 1467 to 375 women were used to examine race, individual biomarkers of allostatic load, and quartiles of the allostatic load index as predictors of preterm birth (n = 150, 10.2%) and small for gestational age (n = 135, 9.2%). There was no evidence of a relationship between maternal preconception allostatic load and either adverse birth outcome in this sample. Further, there was no evidence of effect modification of by race or education. More work is needed in understanding the biological mechanisms linking social inequities to racial disparities in adverse birth outcomes.Paediatric and Perinatal Epidemiology 10/2013; 27(6). DOI:10.1111/ppe.12091 · 2.81 Impact Factor
[Show abstract] [Hide abstract]
- "“Why” questions with a social justice bent often make great discovery questions. For example, one team investigating the causes of premature birth among women in the United States has asked, “Why is the African American and white disparity in infant mortality growing despite reduction efforts, and despite an increasing rate of white low birth weight infants?”32 These types of studies represent a shift in thinking about what constitutes good science: the criteria of significance and impact can include weighted consideration of novel, rigorous science that also addresses a stubborn and puzzling health disparity.33–35 "
ABSTRACT: The speed and effectiveness of current approaches to research translation are widely viewed as disappointing given small gains in real population health outcomes despite huge investments in basic and translational science. We identify critical value questions-ethical, social, economic, and cultural-that arise at moments throughout the research pathway. By making these questions visible, and promoting discussion of them with diverse stakeholders, we can facilitate handoffs along the translational pathway and increase uptake of effective interventions. Who is involved with those discussions will determine which research projects, populations, and methods get prioritized. We argue that some upfront investment in community and interdisciplinary engagement, shaped by familiar questions in ethics, social justice, and cultural knowledge, can save time and resources in the long run because interventions and strategies will be aimed in the right direction, that is, toward health improvements for all. Clin Trans Sci 2012; Volume 5: 445-451.Clinical and Translational Science 12/2012; 5(6):445-451. DOI:10.1111/j.1752-8062.2012.00441.x · 2.11 Impact Factor
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ABSTRACT: The U.S. infant mortality rate (IMR) improved substantially between 1985 and 2001, falling 35 percent from 10.4 to 6.8 per 1,000 live births. Despite these improvements, large racial disparities persist: in 2001, the IMR was 13.2 for blacks compared with 5.6 for whites. Although it is natural to suspect that the black-white IMR gap arises from socioeconomic differences, such an explanation seems at odds with the fact that the IMR for another socioeconomically disadvantaged group, U.S. Hispanics, was 5.4 in 2001, lower than that of whites. In this paper, we systematically examine the differences in IMRs between blacks and whites, assessing when these differences arise and their potential explanations. Specifically, we consider differences in the birthweight distribution, mortality over the first 28 days, mortality over the remaining part of the first year, the correlates of each of these underlying IMR components, and infant death reporting. The main contributions of this paper are three-fold: we provide a transparent and systematic treatment of the underlying components of infant mortality and their correlates, we pay specific attention to how these components fit together, and we present similar results for other racial/ethnic groups to place the black-white gaps in perspective. |
<urn:uuid:aa11e2c7-97ab-4427-8c24-86996175f037> | seed | See what questions
a doctor would ask.
HIV-1G: HIV is an immune system disease caused by the HIV virus. AIDS is a term used when a person infected with HIV has a CD4+ T cell count below 200 or 14% of lymphocytes. AIDS is an advanced form of HIV. To be classified as AIDS the person must also have an AIDS-related condition such as opportunistic infections. Once a person has been diagnosed with AIDS, even if treatment improved their CD4+ T cell count and infections are under control, the person is still considered to have AIDS. HIV is classified into two subtypes - HIV-1 and HIV-2. HIV-1 is further classified into three groups - Group M, N and O. Group M is further classified into 9 subgroups - A to K and CRFs. CRF's are circulating recombinant forms which are a combination of any two subtypes e.g. CRF A/C involves both And C subtypes. HIV-1, Group M, subtype G is most prevalent in Africa and central parts of Europe. This subtype tends to be a more virulent subtype. More detailed information about the symptoms, causes, and treatments of HIV-1G is available below.
Home medical testing related to HIV-1G:
Review possible medical complications related to HIV-1G:
Read more about causes of HIV-1G.
Commonly undiagnosed diseases in related medical categories:
Research related physicians and medical specialists:
Other doctor, physician and specialist research services:
Research quality ratings and patient safety measures for medical facilities in specialties related to HIV-1G:
Choosing the Best Hospital: More general information, not necessarily in relation to HIV-1G, on hospital performance and surgical care quality:
Prognosis for HIV-1G: Death usually occurs between 6 and 19 months after diagnosis of AIDS if not treatment is utilized. Strict adherence to treatment plans (usually antiretroviral medications) can significantly improve long-term outcomes. A number of people will develop a resistance to treatment therapies if they have been on them for more than two decades.
Read about other experiences, ask a question about HIV-1G, or answer someone else's question, on our message boards:
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<urn:uuid:2bbc47a6-77a2-4936-84fd-4df3a9b9f007> | seed | Our genes control many aspects of who we are — from the colour of our hair to our vulnerability to certain diseases — but how are the genes, and consequently the proteins they make themselves controlled?
Researchers have discovered a new group of molecules which control some of the fundamental processes behind memory function and may hold the key to developing new therapies for treating neurodegenerative diseases.
The research, led by academics from the University of Bristol’s Schools of Clinical Sciences, Biochemistry and Physiology and Pharmacology and published in the Journal of Biological Chemistry, has revealed a new group of molecules, called mirror-microRNAs.
MicroRNAs are non-coding genes that often reside within ‘junk DNA’ and regulate the levels and functions of multiple target proteins — responsible for controlling cellular processes in the brain. The study’s findings have shown that two microRNA genes with different functions can be produced from the same piece (sequence) of DNA — one is produced from the top strand and another from the bottom complementary ‘mirror’ strand.
Specifically, the research has shown that a single piece of human DNA gives rise to two fully processed microRNA genes that are expressed in the brain and have different and previously unknown functions. One microRNA is expressed in the parts of nerve cells that are known to control memory function and the other microRNA controls the processes that move protein cargos around nerve cells.
James Uney, Professor of Molecular Neuroscience in the University’s School of Clinical Sciences, said: “These findings are important as they show that very small changes in miRNA genes will have a dramatic effect on brain function and may influence our memory function or likelihood of developing neurodegenerative diseases. These findings also suggest that many more human mirror microRNAs will be found and that they could ultimately be used as treatments for human neurodegenerative diseases such as dementia.”
MicroRNAs can be seen as a novel regulatory layer within the genome, relying on the interaction between different RNA molecules. Through binding to messenger RNA (mRNA), they adjust the levels of proteins. Due to their small size, they are able to regulate many different RNAs. MicroRNAs have already been found throughout the double helix, lying in between genes or in areas of the code for a single gene that would normally be discarded. Such areas that were once considered “junk DNA” are now revealing a more complex and important role. In addition microRNAs can be produced in conjunction with their genes, within which they lie, or be controlled and produced entirely independently.
Helen Scott and Joanna Howarth, the lead authors on the study, added: “We have now found that both sides of the double helix can each produce a microRNA. These two microRNAs are almost a perfect mirror of each other, but due to slight differences in their sequence, they regulate different sets of protein producing RNAs, which will in turn affect different biological functions. Such mirror-microRNAs are likely to represent a new group of microRNAs with complex roles in coordinating gene expression, doubling the capacity of regulation.” |
<urn:uuid:01752a31-3490-4526-a089-27e1d86323e5> | seed | Attention deficit/hyperactivity disorder has long been recognized and treated in children, but has become a commonly diagnosed adult disorder as well. The estimate is that as many as one in three children diagnosed with this entity will actively carry the disease into adulthood.
While ADD and ADHD are associated with other psychiatric diagnoses, there are factors that allow for favorable underwriting.
ADHD is probably the most common neurobehavioral disorder of childhood. While attention deficit disorder centers on inattentiveness and a lack of attention to detail, the hyperactive form includes impulsivity, inability to sit still or concentrate, and interpersonal problems. Early diagnosis may coincide with poor school performance, underachievement in classroom situations, and poor interpersonal relationships. Schools in the United States are doing a better job in early diagnosis and intervention, but even with intervention and medication more than half will have significant problems in adulthood if the disorder persists.
The inability to concentrate or to have difficulty with attention is probably a complaint of most adults, but the diagnosis criteria per the Diagnosis and Statistical Manual of Mental Disorders (DSM) is very specific and revolves around six or more behavior characteristics in structured and leisure environments. Doctors are reluctant to give the initial diagnosis to an adult without a history of the disorder being recognized in childhood. In addition, behavior modification often makes identifying six behavior criteria difficult. Nonetheless, the hyperactive/inattentive details are often just as significant to the prognosis and treatment.
The consequences of persistent ADD and ADHD are predictable—poor performance in school leads to lack of success in the job market, as well as in making a living; plus, difficulty with interpersonal relationships leads to low self-esteem and poor adjustment to the normal trials of everyday living.
Some disorders that go along with ADD/ADHD have worse prognoses. These include conduct disorder—with rules violation, aggressive behavior toward others and violations of the law—and oppositional defiant disorder, where hostile and disobedient behavior is manifested toward authority. Earlier onset of these behaviors is associated with poor long term outcomes.
The early use of medication and pharmacotherapy as well as cognitive behavior therapy has helped many to successfully adjust and achieve more favorable outcomes. Those with ADD/ADHD who fare best are the subsets with less hyperactivity at the root of the behavior, older age at diagnosis, stable job history, and no other coexisting psychiatric problems or diagnoses—applicants such as this can be issued as standard and, on occasion, be given preferred consideration. Some of the most successful people in business have milder forms of ADHD which contribute to more innovative and active thinking.
The biggest problems occur when there are significant other psychiatric issues, particularly depression and alcohol/drug abuse or patterns of behavior that lead to conflicts with both the law and supervisory personnel in work situations. Those are the cases that are generally postponed or declined.
Robert Goldstone, MD, FACE, FLMI
Goldstone, board certified internist and endocrinologist, is vice president and chief medical officer for Pacific Life and Pacific Life and Annuity. He has extensive brokerage and life insurance experience, having been medical director at both MetLife Brokerage and Transamerica Occidental Life. Goldstone is board certified in insurance medicine and the inaugural recipient of the W. John Elder Award for Insurance Medicine Journalism Excellence. He was also honored as a fellow of the prestigious American College of Endocrinology and has written monthly for Broker World since 1990. Goldstone can be reached by telephone at 949-420-8390. Email: [email protected]. |
<urn:uuid:de520a16-9d07-4823-bdbe-bb791ff1ea26> | seed | This study provides new evidence that brief intervention can reduce alcohol use in post partum women. The statistically significant difference in alcohol use at the 6 month follow-up period suggests a positive treatment effect. As the study was conducted in a diverse sample of practices located in rural, urban and small communities, the findings may be generalizable to other outpatient obstetrical settings. The clinical difference is important and suggests providers can expect a 19% reduction in daily alcohol use, 21% reduction in number of drinking days, and 36% reduction in heavy drinking days among their postpartum patients if they follow the brief intervention protocol tested in the Healthy Moms trial. The findings of this BI trial complement recent studies completed during the pre-pregnancy period (Floyd et al., 2007
) and during pregnancy (Chang et al., 2005
; O'Connor et al. 2007
The findings of this trial have important public health implications. Despite numerous public awareness campaigns and the inclusion of warning labels on alcoholic beverages, fetal alcohol spectrum disorders continue to be a significant cause of disability. FASD is the leading known cause of preventable mental retardation/developmental disabilities in the Western World (Floyd et al., 2007
). The disabilities associated with FASD persist throughout a person's lifetime, and are associated with significant costs to families and society (Stratton et al., 1996
). While the prenatal period is clearly an important time to intervene, by the time a woman realizes that she is pregnant, irreversible damage to the fetus may have already occurred (Floyd et al., 1999
). Preventing alcohol exposure with the next pregnancy may provide the best chance we have to prevent FASD (May et al., 2004
The routine postpartum obstetrical visit is an excellent setting for such an intervention. Other settings for intervention may include the offices of pediatricians, family physicians, public health nurses, or clinics associated with the Women, Infants, and Children Program (Tough et al., 2006
). These represent settings where a mother might accompany her children to appointments. We urge medical providers to adopt alcohol screening as a routine part of care, as many have done for the assessment of postpartum depression and parental smoking practices.
A strong link has been established between interpersonal violence, tobacco use, illicit drug use, depression, and high-risk drinking among women (Flynn et al., 2003
; Certain et al, 2007
; Gilchrist et al., 1996
; Little et al., 1990
). Each of these behaviors is associated with significant health problems for women as well their children and families. While there is limited information on the combined treatment of high-risk drinking and other behaviors, behavioral change is a complex process that often requires multiple lifestyle changes at the same time. The results of this trial suggest health care providers can make a difference. Providers can change alcohol use among new mothers.
Health care systems, payors, policy makers, and society need to acknowledge the potential implications of BI research. We have an effective treatment (BI) that can prevent FASD and other adverse effects related to high-risk drinking among women of childbearing age. We have an evidence-based strategy that can reduce the loss of human potential due to irreversibly damaged nervous systems, as occurs in FASD. It is important to offer alcohol screening and BI to all women of childbearing age. This includes women coming in to see their obstetrician for routine postpartum care.
The strengths of the trial include a diverse sample of postpartum women, recruitment of non treatment seeking research subjects, state of the art research procedures, location of the study in 34 primary care offices, and high follow-up rates. Intention-to-treat procedures were used in the analysis. The recruitment rates were similar to many medication and behavioral trials with 24% (235/1209) of non treatment seeking high-risk drinkers randomized into the trial. One of the strengths of the trial was to screen all patients, not just those seeking alcohol treatment. While the high-risk drinking subjects, who did not meet all of our inclusion criteria, may have responded differently to the BI intervention protocol, our sample does represent a large group of women who did reduce their alcohol use. The effect size one could achieve by intervening with 100% of high-risk post partum women remains unclear. Additional research is needed.
Limitations of the trial include relatively small sample size, short follow-up period, absence of changes in alcohol-related harm outcomes, differential loss to follow-up between groups and reliance on patient self report as the primary outcome. We assume this differential loss to follow-up is related to the research burden of the group assigned to the intervention group (4 provider contacts), resistance to talk further about their drinking, shame about their drinking, reluctance to talk to us by their partners alcohol use or presence of interpersonal partner violence.
Another potential limitation of the study is delivery of the brief intervention protocol by clinic nurses. 90% of the interventions were conducted by clinic nurses. With the increasing use of other providers, such as clinic nurses to deliver routine care, the post partum visit was usually performed by clinic nurses, rather than obstetricians. While there is ample evidence that physicians can successful deliver brief intervention protocols our study was not able to answer the question whether BI can be effectively delivered by obstetricians.
Preventing alcohol-exposed pregnancies and the adverse health effects of alcohol on women is an important public health issue. The findings of this trial support the widespread implementation of alcohol screening and brief intervention during the postpartum period. Inclusion of alcohol screening questions within postpartum electronic medical record templates would facilitate the inclusion of routine screening similar to what has occurred with the addition of routine alcohol screening questions on prenatal forms. Screening all new mothers each year (4 million in 2006), during their postpartum visit or well child care visit, is likely to identify an estimated 480,000 high-risk drinkers in the US alone (Jagodzinski and Fleming, 2007
). All of these women, their children, their families and society could potentially benefit, if health care providers spent a few minutes talking to them about their alcohol use. |
<urn:uuid:896db71e-746e-41ee-bf87-ca5f599e1167> | seed | December 5, 2013
Asthma - Children
Asthma is the third major cause of hospitalization in children under age 15. The condition can be very serious in children, particularly those younger than age 5, because their airways are very narrow.
Risk Factors for Life-Threatening Asthma
Asthma death rates have steadily declined and it now is rarely fatal in children Even low mortality numbers are unacceptable, however, since asthma deaths are largely preventable.
Factors associated with an increased risk of death from asthma in children include:
- Previous life-threatening episodes of asthma
- Two or more hospitalizations or more than three emergency visits in the past year
- Using two or more short-acting beta2-agonist inhalers per month
- Lack of adequate and ongoing health care. (Most likely the reason for the higher fatalities rates in minority children.)
- Significant behavioral or psychosocial problems
- Underestimating the severity of an acute attack poses the greatest threat
African-American children have more than six times the death rate of Caucasians in the age groups of 4 years and younger and 15 - 24 years. Hispanic children also have a higher risk.
Some children outgrow their asthma by adulthood. In general, the more severe the childhood asthma, the greater the likelihood that it will persist. There is evidence that severe asthma can cause long-lasting damage and possibly permanent scarring in some patients. The risk for such injury is highest when asthma strikes children in their first 3 - 5 years. There does not appear to be any significant risk for long-term lung damage for children who develop mild-to-moderate persistent asthma between ages 5 - 12. Children adapt well to living with asthma, and even with severe asthma they can function as well as healthy children in virtually all areas of life.
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<urn:uuid:c5322111-1b2c-4e9b-89f9-478c0ac777e7> | seed | Scientists identify cell defects that limit immune system's impact on late-stage tumors
LOS ANGELES (Jan. 21, 2004) – Although vaccines developed to help the immune system fight tumors appear to have an impact against early-stage tumors, they have little if any success in slowing the growth of tumors in later stages. Now researchers writing in the Feb. 1, 2004 issue of The Journal of Immunology identify abnormalities in the immune system's T cells, provide insight into their origin, and describe how these defects can be prevented and "repaired" in animal experiments.
"Conventional thinking and previous studies suggest that the tumor environment is responsible for immune dysfunction in cancer-fighting T lymphocytes that congregate at the site of a tumor. The major unresolved question is the origin and mechanism responsible for immune dysfunction in tumor-infiltrating T cells. We found that damaged T cells arose from a particular cell lineage, within a tumor environment that lacks factors promoting their survival," said Keith L. Black, MD, director of Cedars-Sinai's Maxine Dunitz Neurosurgical Institute, where the mouse studies were conducted. "Furthermore, we were able to influence the cells in a way that decreased the number of dysfunctional cells, a finding that we hope may eventually lead to more effective vaccine therapies against established tumors."
In a localized immune response, T cells are mobilized to attack cells that the immune system recognizes as invaders. Because specific lymphocytes recognize and attack specific immune threats, they are called "antigen-specific." In cancer vaccine experiments, such as those ongoing at the Institute to improve treatment for brain tumors, researchers seek to improve the immune response by helping cancer-fighting cells identify tumor cells as potential targets.
T cell activation is considered a major defense mechanism in the prevention of tumor formation, and in rodent studies T cell responses have been able to eradicate recently established tumors. In both humans and animals, however, T cell mobilization appears to have little effect when directed against advanced tumors.
While many types of T lymphocytes exist, differentiated by their molecular makeup and the roles they play, CD4 and CD8 cells are considered the "normal population" responding to threatening antigens. But in these studies, most T cells present within the tumors were "double-negative," expressing neither CD4 nor CD8, but instead exhibiting abnormal characteristics.
"While most studies assign T cell defectiveness and death to the tumor environment, we now know more about the kinds of T cells that are susceptible and how they become defective. This allowed us to target novel properties to prevent or reverse the defects," said Christopher J. Wheeler, PhD, research scientist and the paper's senior author. "The T cell defects could be incurred independent of their reactivity to the tumor per se, and on a general level involved signals for survival."
T cells normally receive "survival" signals provided by signaling molecules or certain hormones. In the absence of these survival signals, the cells simply die by default.
"These signals are usually available in the body but they evidently are not available to T cells in tumors," said Dr. Wheeler. "We conducted an experiment to test this observation, adding back the molecules that can induce such signals, and we found a reduction in the abnormal T cells."
The recent research also provides new insight into another aspect of the relationship between tumors and defective T cells. Because those T cells responding to a tumor are believed to be specifically reactive to that tumor antigen, it has been assumed – perhaps incorrectly – that the T cell defects were in some way related to antigen-specificity and reactivity.
"We placed non-activated and non-tumor-specific T cells into tumors and found that they readily became defective. This runs counter to the predominant paradigm holding that defectiveness is related to antigen reactivity or specificity. At least experimentally, this is not the case. Of course, in a real tumor, most of the T cells that are present are going to be antigen-specific. Antigen-specificity allows T cells to infiltrate tumors, but this is not necessarily involved in their defectiveness," Dr. Wheeler said.
If the findings in this series of experiments are supported through additional studies and their implications in animals are consistent in humans, they may help researchers devise more effective approaches to immunotherapy. Theoretically, at least, the vaccine would "turn on" the immune system and focus it on the tumor while the promotion of survival signals into the tumor would "repair" defective T cells to help them stay alive to fight.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved. |
<urn:uuid:107604d9-7229-4af9-8b62-7e3075f1cf48> | seed | Small clinical trial supports prior indications that whole grains aid weight control while reducing heart and diabetes risks
by Craig Weatherby
While not exactly startling, the results of a study from Pennsylvania State University resoundingly affirm the value of whole grains, versus the refined grains that dominate American diets.
The hypothesis that diets high in whole grains help reduce risk of obesity, heart disease and diabetes flows largely from epidemiological research. Such studies compare people’s diets with their long-term health outcomes, and can only demonstrate associations, not cause and effect (McKeown NM et al. 2002).
And until recently, no controlled clinical trials directly tested the weight-loss and health-enhancing effects of diets high in whole, unrefined grain foods, versus diets high in refined grain foods such as white bread.
This data gap led researchers at Pennsylvania State University to conduct a controlled clinical trial in 25 obese women and 25 obese men (average age 46) diagnosed with metabolic syndrome (Katcher HI et al. 2008).
How the study worked
For the duration of the 12 week trial, all the participants ate a diet containing 500 calories less than normal, made up of five daily servings of fruits and vegetables, three servings of low-fat dairy products, and two servings of lean meat, fish or poultry.
All were encouraged to engage in moderate physical activity.
To test the effect of whole and refined grains, half were randomly assigned to eat only breads, pasta, and cereal made from whole grains, while the other half were told to avoid whole grain foods.
Participants in the whole grain group were directed to focus on foods that had whole grains as the first ingredient.
(The photo above portrays Paul Helton, one of the study participants, examining the whole-grain and refined foods used in the research.)
Results confirm wisdom of avoiding refined grains
Both groups enjoyed reductions in body weight—between 8 and 11 pounds on average—waist circumference, and the percentage of their weight occurring in the form of fat.
However, the whole-grain group experienced greater falls in the percentage of body fat located in the abdomen, compared to the refined-grain group.
This difference is critical, because the excess abdominal fat that yields an apple-shaped body is linked to a much greater risk of obesity, metabolic syndrome, heart disease, and diabetes (The risks of having a pear-shaped body, with excess fat around the hips and thighs, are much less).
The whole-grain group also enjoyed a big, 38 percent average drop in a key marker of inflammation called C-reactive protein or CRP, high blood levels of which raise people’s risk for diabetes, hypertension and cardiovascular disease.
The researchers noted the large reduction in CRP levels was comparable to those achievable from the strong anti-inflammatory effects of statin drugs.
Their effect on CRP levels could be due to the surprisingly high antioxidant content of whole grains, which was overlooked until recently. Polyphenol antioxidants, like those in the outer layers of whole grains, can exert strong anti-inflammatory effects. See “Whole Grains: Under-Sung Antioxidant Aces.”
Blood levels of total, LDL, and HDL cholesterol decreased in both groups, while fiber and magnesium intakes increased only in the whole-grain group. Magnesium is very important to heart health, and both food factors may discourage or delay the onset of diabetes.
In a press release, renowned nutrition researcher Penny Kris-Etherton, Ph.D., recommended choosing grain foods in which at least 51 percent of the grain comes from whole grain, such as oatmeal, whole grain cereal, brown rice, whole-wheat pasta and snacks such as granola bars and whole-wheat crackers.
To her list we’d add wheat berries, barley, quinoa… and buckwheat, which is the antioxidant-rich fruit of a broadleaf plant and probably healthier than most “real” grains.
As Kris-Etherton said, “This is the first clinical study to prove that a diet rich in whole grains can lead to weight loss and reduce the risk of several chronic diseases.” (PSU 2008)
- Katcher HI, Legro RS, Kunselman AR, Gillies PJ, Demers LM, Bagshaw DM, Kris-Etherton PM. The effects of a whole grain-enriched hypocaloric diet on cardiovascular disease risk factors in men and women with metabolic syndrome. Am J Clin Nutr. 2008 Jan;87(1):79-90. PMID: 18175740
- McKeown NM, Meigs JB, Liu S, Wilson PW, Jacques PF. Whole-grain intake is favorably associated with metabolic risk factors for type 2 diabetes and cardiovascular disease in the Framingham Offspring Study. Am J Clin Nutr. 2002 Aug;76(2):390-8.
- Melanson KJ, Angelopoulos TJ, Nguyen VT, Martini M, Zukley L, Lowndes J, Dube TJ, Fiutem JJ, Yount BW, Rippe JM. Consumption of whole-grain cereals during weight loss: effects on dietary quality, dietary fiber, magnesium, vitamin B-6, and obesity. J Am Diet Assoc. 2006 Sep;106(9):1380-8; quiz 1389-90.
- Newby PK, Maras J, Bakun P, Muller D, Ferrucci L, Tucker KL. Intake of whole grains, refined grains, and cereal fiber measured with 7-d diet records and associations with risk factors for chronic disease. Am J Clin Nutr. 2007 Dec;86(6):1745-53.
- Pennsylvania State University (PSU). Whole grain diets lower risk of chronic disease. February 5, 2008. Accessed online March 2, 2008 at http://live.psu.edu/story/28577 |
<urn:uuid:aa769f06-f0bf-4217-9af9-666d1dc6a7be> | seed | |Classification and external resources|
Sappho (1897) by Ernst Stückelberg
Suicidal ideation is a medical term for thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies greatly from fleeting to detailed planning, role playing, and unsuccessful attempts, which may be deliberately constructed to fail or be discovered, or may be fully intended to result in death. Although most people who undergo suicidal ideation do not go on to make suicide attempts, a significant proportion do. Suicidal ideation is generally associated with depression; however, it seems to have associations with many other psychiatric disorders, life events, and family events, all of which may increase the risk of suicidal ideation. Recurrent suicidal behavior and suicidal ideation is a hallmark of borderline personality disorder. One study found that 73% of patients with borderline personality disorder have attempted suicide, with the average patient having 3.4 attempts. Currently, there are a number of different treatment options for those experiencing suicidal ideation.
- 1 Signs and symptoms
- 2 Risk factors
- 3 Prevention
- 4 Treatment
- 5 See also
- 6 References
- 7 Further reading
- 8 External links
Signs and symptoms
Suicidal ideation has a straightforward definition — suicidal thoughts — but there are some other related signs and symptoms. Some symptoms or co-morbid conditions may include unintentional weight loss, feeling helpless, feeling alone, excessive fatigue, low self-esteem, presence of consistent mania, excessively talkative, intent on previously dormant goals, feel like one's mind is racing. The onset of symptoms like these with an inability to get rid of or cope with their effects, a possible form of psychological inflexibility, is one possible trait associated with suicidal ideation. They may also cause psychological distress, which is another symptom associated with suicidal ideation. Symptoms like these related with psychological inflexibility, recurring patterns, or psychological distress may in some cases lead to the onset of suicidal ideation. Other possible symptoms and warning signs include:
- Insomnia or oversleeping
- Loss of appetite or overeating
- Severe anxiety
- Impaired concentration
- Psychomotor agitation
- Panic attack
- Severe remorse
- Beck Scale for Suicide Ideation
- Columbia Suicide Severity Rating Scale
- The Kessler Psychological Distress Scale (K10)
- This test does not measure suicidal ideation directly, but there may be value in its administration as an early identifier of suicidal ideation. High scores of psychological distress are in some cases associated with suicidal ideation.
There are numerous indicators that one can look for when trying to detect suicidal ideation. There are also situations in which the risk for suicidal ideation may be heightened. The risk factors for suicidal ideation can be divided into 3 categories: psychiatric disorders, life events, and family history.
There are several psychiatric disorders that appear to be comorbid with suicidal ideation or considerably increase the risk of suicidal ideation. The following list includes the disorders that have been shown to be the strongest predictors of suicidal ideation. It should be noted, however, that these are not the only disorders that can increase risk of suicidal ideation. The disorders in which risk is increased the greatest include:
- Major depressive disorder
- Bipolar disorder
- Post-traumatic stress disorder (PTSD)
- Personality disorders
- Psychosis (anxiety or detachment from reality)
- Drug abuse
Prescription drug side effects
Some prescription drugs, such as selective serotonin re-uptake inhibitors, can have suicidal ideation as a side effect. Moreover, these drugs' intended effects can themselves have the unintended or undesired consequence of an increased individual risk and collective rate of suicidal behavior: Among the set of persons taking the medication, a subset feel bad enough to want to commit suicide (or to desire the perceived results of suicide) but are inhibited by depression-induced symptoms, such as lack of energy and motivation, from following through with an attempt. Among this subset, a "sub-subset" may find that the medication alleviates their physiological symptoms (such as lack of energy) and secondary psychological symptoms (e.g., lack of motivation) before or at lower doses than it alleviates their primary psychological symptom of depressed mood. Among this group of persons, the desire for suicide and/or its effects persists even as major obstacles to suicidal action are removed, with the effect that the incidences of suicide attempt and of completed suicide increase.
Life events are strong predictors of increased risk for suicidal ideation. Furthermore, life events can also lead to or be comorbid with the previous listed psychiatric disorders and predict suicidal ideation through those means. Life events that adults and children face can be dissimilar and for this reason, the list of events that increase risk can vary in adults and children. The life events that have been shown to increase risk the greatest are
- Alcohol abuse
- Studies have shown that individuals who binge drink, rather than drink socially, tend to have higher rates of suicidal ideation
- Certain studies associate those who experience suicidal ideation with higher alcohol consumption
- Certain studies associate those who experience suicidal ideation with unemployment
- Not only do some studies show that solitary binge drinking can increase suicidal ideation, but there is a positive feedback relationship causing those who have more suicidal ideation to have more drinks per day in a solitary environment
- Loss of family and/or friends
- Other studies have found that tobacco use is correlated with depression and suicidal ideation
- Unplanned pregnancy
- Bullying, including cyberbullying
- Previous suicide attempts
- Having previously attempted suicide is one of the strongest indicators of future suicidal ideation or suicide attempts
- Military experience
- Military personnel who show symptoms of PTSD, major depressive disorder, alcohol use disorder, and generalized anxiety disorder show higher levels of suicidal ideation
- Community violence
- Undesired changes in body weight
- Women: increased BMI increases chance of suicidal ideation
- Men: severe decrease in BMI increases chance of suicidal ideation
- In general, the obese population has increased odds of suicidal ideation in relation to individuals that are of average-weight
- Exposure and attention to suicide related images or words
- Parents with a history of depression
- Valenstein et al. studied 340 adult offspring whose parents had depression in the past. They found that 7% of the offspring had suicidal ideation in the previous month alone
- Childhood: physical abuse
- Adolescence: physical and sexual abuse
- Family violence
- Childhood residential instability
- Certain studies associate those who experience suicidal ideation with family disruption.
Relationships with parents and friends
According to a study conducted by Ruth X. Liu of San Diego State University, a significant connection was found between the parent–child relationships of adolescents ranging from early, middle and late adolescence and their likelihood of suicidal ideation. The study consisted of measuring relationships between mothers and daughters, fathers and sons, mothers and sons and fathers and daughters. The relationships between fathers and sons during early and middle adolescence shows an inverse relationship to suicidal ideation. Closeness with the father in late adolescence is "significantly related to suicidal ideation". Liu goes on to explain the relationship found between closeness with the opposite sex parent and the child's risk of suicidal thoughts. It was found that boys are better protected from suicidal ideation if they are close to their mothers through early and late adolescence; whereas girls are better protected by having a close relationship with their father during middle adolescence.
An article published in 2010 by Zappulla and Pace found that suicidal ideation in adolescent boys is exacerbated by detachment from the parents when depression is already present in the child. Lifetime prevalence estimates of suicidal ideation among nonclinical populations of adolescents generally range from 60% and in many cases its severity increases the risk of completed suicide.
Early detection and treatment are the best ways to prevent suicidal ideation and suicide attempts. If signs, symptoms, or risk factors are detected early then the individual will hopefully seek treatment and help before attempting to take their own life. In a study of individuals who did commit suicide, 91% of them likely suffered from one or more mental illnesses. However, only 35% of those individuals were treated or being treated for a mental illness. This emphasizes the importance of early detection; if a mental illness is detected, it can be treated and controlled to help prevent suicide attempts. Another study investigated strictly suicidal ideation in adolescents. This study found that depression symptoms in adolescents as early as grade 9 is a predictor of suicidal ideation. Most people with long-term suicidal ideation do not seek professional help.
The previously mentioned studies point out the difficulty that mental health professionals have in motivating individuals to seek and continue treatment. Ways to increase the amount of individuals who seek treatment may include:
- Increasing the availability of therapy treatment in early stage
- Increasing the public’s knowledge on when psychiatric help may be beneficial to them
- Those who have adverse life conditions seem to have just as much risk of suicide as those with mental illness
A study conducted by researchers in Australia set out to determine a course of early detection for suicidal ideation in teens stating that "risks associated with suicidality require an immediate focus on diminishing self-harming cognitions so as to ensure safety before attending to the underlying etiology of the behavior". A Psychological Distress scale known as the K10 was administered monthly to a random sample of individuals. According to the results among the 9.9% of individuals who reported "psychological distress (all categories)" 5.1% of the same participants reported suicidal ideation. Participants who scored "very high" on the Psychological Distress scale "were 77 times more likely to report suicidal ideation than those in the low category".
In a 1-year study conducted in Finland, 41% of the patients who later committed suicide saw a health care professional, most seeing a psychiatrist. Of those, only 22% discussed suicidal intent on their last office visit. In most of the cases, the office visit took place within a week of the suicide, and most of the victims had a diagnosed depressive disorder.
There are many centers where one can receive aid in the fight against suicidal ideation and suicide. Hemelrijk et al. (2012) found evidence that assisting people with suicidal ideation via the internet versus more direct forms such as phone conversations has a greater effect.
Treatment of suicidal ideation can be puzzling due to the fact that several medications have actually been linked to increasing or causing suicidal ideation in patients. Therefore, several alternative means of treating suicidal ideation are often used. The main treatments include: hospitalization, outpatient treatment, and medication/other modalities.
Hospitalization allows the patient to be in a secure, supervised environment to prevent their suicidal ideation from turning into suicide attempts. In most cases, individuals have the freedom to choose which treatment they see fit for themselves. However, there are several circumstances in which individuals can be hospitalized involuntarily. These circumstances are:
- If an individual poses danger to self or others
- If an individual is unable to care for one's self
Hospitalization may also be the best treatment if an individual:
- Has access to lethal means
- Does not have social support or people to supervise them
- Has a suicide plan
- Has symptoms of a psychiatric disorder
Outpatient treatment allows individuals to remain at their place of residence and receive treatment when needed or on a scheduled basis. Before allowing patients the freedom that comes with outpatient treatment, physicians evaluate several factors of the patient. These factors include the patient's level of social support, impulse control and quality of judgment. After the patient passes the evaluation, they are often asked to consent to a "no-harm contract". This is a contract formulated by the physician and the family of the patient. Within the contract, the patient agrees not to harm themselves, to continue their visits with the physician, and to contact the physician in times of need. These patients are then checked on routinely to assure they are maintaining their contract and staying out of troublesome activities.
Prescribing medication to treat suicidal ideation can be difficult. One reason for this is that many medications lift patients' energy levels before lifting their mood. This puts them at greater risk of following through with attempting suicide. Additionally, if a patient has a co-morbid psychiatric disorder, it may be difficult to find a medication that addresses both the psychiatric disorder and suicidal ideation. Therefore, the medication prescribed to one suicidal ideation patient may be completely different from the medication prescribed to another patient. However, there are several medications that seem to work fairly well for treating suicidal ideation:
- Antidepressants – there are several antidepressants that physicians should refrain from prescribing due to their lethal potential in the case of an overdose. A common antidepressant to avoid is Tricyclic.
Antidepressants have been shown to be a very effective means of treating suicidal ideation. One correlational study compared mortality rates due to suicide to the use of SSRI antidepressants within certain counties. The counties which had higher SSRI use had a significantly lower number of deaths caused by suicide. Additionally, an experimental study followed depressed patients for one year. During the first six months of that year, the patients were examined for suicidal behavior including suicidal ideation. The patients were then prescribed antidepressants for the six months following the first six observatory months. During the six months of treatment, experimenters found suicide ideation reduced from 47% of patients down to 14% of patients. Thus, it appears from current research that antidepressants have a helpful effect on the reduction of suicidal ideation.
Although research is largely in favor of the use of antidepressants for the treatment of suicidal ideation, in some cases antidepressants are claimed to be the cause of suicidal ideation. Upon the start of using antidepressants, many clinicians will note that sometimes the sudden onset of suicidal ideation may accompany treatment. This has caused the food and drug administration to issue a warning stating that sometimes the use of antidepressants may actually increase the thoughts of suicidal ideation. Medical studies have found antidepressants help treat cases of suicidal ideation and work especially well with psychological therapy.
- Gliatto, MF; Rai, AK (March 1999). "Evaluation and Treatment of Patients with Suicidal Ideation". American Family Physician 59 (6): 1500–6. PMID 10193592. Retrieved 2007-01-08.
- Soloff, PH; Kevin, GL; Thomas, MK; Kevin, MM; Mann, JJ (1 April 2000). "Characteristics of Suicide Attempts of Patients With Major Depressive Episode and Borderline Personality Disorder: A Comparative Study". American Journal of Psychiatry 157 (4): 601–608. doi:10.1176/appi.ajp.157.4.601. PMID 10739420.
- American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC: Author.
- Valenstein, H; Cronkite, RC; Moos, RH; Snipes, C; Timko, C (2012). "Suicidal ideation in adult offspring of depressed and matched control parents: Childhood and concurrent predictors". Journal of Mental Health 21 (5): 459–468. doi:10.3109/09638237.2012.694504. PMID 22978501.
- Chamberlain, P; Goldney, R; Delfabbro, P; Gill, T; Dal Grande, L (2009). "Suicidal Ideation: The Clinical Utility of the K10". Crisis. 1 30 (1): 39–42. doi:10.1027/0221-5910.30.1.39 (inactive 2014-03-04). PMID 19261567.
- Hemelrijk, E; Van Ballegooijen, W; Donker, T; Van Straten, A; Kerkhof, A (2012). "Internet-based screening for suicidal ideation in common mental disorders". Crisis: the Journal of Crisis Intervention and Suicide Prevention 33 (4): 215–221. doi:10.1027/0227-5910/a000142. PMID 22713975.
- Harris, EC; Barraclough, B (1997). "Suicide as an outcome for mental disorders. A meta analysis". The British Journal of Psychiatry 170: 205–228. doi:10.1192/bjp.170.3.205. PMID 9229027.
- Lemon, TI; Shah, RD (2013). "Needle exchanges – a forgotten outpost in suicide and self-harm prevention". Journal of Psychosomatic Research 74 (6): 551–552. doi:10.1016/j.jpsychores.2013.03.057. (subscription required (. ))
- Lemon, TI (2013). "Suicide ideation in drug users and the role of needles exchanges and their workers". Journal Psych Med 6 (5): 429. doi:10.1016/j.ajp.2013.07.003. PMID 24011693.
- Fergusson, DM; Woodward, LJ; Horwood, LJ (2000). "Risk factors and life processes associated with the onset of suicidal behavior during adolescence and early adulthood". Psychological Medicine 30 (1): 23–39. doi:10.1017/s003329179900135x. PMID 10722173.
- Gonzalez, VM (2012). "Association of solitary binge drinking and suicidal behavior among emerging adult college students". Psychology of Addictive Behaviors 26 (3): 609–614. doi:10.1037/a0026916. PMC 3431456. PMID 22288976.
- Dugas, E; Low, NP; Rodriguez, D; Burrows, S; Contreras, G; Chaiton, M et al. (2012). "Early Predictors of Suicidal Ideation in Young Adults". Canadian Journal of Psychiatry 57 (7): 429–436. PMID 22762298.
- "Cyberbullying Research Summary – Cyberbullying and Suicide". Cyberbullying Research Center. Retrieved 3 July 2012.
- "The relationship between bullying, depression and suicidal thoughts/behaviour in Irish adolescents". Department of Health and Children. Retrieved 3 July 2012.
- Richardson, JD; St Cyr, KC; McIntyre-Smith, AM; Haslam, D; Elhai, JD; Sareen, J (2012). "Examining the association between psychiatric illness and suicidal ideation in a sample of treatment-seeking Canadian peacekeeping and combat veterans with posttraumatic stress disorder PTSD". Canadian Journal of Psychiatry 57 (8): 496–504. PMID 22854032.
- Thompson, R; Litrownik, AJ; Isbell, P; Everson, MD; English, DJ; Dubowitz, H et al. (2012). "Adverse experiences and suicidal ideation in adolescence: Exploring the link using the LONGSCAN samples". Psychology of Violence 2 (2): 211–225. doi:10.1037/a0027107. PMC 3857611. PMID 24349862.
- Carpenter, KM; Hasin, DS; Allison, DB; Faith, MS (2000). "Relationships between obesity and DSM-IV major depressive disorder, suicidal ideation, and suicide attempts: Results from a general population study". American Journal of Public Health 90 (2): 251–257. doi:10.1080/00048670902970825. PMID 19530022.
- Cha, CB; Najmi, S; Park, JM; Finn, CT; Nock, MK (2010). "Attentional bias toward suicide-related stimuli predicts suicidal behavior". Journal of Abnormal Psychology 119 (3): 616–622. doi:10.1037/a0019710. PMC 2994414. PMID 20677851.
- Liu, Ruth X. (December 2005). "Parent-Youth Closeness and Youth's Suicidal Ideation; The Moderating Effects of Gender, Stages of Adolescence, and Race or Ethnicity". Youth & Society 37 (2): 160–162. doi:10.1177/0044118X04272290.
- Zappulla, Carla. "Relations between suicidal ideation, depression, and emotional autonomy from parents in adolescence". Springer Science + Business Media LLC. Retrieved 10 April 2012.
- Cavanagh, JO; Owens, DC; Johnstone, EC (1999). "Life events in suicide and undetermined death in south-east Scotland: a case-control study using the method of psychological autopsy". Social Psychiatry and Psychiatric Epidemiology 34 (12): 645–650. doi:10.1007/s001270050187. PMID 10703274.
- Halgin, Richard P.; Susan Whitbourne (2006). Abnormal psychology: clinical perspectives on psychological disorders. Boston: McGraw-Hill. pp. 267–272. ISBN 0-07-322872-9.
- Gliatto, MF; Rai, AK (1999). "Evaluation and treatment of patients with suicidal ideation". American Family Physician 59: 1500–1513. [clarification needed]
- Simon, GE (2006). "How can we know whether antidepressants increase suicide risk?". American Journal of Psychiatry 163 (11): 1861–1863. doi:10.1176/appu.ajp.163.11.1861 (inactive 2014-03-04). PMID 17074930.
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- Zisook, S; Lesser, IM; Lebowitz, B; Rush, AJ; Kallenberg, G; Wisniewski, SR et al. (2011). "Effect of antidepressant medication treatment on suicidal ideation and behavior in a randomized trial: An exploratory report from the Combining Medications to Enhance Depression Outcomes Study". Journal of Clinical Psychiatry 72 (10): 1322–1332. doi:10.4088/JCP.10m06724. PMID 22075098.
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- Uncapher, H (2000–2001). "Cognitive biases and suicidal ideation in elderly psychiatric inpatients". Omega 42 (1): 21–36. doi:10.2190/6uu8-hk8e-hl0v-q4cu.
- Uncapher, H; Gallagher-Thompson, D; Osgood, NJ (1998). "Hopelessness and suicidal ideation in older adults". The Gerontologist 38 (1): 62–70. doi:10.1093/geront/38.1.62. PMID 9499654.
- Evaluation and Treatment of Patients with Suicidal Ideation
- Suicidal Thoughts
- National Suicide Prevention Lifeline: Warning signs |
<urn:uuid:20d20ae3-9388-47e5-9fbd-83d32c38b803> | seed | Breast cancer cells can be very clever and develop work-around mechanisms to overcome available treatments, and that is the challenge for cancer physicians today, said Dr. Michaela J. Higgins, breast cancer oncologist at Massachusetts General Hospital in Boston.
That is why she spends time away from her clinical rounds and in-patient care to conduct clinical trials and other research to develop new agents to head off the treatment-resistant breast cancer cells.
Higgins focuses her research efforts these days in several areas, including finding effective treatments against one of the most common subtypes of breast cancer, the hormone-positive-receptor.
Generally, breast cancer tends to express the estrogen and progesterone receptors, and those cancers respond to manipulation of those receptors with endocrine or “hormone-blocking” treatments.
“When we block those cancer cells from getting estrogen and progesterone it starves them and stops them from growing and multiplying,” she said. “Even though the vast majority of breast cancer cells retain the estrogen and progesterone receptor, over time, breast cancers can become resistant to those standard endocrine therapies.”
Researchers such as Higgins focus on enhancing the response to those treatments by adding something different.
“What we have learned is that breast cancers over time develop alternative signaling pathways within the cancer cells themselves to overcome whatever treatment we are using,” Higgins said. “Breast cancer cells evolve and develop resistant pathways.”
She likened that to microorganisms which are resistant to antibiotics.
Another area that Higgins is focusing her research on is in treating bone metastases in patients with metastatic breast cancer. That’s because when breast cancer recurs, 75 percent of the time it locks onto bone as opposed to other sites in the body.
“Breast cancer appears to have a predilection for the skeleton, and after that likes to go to the lung, liver and brain,” she said.
New treatments for breast cancer, as for other cancers, cannot occur without patient participation in clinical trials, Higgins said. Collaborations among patients, physicians and research teams are essential, she said.
“That’s how we discover which drugs are promising. Our research requires many thousands of women with breast cancer contributing to what we know,” said Higgins, who noted that participants in trials have access to perhaps life-saving drugs before they are officially approved by the federal Food and Drug Administration (FDA).
Part of that knowing is what oncologists and other breast cancer researchers learn at meetings with their peers. Two conferences in particular, she said, offer up new information on breast cancer drug trials and their results: the American Society of Clinical Oncology annual meeting and the San Antonio Breast Cancer Symposium.
“When results are made available at the conferences and we have robust data that has been peer-reviewed, it can then go to the FDA for approval so that ultimately many patients can get access to the new drugs,” she said. |
<urn:uuid:3d175a87-2070-47a9-a9a0-1a1fcbd0a27c> | seed | Research, medical and policy experts alike have emphasised that moderation and sensible behaviour is the only responsible choice for those who choose to enjoy wine, beer and spirits. Over the last few years, emerging scientific studies have continually revealed that the moderate pattern of drinking as part of a well balanced diet can have positive lifestyle effects. In fact, a recent US government study on alcohol, drinking patterns and diet quality found that “healthier diets were associated with healthier drinking patterns.” The authors examined associations between alcohol and diet quality (Healthy Eating Index (HEI) scores) using cross-sectional, nationally representative data from the 19992000 National Health and Nutrition Examination Survey. Weighted analyses included 3,729 participants aged >20 years. In adjusted analyses among current alcohol drinkers, as quantity increased from 1 to 3 drinks/drinking day, the mean HEI score decreased from 65.3 to 61.9. Specifically, the study reported that those who drank the most alcohol had the poorest diets, while those who drank the least had the best diets. 1
This article will outline some of the prominent medical research findings which underscore the importance of following sensible drinking patterns and enjoying alcohol in moderation as part of a healthy diet and lifestyle.
Moderate and Light Drinking Patterns Found Most Beneficial
Moderate drinkers were found to be in overall better health according to a study conducted by Oregon Health and Science University. The researchers surveyed several thousand men and women members of Kaiser Permanente Northwest and concluded, “For both genders, light to moderate consumption and more frequent drinking were associated with better health and functioning; relationships were stronger among women than men.” The study cautioned, however, that individuals and specifically women who drank heavily were in worse health. Furthermore, the investigators suggested that they did not believe that better health is a result of moderate drinking but that it has been reported that moderate drinkers also tend to lead healthier and more balanced lifestyles. Moderate drinking was defined as one to two drinks per occasion, two or three times a week, or 15 to 29 drinks spread out throughout the month. 2
Stable patterns of light drinking contributed to the lowest all-cause mortality rate according to a Dutch study which analysed whether changes in individual alcohol intake contribute to corresponding changes in mortality. Stable drinkers showed U-shaped all-cause mortality; teetotalers who became light drinkers decreased their risk of dying from heart disease while light drinkers who stopped drinking saw a slight increase in heart disease related problems. Cancer mortality was increased in all heavy drinking groups. Non drinkers were defined as less than once a week, and light drinkers, between 1 and 6 drinks a week. The study also defined moderate drinkers as those who had up to 13 drinks a week and heavy drinkers beyond that. The investigators concluded, “Persons with stable patterns of light and moderate alcohol intake had the lowest all-cause mortality. Individual changes in alcohol intake were followed by corresponding changes to mortality” 3
Another Danish population-based cohort study obtained risk estimates for all-cause mortality for different quantity and frequency of alcohol intake adjusted for various lifestyle factors, including diet. During the follow up, for the same average consumption of alcohol, a less-frequent intake related to a higher risk of death than a more frequent pattern. The researchers wrote, “Drinking pattern and not just the total amount of alcohol consumed is important for the association between alcohol intake and mortality.” 4
Life expectancy benefits were observed among moderate drinkers in a UK study which estimated the deaths and person-years of life lost to age 65 that were attributable to various consumption levels. These included any drinking, drinking within limits, or drinking more than the British Royal Colleges’ limits. The latter are 21 units (8g) per week for men and 14 units per week for women. Most interestingly, deaths attributable to alcohol outweighed those prevented by use for men up to age 54 and for women up to age 64. Among men, those aged 1624 years, and among women, those ages 35-44 years, were at greatest risk of alcohol-related mortality. Men above 75 and women above 85 and older were most likely to benefit. However, the researchers conclude, “Although overall mortality risks and benefits of alcohol consumption appear roughly equal, drinking above recommended limits remains responsible for many deaths and a large loss of person-years of life.” 5
Healthier drinking patterns lead to lower risk for coronary heart disease according to an important review article highlighting that modern epidemiologic studies reveal lower risk of both morbidity and mortality among lighter drinkers. The author of this US study also explained that “when defining ‘heavy’ as greater than or equal to 3 standard drinks per day, the alcohol-mortality relationship is a J-curve with risk highest for heavy drinkers, lowest for light drinkers and intermediate for abstainers.” The investigators explained that lighter drinking is unrelated to increased risk of any cardiovascular condition and, in observational studies, is consistently related to lower risk of CHD and ischemic stroke. A protective hypothesis for CHD is robustly supported by evidence for plausible biological mechanisms attributable to ethyl alcohol. 6
Other more recent studies also found that the protective effect was more a function of frequency of consumption than of volume. In fact, small amounts consumed several times a week reduced risk to a greater extent than the same amount consumed over fewer occasions. 7 Along those lines, a 2004 population-based case control study also focused on the pattern of drinking and myocardial infarction (MI). Participants were selected randomly from two Western New York counties underscored that the results signify that patterns of alcohol use have important cardiovascular health implication, with more frequent consumption giving the greatest protection. 8
In a population-based study of subjects in northwestern New York, the lifetime volume of alcohol intake was not related to the development of metabolic syndrome (MS), but the average intensity (average amount/drink) of alcohol intake showed a positive relation. Frequency of alcohol consumption was protective against some critical health parameters in that more frequent moderate drinkers of both genders were less likely to have low-HDL-cholesterol and less abdominal obesity in women. The authors explained that “while lifetime use of alcohol is somewhat difficult to interpret, these data suggest that frequent drinking of small amounts may protect against many components of the metabolic syndrome.” The study also indicated that larger amounts or binge drinking per occasion are harmful. In fact, increasing intensity of alcohol use increased the risk of the metabolic syndrome in a step-wise fashion. 9
Binge drinking has many negative health outcomes according to research studies from around the world. Three studies brought forward some important aspects with respect to binge drinking and health, further underscoring the results from the above mentioned review study. In fact, a Dutch study suggests that binge drinking disrupts the actions of blood platelets by hindering platelet adhesion to fibrinogen. The researchers concluded specifically, “Rapid intake of alcohol increases platelet aggregation, which might contribute to the increased mortality associated with binge drinking.” 10
Another study found that “subjects reporting binge drinking had an increased risk of dying in comparison with subjects who drank but did not report binging after a myocardial infarction.” This held true whether the subjects binged less than weekly or more than weekly. The definition of binge drinking used here (3+ drinks within 1-2 hours) is different from the usual of 5+ drinks per occasion, but showed similar adverse effects. 11
The Importance of Overall Healthy Dietary Patterns
Alcohol as part of a healthy diet leads to increased life expectancy in line with several research studies. According to a study published in the British Medical Journal, the Mediterranean diet as a well known healthy nutrition concept is associated with longer life expectancy. The major staples of the Mediterranean diet are characterised by a high intake of vegetables, legumes, fruits, and cereals; a moderate to high intake of fish; a low intake of saturated fats, but high intake of unsaturated fats, particularly olive oil; a low intake of dairy products and meat; and a modest intake of alcohol, mostly as wine. Adherence to a Mediterranean style Diet lead to an up to 14%, increase in life expectancy. The authors wrote in the conclusion, “Adherence to a Mediterranean type diet, which relies on plant foods and unsaturated fats, is associated with a significantly longer life expectancy, and may be particularly appropriate for elderly people, who represent a rapidly increasing group in Europe.” 12
Dietary patterns and lifestyle factors are associated with mortality from all causes, coronary heart disease, cardiovascular diseases, and cancer, but few studies have investigated these factors in combination. Therefore, the objective of another study was to investigate the single and combined health effect of dietary and lifestyle factors in a European population. Adhering to a Mediterranean diet, moderate alcohol use, physical activity, and non-smoking were associated with a lower risk of all-cause mortality. Similar results were observed for mortality from coronary heart disease, cardiovascular diseases, and cancer. The combination of these four favourable traits lowered the all-cause mortality rate significantly. In total, lack of adherence to this low-risk pattern was associated with a population attributable risk of 60% of all deaths, 64% of deaths from coronary heart disease, 61% from cardiovascular diseases, and 60% from cancer. The researchers concluded, “Among individuals aged 70 to 90 years, adherence to a Mediterranean diet and healthful lifestyle is associated with a more than 50% lower rate of all-causes and cause-specific mortality.” An accompanying editorial by Harvard University experts also underscored the importance of lifestyle habits in disease prevention and emphasize that dietary factors and physical activity are of major importance. 13
Along those lines a further study found that the Mediterraneanstyle diet improved the functioning of endothelial cells and reduced vascular inflammation in patients with metabolic syndrome, a medical condition that can increase the risk of cardiovascular disease and type 2 diabetes. 14
Healthy lifestyle habits may decrease risk of developing or dying from cancer among post-menopausal women who followed recommended dietary and lifestyle guidelines, with those in highest compliance experiencing the best outcomes. Conversely, those women who followed one or none of the nine recommended guidelines for diet and lifestyle had a 35 percent higher risk of developing cancer and a 42 percent greater risk of dying from cancer than women who adhered to at least six of the recommendations considered for the study. The investigators evaluated women’s cancer risk and other health outcomes based on how many of specific healthy lifestyle categories the women followed as part of their normal lifestyle. Those recommendations included having maximum body mass index less than 25 kg/m2; having gained no more than 11 pounds since age 18; engaging in daily moderate and weekly vigorous physical activity; eating of 5 or more servings of vegetables and fruit daily; consuming more than 400 grams (about 14 ounces) of complex carbohydrate per day; limiting alcohol intake to less than 14 grams per day (one drink); limiting red meat consumption to less than 80 grams per day (about 3 ounces); limiting daily consumption of fat to no more than 30 percent of total caloric intake; and limiting use of sodium to less than 2,400 milligrams per day. 15
Drinking around Mealtime May be Advisable
Other studies from around the world have reported that drinking with meals or around mealtime may enable the alcohol to counter adverse effects of fatty foods during the critical digestive phase. 16, 17, 8
More recently, Italian investigators studied how the timing of alcohol consumption in relation to meals might affect the risk of myocardial infarction (MI) in an Italian population and concluded, “Alcohol drinking during meals was inversely related with risk of acute MI, whereas alcohol drinking outside meals only was unrelated to risk.” 18 In a 2003 Scientific American article, Dr Klatsky summarized the data on moderation and health and explained that drinking patterns (e.g. imbibe slowly and regularly with food) or other factors (e.g. type of consumer and lifestyle habits such as exercise) all may effect the health outcome of alcohol. 19
Drinking patterns are important with respect to overall health. It’s not just how much you drink but the pattern of drinking and even when you drink that can determine the amount of damage to the liver. The effect is most striking for women, according to a report by researchers at the State University of New York at Buffalo. The study found that a woman drinking alone and not eating on a weekend is more likely to be causing damage to her liver than a woman drinking the same amount while dining with a friend. However, the results are different with men, with the amount and frequency of drinking more important than the pattern of drinking, with or without food. The study results showed that a safe level for men is 14 to 27 drinks a week; while for women it is 7 to 14 drinks a week (14g of alcohol in one typical drink). According to the investigators, the findings reinforce the recommendations for both sexes for moderate and slow drinking over a long period of time, rather than over a short period, such as a weekend. The researchers wrote in the conclusion, “These findings support the hypothesis that, in addition to amount, drinking pattern may affect liver function and that difference exist between sexes with regard to the effect of drinking pattern on liver function and potential liver damage.” 20
Relationship of alcohol drinking pattern to risk of hypertension was analysed in a sample of white men and women from western New York. Compared with lifetime abstainers, participants reporting drinking on a daily basis or mostly without food exhibited significantly higher risk of hypertension. When the analyses were restricted to current drinkers, participants consuming alcohol without food exhibited a significantly higher risk of hypertension compared with those drinking mostly with food. For major beverage preference, no steady association with hypertension risk was found across the various types of beverages considered which included wine, beer and spirits. Specifically, the investigators summarized, “In conclusion, drinking outside meals appears to have a significant effect on hypertension risk independent of the amount of alcohol consumed.” 21
Alcohol consumption with or without meals and reduced acute myocardial infarction (MI) risk has also been reported. Researchers undertook this study to determine whether the apparent favorable effect of alcohol on the risk of acute myocardial infarction (MI) may be related to its hypoinsulinemic effect when consumed with meals. They studied how the timing of alcohol consumption in relation to meals might affect the risk of MI in an Italian population with relatively high regular alcohol consumption. The researchers found that compared to nondrinkers, an inverse trend in risk was observed when alcohol was consumed during meals only. However, no consistent trend in risk was found for subjects drinking outside of meals. They further explained that the pattern of risk was similar when they considered people who drank only wine and concluded, “Alcohol drinking during meals was inversely related with risk of acute MI, whereas alcohol drinking outside meals only was unrelated to risk.” 22
The importance of well-balanced and nutritious diets as a potential disease prevention measure has been long acknowledged and featured by leading nutrition and public health experts. 23 These research findings reveal the importance of moderate drinking as an adjunct to healthy meals and a well balanced daily food intake.
Public Health Advice:
Accumulating scientific evidence throughout this past decade suggests that moderate consumption of alcohol beverages does not pose a health risk to the vast majority of healthy individuals around the world who choose to enjoy sensible amounts of spirits, beer and wine. Also, according to the 2005 Dietary Guidelines for Americans, “The consumption of alcohol can have beneficial or harmful effects depending on the amount consumed, age and other characteristics of the person consuming the alcohol and the specifics of the situation.” 24
This emerging research underscores the importance of moderate alcohol consumption as part of a healthy diet and lifestyle. Public health guidelines around the world emphasise moderation and clearly condemn irresponsible drinking patterns such as binge drinking and abuse. Many public health messages also reiterate the importance of an overall healthy diet and lifestyle for those who choose to drink without recommending the consumption with meals but rather as an adjunct to it. As the scientific debate will continue, more research findings on drinking patterns may lead to revised basic messages on the lifestyle benefits of enjoying moderate amounts of wine, beer, and spirits as part of a well balanced diet.
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2. Green, C et al, Gender Differences in the Relationships between Multiple Measures of Alcohol Consumption and Physical and Mental Health. , Alcoholism: Clinical & Experimental Research. 28(5):754-764, May 2004
3. Grosbeak, M et al, Changes in Alcohol Intake and Mortality: A Longitudinal Population-based Study.
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4. Tolstrup JS et al, Drinking Pattern and Mortality in Middle-Aged Men and Women, Addiction, 99(3): 323-330, 2004.
5. White IR, et al. Mortality in England and Wales attributable to any drinking, drinking above sensible limits and drinking above lowest risk levels, Addiction. 2004; 99, 6.
6. Klatsky AL, Alcohol and Cardiovascular Health, Integrative and Comparative Biology, 44, 2004.
7. Mukamal KJ et al, Roles of Drinking Pattern and Type of Alcohol Consumed in Coronary Heart Disease in Men, New England Journal of Medicine, 348(2), 2003.
8. Trevisan M et al, Drinking Pattern and Risk of Non-Fatal Myocardial Infarction: A Population-Based Case-Control Study, Addiction, Vol 99, No 3, 2004.
9. Trevisan M et al, Lifetime Drinking Pattern is related to Risk of Metabolic Syndrome, Circulation 2004; 110: III-833.
10. De Lange D et al, Rapid Intake of Alcohol (Binge Drinking) Inhibits Platelet Adhesion to Fibrinogen under Flow. Alcoholism: Clinical & Experimental Research, 28(10, 2004.The study’s findings are published in the October 2004 issue of Alcoholism: Clinical & Experimental Research.
11. Mukamal KJ et al, Binge Drinking and Mortality Following Acute Myocardial Infarction, Circulation 2004; 110: III-743.
12. Trichopoulou A et al. Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study. BMJ, 2005.
13. Knops, K et al, Mediterranean Diet, Lifestyle Factors, and 10-Year Mortality in Elderly European Men and Women, JAMA. 2004; 292 and Rimm E et al, Diet, Lifestyle, and Longevitythe Next Steps? , JAMA. 2004 or visit http://jama.ama-assn.org/cgi/content/full/292/12/1433
14. Reference: Esposito K et al, Effect of a Mediterranean-Style Diet on Endothelial Dysfunction and Markers of Vascular Inflammation in the Metabolic Syndrome, JAMA. 2004; 292 or visit http://jama.ama assn.org/cgi/content/abstract/292/12/1440
15. James Cerhan et al, Adherence to the AICR Cancer Prevention Recommendations and Subsequent Morbidity and Mortality in the Iowa Women’s Health Study Cohort. Cancer Epidemiology, Biomarkers and Prevention 2004; 13
16. De Lorgeril M et al, Wine Ethanol, Platelets, and Mediterranean Diet, the Lancet, 353:1067, 1999.
17. Hendriks H F J et al, Moderate Doses of Alcoholic Beverages with Dinner and Postprandial High Density Lipoprotein Composition, Alcohol & Alcoholism, 4:403-410, 1998.
18. Augustin LS et al, Alcohol Consumption and Acute Myocardial Infarction: A Benefit of Alcohol Consumed with Meals, Epidemiology, Vol 15, No 6, pp767-769, 2004.
19. Klatsky A, Alcohol and Health: How much is good for you? Scientific American, February 2003.
20. Stranges, S et al, Differential Effects of Alcohol Drinking Pattern on Liver Enzymes in Men and Women. Alcoholism: Clinical & Experimental Research. 28(6): 2004.
21. Stranges S et al, Relationship of alcohol drinking pattern to risk of hypertension. A population-based Study, Hypertension, October 2004 (on line publication)
22. Augustin LS et al, Alcohol consumption and acute myocardial infarction: a benefit of alcohol consumed with meals, Epidemiology, Vol 15, No 6, 2004.
23. Mitka M., Where the Elite Meet To Eat-a CME Course, JAMA, 284(7), 2000.
24. US. Departments of Agriculture and Health and Human Services, Nutrition and Your Health: Dietary Guidelines for Americans, 6th edition, 2005. |
<urn:uuid:36fb1729-3dfb-4cf6-bb02-22b21469e27e> | seed | - Trait anger is a tendency to experience frequent and intense episodes of anger.
- Individuals with high levels of trait anger, along with low levels of anger control, are likely to commit alcohol-related aggression.
- Researchers suggest these individuals refrain from alcohol consumption.
Despite its powerful pharmacological effects on the central nervous system, alcohol does not facilitate aggression in all persons or in all situations. Trait anger – a tendency to experience frequent and intense episodes of anger – has already been identified as a risk factor for alcohol-related aggression. Yet possessing high levels of trait anger does not necessarily guarantee that an intoxicated individual will become aggressive when provoked. A study in the June issue of Alcoholism: Clinical & Experimental Research finds that a person's inability to control the outward expression of their anger plays a key role in alcohol-related aggression.
"Our previous research showed that men with high levels of trait anger are most at risk for becoming violent when they drink," said Peter R. Giancola, associate professor of psychology, director of the University of Kentucky Alcohol Research Laboratory, and corresponding author for the study. "This study adds to that by showing that the combination of high trait anger and low anger control even further increases your risk.'"
"This topic is exceedingly relevant as, generally, alcohol intoxication co-occurs with violence in approximately half of all rapes, murders and assaults, including family violence," added Robert O. Pihl, professor psychology and psychiatry at McGill University. "The significance of this correlation is typically ignored by society, possibly because the nature of the relationship remains argumentative. This study and others like it are slowly illuminating the mechanisms and vulnerabilities involved in the alcohol/aggression relationship."
Researchers examined 164 healthy male social drinkers (159 Caucasians, 5 African Americans) between the ages of 21 and 35 years who were recruited through local advertisements and paid for their participation. Trait anger and anger control were assessed with the State-Trait Anger Expression Inventory. Participants were given either an alcoholic (1g/kg alcohol) or a placebo beverage, and then participated in a laboratory aggression task.
Higher levels of trait anger were associated with increased aggression, but only among men who were intoxicated and also reported low levels of anger control.
"Most if not all individuals who drink and drink heavily do so without becoming violent," said Pihl. "Thus, the phenomenon invariably involves an alcohol effect, plus a specific type of situation, and the inability to deal with that situation. The Giancola paper suggests that the inability to control anger is an important factor in the equation. For individuals who fit the characteristics described by Giancola, drinking during emotionally provocative situations de facto is a license to aggress. Just like in the case of driving, this is a time these individuals should avoid alcohol. Further, these individuals might be wise to avail themselves of numerous intervention programs specifically designed to enhance anger control."
Giancola added "research indicates that alcohol increases aggression by reducing fear, increasing arousal, and impairing cognitive functioning. However, being in this disinhibited state does not mean that one will necessarily become aggressive," he said. "They might also become more talkative, jovial, or sexual." The over-arching aim of his entire research program, said Giancola, is to determine what factors are most important in increasing one's risk for intoxicated aggression.
"Once these risk factors are identified, we will attempt to prevent them in children," he said.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.
Men are not prisoners of fate, but only prisoners of their own minds.
-- Franklin D. Roosevelt |
<urn:uuid:38537196-f0ca-4a8b-9e4f-e27885af52b8> | seed | St. Louis, October 1 -- Women who undergo routine mammograms at Missouri Baptist Medical Center now have the option of adding 3D technology to their screening.
Missouri Baptist is one of the first breast centers in Missouri to offer 3D tomosynthesis for breast cancer screening.1 Breast tomosynthesis allows radiologists to examine breast tissue in 3D, one layer at a time, versus in 2D where overlapping tissue can make it hard to see early signs of cancer.
3D mammography has a higher cancer detection rate than conventional 2D mammography alone.2 Radiologists also report that tomosynthesis technology gives them increased confidence in evaluating dense tissue reducing the number of patients called-back for additional evaluation.3
During a tomosynthesis exam, multiple, low-dose images of the breast are acquired at different angles. These images are then used to produce a series of one-millimeter thick slices that can be viewed as a 3D reconstruction of the breast.
Breast cancer is the second leading cause of cancer death among women, exceeded only by lung cancer. Statistics indicate that one in eight women will develop breast cancer sometime in her lifetime. The stage at which breast cancer is detected influences a woman’s chance of survival. If detected early, the five-year survival rate is 98 percent.4
“We have used 3D technology in diagnostic mammograms for the past 18 months,” said Geoffrey Hamill, MD, chief of mammography at Missouri Baptist. “Our results show tomosynthesis clearly helps us evaluate and detect small cancers not easily seen in dense tissue. We believe screening mammograms with tomosynthesis will be a major benefit for our patients helping us see small cancers sooner and will reduce the number of patients recalled for additional workup of benign findings that are not worrisome.
1 3D Tomosynthesis mammography has been offered at both Missouri Baptist and Barnes-Jewish hospitals for diagnostic mammograms. Barnes-Jewish participated in the initial evaluation of the technology.
2 Skaane P, Gullien R, Eben EB, et. al. Reading time of FFDM and tomosynthesis in a population-based screening program. Radiological Society of North America annual meeting. Chicago, Il, 2011.
3 Ciatto, et.al., Lancet Oncol. 2013 Jun;14(7):583-9
4 Breast Cancer Facts & Figures 2011, American Cancer Society.
About Missouri Baptist Medical Center
Missouri Baptist is a 489-bed acute-care hospital located in west St. Louis County. Recognized a “Best Hospital in St. Louis” by U.S. News, as one of the “Top 100 U.S. Hospitals” for Surgery and “5-Star Rated for Treatment of Heart Attacks” by HealthGrades, Missouri Baptist offers a full continuum of medical and surgical services, and specializes in heart, cancer, gastrointestinal, orthopedic, neurological/spine and women’s health services. Missouri Baptist Medical Center is a member of BJC HealthCare, one of the largest nonprofit health care organizations in the United States and the largest employer in St. Louis. Based in St. Louis, BJC serves residents in Missouri and southern Illinois through its 13 hospitals and multiple health service organizations. www.missouribaptist.org. |
<urn:uuid:ed5ce308-e7ac-4e98-8b21-b077ae5113eb> | seed | Epidermolysis bullosa (EB) is a rare (1 in 50,000) genetic skin disorder that causes skin fragility and blistering resultant from a mutation in one of several genes responsible for skin adherence (Schober-Flores, 2009). All forms of EB result in various extents of skin fragility and blistering because of friction, heat, or trauma (Tidman, Mellerio, & Pope, 2011; Figure 1). The four major types are simplex, junctional, dystrophic, and mixed or Kindler syndrome (Table 1). These types are classified according to level of skin involvement. The mildest form, EB simplex (EBS) is generally nonscarring because the level of skin involvement is more superficial when compared with other more severe types; however, scarring can result from infection. Blistering often presents at birth or shortly thereafter. Wounds in EBS may be chronic, but they tend to lessen in severity with age in many cases (Wright, 2011). In contrast, those with the rare junctional EB type have a more severe phenotype characterized by absent nails, dysplastic teeth, oral lesions as well as esophageal and tracheal involvement (Wright, 2011). Dystrophic EB is among the most disfiguring of the EB types. As with the other forms of EB, this also presents at birth but distinguishes itself by producing scarring and contractures. Dystrophic EB is further classified into two subtypes according to the inheritance pattern, which may be autosomal dominant or recessive. Generally, the dominant form is less severe, although there is evidence suggesting further variations, including a more severe dominant form and less severe recessive form (Tidman et al., 2011). Dominant dystrophic EB is the more common subtype with patients developing bullae over the limbs, trunk, and bony prominences (Tidman et al., 2011). Recessive dystrophic EB is characterized by widespread blistering and erosions involving both skin and mucous membranes. These erosions eventually lead to extensive scarring and mitten-like deformities of the hands and feet. Both types of dystrophic EB may have gastrointestinal (GI) involvement leading to esophageal and anal strictures. The risk of developing aggressive squamous cell carcinoma (SCC) is significantly increased in those patients with the recessive subtype and is one of the major causes of mortality (Tidman et al., 2011). Mixed EB, also known as Kindler syndrome, is a rare form of EB. It is inherited in an autosomal recessive pattern and characterized by poikiloderma, photosensitivity, and skin fragility. Infants born with this type of EB often present with acral blistering. Although the tendency for skin blistering may improve with age, atrophic scarring and poikiloderma tend to be progressive (Tidman et al., 2011).
Because of the extensive time and expertise required to care for children with EB, it is necessary that caregivers coordinate a plan with the child’s medical team. This plan should include but is not limited to ordering dressing supplies, scheduling clinic appointments, and making appropriate referrals. Regular clinic appointments involve the multidisciplinary team including a dermatologist with experience or expertise in EB (usually a pediatric dermatologist) as well as physicians and/or specialists in gastroenterology, nutrition, dentistry, hematology, hand or plastic surgery, orthopedics, ophthalmology, social services, pain management, and physical and occupational therapy. Families with children diagnosed with EB should be directed to a case manager or EB nurse so that they receive the appropriate medical supplies and follow-up care from a dermatologist.
MAKING AND EXPLAINING THE DIAGNOSIS
Discovering that their child is born with blisters or absent skin can be a frightening experience for parents and families. According to Dystrophic EB Research Association (DebRA), EB is known as “the worst disease you never heard of,” most nurses and pediatricians are unfamiliar with this disease. When a child is born with blisters or absent skin, he or she should be transferred to the neonatal intensive care unit for a complete evaluation. If EB is suspected, it is imperative that the neonatal team or pediatrician consults with the nearest EB center to properly diagnose and care for the newborn. The diagnosis is often confirmed with a biopsy of an induced and intact blister sent for immunofluorescence mapping as well as electron microscopy. This testing is limited to select specialty laboratories and/or universities. Clinical presentation may offer a preliminary diagnosis, but tissue studies may be inconclusive requiring genetic testing to confirm the exact diagnosis. Genetic testing is also limited to specialized laboratories and, often times, is not covered by insurance because of the high cost of such tests. Although the newborn is still hospitalized, teaching the family appropriate wound care is a crucial part in preparing the family for discharge. The parent(s) must be able to show the appropriate process for dressing changes. Supplies should be ordered and delivered to the home before discharge. Once the child is discharged home, it is necessary that the child is referred to a dermatologist or a pediatrician who is well educated and experienced in the diagnosis of EB. Although the treatment plan is similar for most types of EB, knowing the exact subtype of EB will help predict the child’s prognosis, further complications, and screening tests that may be helpful. Confirming the diagnosis of EB can create a lot of stress and anxiety for the family, especially when the parents fully understand the disease process and the enormity of the care that will be involved. Providing appropriate education and resources can help reduce the level of stress and anxiety that these parents and families experience.
Infection is a recurrent concern and reality for patients with EB because of loss of skin integrity inherent in the disease caused by the presence of open wounds. Because of skin barrier disruption, most individuals with EB become colonized over time with bacteria. Infection may occur when bacteria reach colony counts of 1,000,000 causing delayed wound healing (Gardner & Frantz, 2004). Symptoms of infection may include a dark red appearance, swelling, tenderness to touch, increased pain, surrounding erythema, and increased drainage from the wound bed. The drainage may appear as yellow or green in color and may have a strong malodor (Schober-Flores, 2009). However, even when the abnormal appearance and malodor are present, it does not always indicate active infection (Gardner & Frantz, 2004). Malodor may be caused by specific types of dressings or even bacterial colonization. The most common bacteria found in the wounds of patients with EB are Staphylococcus aureus and Pseudomonas aeruginosa, which contribute to delayed wound healing (Lara-Corrales, Arbuckle, Zarinehbaf, & Pope, 2010). Because management and prevention of infection is a constant concern, especially in the recessive subtype, dilute bleach baths can be very beneficial in helping to prevent and treat bacterial overgrowth (Schober-Flores, 2009). According to DebRA, the recommendation for bleach baths is 1/4 cup of household bleach in a half-full bathtub of water or 1–2 teaspoons per gallon of water. The bleach–water solution should be mixed before coming in contact with the skin. Although there are no specific guidelines, most EB clinicians recommend soaking for approximately 10 minutes 2–3 times per week or, if active infection is present, with each dressing change. To prevent itching, it is important to rinse the skin with fresh water after soaking in bleach water. Pool salts anecdotally have been implicated to alleviate potential stinging and itching associated with the use of bleach in the bath water. Pool salts can be used in conjunction with bleach water to create an isotonic solution. To date, there have been no studies reported that compared these methods for patients with wounds of any type. Lindfors (2004) reported that, in her sample, patients who were treated with normal saline alone showed an increase in aerobic bioburden levels as compared with the patients treated with an antimicrobial wound cleanser consisting of 0.057% sodium hypochlorite in an isotonic saline solution. In addition, those patients treated with the antimicrobial solution exhibited a greater reduction in wound size when compared with the patients treated with saline alone. This finding suggests that wound healing is potentiated with the use of the antimicrobial wound cleanser. The paucity of studies in this area, however, limits the generalizability of this finding to this population.
While caring for someone with EB and performing dressing changes, it is important to assess not only the wound but also the surrounding tissue. The components of a nursing assessment should include monitoring for characteristics of infection such as erythema, malodor, increased pain, or increased drainage and for improvement in the wound (Table 2). Close attention should be directed at the amount of moisture present in the wound bed. If the tissue appears white or “macerated,” there may be too much moisture because of drainage, the amount of topical ointments applied may be too excessive, or inappropriate dressing materials have been used. In contrast, if the wound and surrounding tissue appears pink and healthy, then the correct moisture level has been achieved. Choosing the correct dressing product is crucial in promoting wound healing (Schober-Flores, 1999). Whereas some products are designed to provide moisture, others are designed to reduce it. It is important to understand what each product is designed for before using it on affected skin.
A study reported by Fine, Johnson, Weiner, and Suchindran (2004) assessed activities of daily living, mobility, and pain in different subtypes of EB. Fine and colleagues explained that cutaneous pain is a common occurrence in the more severe types of EB regardless of patient age. This report also identified that all major types of EB required at least partial dependency on caregivers especially in such activities as walking and personal hygiene (Fine et al., 2004). Controlling the pain associated with chronic wounds and daily dressing changes can be a very difficult challenge. Parents should be mindful of the pain involved with recurrent blistering and infection. For some of the more severe forms of EB, analgesics or opiates may be required for dressing changes. Also, a nighttime dose of amitryptyline may prove to be beneficial for some patients as this has been indicated for chronic pain. Because patients with EB experience pain daily, it is imperative that caregivers as well as the medical team be aware of the most appropriate interventions to help reduce the amount of pain these individuals experience on a daily basis. It has been postulated that adequate pain interventions can be significantly beneficial in patients’ coping strategies with this disease (Fine et al., 2004).
Regardless of the EB type, itching or pruritus is a daily challenge for EB patients. Factors such as open wounds, healing wounds, bacterial colonization, or infection can all be cause for pruritus. Interventions such as a nighttime dose of doxepin may be helpful in treating pruritus.
Most feeding issues arise from blistering and erosions within the GI tract. Large amounts of protein, blood, and fluids are lost from open wounds on the skin as well as in the GI tract. In addition, the chronic and/or extensive open wounds result in an increased demand for protein for wound healing to occur. Patients with involvement of the digestive tract may develop dysphagia and constipation, secondary to scarring and strictures of mucous membranes. Because of chronic wound development and healing, inflammation, and GI involvement, suboptimal nutrition commonly results in the delay of growth and development. It is estimated that two to four times the normal calories and protein are needed to heal wounds and prevent iron deficiency anemia as well as allow for normal growth and development to occur (Schober-Flores, 1999). Supplements can be very helpful in maintaining the nutritional needs of children with EB. Examples of these supplements may include Pediasure, Ensure, and Nutren. Iron supplementation may also be required if severe anemia occurs. Given the diet restriction and pain associated with this diagnosis, consulting a nutritionist is helpful.
When an infant is born and diagnosed with EB, blisters in the mouth may make eating very painful; therefore, a Haberman Feeder can be helpful for infants who have blisters or erosions in the mouth. The nipple contains a disk insert and valve that helps control the flow of liquid and also reduces the amount of air the child may swallow.
For older children with EB, eating can be particularly difficult. Allowing the children to experiment with different foods will allow them the opportunity to have some control over their disease. Patients should be encouraged to eat soft or pureed foods and avoid extreme temperatures and spicy foods. Foods that are served at room temperature and nonacidic are easier to swallow. Because the entire GI tract may be affected and the esophagus may be eroded with blisters, esophageal strictures may result. As this can cause painful and difficult swallowing, dilatations or surgical interventions may be required such as placing a permanent gastrostomy tube to ensure proper nutrition.
The need for iron supplementation and pain medication, along with a diet low in fiber and fluids, may contribute to constipation in the patient diagnosed with EB. Constipation may also be a result from anal ulcerations and the pain associated with passing stool near an open wound. Because of this, children may withhold from having a bowel movement to avoid the pain. To help alleviate the problems of constipation, a stool softener or increased fiber intake may be beneficial (Schober-Flores, 1999). As with the use of all supplements or medications, the patient should be followed closely by a gastroenterologist and a licensed nutritionist, as they are often part of the multidisciplinary team of the EB clinics.
SQUAMOUS CELL CARCINOMA
Recurrent, painful, or abnormal-appearing nonhealing wounds are reason to be concerned for Squamous Cell Carcinoma (SCC). As dystrophic EB patients tend to have more severe and nonhealing wounds, they are at greater risk of developing SCCs in comparison with other EB types (Pourreyron et al., 2007). SCCs tend to be aggressive in EB patients and may present with multiple foci or metastatic disease requiring the expertise of an experienced surgeon and oncologist for treatment. However, regardless of the type of EB, routine full-body skin examinations are highly recommended. According to Venugopal and Murrell (2010), full-body skin examinations should be every 3–6 months from ages 10–16 years and every 3 months from age 16 years and up and can be more frequent if warranted. Family members or primary caregivers are encouraged to pay close attention to wounds that have been present for at least 1 month with no improvement. If there is concern for a nonhealing wound, this should be reported to the patient’s provider. The use of serial photographs for wounds may be helpful to both the patient and the dermatologist.
Managing a Home Care Plan
Children with EB have extensive needs, and to achieve those needs, parents must work closely with the pediatrician, dermatologist, or if possible, the entire multidisciplinary EB team. Patient education should extend to all of the child’s caregivers to provide the best quality of life and outcomes for the child, whereas goals of therapy should allow for as normal a life as possible. Although the treatment plan is similar among most types of EB, the individual child’s needs may vary. For example, a child with EBS may live independently as an adult, but a child with recessive dystrophic will likely require dependence on a caregiver throughout his or her life. An article published in 2004 by Fine et al. confirmed that some level of supervision is needed one or more times per day for most children with severe types of EB. Caring for a child with EB can be extremely stressful, but with proper education, sufficient supplies, familial support, and a daily care plan, the challenges of EB can be minimized.
With time, each family will begin to develop a plan that works best for their child(ren) as each child has unique needs. For example, a dressing that works for one child may not be the best choice for another child. Most parents find it helpful to talk with other EB parents as they have experience first hand, and because EB is so rare, parents may find it helpful to join local or national support groups.
Despite the long hours of wound care and frequent doctor appointments, these children also need to experience life as any other child without EB would. The psychosocial development of children is equally as important as physical development; therefore, play time and limit setting should be consistent and appropriate for the developmental level of the child.
Because most of these children attend school, the need for an individualized education plan (IEP) is necessary to maintain as normal an education experience as possible. An IEP allows the child to receive the proper education while addressing the individual’s special needs. An IEP would also allow the child to have a personal aid if necessary and/or accommodate more time between classes at school.
Dressing changes are one of the main challenges facing those with EB, particularly for the more severe forms of EB. Being well prepared for dressing changes will make the process much easier, faster, less painful, and less stressful for both the parent and child. When ordering supplies, it is best to plan ahead as it may take up to a week to receive supplies. Dressing supplies need to be ordered from a wound supply company often depending on the patient’s insurance plan. Supplies are delivered on a monthly basis. Dressing changes can be exhausting for both parent and child as daily wound care regimens may take 2–3 hours or longer for some individuals. Whether the dressing change is accomplished in the morning or evening, it is best to have a routine. Over time, this routine will become easier and the parent(s) will become more confident with each dressing change. As EB children are susceptible to infection, having a clean area to perform the dressing change should always be a priority. Initially, all of the supplies should be opened and prepared before removing soiled dressings. If the child is old enough to soak in a bathtub alone, then the parent can prepare the dressing materials during this time. This prevents the child’s skin from being exposed and unprotected for longer than necessary. In addition, during the bathing routine, bleach baths are useful in helping to prevent infection; however, this should be directed by a physician. Because the time and energy involved in dressing changes is strenuous, allowing other family members or close friends to learn the process may help ease the burden of the primary caregiver. Table 3 lists useful supplies when performing dressing changes. Dressing changes generally require three layers of protection. The contact layer consists of products that are nonadhesive. If any product sticks to the skin, it will likely tear the skin. The second layer is a gauze wrap, which holds the contact layer in place. Lastly, the third layer such as Surgilast or Xspan is used to keep the gauze secure and provides added protection. Topical antibiotic use is recommended in short intervals depending on the wound and is often suggested as an alternative to oral agents because of the concern for resistance in pathogens to antibiotic therapy. As with all antibiotic use, whether over the counter or prescription, this should be directed by a physician. Prescription agents generally have better coverage for skin pathogens and have generally been tolerated well but require an order by a provider or physician. If an infection is suspected and has not improved within 2–3 days of using a topical antibiotic, it is recommended that the patient consult with his or her physician.
Caring for a child with EB carries an abundance of daily challenges. DebRA has been helping children with EB for over 30 years by providing various resources, emergency wound supplies, and a nurse educator who is available to answer questions. The diagnosis of EB inevitably carries a financial burden. An abundance of dressing supplies is required for the severe forms of EB and is very costly. Insurance companies vary on wound supply coverage. However, if a patient’s medical insurance results in limited coverage, there are organizations available to help with the cost of these necessary items. DebRA has developed programs such as the New Family Advocate Program, which provides products and information to families who have a newborn with EB. Also, the DebRA Wound Care Clearing House provides wound care and bandage supplies to families free of charge. In fact, up to $100,000 worth of supplies are provided to families each year. DebRA also has a family crisis fund, which helps families with unreimbursed medical expenses. Currently, the maximum amount allotted for each family is $1,200 per year. As part of the dressing change regimen, a lubricant such as Aquaphor may be used as an emollient to prevent dressings from adhering to healing skin. Beiersdorf, the manufacturer of Aquaphor, provides a program that offers a free supply of Aquaphor to those with EB. Vaseline (petrolatum jelly) is also a common emollient used with dressings. It is affordable and easy to access. Although there are many home health supply companies that can provide the wound care supplies needed for these children, National Rehab, Hollister Wound Care, Edgepark, and Direct Medical are a few corporations who have a special interest in developing new products for EB and helping families obtain needed supplies. National Rehab supports DebRA’s mission and has developed a program to support the EB community, including a Web site dedicated for EB families. This Web site, www.ebnurse.org, allows families to access current articles, post questions to the EB nurse, learn tips from other EB families, and become educated about the needs of children and families with EB. Information about pertinent clinical trials is also available on this site (Table 4).
EB families and researchers are both focused on finding a cure for EB. Stem cell transplant, gene transfer therapy, and improvements in wound care management are largely studied topics in EB research. A general resource for all clinical trials is www.clinicaltrials.gov, which provides an up-to-date list of completed and active clinical trials for EB (Table 4).
To date, there are four major multidisciplinary EB clinics in the United States: Cincinnati Children’s Hospital, Children’s Hospital Colorado, Lucille Packard Children’s Hospital, and Phoenix Children’s Hospital. These specialty clinics are composed of multidisciplinary teams including pediatric dermatologists, nutritionists, ophthalmologists, physical and occupational therapists, hand/plastic surgeons, gastroenterologists, dermatology nurses, and social workers. Pediatric dentists trained in treating children with EB may also be called to consult on related oral conditions and dental health in these children. In addition, having a general pediatrician as part of the multidisciplinary team to help manage the care for these children benefits the entire team, including the children. Because there are only four major specialty centers in the country, it may be geographically difficult for some families to attend a clinic on a regular basis. It is imperative although, at some point, for children with EB to be evaluated and followed by an EB specialty clinic to ensure that the care requirements are met and families are aware of available resources.
Because of the complexity of the more severe forms of EB, these children spend much of their time doing dressing changes or attending doctor appointments. These children do not always have the same opportunities as other children without EB. Patients with EB will never feel “normal.” Their skin does not look normal, and they often cannot participate in the same activities as unaffected children. Fortunately, various camps and programs have been created for those with genetic skin diseases such as EB. These specialty camps allow children to be surrounded by others who share the same feelings, worries, and daily struggles of having a genetic skin disease. For example, Camp Discovery, supported by the American Academy of Dermatology, is a week-long camp for children with chronic skin conditions such as EB. At Camp Discovery, children have the opportunity to create new friendships and participate in activities such as fishing, swimming, boating, and arts and crafts. In addition, Camp Wonder, sponsored by the Children’s Skin Disease Foundation, offers children with serious and fatal skin conditions the chance to participate in activities with other children who have similar skin conditions. The advantage to campers is that their medical and social needs are met during the time at camp and it is an ideal setting to address the feelings of isolation because of the restrictions required by their skin condition.
According to Schober-Flores (2003), the greatest challenges in caring for a child with EB, regardless of type, include wound care, nutrition, education, and social support. Because there are numerous complications associated with EB, parents must pay careful attention to all potential complications, which may include infection, pain, malnutrition, and development of SCC. They are strongly encouraged to report any changes to the pediatrician or dermatologist. Not only are there physical complications but social issues as well. The nurse can assist families in understanding the implications of the diagnosis as well as developing a workable home plan to include both dressing changes and management of potential complications. Psychological support is very important for children with EB throughout their lifetime but especially when they reach school age, and as EB affects the entire family, this support is equally important. The nurse can also work in conjunction with other care providers and schools to ensure respite for parents and to achieve maximum psychosocial development.
The challenges associated with EB are physically, emotionally, and financially taxing. Through educating EB families and providing the necessary resources, EB children and their families can be afforded as normal a life as possible to reach their maximum potential. The chronicity and complexity of the needs of children with EB require a multidisciplinary approach in which nurses can provide families with the support they require to be successful in the management of their child’s care. |
<urn:uuid:4971741d-e856-4c34-848a-db8d477e01eb> | seed | Reconciling Survey and Surveillance-based Estimates
17-18 February 2003
Tropical Diseases Research Centre (Ndola, Zambia),
UNAIDS and WHO
The estimation of the number of people infected with HIV in countries, regions and globally is an important process for purposes of advocacy, programme planning and evaluation. National estimates of prevalence in countries with generalized epidemics are based on data generated by surveillance systems that focus on pregnant women who attend a selected number of sentinel antenatal clinics. UNAIDS/WHO, in close consultation with the countries, use a six-step method to obtain estimates of HIV prevalence for men and women, and an increasing number of countries have adopted these methods to develop national estimates. The major assumption is that prevalence among pregnant women is a good approximation of prevalence among the adult population (age 15-49), based on direct comparisons of adult population and antenatal clinic HIV prevalence in the same communities.
Recently, several countries have conducted national population-based surveys that include HIV testing and more countries are planning to do so in the near future. Technological developments, such as the use of blood-spotted filter paper or oral mucosal transudate for sample collection, have facilitated the collection of biological data in household surveys. Concerns about the accuracy of national estimates of adult female and male HIV prevalence based on data generated by antenatal clinic based surveillance systems have stimulated the public health demand for more representative data on HIV prevalence for the whole population. This consultation will review results and estimates of adult prevalence of HIV from three recent national surveys and compare the finding to those based on sentinel surveillance systems.
- To share the methods, results and issues related to recent population-based surveys with HIV data collection, including sampling methods and laboratory procedures
- To present comparisons of HIV prevalence estimates from national surveys and from antenatal clinic based surveillance, in defined geographical entities (e.g. in rural versus urban areas, in provinces, in specific antenatal clinics and their catchment areas)
- To present results from further analysis with regard to non-response
- To discuss how surveys can be used to improve national surveillance system based estimates of HIV prevalence
UNAIDS/WHO Estimates: how are they made?
Comparison of prevalence among ANC clinic attenders and the general population in selected small-area population-based studies
Mali: issues arising from the national population-based survey
South Africa: issues arising from the comparison of national DHS and data from the surveillance results
Zimbabwe: issues arising from the comparison of national DHS and data from the surveillance results
Working groups (illustrative questions):
- How to deal with non-response issues?
- What laboratory procedures are most suitable for surveys and surveillance?
- Can survey data be used to adjust ANC clinic based estimates?
- How can surveys best be integrated in surveillance systems?
- How can the design of national surveys be improved to provide better surveillance data? |