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Like people, horses can be allergic to various substances, including plant particles and other substances in the air (called allergic inhalant dermatitis or atopy) or in food. These substances are called allergens. Allergens are substances that, when inhaled or absorbed through the skin, respiratory tract, or gastrointestinal tract, stimulate histamine production, leading to inflammation. Allergic reactions can also be triggered by medications or vaccination. Airborne Allergies (Atopy) Horses often live in environments that have a high level of dust, mold, or other common allergens in the air. While the horse's immune system normally provides protection for the animal, the immune system of some horses overreacts to the presence of one or more airborne allergens. Airborne allergens can adversely affect the skin. The most common skin problems associated with the inhalation of allergens include hives and rashes (see Skin Disorders of Horses: Hives (Urticaria) in Horses). However, itching (see Skin Disorders of Horses: Itching (Pruritus) in Horses) is also a common allergic reaction to such things as hay dust, mold, mildew, pollen, and dust mites. Once an allergy is diagnosed, treatment usually involves avoiding the allergen, if possible, and use of corticosteroids to control the inflammatory reaction. If a horse is allergic to dust in the environment, you may consider keeping it outside rather than stabling it. Feeding the horse haylage or some other feed with little dust may also help. Conversely, if the horse has seasonal pollen allergies, it can be kept inside during the months when pollen is normally present. Allergy testing is also available in some areas. Allergy testing allows your veterinarian or veterinary dermatologist to identify the specific allergens that are a problem for your horse and to formulate an allergy vaccine, if appropriate. Horses can also develop food allergies, although documented cases are rare. For example, there are reports that certain types of grains or hay have caused hives in horses. In some cases, the food allergies were associated with high-protein food concentrates. One common approach to identifying a food allergy starts with a trial or elimination diet. The horse receives a diet that does not include any of the foods previously fed, including supplements. For horses that have been on pasture, the diet may include a change of pasture or isolation from pasture. The trial diet is normally provided for up to 3 months. If signs of the allergy improve or resolve during this period, then a food allergy is likely. To confirm the food allergy, the previously fed foods must be returned to the diet 1 at a time. If signs return in response to a particular food given, then that food is likely the cause. The suspect food is again eliminated from the diet. If the signs resolve (often in less than 14 days), the food allergy is usually confirmed. Once the offending allergens are identified, control of the food allergy involves strict avoidance of the food. Concurrent diseases may complicate the identification of underlying food allergies. Infrequently, a horse will react to new food allergens as it ages. Last full review/revision July 2011 by Karen A. Moriello, DVM, DACVD; John E. Lloyd, BS, PhD; Bertrand J. Losson, DVM, PhD, DEVPC; Wayne Rosenkrantz, DVM, DACVD; Patricia A. Talcott, MS, DVM, PhD, DABVT; Alice E. Villalobos, DVM, DPNAP; Patricia D. White, DVM, MS, DACVD; Thomas R. Klei, PhD; David Stiller, MS, PhD; Stephen D. White, DVM, DACVD; Carol S. Foil, DVM, MS, DACVD

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For additional information on FGIDs, please see: Functional gastrointestinal disorders (FGIDs) can affect any part of the gastrointestinal (GI) tract, including the esophagus, stomach and intestines. They are disorders of function (how the GI tract works), not structural or biochemical abnormalities. As a result, x-rays, blood tests and endoscopies can show essentially normal results. FGIDs are also not psychiatric disorders, although stress and psychological difficulties can make FGID symptoms worse. Approximately 25 million Americans have a functional GI disorder. FGIDs account for 40% of a gastroenterologist's practice. 50- 80% of persons with a functional GI disorder do not consult physicians, although they may take over-the-counter medications and report significantly higher rates of job or school absenteeism and disability. The most common FGIDs are Irritable Bowel Syndrome (IBS) - which is altered bowel consistency combined with abdominal pain that is usually relieved with a bowel movement - and Functional Dyspepsia - ulcer-like symptoms with upper-GI pain and a feeling of indigestion or symptoms of milder discomfort with fullness and possibly nausea soon after eating. There are three primary features of FGIDs - motility, sensation, and brain-gut dysfunction: - Motility is the muscular activity of the GI tract. Normal motility (e.g., peristalsis) is an orderly sequence of muscular contractions from the top to the bottom. In FGIDs, the motility is abnormal - there can be muscular spasms that can cause pain, and the contractions can be very rapid (fast motility is diarrhea) or very slow (slow motility is constipation). - Sensation is how the nerves of the GI tract respond to stimuli (for example, digesting a meal). In FGIDs, the nerves are sometimes so sensitive that even normal contractions can bring on pain or discomfort. - Brain-gut dysfunction relates to the disharmony in the way the brain and GI system communicate. With FGIDs, the regulatory conduit between the brain and gut function may be impaired and this can lead to increased pain and bowel difficulties which can be worsened by stress. Attention to FGIDs is increasing, as reflected in growing support for research in this area. The UNC Center for Functional GI & Motility Disorders is engaged in several research projects funded through the National Institutes of Health (NIH) and pharmaceutical companies. Research is focused on understanding mechanisms that may cause this group of disorders, treatment options to improve the symptoms, and understanding the complexity of symptoms. Publication of these research findings in peer-reviewed scientific journals helps to educate other physicians about this rapidly expanding field. Current State of Knowledge about FGIDs It is safe to assume from writings of physicians and historians that FGIDs have existed throughout history. But, the lack of identifiable cause prevented their classification as diseases and may have made their diagnosis and treatment "second class" in medical school, residency training, and research. There were only occasional reports of these disorders until the middle of the century, when systematic investigation began. Scientific attention to understanding and caring for patients with FGIDs developed only within the past 20 years and since then has grown steadily. Part of the reason for this growing interest relates to the symptoms being viewed as a syndrome with treatment options, as well as the use of new investigative techniques in GI physiology. Additional research is still needed with regard to the pathophysiology, classification and treatment of FGIDs, given their health care impact. But, research on the psychosocial aspects of FGIDs has led to three general observations: - Psychological stress exacerbates GI symptoms -- The evolving theory suggests that chronic GI symptoms are generated by a combination of intestinal motor, sensory and central nervous system (CNS) activity. The mechanism for these associations relates to the existence of bi-directional pathways between the central and enteric nervous systems, the so-called "brain-gut" axis. These bi-directional pathways provide the linkage between sensation in the gut and intestinal motor function. External stressors and cognitive information (emotion, thought) have, by virtue of their neural connections to the brain, the capability to affect GI sensation, motility and secretion. Conversely, not only does the brain affect the gut, but activity in the gut affects central pain perception, mood and behavior. - Psychosocial disturbances amplify illness experience and adversely affect health status -- Patients with FGIDs can show greater psychological difficulties than healthy research subjects or other medical patients. For example, research has shown that persons with IBS who do not consult a physician are psychologically similar to healthy (non-IBS) study subjects. This shows that IBS is not a psychiatric disorder; instead, it shows that psychosocial factors affect the individual's illness experience/perception and health outcomes, including physician consultation practices. - Having a functional GI disorder impairs quality of life -- Any chronic illness, including IBS, will affect a person's health-related quality of life (i.e., one's general well-being, ability to carry out day-to-day activities, concerns about the illness, satisfaction with health care). The investigation of clinical and psychosocial outcomes - including quality of life - is still relatively new in the field of gastroenterology.

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WHO Report on Global Surveillance of Epidemic-prone Infectious Diseases - Yellow fever Several different species of the Aedes and Haemogogus (South America only) mosquitos transmit the yellow fever virus. These mosquitos are either domestic (i.e. they breed around houses), wild (they breed in the jungle) or semi-domestic species (they display a mixture of habits). Any region populated with these mosquitos can potentially harbour the disease. There are three types of transmission cycles for yellow fever: sylvatic, intermediate and urban. All three cycles exist in Africa, but in South America, only sylvatic and urban yellow fever occur. Sylvatic (or jungle) yellow fever In tropical rainforests, yellow fever occurs in monkeys that are infected by wild mosquitos. The infected monkeys can then pass the virus onto other mosquitos that feed on them. These infected mosquitos bite humans entering the forest resulting in sporadic cases of yellow fever. The majority of cases are young men working in the forest (logging, etc.). On occasion, the virus spreads beyond the affected individual. Intermediate yellow fever In humid or semi-humid savannahs of Africa, small-scale epidemics occur. These behave differently from urban epidemics; many separate villages in an area suffer cases simultaneously, but fewer people are infected. Semi-domestic mosquitos infect both monkey and human hosts. This area is often called the "zone of emergence", where increased contact between man and infected mosquitos leads to disease. This is the most common type of outbreak seen in recent decades in Africa. It can shift to a more severe urban-type epidemic if the infection is carried into a suitable environment (with the presence of domestic mosquitos and unvaccinated humans). Urban yellow fever Large epidemics can occur when migrants introduce the virus into areas with high human population density. Domestic mosquitos (of one species, Aedes aegypti) carry the virus from person to person; no monkeys are involved in transmission. These outbreaks tend to spread outwards from one source to cover a wide area. The potential for large-scale urban epidemics exists in many parts of the world. The density and habitats of Aedes aegypti, one of the mosquitos that transmits yellow fever, have expanded in both urban and rural areas. This mosquito is infesting regions where it was previously eradicated. Therefore, although yellow fever has never been reported from Asia, this region is at risk because the appropriate mosquitos and primates are present. In addition, in the past, yellow fever outbreaks also occurred in Europe, the Caribbean islands and Central and North America - they must still be considered at risk for yellow fever epidemics even though the virus is not felt to be present in these areas now.

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Approach to otitis, client education leads to success (Proceedings) Treatment of otitis externa is dependent on identifying and controlling the predisposing factors, primary and secondary causes and perpetuating factors whenever possible. Inadequate treatment and reversal of the progressive pathologic responses, tympanic membrane alterations, and otitis media often leads to treatment failures or recurrences. Even though externally and to the client the ears seem better, adequate treatment can only be determined by otoscopic examination and follow up cytological examination of material from the ear canal. The treatment of otitis externa often requires a complete plan that will involve the use of multiple components. It is essential for these components to be successful that there is good client compliance. In general achieving compliance is greatly facilitated when the client understands the problems and corresponding goals. It is critical that follow up examinations are performed and clients or the clinic effectively keep the ear canal clean from excessive build up of debris, microbes or exudates. The client must be able to properly apply topical medications or an alternative form of therapy is required. PSPP System© For Otitis Externa This is done by entering a list of potential components of their pets ear disease and explaining them to the owners in a visual method, with simple drawings. The drawings help educate the owner about normal ear anatomy and physiology as well as perpetuating factors that may occur. Each patient has their information entered into the table. Tests and treatments for each component of the pets problem are listed and categorized prognostically, cured, requires long term management to achieve control or will require life long treatment. This simple system greatly facilitates educating clients about their pets problem. It gives the client reasonable expectations about the prognosis and what will be involved in "fixing" their pet. This results in improved client compliance and minimizes client frustration and searching for a "better" veterinarian. Why Clean Ears Thorough cleaning of the ear canals is extremely important for the effective management of otitis externa. It is often the most important step and if one treatment only was allowed to manage ear cases the it would definitely be cleaning as not single topical product is as effective. Different types of debris may occur in ears and there presence can impact otitis and the response to therapy. In normal ears little debris is present and it is composed of keratinocytes, cerumen and some microorganisms. In otitis cases there are multiple reasons why it is important to clean out excessive or abnormal debris. The debris can hinder the penetration of topical agents to the affected tissue requiring treatment, and large deposits may prevent medication from reaching the deeper parts of the horizontal canal, tympanum or middle ear when the tympanum has been compromised. This leads to the number one rule of topical therapy, the ingredient must reach the site to be treated. The debris can protect microbes that are rolled in or attached to keratinocytes and covered with a protective lipid layer. These organisms may survive therapy and then infect the ear again. Larger clumps of debris may remain in folds, middle ears and false middle ear cavities where they sequester organisms. Retained debris may also contain pro inflammatory material such as microbial byproducts and toxins as well as mediators released from inflammatory cells that may be present. Purulent exudates interfere with and bind to antibiotics such as polymyxin and aminoglycosides. Complete otoscopic examination with visualization of canal and tympanum pathology will often require cleaning. In some cases the use of a stronger topical agent or overuse of antibiotics can be prevented by regular intervals of ear cleaning, especially if disinfectants are included in the cleaning process. When progressive pathologic changes result in abnormal epithelial migration or folding in the canal lumen then cleaning will be required until this normal physiologic function returns. Cleaning of the ear canals is extremely important for the effective management of chronic otitis externa. Cleaning the ear canal is a lot like cleaning a skin fold lesion. With chronicity the lining of the ear canal is thrown into proliferative folds. Management of fold dermatitis requires surgical removal or keeping the skin folds clean. Without surgery successful control often requires keeping the skin folds clean indefinitely or until the ear canal normalizes and the folds are resolved. In chronic cases with otitis media this also includes cleaning the bulla or false middle ear.

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Researchers identify cell group key to Lyme disease arthritisDecember 3rd, 2008 in Medicine & Health / Medical research A research team led by the La Jolla Institute for Allergy & Immunology and Albany Medical College has illuminated the important role of natural killer (NK) T cells in Lyme disease, demonstrating that the once little understood white blood cells are central to clearing the bacterial infection and reducing the intensity and duration of arthritis associated with Lyme disease. "Our findings are that the NK T cells are critical to preventing the chronic inflammatory infection that causes Lyme arthritis and they participate in clearing the bacteria which cause it," said Mitchell Kronenberg, Ph.D., the La Jolla Institute's president & scientific director and co-senior author on the study, which used a mouse model of Lyme disease. Lyme disease is caused by Borrelia burgdorferi, a bacterium transmitted to humans by the bite of infected deer ticks. Typical symptoms include fever, headache, fatigue, and sometimes skin rashes. If left untreated, it can spread to the joints, the heart and the nervous system, and it can lead to serious health problems. Lyme disease currently is the most common vector (insect)-borne disease in the United States. "What this study demonstrates is that NK T cells are an important part of our defense against Lyme disease," said Timothy J. Sellati, Ph.D., an associate professor at Albany Medical College and co-senior author on the study. "This offers the possibility that we can exploit that knowledge therapeutically and potentially develop immunological agents that can trigger more NK T cells to aide in fighting this disease." Sellati added that "NK T cells alone cannot clear Lyme disease, but are a key part of a collective immune defense." The study's findings are outlined in a paper, "NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi," published this week in the online version of the journal Proceedings of the National Academy of Sciences. In an earlier study published in Nature Immunology, Kronenberg, Sellati and co-workers had shown that a glycolipid, a type of fat, found in the membrane of Borrelia burgdorferi triggered an immune response from the NK T cells. "We had found that if you gave that lipid to mice or humans, it would activate NK T cells," Kronenberg said. While this suggested the cells might play a significant role in Lyme disease, "we were missing in vivo (in the body) evidence showing that the NK T cells were activated following infection and were important for killing and clearing the Lyme disease bacteria," he said, noting that the latest study demonstrates this in an animal model. Sellati said the finding is particularly important because it opens new lines of investigation as to the causes of chronic Lyme disease. "That's what's so exciting when you identify a new cell type as playing a central role in preventing the disease process," he said. "So in those individuals who have a more severe form of the disease, you can study their NK T cells and see if there's some deficiency that prevents those NK T cells from killing and clearing the bacteria." In their studies, the researchers worked to model the natural route of Lyme disease infection as closely as possible. "The way people typically get Lyme disease is that they're out hiking and they get bitten by a deer tick," said Kronenberg. "So what we did in the lab was to get ticks infected with Borrelia burgdorferi from collaborators at the University of Connecticut Health Science Center and then used those ticks to infect mice in a confined and controlled environment." The researchers used one group of mice genetically engineered not to have NK T cells, while the control group had the cells. "The mice that didn't have NK T cells were not as capable of clearing the (Lyme disease) bacteria," Kronenberg said. "And they developed a chronic arthritis, while the control mice did not." He said the results were quite marked. "You could see under the microscope more numerous inflammatory cells in the joints of the mice that lacked the NK T cells weeks after infection." Discovered in the 1990s, NK T cells are disease-fighting white blood cells of the immune system whose inner workings are still being defined. While most T cells respond to foreign proteins to protect the body, NK T cells are unique in that they respond to glycolipids, which are natural biochemicals made of linked fat and sugar. Prized for initiating a fast and vigorous immune response, NK T cells are emerging as a subject of significant scientific interest because of their potential for fighting bacterial infections and cancer. Kronenberg and Sellati have been among the nation's leaders in studying these cells. Kronenberg's laboratory was among the first to identify bacteria which naturally induce an immune response from the NK T cells. Thus far, he has identified two such bacteria— Borrelia burgdorferi and Sphingomonas species, a fairly benign bacteria found throughout the environment. However, he believes many other types of bacteria may also trigger the NK T cells. "This is an exciting possibility that needs to be further explored as it could lead to the development of treatments for many bacterial diseases." Source: La Jolla Institute for Allergy and Immunology "Researchers identify cell group key to Lyme disease arthritis." December 3rd, 2008. http://phys.org/news147538659.html

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Leber's hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease affecting the optic nerve and often characterized by sudden vision loss in young adult carriers. Prevalence of the disease is not well known but is estimated at 1/15,000 - 1/50,000 people worldwide. Sudden, painless, acute or subacute central vision loss is often noted between the ages of 18 to 30. It affects both eyes simultaneously or sequentially with vision loss in the second eye occurring weeks to months after the first. Visual loss generally occurs subacutely (over a period of several weeks) and then stabilizes. However, many patients will continue to expand the size of their central scotoma which, over a period of years, produces a more profound level of blindness. Other neurological symptoms can also be present. These abnormalities are known as Leber ``plus'' (see this term), and include motor disorders, dystonia, postural tremor and cerebellar ataxia. LHON is caused by mutations in the mitochondrial DNA (mtDNA). Over 90% have been identified to occur at nucleotide positions 11778, 3460 or 14484. All produce defects in the mtDNA respiratory chain complex I subunit genes MT-ND1, MT-ND4 and MT-ND6. Since LHON is seen more frequently in males and not all individuals with these mtDNA mutations develop LHON (incomplete penetrance), other genetic or epigenetic factors may have an effect on the development of this disease. Diagnosis is based on an ophthalmoscopic examination. Swelling of the optic nerve head, vascular tortuosity, peripapillary telangiectasia, microangiopathy and central scotomas on visual field testing are all signs of LHON. An optical coherence tomography (OCT) scan confirms swelling of the retinal nerve fiber layer. Red-green dyschromatopsia during color vision testing and pseudopapilledema during fluorescein angiography are also observed. Snellen vision acuities of 20/200 or worse are typical. Optic neuritis, a common sign of multiple sclerosis (MS; see this term) is one of the first diseases to eliminate. Other genetic optic neuropathies such as Wolfram syndrome, and classic type autosomal dominant optic atrophy (see these terms) should also be excluded. Since LHON is a maternally-inherited disease, female carriers will pass the mutation to all their children but father carriers will not. The presence of a mutation can be found by genetic testing but does not imply that the disease will manifest itself. As of yet there is no cure for LHON. Low-vision aids are the primary supportive care offered to patients. Several compounds have shown positive results in recovering vision. Idebenone (granted an orphan drug designation for this disease in 2007), a synthetic analogue of coenzyme Q10, has resulted in visual improvement after one year. Third generation quinones are now being tested as well. It is important that patients refrain from alcohol, tobacco and certain antibiotics that also interfere with mitochondrial oxidative phosphorylation. The age of symptom onset (younger patients having a more favorable prognosis) and the causative mutation (patients with MT-ND6 mutations showing highest recovery rates) are factors that determine the disease outcome. Some patients, especially with the 14484 mutation, show spontaneous partial recovery 1-2 years after onset. In 30 to 50 % of male carriers and 80 to 90 % of women carriers, blindness will not ensue. Complete blindness (no light perception) is rare. While visual field improvement is usually incomplete, the recovery in visual acuity can be dramatic. - Pr Alfredo SADUN

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Researchers have identified the primary player of the biochemical bugle call that musters the body’s defenders against viral infection. Scientists at Washington University School of Medicine in St. Louis have shown that a key molecule, MDA5, is essential for producing enough interferon (the bugle call) to rally virus-fighting cells during certain viral infections. In mice, the lack of MDA5 forces the immune system to rely on less effective defenders, which may give the virus opportunities to establish or expand a chronic infection. Like the cavalry charge in classic movies, timing is critical in fighting a viral infection. If a surge of interferon comes early enough, the immune system can limit or clear a virus. If the boost is too late, though, the defenses may already be overwhelmed. “If an injection of interferon is given within a certain time frame in the infectious process, we found that it was possible to decrease viral spread and bolster antiviral CD8 T cell responses in our mouse model,” says first author Yaming Wang, a predoctoral trainee in immunobiology. “Adding interferon may also boost the power of antiviral vaccines that are being designed to help the immune system recognize and attack chronic viral infections such as HIV.” The research appears June 14 in Cell Host and Microbe. Viruses can cause both temporary and chronic infections. In chronic infections, the virus goes into periods of relative quiescence that limit its spread and diminish conflicts with the immune system. Those periods are often interrupted by flare-ups when the virus shifts gears and becomes more active again. Interferon, which is made by the body in many forms, is named for its ability to interfere with viral replication. It is currently used with antiviral medications to treat patients with hepatitis C who are having flare-ups. “Interferon puts cells into an antiviral state,” says senior author Marco Colonna, MD, professor of medicine and of pathology and immunology. “This prevents viruses from infecting cells or reproducing in them.” Some forms of interferon also summon critical immune CD8 T cells to infection sites, where the T cells either fight the infection directly or store information about the virus to speed recognition if it returns. Wang and his colleagues showed that MDA5 is the major source of interferon during a meningitis-type infection known as lymphocytic choriomeningitis virus. Interferon production by a specialized immune cell, the plasmacytoid dendritic cell, dropped off rapidly within the first day of infection, but MDA5 continued to boost interferon production for three to four days. Prolonging interferon production allows infection-fighting cells to stay in the battle longer, but also increases the risk that those same cells could cause autoimmune damage. The results suggest that timing and balance are critical, according to co-author Melissa Swiecki, PhD, a postdoctoral research associate. “As we consider the implications of these results for expanding or refining our use of interferon in the clinic, timing and magnitude are going to be the key words. Can we find ways to get patients interferon when they need it and in just the right amount?” Swiecki says. Colonna and his colleagues are planning follow-up studies in humans. Wang Y, Swiecki M, Cella M, Alber G, Schreiber RD, Gilfillan S, Colonna M. Timing and magnitude of type I interferon responses by distinct viral sensors impact CD8 T cell exhaustion and chronic infection. Cell Host and Microbe, June 14, 2012. from the National Heart, Lung, and Blood Institute (training grant 2T32HL007317-31); the National Institute of Diabetes and Digestive and Kidney Diseases (training grant 5T32DK007296); and the National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (grant A1067854) supported this Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

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|Structure - Activity Relationships| |Biochemical Mechanism of Action| Coumarin and its derivatives are principal oral anticoagulants. Coumarin is water insoluble, however 4-hydroxy substitution confers weakly acidic properties to the molecule that makes it water soluble under slightly alkaline conditions (Equation below). The structures of coumarin and its derivatives are as shown below. Warfarin is marketed as the sodium salt. It has one chiral center. The S(-) isomer is about 5 - 8 times more potent than the R(+) isomer, however, commercial warfarin is a racemic mixture. Click on the appropriate hyperlinks to visualize the three-dimensional structures of individual coumarins. Structure - Activity Relationships Coumarin and 4-hydroxycoumarin do not possess anticoagulant activity. Link, who pioneered the isolation and characterization of bihydroxycoumarin (dicoumarol) from sweet clover, concluded that the minimal requirements for anticoagulant activity are 4-hydroxy group, a 3-substituent, and a bis molecule (see below). Coumarins exert their effect in vivo only after a latent period of 12 to 4 hours and their effect lasts for 1.5 to 5 days. The observed slow onset may be due to the time required to decrease predrug prothrombin blood levels, whereas the long duration of action observed with warfarin may be due to the lag time required for the liver to resynthesize prothrombin to predrug blood levels. Coumarins and 1,3-indandiones (later section) interact with certain drugs. For example, the action of oral anticoagulants can be enhanced by drugs such as phyenylbutazone and salicylates while antagonized by barbiturates and vitamin K. Biochemical Mechanism of Action Coumarins are competitive inhibitors of vitamin K in the biosynthesis of prothrombin. The coagulation cascade relies on the conversion of prothrombin to thrombin in a very important step. However, this conversion depends on the presence of 10 g-carboxyglutamic acid (GLA) residues in the N-terminus of prothrombin. The multiple Gla residues form a binding site for Ca+2. Under normal circumstances 10 glutamic acid (Glu) residues of prothrombin are converted to Gla residues in a post-translational modification. This post-translation modification is catalyzed by an enzymes vitamin K reductase and vitamin K epoxide reductase. Vitamin K is a co-factor in this conversion reaction. Thus it cycles between a reduced form and an epoxide form. Because of their structural similarity with vitamin K coumarins are thought to bind the enzymes, vitamin K reductase and vitamin K epoxide reductase, without facilitating the conversion of Glu residues of prothrombin to Gla. Thus prothrombin cannot be acted upon by factor Xa. [top] [session home] [home] [department of medicinal chemistry] [school of pharmacy] ©2000 VCU School of Pharmacy Revised: January 5, 2000 Questions or Comments : Dr. Umesh R. Desai

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Volume 20, Number 4—April 2014 Contact Investigation for Imported Case of Middle East Respiratory Syndrome, Germany On March 19, 2013, a patient from United Arab Emirates who had severe respiratory infection was transferred to a hospital in Germany, 11 days after symptom onset. Infection with Middle East respiratory syndrome coronavirus (MERS-CoV) was suspected on March 21 and confirmed on March 23; the patient, who had contact with an ill camel shortly before symptom onset, died on March 26. A contact investigation was initiated to identify possible person-to-person transmission and assess infection control measures. Of 83 identified contacts, 81 were available for follow-up. Ten contacts experienced mild symptoms, but test results for respiratory and serum samples were negative for MERS-CoV. Serologic testing was done for 53 (75%) of 71 nonsymptomatic contacts; all results were negative. Among contacts, the use of FFP2/FFP3 face masks during aerosol exposure was more frequent after MERS-CoV infection was suspected than before. Infection control measures may have prevented nosocomial transmission of the virus. Middle East respiratory syndrome coronavirus (MERS-CoV) infection was initially reported to the World Health Organization (WHO) in September 2012 (1,2). By November 11, 2013, a total of 153 laboratory-confirmed cases of human infection with MERS-CoV had been identified; 64 (42%) of those with confirmed cases had died (3). Most (63%) case-patients had severe respiratory disease; 76% also had >1 underlying chronic condition (4). The median age of case-patients was 50 years (range 14 months to 94 years). All cases were directly or indirectly related to countries in the Middle East or on the Arabian Peninsula. MERS-CoV shows a close genetic relationship with coronaviruses found in bats (1,5–10), but no zoonotic link has been confirmed. Person-to-person transmission has been reported in the work environment, among family contacts, or to health care workers (HCWs) (11–13). Although situations involving consecutive human transmission events have been documented (13), none of the known clusters have led to sustained person-to-person transmission in the general population. In Europe, single imported infections have been reported in the United Kingdom, Germany, France, and Italy, and secondary cases have been reported in the United Kingdom, France, and Italy (12,14,15). Because a large proportion of cases are fatal and the virus could acquire the ability to spread more efficiently (as was the case with severe acute respiratory syndrome coronavirus), WHO has recommended thorough contact investigations for confirmed human cases to identify, quantify, and prevent person-to-person transmission (16). In Germany, MERS-CoV infection was initially reported in a person from Qatar (17). He was in his third week of illness and was already on mechanical ventilation when he was admitted to a hospital in Essen in October 2012. A retrospective contact investigation found no indication of person-to-person transmission to contacts in Germany (17). On March 23, 2013, the Institute for Virology of the University of Bonn reported an imported case of MERS-CoV infection to the Department of Health and Environment in Munich (City Health Department). A 73-year-old man from Abu Dhabi, United Arab Emirates, had been admitted to a hospital in Munich and had positive test results for MERS-CoV infection (Figure 1). Clinical details and virologic findings have been reported elsewhere (18). Briefly, the patient had underlying multiple myeloma and had received several modes of treatment, including high-dose chemotherapy and autologous stem-cell transplantation in 2009. On March 8, 2013, influenza-like illness with fever and cough developed in the patient. After his symptoms worsened, he was hospitalized in his country on March 10 with a diagnosis of pneumonia; he was intubated on March 17 and transferred by flight ambulance services to Germany on March 19, eleven days after illness onset, for further intensive care treatment and mechanical ventilation. General infection control guidelines of the Munich hospital required that patients from areas such as the Middle East, where prevalence of multidrug-resistant pathogens is high, be isolated until colonization or infection with a multidrug-resistant pathogen is ruled out. This rule is particularly enforced when patients have been previously hospitalized in the country of origin. Thus, at the time of hospital admission in Germany, the patient was isolated from other patients. When MERS-CoV infection was suspected and included in the differential diagnosis on March 21, standard hygiene measures for HCWs were changed to infection control measures as recommended for severe acute respiratory syndrome patients, including the use of FFP2 face masks for usual patient care (19). MERS-CoV infection was diagnosed in the patient on March 23; he died on March 26 of multiorgan failure and acute respiratory distress syndrome. After MERS-CoV infection was diagnosed, the City Health Department, in cooperation with the state health department, the Institute for Virology in Bonn, and the Robert Koch Institute, initiated an investigation to 1) monitor all contacts of the patient to identify possible person-to-person transmission, 2) assess infection control measures, and 3) explore possible sources for the patient’s infection to prevent further cases. For the investigation, the City Health Department assessed all contact persons (contacts) retrospectively and monitored them prospectively. All contacts received a questionnaire for retrospective documentation and prospective daily self-monitoring of symptoms, exposure to the patient, and infection control measures applied. For every day from March 19 through April 5, information was collected about the contacts’ distance from the patient (<2 meters vs. >2 meters); type of contact with the patient (aerosol-producing procedures, non–aerosol-producing procedures, care of patient, handling of urine catheter, handling of respiratory samples in the laboratory, handling of urine samples in the laboratory); type of protection used (surgical mask, FFP1 mask, FFP2 mask, FFP3 mask, gown, gloves, protective glasses); and symptoms experienced by the contacts (cough, fever, temperature, sore throat, diarrhea, shortness of breath). An aerosol-producing procedure was defined as respiratory suction, bronchoalveolar lavage, intubation, or bronchoscopy. On the basis of the self-reported information in the questionnaires and personal interviews with the contacts, we divided contacts into 2 groups. Close-distance contacts had face-to-face contact with the patient (<2 meters from the patient) or direct contact with secretions or body fluids of the patient, irrespective of protective measures worn. All other contacts were classified as less-close-distance contacts. According to WHO recommendations on the duration of follow-up at that time, close-distance contacts were asked to contact the City Health Department daily for 10 days after the last exposure to the patient. Those who failed to do so were contacted by the City Health Department, supported by the occupational health service of the hospital. Less-close-distance contacts were asked to report to the City Health Department only in case of onset of symptoms. Respiratory illnesses in contacts that occurred 1–10 days after exposure to the patient were assessed through the City Health Department by telephone contact with the contact; a respiratory tract sample was taken from any contact with respiratory illness. In addition, attempts were made to obtain paired serologic samples from all contacts, the first taken immediately after contact and the second >28 days after the last exposure. Because the MERS-CoV patient was on mechanical ventilation and could not be interviewed, family contacts who had accompanied him to Germany were interviewed about the onset of his symptoms and possible exposures in the 10 days before disease onset. For the interview, a structured questionnaire was used, and information collected was documented on paper. PCR testing and serologic testing were done as described (17,20). Serum samples from contacts were tested for MERS-CoV antibodies if a serum sample was taken >28 days after last exposure. In addition, serum samples were tested for antibodies against influenza A, B, and C; rhinovirus A, B, and C; parainfluenzavirus 1, 2, 3, and 4; respiratory syncytial virus A and B; human metapneumovirus; coronavirus 229E, NL63, OC43, and HKU1; and adenovirus. All samples were analyzed at the Institute for Virology of the University of Bonn. Data from the City Health Department’s contact monitoring, the contacts’ questionnaires, and the laboratory findings were integrated in 1 database. Results were validated and analyzed by using Stata version 12.0 (StataCorp, College Station, TX, USA). The City Health Department identified 83 contacts. Of these, 69 (83%) were classified as close-distance contacts and 14 (17%) as less-close-distance contacts (Table). Four (5%) of the contacts were members of the patient’s family, 16 (19%) were physicians, 25 (30%) were nursing staff, 20 (24%) were laboratory personnel, and 18 (22%) were part of other professional groups. Clinical follow-up was available for 81 (98%) contacts. A respiratory symptom or fever developed in 10 (12%) contacts. Of these, swab specimens were collected from 9 (90%) and blood samples from 7 (70%). All 9 swab specimens were negative for MERS-CoV; 1 (11%) was positive for CoV NL-63, and 2 (22%) were positive for rhinovirus. All 7 serum samples were negative for MERS-CoV antibodies. All symptomatic contacts had >1 sample type (respiratory swab or serum) collected for laboratory testing; results of PCR and serologic testing were available from 6 (60%), PCR only from 3 (30%), and serologic testing only from 1 (10%). In addition, serologic test results were available for 53 (75%) of the 71 nonsymptomatic contacts; all were negative for MERS-CoV antibodies. Overall, persons for whom serologic testing results were available were more likely to be close-distance contacts than were persons without available serologic results (p = 0.007; Table). The 4 family members who accompanied the patient were his wife, daughter, son, and son-in-law. Their ages were 35–37 years, and none reported symptoms. The patient’s children and son-in-law had their last contact with the patient on March 20 and his wife on March 23. Because no protection measures had been used until after March 20, the family members were considered at high risk for infection. All 4 provided respiratory swab and serum samples on March 24; all samples had negative results. Serum samples taken >28 days after last exposure to the patient were not available. MERS-CoV infection was added to the differential diagnosis for the patient on March 21. The daily numbers of HCWs who had any contact with him (regardless of protection measures) and of those who had aerosol exposure were lower after that date than before (Figure 2): 4.4 HCW per illness day vs. 7.5 HCW per illness day (p = 0.05) and 2.8 HCW per illness day vs. 6 HCW per illness day (p = 0.03). Among HCWs with aerosol exposure, 1 (8%) of 12 daily exposures occurred while FFP2 or FFP3 masks were being used before March 21; after that date, 11 (79%) of 14 daily exposures occurred while FFP2 or FFP3 masks were being used (p<0.01). The patient was a 73-year-old married man from Abu Dhabi, United Arab Emirates; he had a medical history of multiple myeloma. At the time of his MERS-CoV infection, he was receiving corticosteroid therapy. His profession was camel breeding; in the 2 weeks before his onset of illness, 1 of his camels was reported to have had a respiratory illness. In the questionnaire, we did not differentiate between dromedary (Camelus dromedaries) and Bactrian (C. bactrianus) camels. His neighborhood had palm trees, and bats were known to dwell in the area. The patient had no known contact with other MERS-CoV patients, had no personal contacts in Qatar or Jordan, and had no travel history in the 10 days before illness onset. He consumed different types of fruit juices and cooked goat meat, beef, and sheep meat, but no raw meat. He ate dates from his region, but he reportedly did not consume date or palm syrup. Other than the camels on his farm, he had no contact with animals; he did not practice falconry and did not visit camel racetracks or animal markets. We describe the case and contact investigation of a confirmed case of MERS-CoV infection that was imported to Germany. We did not identify person-to-person transmission from the patient to any of the contacts. As with the previous imported case in this country, the patient was already on mechanical ventilation when he was transferred to Germany. However, whereas the previous case was in the late third week of illness, this patient was in the second week of illness. Sample from this patient taken from different body locations and at different times were positive for MERS-CoV by PCR, and the viral load detected was several logs higher than in samples from the patient with the previous imported case (18,20). These results indicate that this patient may have been more infectious than the previous patient. Nosocomial transmission from MERS patients to HCWs has been documented (13,21,22). In our study, the patient was isolated during the first 2 days of his hospital stay (before MERS was suspected), although the reason for this intervention was the hospital’s policy to isolate every patient from the Middle East, irrespective of the assumed diagnosis, because of perceived increased risk of carrying drug-resistant pathogens, rather than any special measures taken because of the patient’s respiratory illness. After MERS was suspected, HCWs used FFP2 masks significantly more frequently than they had before, and fewer HCWs had daily contact with the patient. Our result suggest that, in the later stages of this disease, the combination of standard protection measures (use of surgical masks for potentially aerosol-generating procedures), cautious handling of the patient (because of his potential to harbor drug-resistant bacteria), and possible decreased infectiousness compared with the first week of illness may have prevented transmission to HCWs. These findings also underline the importance of following WHO recommendations on infection prevention and control when managing a patient who may be infected with a pathogen that could lead to nosocomial transmission (23). Regarding possible sources of infection, an extensive interview was conducted with family members because the patient could not be interviewed. The patient’s illness was likely a primary case, and possible exposures that might have caused the MERS-CoV infection were explored. Of note were the presence of bats in the neighborhood of his residence, the patient’s profession as camel breeder, and his contact with a camel that was reported to have had a respiratory illness before his own illness onset. Bats are a likely reservoir for MERS-related CoV (5,8), and serum samples from Omani racing camels have shown to have neutralizing antibodies against MERS-CoV (24). These findings suggest these animals’ possible relevance (e.g., as intermediate hosts) for human acquisition of MERS-CoV. Two complementary monitoring instruments for contact persons were used: active follow-up with daily telephone contact and a self-administered monitoring questionnaire. Both methods have merits, and a combination of both is likely to ensure the most thorough contact follow-up. Advantages of personal interviews on the telephone are immediacy and the possibility for the interviewer to receive intangible information, such as the self-assessment of symptoms, as well as the opportunity to answer questions from the contacts. This process enables a more specific way to judge a person’s health status. On the other hand, a daily monitoring questionnaire provides detail in clinical information, exposure, and protection measures that might be used for more in-depth analyses (e.g., when a few contacts have become infected). Such a questionnaire could be expanded to include a section for contact persons to fill in the names of persons with whom they had face-to-face contact during each day. This information might become crucial for second-generation contact tracing when contacts under observation become infected. Rapid availability of this type of information is essential for efficient investigation of clusters or outbreaks similar to those that have been reported already (13). In conclusion, we conducted a contact investigation of an imported case of MERS-CoV infection in Germany. Laboratory testing of symptomatic and asymptomatic contacts of the index case-patient did not indicate transmission of the virus. Furthermore, we documented the change from standard hygiene to infection control measures after MERS-CoV was suspected, an adaptation that may have prevented nosocomial transmission. Exposure to camels as a possible etiologic mechanism for human MERS-CoV infection requires further evidence from other studies. Dr Reuss is an epidemiologist at the Respiratory Infections Unit, Robert Koch Institute, Berlin, Germany. Her research interests include emerging infectious respiratory diseases, pandemic preparedness, and influenza vaccination. - Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814–20. - World Health Organization. Novel coronavirus infection in the United Kingdom. 2012 [cited 2013 Dec 18]. http://www.who.int/csr/don/2012_09_23/en/index.html - World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV)—update. 2013 Nov 11 [cited 2013 Dec 18]. http://www.who.int/csr/don/2013_11_11_coronavirus/en/index.html - The WHO. MeRS-Cov Research Group. State of knowledge and data gaps of Middle East respiratory syndrome coronavirus (MERS-CoV) in humans. PLoS Curr. 2013;5:••• . - Annan A, Baldwin HJ, Corman VM, Klose SM, Owusu M, Nkrumah EE, Human betacoronavirus 2c EMC/2012–related viruses in bats, Ghana and Europe. Emerg Infect Dis. 2013;19:456–9. - Anthony SJ, Ojeda-Flores R, Rico-Chavez O, Navarrete-Macias I, Zambrana-Torrelio CM, Rostal MK, Coronaviruses in bats from Mexico. J Gen Virol. 2013;94:1028–38. - Cotten M, Lam TT, Watson SJ, Palser AL, Petrova V, Grant P, Full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus. Emerg Infect Dis. 2013;19:736–42B. - Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR, Schoeman MC. Close relative of human Middle East respiratory syndrome coronavirus in bat, South Africa. Emerg Infect Dis. 2013;19:1697–9. - van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio. 2012;3:e00473–12. - Wacharapluesadee S, Sintunawa C, Kaewpom T, Khongnomnan K, Olival KJ, Epstein JH, Group C betacoronavirus in bat guano fertilizer, Thailand. Emerg Infect Dis. 2013;19:1349–51. - World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV)–update. 2013 Jun 5 [cited 2013 Dec 18]. http://www.who.int/csr/don/2013_06_05/en/index.html - Health Protection Agency (HPA) UK Novel Coronavirus Investigation Team. Evidence of person-to-person transmission within a family cluster of novel coronavirus infections, United Kingdom, February 2013. Euro Surveill. 2013;18:20427 . - Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DA, Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013;369:407–16. - Guery B, Poissy J, el Mansouf L, Sejourne C, Ettahar N, Lemaire X, Clinical features and viral diagnosis of two cases of infection with Middle East respiratory syndrome coronavirus: a report of nosocomial transmission. Lancet. 2013;381:2265–72. - Puzelli S, Azzi A, Santini MG, Di Martino A, Facchini M, Castrucci MR, Investigation of an imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in Florence, Italy, May to June 2013. Euro Surveill. 2013;18:20564 . - World Health Organization. Interim surveillance recommendations for human infection with Middle East respiratory syndrome coronavirus. 2013 [cited 2013 Dec 18]. http://www.who.int/csr/disease/coronavirus_infections/InterimRevisedSurveillanceRecommendations_nCoVinfection_27Jun13.pdf - Buchholz U, Muller MA, Nitsche A, Sanewski A, Wevering N, Bauer-Balci T, Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October–November 2012. Euro Surveill. 2013;18:20406 . - Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. Lancet Infect Dis. 2013;13:745–51. - Robert Koch Institute. Empfehlungen des Robert Koch-Institutes für die hygienemaßnahmen und infektionskontrolle bei patienten mit schwerem akutem respiratorischem syndrom (SARS). 2003 [cited 2013 Dec 18]. http://www.rki.de - Corman VM, Muller MA, Costabel U, Timm J, Binger T, Meyer B, Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill. 2012;17:20334. - European Center for Disease Prevention and Control. Updated rapid risk assessment: severe respiratory disease associated with Middle East respiratory syndrome coronavirus (MERS-CoV). 2013 [cited 2013 Dec 18]. http://www.ecdc.europa.eu/en/publications/Publications/MERS-CoV-novel-coronavirus-risk-assessment.pdf - Memish ZA, Zumla AI, Assiri A. Middle East respiratory syndrome coronavirus infections in health care workers. N Engl J Med. 2013;369:884–6. - World Health Organization. Infection prevention and control of epidemic- and pandemic-prone acute respiratory diseases in health care. WHO Interim Guidelines. 2007 [cited 2013 Dec 18]. http://www.who.int/csr/resources/publications/WHO_CDS_EPR_2007_6c.pdf - Reusken CBEM, Haagmans BL, Müller MA, Gutierrez C, Godeke G-J, Meyer B, Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis. 2013;13:859–66. Suggested citation for this article: Reuss A, Litterst A, Drosten C, Seilmaier M, Böhmer M, Graf P, et al. Contact investigation for imported case of Middle East respiratory syndrome, Germany. Emerg Infect Dis [Internet]. 2014 Apr [date cited]. http://dx.doi.org/10.3201/eid2004.131375 1Postgraduate Training for Applied Epidemiology, Robert Koch Institute, Berlin, Germany, associated with European Programme for Intervention Epidemiology Training, European Centre for Disease Prevention and Control, Stockholm, Sweden. - Page created: March 12, 2014 - Page last updated: March 12, 2014 - Page last reviewed: March 12, 2014 - Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) Office of the Director (OD)

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Riboflavin transporter deficiency (RTD) is a progressive motor neuron disorder characterized by respiratory insufficiency, sensorineural deafness and progressive ponto-bulbar palsy. 80 cases have been reported in the literature to date. RTD onset may occur from infancy through adolescence. Childhood and adolescent presentation with bulbar palsy and muscle weakness is often preceded by sensorineural deafness; some patients are reported to remain free of additional symptoms after the onset of deafness for weeks, others for a decade. Patients presenting at a young age (before age 4) often present with respiratory compromise due to diaphragmatic paralysis and demonstrate a very rapid progression. Bulbar palsy manifests with facial weakness, ptosis and reduced horizontal eye movements, dysphagia and slurred speech. Motor neuron limb signs may be displayed as adducted shoulders sloping asymmetrically with winging scapula, ankle contractures and abnormally sharp deep tendon reflexes. Gait alteration may also be observed. Retinitis pigmentosa and macular hyperpigmentation have been reported in some cases. Autonomic dysfunction (reported in 7% of late-onset cases), tremor (8%) and epilepsy (4%) have been reported. Mutations in SLC52A2 (8q24.3) and SLC52A3 (20p13, previously known as C20orf54) have been linked to RTD. These two genes, along with SLC52A1, encode putative riboflavin transporter proteins; their role in the nervous system has yet to be elucidated. Neuronal loss in the motor nuclei of the cranial nerves, situated at the level of the spinal bulb and degeneration of the anterior horn cells of the spinal cord is described in childhood onset cases. Mutational analysis of all three riboflavin transporter genes may be performed. Abnormalities in plasma flavin levels and abnormalities in the acylcarnitine profile have been observed in some but not in all patients, protein levels of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) may be reduced. Amyotrophic lateral sclerosis, Joubert syndrome, Madras motor neuron disease and Nathalie syndrome (see these terms) share many symptoms with RTD. Glutaric acidemia type 2 (see this term) may resemble early-onset RTD, however laboratory analyses revealing dicarboxylic glutaric, and ethylmalonic aciduria and suberylglycine with very low carnitine levels in plasma exclude RTD. Inheritance is autosomal recessive. Symptomatic treatment must be addressed promptly in early onset cases: assisted ventilation, tracheostomy when necessary, and maintenance of nutrition via gastrostomy may be required. As some symptoms may be irreversible, daily administration of riboflavin (10 mg/kg per day in 3 doses) should be started prior to definitive diagnosis. Regular clinical evaluation during the course of treatment must be accompanied by neurological examination and testing of cranial nerves, hearing tests, electrocardiograms and ultrasound studies of the diaphragm. Progression is highly variable, life expectancy in untreated patients presenting before age 4 is less than 1 year with 85% mortality, untreated patients presenting during childhood (4-10 years) and adolescence (11-17 years) fare better (53% and 19% mortality respectively) and have a life-expectancy of over 10 years post-onset. The disorder becomes generalized leading to hypotonia, amyotrophy and progressive paralysis; respiratory insufficiency is the cause of death. Riboflavin treatment has yielded significant clinical improvement in all but one patient treated to date. Long-term studies are ongoing. Last update: May 2013

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Telomere and Telomerase Researchers hope to determine if the DNA is shortened in your body and determine if there is an increase in the protein that shortens DNA called telomerase. |Study Design:||Observational Model: Case-Only Time Perspective: Cross-Sectional |Official Title:||Telomere and Telomerase| - Identification and resolution of telomere dysfunction-induced focus (TIF) and normalization of telomerase activity [ Time Frame: up to 24 weeks ] [ Designated as safety issue: No ] Advancing myelodysplasia is associated with progressive telomere attrition and clonal chromosomal evolution. Based on this hypothesis, we expect to see identification of TIF by immunostaining and increase in Telomerase activity in peripheral blood granulocytes of patients with advanced Myelodysplastic Syndrome (MDS) and acute myeloid leukemia. We also expect to see resolution of TIF and normalization of telomerase activity upon treatment. Biospecimen Retention: Samples With DNA Two teaspoons of blood will be collected - one teaspoon before subject begins treatment for disease and one teaspoon will be collected when subject completes treatment. |Study Start Date:||September 2010| |Study Completion Date:||February 2011| |Primary Completion Date:||February 2011 (Final data collection date for primary outcome measure)| advanced Myelodysplastic Syndrome or acute myeloid leukemia advanced MDS and AML with/without associated cytogenetic abnormality Genetic: Blood sample Blood samples will be collected before and after treatment completion. A telomere is a region of repetitive DNA at the end of chromosomes, which protects the end of the chromosome from destruction. Telomeres can be viewed as the tips on the ends of shoelaces that keep them from unraveling. Telomeres compensate for incomplete semi-conservative DNA replication at chromosomal ends. In absence of a reparative process, DNA sequences would be lost in every replicative phase until they reached a critical level, at which point cell division would stop. Loss of telomeres leads to chromosome end-to-end fusion, chromosome re-arrangements, and genome instability. Telomerase is a "ribonucleoprotein complex" composed of a protein component and an RNA primer sequence which acts to protect the terminal ends of chromosomes. Telomerase is the natural enzyme which promotes telomere repair. It is however not active in most cells. It certainly is active though in stem cells, germ cells, hair follicles and in 90 percent of cancer cells. Telomerase functions by adding bases to the ends of the telomeres. As a result of this telomerase activity, these cells seem to possess a kind of immortality. Progressive shortening or attrition of telomere length with consequent genomic instability leading to cancer has been described in various hematological malignancies including acute and chronic myeloid leukemia. Reduced telomere length has been documented in patients with the progressive BM failure syndrome called Dyskeratosis Congenita. Abnormalities in these patients include skin pigmentation, nail dystrophy and leukoplakia. Mutations in the telomere maintenance mechanism have been implicated in the pathogenesis of this heterogeneous condition. Myelodysplastic syndrome is an acquired clonal stem cell disorder characterized by in-effective hematopoiesis, increased intra-medullary apoptosis and peripheral cytopenia. A number of such patients will eventually develop worsening cytopenia evolving into acute myeloid leukemia. A number of studies have investigated telomerase activity and telomere length in patients with MDS and AML. Telomere shortening was significantly more pronounced in patients with cytogenetic alterations as compared to patients with normal karyotypes. Genomic instability develops with progressive telomere shortening. The Telomere attrition related genome instability is a stress that leads to up-regulation of specified DNA damage foci. These telomere-associated DNA damage points are often called as Telomere Dysfunction-Induced Focus (TIF). Please refer to this study by its ClinicalTrials.gov identifier: NCT01176422 |United States, Kansas| |University of Kansas Medical Center, Westwood Campus| |Westwood, Kansas, United States, 66205| |Principal Investigator:||Siddhartha Ganguly, MD||University of Kansas Medical Center|

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Back around 2002, I noted that the genetic code appears to funnel one of the most common base pair substitutions, the C-to-T transitions caused by deamination of the cytosine. Put simply, codons containing a C specified a wide range of amino acids, but when that C is converted to T, the new set of codons all converge on the most hydrophobic amino acids. The original analysis is found here. To see this for yourself, the figure below represents a hydrophobicity scale for the 20 amino acids based on 47 published attempts to quantify hydrophobicity: Now consider the effect of cytosine deamination using this scale: Scale on left are the amino acids coded for by C-containing codons which is converted to scale on right by the deamination of those cytosines. But what if we did the same analysis, but this time restrict our focus to the cytosines that are followed by guanines – the CpG sequences discussed here, given that such sequence is the most likely to exploit the effects of deamination? Scale on left are the amino acids coded for by CG-containing codons which is converted to scale on right by the deamination of those cytosines. Codons that all ended with C followed by a G ((–C)G) are excluded since all such base pair substitutions are silent. Whoa. The IHE effect has been tightened up. Is this just a coincidental relationship? Consider if we looked at the same changes using something known as the OMH scale. As this paper explained (see Figure A.1C.3), “the OMH scale (Sweet and Eisenberg, 1983) is a measure of how likely a given amino acid will be replaced by a different hydrophobic or “buried” amino acid in a protein. In effect, this scale is how evolution views the hydrophobicity of an amino acid.” The green box shows the amino acids coded for by CG-containing codons which is converted to the set in the red box by the deamination of those cytosines. Is this just a coincidental relationship? Remember, as this paper notes, “Methylated cytosines can easily be converted to thymine residues via deamination and this mutational process has the highest rate among all base substitutions.”

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Amniotic fluid is an important part of pregnancy and fetal development. This watery fluid is inside a casing called the amniotic membrane (or sac) and fluid surrounds the fetus throughout pregnancy. Normal amounts may vary, but, generally, women carry about 500 to 1000 ml of amniotic fluid. Amniotic fluid helps protect and cushion the fetus and plays an important role in the development of many of the fetal organs including the lungs, kidneys, and gastrointestinal tract. Fluid is produced by the fetal lungs and kidneys. It is taken up with fetal swallowing and sent across the placenta to the mother's circulation. Too much or too little amniotic fluid is associated with abnormalities in development and pregnancy complications. Differences in the amount of fluid may be the cause or the result of the problem. Hydramnios is a condition in which there is too much amniotic fluid around the fetus. It occurs in about 1 percent of all pregnancies. It is also called polyhydramnios. There are several causes of hydramnios. Generally, either too much fluid is being produced or there is a problem with the fluid being taken up, or both. Factors that are associated with hydramnios include the following: Gastrointestinal abnormalities that block the passage of fluid Abnormal swallowing due to problems with the central nervous system or chromosomal abnormalities Twin-to-twin transfusion syndrome Congenital infection (acquired in pregnancy) Too much amniotic fluid can cause the mother's uterus to become overdistended and may lead to preterm labor or premature rupture of membranes (the amniotic sac). Hydramnios is also associated with birth defects in the fetus. When the amniotic sac ruptures, large amounts of fluid leaving the uterus may increase the risk of placental abruption (early detachment of the placenta) or umbilical cord prolapse (when the cord falls down through the cervical opening) where it may be compressed. The following are the most common symptoms of hydramnios. However, each woman may experience symptoms differently. Symptoms may include: Rapid growth of uterus Discomfort in the abdomen The symptoms of hydramnios may resemble other medical conditions. Always consult your doctor for a diagnosis. In addition to a complete medical history and a physical examination, hydramnios is usually diagnosed with ultrasound (a test using sound waves to create a picture of internal structures) by measuring pockets of fluid to estimate the total volume. In some cases, ultrasound is also helpful in finding a cause of hydramnios, such as multiple pregnancy or a birth defect. Specific treatment for hydramnios will be determined by your doctor based on: Your pregnancy, overall health, and medical history Extent of the condition Your tolerance for specific medications, procedures, or therapies Expectations for the course of the condition Your opinion or preference Treatment for hydramnios may include: Cosely monitoring the amount of amniotic fluid and frequent follow-up visits with the physician Medication (to decrease fetal urine production) Amnioreduction--amniocentesis (inserting a needle through the uterus and into the amniotic sac) to remove some of the amniotic fluid; this procedure may need to be repeated. Delivery (if complications endanger the well-being of the fetus or mother, then an early delivery may be necessary) The goal of treatment is to relieve the mother's discomfort and continue the pregnancy. Oligohydramnios is a condition in which there is too little amniotic fluid around the fetus. It occurs in about 4 percent of all pregnancies. There are several causes of oligohydramnios. Generally, it is caused by conditions that prevent or reduce amniotic fluid production. Factors that are associated with oligohydramnios include the following: Premature rupture of membranes (before labor) Intrauterine growth restriction (poor fetal growth) Birth defects, especially kidney and urinary tract malformations Amniotic fluid is important in the development of fetal organs, especially the lungs. Too little fluid for long periods may cause abnormal or incomplete development of the lungs called pulmonary hypoplasia. Intrauterine growth restriction (poor fetal growth) is also associated with decreased amounts of amniotic fluid. Oligohydramnios may be a complication at delivery, increasing the risk for compression of the umbilical cord and aspiration of thick meconium (baby's first bowel movement). The following are the most common symptoms of oligohydramnios. However, each woman may experience symptoms differently. Symptoms may include: Leaking of amniotic fluid when the cause is rupture of the amniotic sac Decreased amount of amniotic fluid on ultrasound The symptoms of the oligohydramnios may resemble other medical conditions. Always consult your doctor for a diagnosis. In addition to a complete medical history and physical examination, a diagnosis is usually made using ultrasound. Pockets of amniotic fluid can be measured and the total amount estimated. Ultrasound can also show fetal growth, the structure of the kidneys and urinary tract, and detect urine in the fetal bladder. Doppler flow studies (a type of ultrasound used to measure blood flow) may be used to check the arteries in the kidneys, and the blood flow through the placenta. Specific treatment for oligohydramnios will be determined by your doctor based on: Treatment for oligohydramnios may include: Closely monitoring the amount of amniotic fluid and frequent follow-up visits with the doctor Amnioinfusion--instilling a special fluid into the amniotic sac to replace lost or low levels of amniotic fluid. Amnioinfusion may be given in a woman in labor whose membranes have ruptured. Amnioinfusion will not be given if the woman is not in labor. Delivery (if oligohydramnios endangers the well-being of the fetus, then an early delivery may be necessary)

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This information is for reference purposes only. It was current when produced and may now be outdated. Archive material is no longer maintained, and some links may not work. Persons with disabilities having difficulty accessing this information should contact us at: https://info.ahrq.gov. Let us know the nature of the problem, the Web address of what you want, and your contact information. Please go to www.ahrq.gov for current information. Azithromycin is the most cost-effective option for preventing a common, serious infection among AIDS patients Azithromycin is the most cost-effective medication to prevent the common, serious disseminated infection, Mycobacterium avium complex (MAC), among AIDS patients if begun when their CD4 cell count has declined to 50/ul, concludes a new study. This is the point at which so-called opportunistic infections like MAC and cytomegalovirus (CMV) attack these patients' weakened immune systems and reduce their survival chances. Researchers from Johns Hopkins School of Public Health, Yale School of Medicine, Harvard School of Public Health, and Boston University's Schools of Medicine and Public Health developed a simulation model in which one hypothetical patient at a time was followed from a CD4 lymphocyte cell count between 201 and 300/ul to death. Using several AIDS databases and clinical trial results, they projected costs, life expectancy, and cost-effectiveness of five different drug regimens to prevent MAC in patients with AIDS: initial therapy with azithromycin, rifabutin, clarithromycin, azithromycin/ rifabutin combination therapy, and clarithromycin/rifabutin combination therapy. Initiating azithromycin prophylaxis (and changing to clarithromycin and then rifabutin if needed because of drug toxicity) after a patient's CD4 count had fallen to 50/ul was the best option. It had a cost-effectiveness ratio of $25,000 per quality-adjusted life year (QALY) saved compared with only using prophylaxis for Pneumocystis carinii pneumonia (PCP) and decreased to $21,000 per QALY if the risk of MAC was lower, as appears to be the case with currently used combination antiretroviral therapy. Overall, baseline results suggest that it would cost $4.3 billion to care for 100,000 patients with AIDS from a CD4 count of 300/ul to death, if PCP prophylaxis were the only prophylaxis used. An additional $89 million would buy azithromycin prophylaxis for MAC, which would increase survival by about 3,600 years for the entire group. This research was supported by the Agency for Healthcare Research and Quality (HS07317). Details are in "The cost-effectiveness of prophylaxis for Mycobacterium avium complex in AIDS," by Julie A. Scharfstein, A. David Paltiel, Milton C. Weinstein, Elena Losina, Kenneth A. Freedberg, and others, in the International Journal of Technology Assessment in Health Care 15(3), pp. 531-547, 1999. Return to Contents Proceed to Next Article

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- Tourette syndrome Name = Tourette syndrome Georges Gilles de la Tourette ICD10 = F95.2 ICD9 = 307.23 MedlinePlus = 000733 eMedicineSubj = med eMedicineTopic = 3107 eMedicine_mult = eMedicine2|neuro|664 DiseasesDB = 5220 OMIM = 137580 MeshID = D005879 Tourette syndrome (also called Tourette's syndrome, Tourette's disorder, Gilles de la Tourette syndrome, GTS or, more commonly, simply Tourette's or TS) is an inherited neuropsychiatric disorder with onset in childhood, characterized by the presence of multiple physical (motor) tics and at least one vocal (phonic) tic; these tics characteristically wax and wane. Tourette's is defined as part of a spectrum of tic disorders, which includes transient and chronic tics. Tourette's was once considered a rare and bizarre syndrome, most often associated with the exclamation of obscene words or socially inappropriate and derogatory remarks ( coprolalia). However, this symptom is present in only a small minority of people with Tourette's.Schapiro NA. "Dude, you don't have Tourette's:" Tourette's syndrome, beyond the tics. "Pediatr Nurs." 2002 May–Jun;28(3):243–6, 249–53. PMID 12087644 [http://www.medscape.com/viewarticle/442029 Full text (free registration required).] ] Tourette's is no longer considered a rare condition, but it may not always be correctly identified because most cases are classified as mild. Between 1 and 10 children per 1,000 have Tourette's;Lombroso PJ, Scahill L. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17937978 "Tourette syndrome and obsessive-compulsive disorder".] "Brain Dev". 2008 Apr;30(4):231–7. PMID 17937978] as many as 10 per 1,000 people may have tic disorders,Scahill L, Williams S, Schwab-Stone M, Applegate J, Leckman JF. "Disruptive behavior problems in a community sample of children with tic disorders". "Adv Neurol." 2006;99:184–90. PMID 16536365] with the more common tics of eye blinking, coughing, throat clearing, sniffing, and facial movements. People with Tourette's have normal life expectancyand intelligence. The severity of the tics decreases for most children as they pass through adolescence, and extreme Tourette's in adulthood is a rarity. Notable individuals with Tourette's are found in all walks of life. [ [http://www.tsa-usa.org/People/LivingWithTS/LivingTS.htm Portraits of adults with TS.] Tourette Syndrome Association. Retrieved on January 4, 2007.] Genetic and environmental factors each play a role in the etiologyof Tourette's, but the exact causes are unknown. In most cases, medication is unnecessary. There is no effective medication for every case of tics, but there are medications and therapies that can help when their use is warranted. Explanation and reassurance alone are often sufficient treatment;Zinner (2000).] education is an important part of any treatment plan. [Peterson BS, Cohen DJ. "The treatment of Tourette's Syndrome: multimodal, developmental intervention". "J Clin Psychiatry." 1998;59 Suppl 1:62–72; discussion 73–4. PMID 9448671. Quote: "Because of the understanding and hope that it provides, education is also the single most important treatment modality that we have in TS."] eponymwas bestowed by Jean-Martin Charcot(1825–93) on behalf of his resident, Georges Albert Édouard Brutus Gilles de la Tourette (1859–1904), a French physician and neurologist, who published an account of nine patients with Tourette's in 1885. Tics are sudden, repetitive, stereotyped, nonrhythmic movements (motor tics) and utterances (phonic tics) that involve discrete muscle groups.Leckman JF, Bloch MH, King RA, Scahill L. "Phenomenology of tics and natural history of tic disorders". "Adv Neurol." 2006;99:1–16. PMID 16536348] Motor tics are movement-based tics, while phonic tics are involuntary sounds produced by moving air through the nose, mouth, or throat. Tourette's is one of several tic disorders, which are classified by the " Diagnostic and Statistical Manual of Mental Disorders" (DSM) according to type (motor or phonic tics) and duration (transient or chronic). Transient tic disorder consists of multiple motor tics, phonic tics or both, with a duration between four weeks and twelve months. Chronic tic disorder is either single or multiple, motor or phonic tics (but not both), which are present for more than a year. Tourette's is diagnosed when multiple motor tics, and at least one phonic tic, are present for more than a year. American Psychiatric Association(2000). [http://www.mindsite.com/dsm_iv/tourette_s_disorder "Diagnostic criteria for 307.23 Tourette's Disorder".] "Diagnostic and Statistical Manual of Mental Disorders", 4th ed., text revision ( DSM-IV-TR), ISBN 0890420254. Retrieved on July 22, 2008.] Tic disorders are defined similarly by the World Health Organization(International Statistical Classification of Diseases and Related Health Problems, ICD-10codes). [ [http://www.who.int/classifications/apps/icd/icd10online/?gf90.htm+f950 ICD Version 2006.] World Health Organization. Retrieved on October 25, 2006.] Although Tourette's is the more severe expression of the spectrum of tic disorders,Bagheri, Kerbeshian & Burd (1999).] most cases are mild. [http://web.archive.org/web/20060524115004/http://www.tsa-usa.org/what_is/whatists.html What is Tourette syndrome?] Tourette Syndrome Association. Archived May 24, 2006.] The severity of symptoms varies widely among people with Tourette's, and mild cases may be undetected. Tics are movements or sounds "that occur intermittently and unpredictably out of a background of normal motor activity",The Tourette Syndrome Classification Study Group. [http://web.archive.org/web/20060426232033/http://www.tsa-usa.org/research/definitions.html "Definitions and classification of tic disorders".] "Arch Neurol." 1993 Oct;50(10):1013–16. PMID 8215958 Archived April 26, 2006.] having the appearance of "normal behaviors gone wrong".Dure LS 4th, DeWolfe J. "Treatment of tics". "Adv Neurol." 2006;99:191–96. PMID 16536366] The tics associated with Tourette's constantly change in number, frequency, severity and anatomical location. Waxing and waning—the ongoing increase and decrease in severity and frequency of tics—occurs differently in each individual. Tics also occur in "bouts of bouts", which vary for each person. Coprolalia(the spontaneous utterance of socially objectionable or taboo words or phrases) is the most publicized symptom of Tourette's, but it is not required for a diagnosis of Tourette's. According to the Tourette Syndrome Association, fewer than 15% of Tourette's patients exhibit coprolalia. [http://web.archive.org/web/20060106020124/http://www.tsa-usa.org/what_is/Faqs.html Tourette Syndrome: Frequently Asked Questions.] Tourette Syndrome Association. Archived January 6, 2006.] Echolalia(repeating the words of others) and palilalia(repeating one's own words) occur in a minority of cases, while the most common initial motor and vocal tics are, respectively, eye blinking and throat clearing. [Malone DA Jr, Pandya MM. "Behavioral neurosurgery". "Adv Neurol." 2006;99:241–47. PMID 16536372] In contrast to the abnormal movements of other movement disorders (for example, choreas, dystonias, myoclonus, and dyskinesias), the tics of Tourette's are stereotypic, temporarily suppressible, nonrhythmic, and often preceded by a premonitory urge. [Jankovic J. "Differential diagnosis and etiology of tics". "Adv Neurol." 2001;85:15–29. PMID 11530424] Immediately preceding tic onset, most individuals with Tourette's are aware of an urge [Cohen AJ, Leckman JF. "Sensory phenomena associated with Gilles de la Tourette's syndrome". "J Clin Psychiatry". 1992 Sep;53(9):319–23. PMID 1517194] Prado HS, Rosário MC, Lee J, Hounie AG, Shavitt RG, Miguel EC. [http://cnsspectrums.com/aspx/article_pf.aspx?articleid=1540 "Sensory phenomena in obsessive-compulsive disorder and tic disorders: a review of the literature".] "CNS Spectr." 2008;13(5):425–32. PMID 18496480. Retrieved on May 31, 2008.] that is similar to the need to sneeze or scratch an itch. Individuals describe the need to tic as a buildup of tension, pressure, or energyBliss J. "Sensory experiences of Gilles de la Tourette syndrome". "Arch Gen Psychiatry". 1980 Dec;37(12):1343–47. PMID 6934713 ] which they consciously choose to release, as if they "had to do it"Kwak C, Dat Vuong K, Jankovic J. "Premonitory sensory phenomenon in Tourette's syndrome". "Mov Disord". 2003 Dec;18(12):1530–33. PMID 14673893] to relieve the sensation or until it feels "just right". Examples of the premonitory urge are the feeling of having something in one's throat, or a localized discomfort in the shoulders, leading to the need to clear one's throat or shrug the shoulders. The actual tic may be felt as relieving this tension or sensation, similar to scratching an itch. Another example is blinking to relieve an uncomfortable sensation in the eye. These urges and sensations, preceding the expression of the movement or vocalization as a tic, are referred to as "premonitory sensory phenomena". Published descriptions of the tics of Tourette's identify sensory phenomena as the core symptomof the syndrome, even though they are not included in the diagnostic criteria. [Scahill LD, Leckman JF, Marek KL. "Sensory phenomena in Tourette's syndrome". "Adv Neurol". 1995;65:273–80. PMID 7872145] [Miguel EC, do Rosario-Campos MC, Prado HS, "et al." "Sensory phenomena in obsessive-compulsive disorder and Tourette's disorder". "J Clin Psychiatry". 2000 Feb;61(2):150–56. PMID 10732667] Tics are described as semi-voluntary or "unvoluntary"," because they are not strictly "involuntary"—they may be experienced as a "voluntary" response to the unwanted, premonitory urge. A unique aspect of tics, relative to other movement disorders, is that they are suppressible yet irresistible; they are experienced as an irresistible urge that must eventually be expressed. People with Tourette's are sometimes able to suppress their tics to some extent for limited periods of time, but doing so often results in an explosion of tics afterward. People with Tourette's may seek a secluded spot to release their symptoms, or there may be a marked increase in tics, after a period of suppression at school or at work. Some people with Tourette's may not be aware of the premonitory urge. Children may be less aware of the premonitory urge associated with tics than are adults, but their awareness tends to increase with maturity. They may have tics for several years before becoming aware of premonitory urges. Children may suppress tics while in the doctor's office, so they may need to be observed while they are not aware they are being watched.Black, KJ. [http://www.emedicine.com/neuro/topic664.htm Tourette Syndrome and Other Tic Disorders.] "eMedicine" (March 22, 2006). Retrieved on June 27, 2006.] The ability to suppress tics varies among individuals, and may be more developed in adults than children. Although there is no such thing as a "typical" case of Tourette syndrome, the condition follows a fairly reliable course in terms of the age of onset and the history of the severity of symptoms. Tics may appear up to the age of eighteen, but the most typical age of onset is from five to seven. A 1998 study published by Leckman "et al" of the Yale Child Study CenterLeckman JF, Zhang H, Vitale A, "et al." [http://childpsych.columbia.edu/brainimaging/PDF/PD10298.pdf "Course of tic severity in Tourette syndrome: the first two decades"] (PDF). "Pediatrics". 1998;102 (1 Pt 1):14–19. PMID 9651407. Retrieved on October 28, 2006.] showed that the ages of highest tic severity are eight to twelve (average ten), with tics steadily declining for most patients as they pass through adolescence. The most common, first-presenting tics are eye blinking, facial movements, sniffing and throat clearing. Initial tics present most frequently in midline body regions where there are many muscles, usually the head, neck and facial region. This can be contrasted with the stereotyped movements of other disorders (such as stims and stereotypies of the autism spectrum disorders), which typically have an earlier age of onset, are more symmetrical, rhythmical and bilateral, and involve the extremities (e.g., flapping the hands).Rapin I. "Autism spectrum disorders: relevance to Tourette syndrome". "Adv Neurol." 2001;85:89–101. PMID 11530449] Tics that appear early in the course of the condition are frequently confused with other conditions, such as allergies, asthma, and vision problems: pediatricians, allergists and ophthalmologists are typically the first to see a child with tics. Among patients whose symptoms are severe enough to warrant referral to clinics, obsessive-compulsive disorder(OCD) and attention-deficit hyperactivity disorder(ADHD) are often associated with Tourette's. Not all persons with Tourette's have ADHD or OCD or other comorbidconditions (co-occurring diagnoses other than Tourette's), although in clinical populations, a high percentage of patients presenting for care do have ADHD.Spencer T, Biederman J, Harding M, "et al." "Disentangling the overlap between Tourette's disorder and ADHD". "J Child Psychol Psychiatry". 1998 Oct;39(7):1037–44. PMID 9804036] One author reports that a ten-year overview of patient records revealed about 40% of patients with Tourette's have "TS-only" or "pure TS", referring to Tourette syndrome in the absence of ADHD, OCD and other disorders.Denckla MB. "Attention-deficit hyperactivity disorder (ADHD) comorbidity: a case for "pure" Tourette syndrome?" "J Child Neurol". 2006 Aug;21(8):701–3. PMID 16970871] Denckla MB. "Attention deficit hyperactivity disorder: the childhood co-morbidity that most influences the disability burden in Tourette syndrome". "Adv Neurol." 2006;99:17–21. PMID 16536349] Another author reports that 57% of 656 patients presenting with tic disorders had uncomplicated tics, while 43% had tics plus comorbid conditions. "Full-blown Tourette's" is a term used to describe patients who have significant comorbid conditions in addition to tics. The exact cause of Tourette's is unknown, but it is well established that both genetic and environmental factors are involved.Walkup JT, Mink JW, Hollenback PJ, (eds). "Advances in Neurology, Vol. 99, Tourette Syndrome." Lippincott, Williams & Wilkins, Philadelphia, PA, 2006, p. xv. ISBN 0-7817-9970-8] Genetic studies have shown that the overwhelming majority of cases of Tourette's are inherited, although the exact mode of inheritance is not yet known, [Robertson MM (2000), p. 425.] and no gene has been identified. In some cases, tics may not be inherited; these cases are identified as "sporadic" Tourette syndrome (also known as tourettism) because a genetic link is missing.Mejia NI, Jankovic J. [http://www.scielo.br/pdf/rbp/v27n1/23707.pdf "Secondary tics and tourettism"] (PDF). "Rev Bras Psiquiatr". 2005;27(1):11–17. PMID 15867978] A person with Tourette's has about a 50% chance of passing the gene(s) to one of his or her children, but Tourette's is a condition of variable expression and incomplete penetrance. [van de Wetering BJ, Heutink P. "The genetics of the Gilles de la Tourette syndrome: a review". "J Lab Clin Med." 1993 May;121(5):638–45. PMID 8478592] Thus, not everyone who inherits the genetic vulnerability will show symptoms; even close family members may show different severities of symptoms, or no symptoms at all. The gene(s) may express as Tourette's, as a milder tic disorder (transient or chronic tics), or as obsessive compulsive symptoms without tics. Only a minority of the children who inherit the gene(s) have symptoms severe enough to require medical attention. Gender appears to have a role in the expression of the genetic vulnerability: males are more likely than females to express tics. Non-genetic, environmental, infectious, or psychosocialfactors—while not causing Tourette's—can influence its severity. Autoimmuneprocesses may affect tic onset and exacerbation in some cases. In 1998, a team at the National Institute of Mental Healthproposed a hypothesis that both obsessive-compulsive disorder (OCD) and tic disorders may arise in a subset of children as a result of a poststreptococcal autoimmune process. [Swedo SE, Leonard HL, Garvey M, "et al". [http://ajp.psychiatryonline.org/cgi/reprint/155/2/264 "Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases"] (PDF). "Am J Psychiatry." 1998 Feb;155(2):264–71. PMID 9464208 Retrieved on September 11, 2007.] Children who meet five diagnostic criteria are classified, according to the hypothesis, as having Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections ( PANDAS). [http://intramural.nimh.nih.gov/pdn/web.htm PANDAS.] NIH. Retrieved on November 25, 2006.] This contentious hypothesis is the focus of clinical and laboratory research, but remains unproven.Swerdlow, NR. "Tourette Syndrome: Current Controversies and the Battlefield Landscape". "Curr Neurol Neurosci Rep". 2005, 5:329–31. PMID 16131414] [Kurlan R, Kaplan EL. [http://pediatrics.aappublications.org/cgi/reprint/113/4/883.pdf "The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms: hypothesis or entity? Practical considerations for the clinician"] (PDF). "Pediatrics." 2004 Apr;113(4):883–86. PMID 15060240 Retrieved on January 25, 2007.] The exact mechanism affecting the inherited vulnerability to Tourette's has not been established, and the precise etiology is unknown. Tics are believed to result from dysfunction in cortical and subcortical regions, the thalamus, basal gangliaand frontal cortex. Neuroanatomic models implicate failures in circuits connecting the brain's cortex and subcortex, and imaging techniques implicate the basal ganglia and frontal cortex. [Haber SN, Wolfer D. "Basal ganglia peptidergic staining in Tourette syndrome. A follow-up study". "Adv Neurol". 1992;58:145–50. PMID 1414617 * Peterson B, Riddle MA, "et al." "Reduced basal ganglia volumes in Tourette's syndrome using three-dimensional reconstruction techniques from magnetic resonance images". "Neurology". 1993;43:941–49. PMID 8492950 * Moriarty J, Varma AR, "et al." "A volumetric MRI study of Gilles de la Tourette's syndrome". "Neurology". 1997;49:410–5. PMID 9270569] Some forms of OCD may be genetically linked to Tourette's. [Pauls DL, Towbin KE, Leckman JF, "et al." "Gilles de la Tourette's syndrome and obsessive-compulsive disorder. Evidence supporting a genetic relationship". "Arch Gen Psychiatry". 1986 Dec;43(12):1180–82. PMID 3465280] A subset of OCD is thought to be etiologically related to Tourette's and may be a different expression of the same factors that are important for the expression of tics. [Miguel EC, do Rosario-Campos MC, Shavitt RG, "et al." "The tic-related obsessive-compulsive disorder phenotype and treatment implications". "Adv Neurol." 2001;85:43–55. PMID 11530446] The genetic relationship of ADHD to Tourette syndrome, however, has not been fully established. According to the revised fourth edition of the "Diagnostic and Statistical Manual of Mental Disorders" ( DSM-IV-TR), Tourette’s Disorder may be diagnosed when a person exhibits both multiple motor and one or more vocal tics (although these do not need to be concurrent) over the period of a year, with no more than three consecutive tic-free months. The previous DSM-IV included a requirement for "marked distress or significant impairment in social, occupational or other important areas of functioning", but this requirement was removed in the most recent update of the manual, in recognition that clinicians see patients who meet all the other criteria for Tourette's, but do not have distress or impairment. [ [http://dsmivtr.org/2-3changes.cfm Summary of Practice: Relevant changes to DSM-IV-TR.] "Diagnostic and Statistical Manual of Mental Disorders." Retrieved on January 25, 2007.] The onset must have occurred before the age of 18, and cannot be attributed to the "direct physiological effects of a substance or a general medical condition". Hence, other medical conditions that include tics or tic-like movements—such as autismor other causes of tourettism—must be ruled out before conferring a Tourette's diagnosis. There are no specific medical or screening tests that can be used in diagnosing Tourette's;Swain JE, Scahill L, Lombroso PJ, King RA, Leckman JF. "Tourette syndrome and tic disorders: a decade of progress". "J Am Acad Child Adolesc Psychiatry". 2007 Aug;46(8):947–68 PMID 17667475 ] it is frequently misdiagnosed or underdiagnosed, partly because of the wide expression of severity, ranging from mild (the majority of cases) or moderate, to severe (the rare, but more widely-recognized and publicized cases).The diagnosis is made based on observation of the individual's symptoms and family history, and after ruling out secondary causes of tic disorders. In patients with a typical onset and a family history of tics or obsessive–compulsive disorder, a basic physical and neurological examination may be sufficient. If a physician believes that there may be another condition present that could explain tics, tests may be ordered as necessary to rule out that condition. An example of this is when diagnostic confusion between tics and seizureactivity exists, which would call for an EEG, or if there are symptoms that indicate an MRIto rule out brain abnormalities.Scahill L, Erenberg G, Berlin CM Jr, Budman C, Coffey BJ, Jankovic J, Kiessling L, King RA, Kurlan R, Lang A, Mink J, Murphy T, Zinner S, Walkup J; Tourette Syndrome Association Medical Advisory Board: Practice Committee. "Contemporary assessment and pharmacotherapy of Tourette syndrome". "NeuroRx." 2006 Apr;3(2):192–206. PMID 16554257] TSH levels can be measured to rule out hypothyroidism, which can be a cause of tics. Brain imagingstudies are not usually warranted. In teenagers and adults presenting with a sudden onset of tics and other behavioral symptoms, a urine drug screen for cocaineand stimulantsmight be necessary. If a family history of liver diseaseis present, serum copper and ceruloplasminlevels can rule out Wilson's disease. However, most cases are diagnosed by merely observing a history of tics. Secondary causes of tics (not related to inherited Tourette syndrome) are commonly referred to as tourettism. Dystonias, choreas, other genetic conditions, and secondary causes of tics should be ruled out in the differential diagnosisfor Tourette syndrome. Other conditions that may manifest tics or stereotyped movements include developmental disorders, autism spectrum disorders, [Ringman JM, Jankovic J. "Occurrence of tics in Asperger's syndrome and autistic disorder". "J Child Neurol." 2000 Jun;15(6):394–400. PMID 10868783] and stereotypic movement disorder; [Jankovic J, Mejia NI. "Tics associated with other disorders". "Adv Neurol." 2006;99:61–8. PMID 16536352] Freeman, RD. [http://www.tourette-confusion.blogspot.com/ Tourette's Syndrome: minimizing confusion] . Roger Freeman, MD, blog. Retrieved on February 8, 2006.] Sydenham's chorea; idiopathicdystonia; and genetic conditions such as Huntington's disease, neuroacanthocytosis, Hallervorden-Spatz syndrome, Duchenne muscular dystrophy, Wilson's disease, and tuberous sclerosis. Other possibilities include chromosomal disorders such as Down syndrome, Klinefelter's syndrome, XYY syndromeand fragile X syndrome. Acquired causes of tics include drug-induced tics, head trauma, encephalitis, stroke, and carbon monoxide poisoning. The symptoms of Lesch-Nyhan syndromemay also be confused with Tourette syndrome. Most of these conditions are rarer than tic disorders, and a thorough history and examination may be enough to rule them out, without medical or screening tests. Although not all people with Tourette's have comorbid conditions, most Tourette's patients presenting for clinical care at specialty referral centers may exhibit symptoms of other conditions along with their motor and phonic tics. Associated conditions include attention-deficit hyperactivity disorder (ADD or ADHD), obsessive–compulsive disorder (OCD), learning disabilitiesand sleep disorders. [http://www.ninds.nih.gov/disorders/tourette/detail_tourette.htm Tourette Syndrome Fact Sheet] . National Institute of Neurological Disorders and Stroke/ National Institutes of Health(NINDS/NIH), February 14, 2007. Retrieved on May 14, 2007.] Disruptive behaviors, impaired functioning, or cognitiveimpairment in patients with comorbid Tourette's and ADHD may be accounted for by the comorbid ADHD, highlighting the importance of identifying and treating comorbid conditions. [Sukhodolsky DG, Scahill L, Zhang H, "et al." "Disruptive behavior in children with Tourette's syndrome: association with ADHD comorbidity, tic severity, and functional impairment". "J Am Acad Child Adolesc Psychiatry". 2003 Jan;42(1):98–105. PMID 12500082 * Hoekstra PJ, Steenhuis MP, Troost PW, "et al." "Relative contribution of attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and tic severity to social and behavioral problems in tic disorders". "J Dev Behav Pediatr". 2004 Aug;25(4):272–79. PMID 15308928 * Carter AS, O'Donnell DA, Schultz RT, "et al." "Social and emotional adjustment in children affected with Gilles de la Tourette's syndrome: associations with ADHD and family functioning. Attention Deficit Hyperactivity Disorder". "J Child Psychol Psychiatry". 2000 Feb;41(2):215–23. PMID 10750547] Disruption from tics is commonly overshadowed by comorbid conditions that present greater interference to the child. Tic disorders in the absence of ADHD do not appear to be associated with disruptive behavior or functional impairment, while impairment in school, family, or peer relations is greater in patients who have more comorbid conditions and often determines whether therapy is needed. Because comorbid conditions such as OCD and ADHD can be more impairing than tics, these conditions are included in an evaluation of patients presenting with tics. "It is critical to note that the comorbid conditions may determine functional status more strongly than the tic disorder," according to Samuel Zinner, MD. The initial assessment of a patient referred for a tic disorder should include a thorough evaluation, including a family history of tics, ADHD, obsessive–compulsive symptoms, and other chronic medical, psychiatric and neurological conditions. Children and adolescents with TS who have learning difficulties are candidates for psychoeducational testing, particularly if the child also has ADHD. Undiagnosed comorbid conditions may result in functional impairment, and it is necessary to identify and treat these conditions to improve functioning. Complications may include depression, sleep problems, social discomfort and self-injury. The treatment of Tourette's focuses on identifying and helping the individual manage the most troubling or impairing symptoms. Most cases of Tourette's are mild, and do not require pharmacological treatment; instead, psychobehavioral therapy, education, and reassurance may be sufficient. [Robertson MM, (2000), p. 435.] Treatments, where warranted, can be divided into those that target tics and comorbid conditions, which, when present, are often a larger source of impairment than the tics themselves. Not all people with tics have comorbid conditions, but when those conditions are present, they often take treatment priority. There is no cure for Tourette's and no medication that works universally for all individuals without significant adverse effects. Knowledge, education and understanding are uppermost in management plans for tic disorders. The management of the symptoms of Tourette's may include pharmacological, behavioral and psychological therapies. While pharmacological intervention is reserved for more severe symptoms, other treatments (such as supportive psychotherapy or cognitive behavioral therapy) may help to avoid or ameliorate depression and social isolation, and to improve family support. Educating a patient, family, and surrounding community (such as friends, school, and church) is a key treatment strategy, and may be all that is required in mild cases.Stern JS, Burza S, Robertson MM. "Gilles de la Tourette's syndrome and its impact in the UK". "Postgraduate Medicine Journal." 2005 Jan;81(951):12–9. PMID 15640424 ] (Luvox)—may be prescribed when a Tourette's patient also has symptoms of obsessive–compulsive disorder. Because children with tics often present to physicians when their tics are most severe, and because of the waxing and waning nature of tics, it is recommended that medication not be started immediately or changed often. Frequently, the tics subside with explanation, reassurance, understanding of the condition and a supportive environment. When medication is used, the goal is not to eliminate symptoms: it should be used at the lowest possible dose that manages symptoms without adverse effects, given that these may be more disturbing than the symptoms for which they were prescribed. Cognitive behavioral therapy(CBT) is a useful treatment when OCD is present, [Coffey BJ, Shechter RL. "Treatment of co-morbid obsessive compulsive disorder, mood, and anxiety disorders". "Adv Neurol." 2006;99:208–21. PMID 16536368] and there is increasing evidence supporting the use of habit reversal in the treatment of tics. [Himle MB, Woods DW, Piacentini JC, Walkup JT. "Brief review of habit reversal training for tourette syndrome". "J Child Neurol." 2006 Aug;21(8):719–25. PMID 16970874] Relaxation techniques, such as exercise, yoga or meditation, may be useful in relieving the stress that may aggravate tics, but the majority of behavioral interventions (such as relaxation training and biofeedback, with the exception of habit reversal) have not been systematically evaluated and are not empirically supported therapies for Tourette's. [Woods DW, Himle MB, Conelea CA. "Behavior therapy: other interventions for tic disorders". "Adv Neurol." 2006;99:234–40. PMID 16536371] Tourette syndrome is a spectrum disorder—its severity ranges over a spectrum from mild to severe. The majority of cases are mild and require no treatment. In these cases, the impact of symptoms on the individual may be mild, to the extent that casual observers might not know of their condition. The overall prognosis is positive, but a minority of children with Tourette syndrome have severe symptoms that persist into adulthood.Walkup JT, Mink JW, Hollenback PJ, (eds). "Advances in Neurology, Vol. 99, Tourette Syndrome." Lippincott, Williams & Wilkins, Philadelphia, PA, 2006, p. xv.] A study of 46 subjects at 19 years of age found that the symptoms of 80% had minimum to mild impact on their overall functioning, and that the other 20% experienced at least a moderate impact on their overall functioning. The rare minority of severe cases can inhibit or prevent individuals from holding a job or having a fulfilling social life. In a follow-up study of thirty-one adults with Tourette's, all patients completed high school, 52% finished at least two years of college, and 71% were full-time employed or were pursuing higher education.Pappert EJ, Goetz CG, Louis ED, "et al." "Objective assessments of longitudinal outcome in Gilles de la Tourette's syndrome." "Neurology." 2003 Oct 14;61(7):936–40. PMID 14557563] Regardless of symptom severity, individuals with Tourette's can expect to live a normal life span. Although the symptoms may be lifelong and chronic for some, the condition is not degenerative or life-threatening. Intelligence is normal in those with Tourette's, although there may be learning disabilities. There is no reliable means of predicting the outcome for a particular individual. The gene or genes associated with Tourette's have not been identified, and there is no potential "cure". Several studies have demonstrated that the condition in most children improves with maturity. Tics may be at their highest severity at the time that they are diagnosed, and often improve with understanding of the condition by individuals and their families and friends. The statistical age of highest tic severity is typically between eight and twelve, with most individuals experiencing steadily declining tic severity as they pass through adolescence. One study showed no correlation with tic severity and the onset of puberty, in contrast with the popular belief that tics increase at puberty. In many cases, a complete remission of tic symptoms occurs after adolescence. [Burd L, Kerbeshian PJ, Barth A, "et al." "Long-term follow-up of an epidemiologically defined cohort of patients with Tourette syndrome". "J Child Neurol". 2001;16(6):431–37. PMID 11417610] However, a study using videotape to record tics in adults found that, although tics diminished in comparison with childhood, and all measures of tic severity improved by adulthood, 90% of adults still had tics. Half of the adults who considered themselves tic-free still displayed evidence of tics. It is not uncommon for the parents of affected children to be unaware that they, too, may have had tics as children. Because Tourette's tends to subside with maturity, and because milder cases of Tourette's are now more likely to be recognized, the first realization that a parent had tics as a child may not come until their offspring is diagnosed. It is not uncommon for several members of a family to be diagnosed together, as parents bringing children to a physician for an evaluation of tics become aware that they, too, had tics as a child. Children with Tourette's may suffer socially if their tics are viewed as "bizarre". If a child has disabling tics, or tics that interfere with social or academic functioning, supportive psychotherapyor school accommodations can be helpful. Because comorbidconditions (such as ADHD or OCD) can cause greater impact on overall functioning than tics, a thorough evaluation for comorbidity is called for when symptoms and impairment warrant. A supportive environment and family generally gives those with Tourette's the skills to manage the disorder. [Leckman & Cohen (1999), p. 37. "For example, individuals who were misunderstood and punished at home and at school for their tics or who were teased mercilessly by peers and stigmatized by their communities will fare worse than a child whose interpersonal environment was more understanding and supportive."] [Cohen DJ, Leckman JF, Pauls D. "Neuropsychiatric disorders of childhood: Tourette’s syndrome as a model". "Acta Paediatr Suppl" 422; 106–11, Scandinavian University Press, 1997. "The individuals with TS who do the best, we believe, are: those who have been able to feel relatively good about themselves and remain close to their families; those who have the capacity for humor and for friendship; those who are less burdened by troubles with attention and behavior, particularly aggression; and those who have not had development derailed by medication."] People with Tourette's may learn to camouflage socially inappropriate tics or to channel the energy of their tics into a functional endeavor. Accomplished musicians, athletes, public speakers, and professionals from all walks of life are found among people with Tourette's. Outcomes in adulthood are associated more with the perceived significance of having severe tics as a child than with the actual severity of the tics. A person who was misunderstood, punished, or teased at home or at school will fare worse than children who enjoyed an understanding and supportive environment. A study of eight children, age 8–17, found that children with Tourette syndrome were quicker at processing certain mental grammar skills than are children without the condition. The abnormalities that lead to tics may also lead to "other rapid behaviors, including the cognitive processing of rule-governed forms in language and other types of procedural knowledge". [Walenski M, Mostofsky SH, Ullman MT. "Speeded processing of grammar and tool knowledge in Tourette's syndrome". "Neuropsychologia" 2007;45(11):2447–2460. DOI|10.1016/j.neuropsychologia.2007.04.001] Tourette syndrome is found among all social, racial and ethnic groups, [Robertson MM, (2000), p. 427.] has been reported in all parts of the world,Robertson MM (August 1, 2005). "Tourette syndrome". "Psychiatry" 4 (8): 92–97. DOI|10.1383/psyt.2005.4.8.92] and is three to four times more frequent among males than among females. [Bagheri, Kerbeshian and Burd (1999) report that TS is "three to nine times more frequent in males than in females". Zinner (2000) says, "Data from most studies suggest ... [a] male:female ratio typically ranging from 2:1 to 4:1." Leckman & Cohen (1999), p. 180, Table 10.1 report a range based on six studies of 1.6:1 to 9.3:1 male:female ratio. Robertson, MM (2000), p. 427 says, "TS is ... three to four times more common in males (Robertson, 1989, 1994; Staley "et al"., 1997; Tanner and Goldman, 1997; Robertson and Baron-Cohen, 1998)", reflecting the most commonly reported ratio (3:1 to 4:1) from the Tourette Syndrome Association. What is Tourette syndrome? and the National Institute of Neurological Disorders and Stroke/ National Institutes of Health(NINDS/NIH) Tourette Syndrome Fact Sheet.] The tics of Tourette syndrome begin in childhood and tend to remit or subside with maturity; thus, a diagnosis may no longer be warranted for many adults, and prevalenceis much higher among children than adults. Children are five to twelve times more likely than adults to be identified as having tic disorders; [Leckman JF, Peterson BS, Pauls DL, Cohen DJ. "Tic disorders". "Psychiatr Clin North Am." 1997 Dec;20(4):839–61. PMID 9443353] as many as 1 in 100 people experience tic disorders, including chronic tics and transient tics in childhood. Discrepancies across current and prior prevalence estimates come from several factors: ascertainment biasin earlier samples drawn from clinically referred cases, assessment methods that may fail to detect milder cases, and differences in diagnostic criteria and thresholds.Scahill, L. "Epidemiology of Tic Disorders". "Medical Letter: 2004 Retrospective Summary of TS Literature." Tourette Syndrome Association. The [http://www.tsa-usa.org/Medical/images/MedLetr2004_M114g_pg1.pdf first page] (PDF), is available without subscription. Retrieved on June 11, 2007.] There were few broad-based community studies published before 2000 and until the 1980s, most epidemiological studies of Tourette syndrome were based on individuals referred to tertiary careor specialty clinics. [Zohar AH, Apter A, King RA "et al." "Epidemiological studies". In J.F. Leckman & D.J. Cohen (Eds.), "Tourette's syndrome – tics, obsessions, compulsions: Developmental psychopathology and clinical care" (pp. 177–92). Wiley & Sons, 1999. ISBN 0-471-16037-7 ] Children with milder symptoms are unlikely to be referred to specialty clinics, so these studies have an inherent bias towards more severe cases. [Coffey BJ, Park KS. "Behavioral and emotional aspects of Tourette syndrome". "Neurol Clin." 1997 May;15(2):277–89. PMID 9115461] Studies of Tourette syndrome are vulnerable to error because tics vary in intensity and expression, are often intermittent, and are not always recognized by clinicians, patients, family members, friends or teachers;Soliman, E. [http://www.emedicine.com/med/topic3107.htm Tourette Syndrome.] "eMedicine" (August 5, 2005). Retrieved on June 28, 2006.] approximately 20% of persons with Tourette syndrome do not recognize that they have tics. Recent studies—recognizing that tics may often be undiagnosed and hard to detect—use direct classroom observation and multiple informants (parent, teacher, and trained observers), and therefore record more cases than older studies relying on referrals.Leckman JF. "Tourette's syndrome". "Lancet". 2002 Nov 16;360(9345):1577–86. PMID 12443611] As the diagnostic threshold and assessment methodology have moved towards recognition of milder cases, the result is an increase in estimated prevalence. Tourette syndrome was once thought to be rare: in 1972, the US National Institutes of Health(NIH) believed there were fewer than 100 cases in the United States, [Cohen DJ, Jankovic J, Goetz CG, (eds). "Advances in neurology, Vol. 85, Tourette syndrome." Lippincott, Williams & Wilkins, Philadelphia, PA, 2001, p. xviii. ISBN 0-7817-2405-8] and a 1973 registry reported only 485 cases worldwide. [Abuzzahab FE, Anderson FO. "Gilles de la Tourette's syndrome; international registry". "Minnesota Medicine". 1973 Jun;56(6):492–6. PMID 4514275] However, multiple studies published since 2000 have consistently demonstrated that the prevalence is much higher than previously thought. [Scahill, L. "Epidemiology of Tic Disorders". "Medical Letter: 2004 Retrospective Summary of TS Literature." Tourette Syndrome Association. The [http://www.tsa-usa.org/Medical/images/MedLetr2004_M114g_pg1.pdf first page] (PDF), is available without subscription. Retrieved on June 11, 2007. * Kadesjö B, Gillberg C. "Tourette's disorder: epidemiology and comorbidity in primary school children". "J Am Acad Child Adolesc Psychiatry". 2000 May;39(5):548–55. PMID 10802971 * Kurlan R, McDermott MP, Deeley C, "et al." "Prevalence of tics in schoolchildren and association with placement in special education". "Neurology". 2001 Oct 23;57(8):1383–8. PMID 11673576 * Khalifa N, von Knorring AL. "Prevalence of tic disorders and Tourette syndrome in a Swedish school population". "Dev Med Child Neurol". 2003 May;45(5):315–19. PMID 12729145 * Hornsey H, Banerjee S, Zeitlin H, Robertson M. "The prevalence of Tourette syndrome in 13–14-year-olds in mainstream schools". "J Child Psychol Psychiatry". 2001 Nov;42(8):1035–39. PMID 11806685] The emerging consensus is that 1–10 children per 1,000 have Tourette's, with several studies supporting a tighter range of 6–8 children per 1,000. Using year 2000 census data, a prevalence range of 1–10 per 1,000 yields an estimate of 53,000–530,000 school-age children with Tourette's in the US and a prevalence range of 6–10 per 1,000 means that 64,000–106,000 children aged 5–18 years may have Tourette's in the UK. Most of these children are undiagnosed and have mild symptoms without distress or impairment. History and research directions A French doctor, Jean Marc Gaspard Itard, reported the first case of Tourette syndrome in 1825, [Itard JMG. "Mémoire sur quelques functions involontaires des appareils de la locomotion, de la préhension et de la voix". "Arch Gen Med." 1825;8:385–407. From Newman, Sara. "Study of several involuntary functions of the apparatus of movement, gripping, and voice" by Jean-Marc Gaspard Itard (1825) "History of Psychiatry". 2006 17: 333–39. DOI|10.1177/0957154X06067668] describing Marquise de Dampierre, an important woman of nobility in her time. Jean-Martin Charcot, an influential French physician, assigned his resident Georges Albert Édouard Brutus Gilles de la Tourette, a French physician and neurologist, to study patients at the Salpêtrière Hospital, with the goal of defining an illness distinct from hysteriaand from chorea. In 1885, Gilles de la Tourette published an account of nine patients, "Study of a Nervous Affliction", concluding that a new clinical category should be defined. [Gilles de la Tourette G, Goetz CG, Llawans HL, trans. "Étude sur une affection nerveuse caractérisée par de l'incoordination motrice accompagnée d'echolalie et de coprolalie". In: Friedhoff AJ, Chase TN, eds. "Advances in Neurology: Volume 35. Gilles de la Tourette syndrome." New York: Raven Press; 1982;1–16. Discussed at Black, KJ. [http://www.emedicine.com/neuro/topic664.htm Tourette Syndrome and Other Tic Disorders.] "eMedicine" (March 22, 2006). Retrieved on June 27, 2006. [http://www.bium.univ-paris5.fr/histmed/medica/cote?epo0383 Original text (in French).] Retrieved on January 25, 2007.] The eponym was later bestowed by Charcot after and on behalf of Gilles de la Tourette. [Enersen, Ole Daniel. [http://www.whonamedit.com/doctor.cfm/357.html Georges Albert Édouard Brutus Gilles de la Tourette.] WhoNamedIt.com Retrieved on May 14, 2007.] Little progress was made over the next century in explaining or treating tics, and a psychogenic view prevailed well into the 20th century. The possibility that movement disorders, including Tourette syndrome, might have an organic origin was raised when an encephalitis epidemicfrom 1918–1926 led to a subsequent epidemic of tic disorders.Blue, Tina. [http://ri.essortment.com/tourettesyndrom_rnkl.htm Tourette syndrome.] "Essortment " 2002. Pagewise Inc. Retrieved on May 14, 2007.] During the 1960s and 1970s, as the beneficial effects of haloperidol(Haldol) on tics became known, the psychoanalytic approach to Tourette syndrome was questioned. [Rickards H, Hartley N, Robertson MM. "Seignot's paper on the treatment of Tourette's syndrome with haloperidol. Classic Text No. 31". "Hist Psychiatry." 1997 Sep;8 (31 Pt 3):433–36. PMID 11619589] The turning point came in 1965, when Arthur K. Shapiro—described as "the father of modern tic disorder research" [Gadow KD, Sverd J. "Attention deficit hyperactivity disorder, chronic tic disorder, and methylphenidate". "Adv Neurol." 2006;99:197–207. PMID 16536367] —treated a Tourette’s patient with haloperidol, and published a paper criticizing the psychoanalytic approach. Since the 1990s, a more neutral view of Tourette's has emerged, in which biological vulnerability and adverse environmental events are seen to interact. In 2000, the American Psychiatric Associationpublished the DSM-IV-TR, revising the text of DSM-IV to no longer require that symptoms of tic disorders cause distress or impair functioning. [ [http://www.psychnet-uk.com/dsm_iv/_misc/what_is_dsm_iv_tr.htm What is DSM-IV-TR?] Psychnet-UK. Retrieved on May 14, 2007.] Findings since 1999 have advanced TS science in the areas of genetics, neuroimaging, neurophysiology, and neuropathology. Questions remain regarding how best to classify Tourette syndrome, and how closely Tourette's is related to other movement disorders or psychiatric disorders. Good epidemiologicdata is still lacking, and available treatments are not risk free and not always well tolerated.Walkup JT, Mink JW, Hollenback PJ, (eds). (2006) pp. xvi–xviii] High-profile media coverage focuses on treatments that do not have established safety or efficacy, such as deep brain stimulation, and alternative therapies involving unstudied efficacy and side effects are pursued by many parents. ociety and culture Not everyone with Tourette's wants treatment or a "cure", especially if that means they may "lose" something else in the process. [Sacks, O (1985). "". Harper and Row, New York, pp. 92–100. ISBN 0-684-85394-9] Leckman & Cohen (1999), p. 408. ISBN 0-471-16037-7 ] Some people believe that there may be latent advantages associated with genetic vulnerability to the syndrome. There is evidence to support the clinical lore that children with "TS-only" (Tourette's in the absence of comorbidconditions) are unusually gifted: neuropsychological studies have identified advantages in children with TS-only. [Schuerholz LJ, Baumgardner TL, Singer HS, "et al." "Neuropsychological status of children with Tourette's syndrome with and without attention deficit hyperactivity disorder". "Neurology." 1996 Apr;46(4):958–65. PMID 8780072] One study found that children with TS-only are faster than the average for their age group on timed motor coordination. [Schuerholz LJ, Cutting L, Mazzocco MM, "et al." "Neuromotor functioning in children with Tourette syndrome with and without attention deficit hyperactivity disorder". "J Child Neurol." 1997 Oct;12(7):438–42. PMID 9373800] Notable individuals with Tourette syndrome are found in all walks of life, including musicians, athletes and authors. The best-known example of a person who may have used obsessive–compulsive traits to advantage is Dr Samuel Johnson, the 18th-century English man of letters, who had Tourette syndrome as clearly evidenced by the writings of James Boswell. [ [http://web.archive.org/web/20050407083830/http://www.tsa-usa.org/what_is/johnson.html Samuel Johnson.] Tourette Syndrome Association. Archived April 7, 2005.] [Pearce JM. [http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1294650&blobtype=pdf "Doctor Samuel Johnson: 'the great convulsionary' a victim of Gilles de la Tourette's syndrome"] (PDF). "Journal of the Royal Society of Medicine". 1994 Jul;87(7):396–9. PMID 8046726] Johnson wrote " A Dictionary of the English Language" in 1747, and was a prolific writer, poet, and critic. Although it has been speculated that Mozart had Tourette's,Simkin, Benjamin. "Medical and Musical Byways of Mozartiana." Fithian Press, 2001. ISBN 1-56474-349-7 [http://www.danielpublishing.com/books/suppl/simkin.html Review,] Retrieved on May 14, 2007. * Simkin B. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1286388 "Mozart's scatological disorder".] "BMJ". 1992 Dec 19–26;305(6868):1563–7. PMID 1286388] [http://web.archive.org/web/20050407060420/http://www.tsa-usa.org/what_is/Mozart.html Did Mozart really have TS?] Tourette Syndrome Association. Archived April 7, 2005.] no Tourette's expert or organization has presented credible evidence to show that this was the case, and there are problems with the available data. [Kammer T. [http://www.uni-ulm.de/~tkammer/pdf/Kammer_2007_Mozart_preprint.pdf "Mozart in the neurological department—who has the tic?"] (PDF). "Front Neurol Neurosci." 2007;22:184–92. PMID 17495512 DOI|10.1159/0000102880 Retrieved on September 10, 2007 * Ashoori A, Jankovic J. "Mozart's movements and behaviour: a case of Tourette's syndrome?" "J Neurol Neurosurg Psychiatry". 2007 Nov;78(11):1171–5 DOI|10.1136/jnnp.2007.114520 PMID 17940168. * Sacks O. "Tourette's syndrome and creativity". "BMJ." 1992 Dec 19–26;305(6868):1515–6. PMID 1286364] The entertainment industry often depicts those with Tourette syndrome as social misfits whose only tic is coprolalia, which has furthered stigmatization and the public's misunderstanding of those with Tourette's.Holtgren, Bruce. "Truth about Tourette's not what you think". " Cincinnati Enquirer" (January 11, 2006). "As medical problems go, Tourette's is, except in the most severe cases, about the most minor imaginable thing to have. ... the freak-show image, unfortunately, still prevails overwhelmingly. The blame for the warped perceptions lies overwhelmingly with the video media – the Internet, movies and TV. If you search for 'Tourette' on Google or YouTube, you'll get a gazillion hits that almost invariably show the most outrageously extreme examples of motor and vocal tics. Television, with notable exceptions such as Oprah, has sensationalized Tourette's so badly, for so long, that it seems beyond hope that most people will ever know the more prosaic truth."] The coprolalic symptoms of Tourette's are also fodder for radio and television talk shows in the US [ [http://web.archive.org/web/20011006192716/http://tsa-usa.org/drlaura.html Oprah and Dr. Laura – Conflicting Messages on Tourette Syndrome. Oprah Educates; Dr. Laura Fosters Myth of TS as "Cursing Disorder".] Tourette Syndrome Association(May 31, 2001). Archived October 6, 2001. * [http://www.tsa-usa.org/news/DrPhil.htm Letter of response to Dr. Phil.] Tourette Syndrome Association. Retrieved on May 8, 2006. * [http://tsa-usa.org/news/Garrison-Keillor.htm Letter of response to Garrison Keillor radio show.] Tourette Syndrome Association. Retrieved on May 8, 2006. * [http://www.dailymail.co.uk/tvshowbiz/article-386969/Big-Brother-Tourettes-housemate-exploited.html Big Brother: Tourette's housemate 'exploited'] . Mail online, (May 19, 2006). Retrieved on September 19, 2008.] and in the British media.Guldberg, Helene. [http://www.spiked-online.com/index.php?/site/article/321/ Stop celebrating Tourette's.] "Spiked" (May 26, 2006). Retrieved on December 26, 2006.] Notes:note label|TradeName|A|A Medication trade names may differ between countries. In general, this article uses North American trade names. * Bagheri MM, Kerbeshian J, Burd L. [http://www.aafp.org/afp/990415ap/2263.html "Recognition and management of Tourette's syndrome and tic disorders".] "American Family Physician". 1999; 59:2263–74. PMID 10221310 Retrieved on October 28, 2006. * Leckman JF, Cohen DJ. "Tourette's Syndrome—Tics, Obsessions, Compulsions: Developmental Psychopathology and Clinical Care." John Wiley & Sons, Inc., New York, 1999. ISBN 0-471-16037-7 [http://info.med.yale.edu/chldstdy/tsocd/tsbook.htm Outline.] Retrieved on October 28, 2006. * Robertson MM. [http://brain.oxfordjournals.org/cgi/reprint/123/3/425.pdf "Tourette syndrome, associated conditions and the complexities of treatment"] (PDF). "Brain". 2000;123 Pt 3:425–62. PMID 10686169 Retrieved on January 25, 2007. * [http://web.archive.org/web/20060106020124/http://www.tsa-usa.org/what_is/Faqs.html Tourette Syndrome: Frequently Asked Questions.] Tourette Syndrome Association. Retrieved on January 6, 2006. * [http://web.archive.org/web/20060524115004/http://www.tsa-usa.org/what_is/whatists.html What is Tourette syndrome?] Tourette Syndrome Association. Archived May 24, 2006. * The Tourette Syndrome Classification Study Group. [http://web.archive.org/web/20060426232033/http://www.tsa-usa.org/research/definitions.html "Definitions and classification of tic disorders".] "Arch Neurol." 1993 Oct;50(10):1013–16. PMID 8215958 Archived April 26, 2006. * Walkup, JT, Mink, JW, Hollenback, PJ, (eds). "Advances in Neurology, Vol. 99, Tourette syndrome." Lippincott, Williams & Wilkins, Philadelphia, PA, 2006. ISBN 0-7817-9970-8 * Zinner SH. "Tourette disorder". "Pediatr Rev". 2000;21(11):372–83. PMID 11077021 *Kushner, HI. "A cursing brain?: The histories of Tourette syndrome". Harvard University Press, 2000. ISBN 0-674-00386-1. *Olson, S. [http://www.tsa-usa.org/Medical/images/Science_Mag_0904.pdf "Making Sense of Tourette's"] (PDF). "Science." 2004 Sep 3;305(5689):1390–92. PMID 15353772 * [http://www.tourette-confusion.blogspot.com/ Tourette's Syndrome: minimizing confusion] —a blog by Roger Freeman, MD, clinical head of the Neuropsychiatry Clinic, British Columbia's Children's Hospital, professional advisory board member of the Tourette Syndrome Foundation of Canada, and former member of the Tourette Syndrome AssociationMedical Advisory Board. Dr. Freeman has over 180 journal-published articles on [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi PubMed.] * [http://tsa-usa.org/ZNewDiag01/content.html Tourette syndrome: Newly diagnosed] —a 3-hour video/slide presentation by John Walkup, MD, deputy director of the Division of Child and Adolescent Psychiatry, Johns Hopkins Hospitaland 2007 Chair of the Tourette Syndrome AssociationMedical Advisory Board Wikimedia Foundation. 2010. Look at other dictionaries: Tourette syndrome — Rare neurological disease that causes repetitive motor and vocal tics. Named for Georges Gilles de la Tourette, who first described it in 1885, it occurs worldwide, is usually inherited, generally begins at ages 2–15, and is three times more… … Universalium Tourette syndrome — A tic disorder characterized by the presence of chronic vocal and motor tics, probably based on differences in or damage to the basal ganglia of the brain. Tourette syndrome usually emerges between the ages of 6 and 18 and is somewhat more common … Medical dictionary Tourette syndrome — noun A neurological disorder characterized by the presence of physical and vocal tics. Tourette syndrome is a condition characterized by involuntary vocalizations exacerbated by stress. Syn: Tourettes syndrome, Tourettes disorder, Gilles de la… … Wiktionary Tourette syndrome — (pref.), Tourette’s syndrome (alt.). Neurological disorder named for the French physician Georges Gilles de la Tourette (1859–1904) … Bryson’s dictionary for writers and editors Tourette syndrome — noun see Tourette s syndrome … New Collegiate Dictionary tourette syndrome — noun see tourette s syndrome … Useful english dictionary Tourette syndrome — see Tourette s syndrome … English dictionary Tourette Syndrome Association — The Tourette Syndrome Association (TSA), based in Bayside, New York, United States, is a non profit voluntary organization and the only national health related organization serving people with Tourette syndrome. It was founded in 1972 by five… … Wikipedia Tourette Syndrome Foundation of Canada — The Tourette Syndrome Foundation of Canada (or TSFC) is a Canadian voluntary organization based in Toronto, Ontario. It was formed in 1976, [* Kushner, HI. A cursing brain?: The histories of Tourette syndrome . Harvard University Press, 2000, p.… … Wikipedia History of Tourette syndrome — Tourette syndrome is an inherited neurological disorder with onset in childhood, characterized by the presence of multiple physical (motor) tics and at least one vocal (phonic) tic. BehaveNet. [http://web.archive.org/web/20050310121149/http://www … Wikipedia

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OK, we’ve finished reading the Feb 2011 edition of @EBMedicine‘s Pediatric Emergency Medicine Practice article on pneumonia: Jadavji T (2011). An Evidence-Based Review Of Pediatric Pneumonia In The ED. Pediatric Emergency Medicine Practice, 8(2). [Abstract and subscription link] Let’s not muck around — here are 8 Q-and-As to test whether you’re a (wo)man or an amoeba when it comes to childhood pneumonia… Q1. From a global perspective, how important is childhood pneumonia? Pneumonia is the no. 1 killer of children worldwide. There are over 2 million deaths per year from pneumonia, accounting for 1 in 5 deaths of children under 5 years of age. This is more than AIDS, malaria and measles combined. Q2. How is pneumonia diagnosed? Definitions of pneumonia are hard to pin down! In the simplest clincal terms, pneumonia is simply an infection resulting in lower respiratory tract dysfunction in the presence of radiographic abnormalities on chest x-ray. A chest radiograph should be considered in children with prolonged cough, high or prolonged fever and in the presence of focal respiratory signs other than wheeze (especially if there are multiple signs and symptoms). In resource poor settings, WHO guidelines for pneumonia in children aged 2 months to 5 years states that a clinical diagnosis can be made if the child has a cough and fast or difficult breathing. Tachypnea according to age is defined as: - RR>60 if <2 months, RR>50 if 2 months to 12 months, and RR>40 if 12 months or older. Q3. How should respiratory rate be measured? Respiratory rate should be measured by observation of an awake child who is not crying over 60 seconds. Measurement of respiratory rate will vary according to: - method of measurement: lower respiratory rate for observation than electronic measurement, which are both less than for measurement by auscultation. - duration of measurement: increased RR if measured over 15 seconds rather than 60 seconds. - child activity: respiratory rate is increased if crying or active, decreased if asleep. Q4. What is occult pneumonia? Occult pneumonia refers to the presence of CXR abnormalities consistent with pneumonia in a febrile child with no evidence of tachypnea or focal respiratory signs. In the current post-vaccination age, about 5-7% of cases of diagnosed pneumonia are occult. Q5. How can viral pneumonia be distinguished from bacterial pneumonia? Viral and bacterial causation cannot be reliably distinguished in usual clinical practice. In modern times, even with a comprehensive search for a cause, the underlying etiology of pneumonia remains unknown in over 20% of cases. Furthermore, viral and bacterial causes may coexist. Traditionally the appearance of the chest radiograph was felt to help distinguish between viral and bacterial causation: - Viral pneumonias classically show perihilar bronchial thickening, interstitial opacities and hyperinflation. - Bacterial pneumonias classically cause lobar consolidation. In reality, either radiographic appearance may be seen in viral or bacterial causes. Age is the best predictor of the likely cause of pneumonia in children. Q6. What is the likely cause of pneumonia in the following age groups (in order!): 1 month to 2 years (NB. 3 weeks to 3 years: pneumonitis syndrome may be caused by: Chlamydia pneumoniae, RSV, parainfluenza virus, Bordetella pertussis) 2 – 5 years Mycoplasma pneumoniae, Chlamydia pneumoniae, Streptococcus pneumoniae, non-typeable Haemophilus influenzae, influenza A, other respiratory viruses The choice of antibiotics depends on the likely cause, and the severity of illness, and should be guided by local practice guidelines and sensitivity patterns. Q7. Which children with pneumonia require admission? There is little evidence to guide us in deciding who to admit to hospital. Hospitalisation should be considered when: - age < 6months (more likely to rapidly deteriorate) - hypoxemia (Sp02 <92% OA) - toxic appearance or severe respiratory distress - suspected complications (e.g. empyema) - vomiting, dehydration or not tolerating oral intake - social circumstances Q8. How has the epidemiology of pneumonia in children changed since the introduction of pneumococcal vaccination? The introduction of pneumococcal vaccination has decreased the rates of pneumonia, and in particular has reduced rates of pneumococcal hospitalisations. However, the rates of empyema complicating pneumonia have increased, although pneumococcal disease is now less likely to be the cause. MRSA should be considered in this setting, along with the administration of vancomycin.

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Symptoms and Signs of Upset Stomach (Gastritis) in Dogs Effects of Gastritis Gastritis, which refers to irritation and inflammation of the sensitive lining of the stomach, can come on suddenly (called “acute gastritis”), or can develop slowly over time (called “chronic gastritis”). Either way, it is always an uncomfortable condition for affected animals, who will be nauseous and have mild to severe stomach pain, depending upon the nature and extent of their gastrointestinal inflammation. They probably will lose their appetite and become listless, lethargic and depressed. They just will feel lousy. These fairly classic symptoms are pretty much the same as those experienced by people who develop gastritis. They are never pleasant and, in rare cases, can become extremely dangerous to the animal in question. Symptoms of Gastritis The hallmarks of both acute and chronic canine gastritis are vomiting and intense abdominal pain. Owners of affected animals will probably notice one or more of the following clinical signs: - Vomiting (severe; persistent in chronic cases; sudden onset and extreme in acute cases; may be tinged with bile [be yellow-ish], flecked with fresh blood [this is called “hematemesis”] and/or contain digested blood [this looks like used coffee-grounds]) - Abdominal pain (can range from mild to extremely severe; can be debilitating; head hanging over the water bowl; “praying” or “bowing” stance) - Dehydration (from fluid loss due to vomiting) - Loss of appetite (inappetence; anorexia) - Weight loss - Diarrhea (+/-) - Blood in the stool (melena; caused by stomach ulceration; not especially common except in severe cases of gastritis) - Dull hair coat; unkempt condition - Pale mucous membranes (pallor; associated with blood loss) - Yellow mucous membranes (jaundice; usually associated with ingestion of toxins) - Drooling; excessive salivation (ptyalism; usually associated with ingestion of toxins) Most dogs with gastritis produce a frothy, bile-tinged vomitus, and in many cases there are flecks of blood in the vomitus as well. Sometimes, if the stomach lining becomes so disrupted that it bleeds, the vomitus will be very dark and the digested blood will look like wet coffee grounds. Any dog with persistent attacks of vomiting should be seen by a veterinarian as soon as possible. Chronic vomiting must be distinguished from chronic regurgitation. Vomiting is an active event almost always accompanied by strong, unpleasant abdominal contractions. Regurgitation, on the other hand, is a passive reflexive process where undigested food suddenly “comes up” through the esophagus and out the mouth, without much prior warning or abdominal force. Dogs at Increased Risk There is no particular breed or gender predisposition to developing gastritis. Dogs that enjoy rummaging around in garbage, eating spoiled food or swallowing indigestible foreign objects are at an increased risk of gastrointestinal irritation and inflammation, as are dogs that eat animal feces or plant matter on a regular basis. Small, flat-faced (brachycephalic) breeds, such as Boston Terriers, Pugs and Bulldogs, as well as Lhasa Apsos, Shih Tzus, Basenjis, Drentse Patrijshonds and Miniature Poodles, are prone to developing hypertrophic gastropathy, which is a thickening of the stomach lining that tends to occur in middle-aged dogs and causes vomiting several hours after a meal. The cause of this particular type of gastritis is not well understood. Young, large-breed male dogs living along the Gulf Coast of the United States may be predisposed to developing a type of granulomatous gastritis that is caused by certain species of fungal microorganisms, especially during the fall, winter and spring months.

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- Hot flashes: Hot flashes are the most common symptom of menopause. According to some studies, hot flashes occur in as many as 75% of perimenopausal women. Hot flash symptoms vary among women. Commonly, a hot flash is a feeling of warmth that spreads over the body, lasting from around 30 seconds to a few minutes. Flushed (reddened) skin, palpitations (feeling a strong heartbeat), and sweating often accompany hot flashes. Hot flashes often increase skin temperature and pulse, and they can cause insomnia, or sleeplessness. Hot flashes usually last 2 to 3 years, but many women can experience them for up to 5 years or longer. An even smaller percentage may have them for more than 15 years. - Urinary incontinence and burning on urination - Vaginal changes: Because estrogen affects the vaginal lining, perimenopausal women may also have pain during intercourse and may note a change in vaginal discharge. - Breast changes: Menopause may cause changes in the shape of the breasts. - Thinning of the skin - Bone loss: Rapid bone loss is common during the perimenopausal years. Most women reach their peak bone density when aged 25 to 30 years. After that, bone loss averages 0.13% per year. During perimenopause, bone loss accelerates to about a 3% loss per year. Later, it drops off to about a 2% loss per year. No pain is usually associated with bone loss. However, bone loss can cause osteoporosis, a condition that increases the risk of bone fractures. These fractures can be intensely painful and can interfere with daily life. They also can increase the risk of death. - Cholesterol: Cholesterol profiles also change significantly at the time of menopause. Total cholesterol and LDL ("bad") cholesterol levels increase. Increased LDL cholesterol is associated with an increased risk of heart disease. - Heart disease risk increases after menopause, although it is unclear exactly how much is due to aging and how much is caused by the hormonal changes that occur at the time of menopause. Women who undergo premature menopause or have their ovaries removed surgically at an early age are at an increased risk of heart disease. - Weight gain: A three year study of healthy women nearing menopause found an average gain of five pounds during the three years. Hormonal changes and aging are both possible factors in this weight gain. Medically Reviewed by a Doctor on 5/9/2014 Must Read Articles Related to Menopause Female Sexual Problems Long considered a taboo subject, women's sexuality is now openly discussed and portrayed on television, in magazines, and on the internet. Symptoms of female se...learn more >> Hot Flashes and Menopause Hot flashes are a common condition experienced by women in the perimenopause and menopause transition. The exact cause of the hot flashes is not clear. Symptoms...learn more >> Pain During Intercourse Pain during intercourse (dyspareunia) is pain or discomfort in a woman's labial, vaginal, or pelvic areas during or after sexual intercourse. Pain during interc...learn more >> Patient Comments & Reviews The eMedicineHealth doctors ask about Menopause:

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A ketogenic diet is a high-fat, adequate-protein, and very-low-carbohydrate diet which has been found to help many children whose seizures are not well-controlled by anti-seizure medications. In some children, the ketogenic diet is combined with standard anticonvulsant medications. While the actual mechanism of the ketogenic diet's effectiveness against seizures is unknown, many children on the diet are able to have their epilepsy medication dose lowered, decreasing unwanted medication side effects. Because this is a medical treatment, the ketogenic diet must be supervised by a medical team, consisting of a neurologist and dietitian, who can anticipate and manage possible nutritional deficits or other medical side effects or complications. The team helps children and their families establish and maintain the diet, and learn how to incorporate the diet into daily living. Children on the ketogenic diet are seen several times throughout the year for close monitoring, while they continue to follow with their primary neurologist for potential medication changes. In addition, the team also implements the Modified Atkins Diet and Low-Glycemic Index Therapy, other dietary therapies for which there is increasing data about benefit in the treatment of difficult-to-treat epilepsy. Conditions treated by the Ketogenic Diet Team include: - Epilepsy such as Myoclonic Astatic Epilepsy and other epilepsies - Glucose transporter type-1 deficiency - Lennox Gastaut syndrome - Pyruvate dehydrogenase deficiency - Dravet syndrome What is a ketogenic diet? The ketogenic diet is sometimes offered to children who continue to have seizures while on seizure medication. When medications do not work, a ketogenic diet may be considered. No one knows exactly how the diet works, but some children do become seizure-free when put on the diet. However, the diet does not work for everyone. What does the diet consist of? The ketogenic diet is very high in fat (about 90 percent of the calories come from fat). Protein is given in amounts to help promote growth. A very small amount of carbohydrate is included in the diet. This very high-fat, low-carbohydrate diet causes the body to make ketones. Ketones are made by the body from protein. They are made for energy when the body does not get enough carbohydrates for energy. If your child eats too many carbohydrates, then his/her body may not make ketones. The presence of ketones is important to the success of the diet. - Heavy cream - Cream cheese - Fruit and fruit juice - Breads and cereals - Vegetables (corn, peas, and potatoes) - Snack foods (chips, snack cakes, crackers) Your child's physician will determine if this diet is right for your child. When the ketogenic diet is started, your child will be admitted to the hospital. It may take four to five days in the hospital to get the diet started and for you to learn how to plan the diet. While in the hospital, your child may not be able to eat for one to two days until ketones are measured in the urine. Once ketones are present in the urine, special high-fat, low-carbohydrate shakes may be started. These are sometimes called keto shakes. After several meals of keto shakes, your child will be started on solid foods. You may also be taught how to check your child's urine for ketones. The dietitian will help determine how much fat, protein and carbohydrate your child is allowed to have, usually divided into three meals a day. The ketogenic diet can by very challenging to prepare and requires that all foods be weighed using a food scale. The ketogenic diet is not nutritionally balanced, therefore, vitamin and mineral supplements are needed. Some medications and other products, such as toothpaste and mouthwash, contain carbohydrates. It is important to avoid these products if your child is on the ketogenic diet. Your child may not make ketones in their urine if too many carbohydrates are included in the diet. Your child's physician and dietitian can give you a list of medications, and other products, that are free of carbohydrates. How long is the diet used? Children usually stay on the diet about two years. The diet is then slowly changed back to a regular diet. Sample ketogenic meal: - 60g heavy cream - 21g strawberries - 53g eggs - 10g cheddar cheese - 10g bacon - 21g butter Sample ketogenic shake: - 500g Ross Carbohydrate-free Formula (concentrate) - 270g heavy cream - 13g Egg Beaters®

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Chlamydiosis is a highly contagious infection that commonly occurs in sheep flocks of the western U.S. However, because laboratory confirmation of chlamydial abortion can be difficult, the true incidence is not easy to quantify and many infections are not reported. The organism that causes chlamydiosis is Chlamydia psittaci. Among flocks were the disease has been present for several years, most of the older ewes are immune and the annual abortion rate is around 1 to 5 percent (primarily due to ewe lambs and yearling ewes aborting during their first pregnancy). However, in recently infected flocks, or among nonimmune ewes recently introduced to an infected flock, the abortion rate can be as high as 30 percent. Lambs born weak at birth also are common. The infective organism is excreted in high numbers in the aborted fetal membranes and fluids. Transmission often occurs when susceptible ewes lick the aborted fetus or consume feed or water that is contaminated by the aborted fluids or tissues. Once ingested, the infective agent incubates and can cause abortion within about 60 to 90 days. Ewes that become infected late in gestation may have weak lambs. Nonpregnant ewes and lambs and ewes in the final stages of gestation may become infected and harbor the organism until the next pregnancy, when they abort. Aborting ewes generally do not get sick unless secondary infection occurs. Treatment of chlamydiosis usually is not an issue because ewes normally show no signs prior to abortion. However, prevention depends on interrupting the infective cycle. Removing afflicted ewes from the flock for several days after abortion and discarding the aborted fetus and fluids will lower the level of contamination. Additionally, feeding farm flock sheep in feeders may prevent them ingesting feed that has been contaminated on the ground. Vaccinating ewes will increase their disease resistance, but the resistance is neither absolute nor long-lasting. In flocks infected with Chlamydia psittaci, adding tetracyclines to feed for daily consumption throughout the lambing period may reduce the incidence of abortion. In flocks that experience some chlamydial abortions annually, prophylactic administration of tetracyclines in the feed during gestation may be beneficial.

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Infertility occurs in many couples around the world. It is believed that about 14% of couples face infertility problems. According to worldwide statistics, 2 million married couples face infertility problems and, unfortunately, this number is growing every year. It’s important to note that infertility is not a disease and can occur in perfectly healthy men and women. The term “infertility” only means that there was no pregnancy in specific partners over time. The diagnosis of infertility Infertility’s diagnosed in the absence of pregnancy after one year of regular sexual intercourse without contraception. According to research on fertile couples, approximately 30% of healthy couples conceive within the first 3 months of intercourse, 60% after 6-7 months, and the 10% within 8-12 months. Female Infertility Causes Infertility in women is divided into primary and secondary infertility. Primary infertility occurs when a couple that has never achieved pregnancy before is unable to after 12 months of trying to conceive. Secondary infertility occurs when a couple has achieved pregnancy before but is now unable to. A woman can be infertile for many reasons.A common cause of infertility is an ovarian cyst. Another common cause is a disease of the fallopian tubes causing tubal infertility (tubal factor). Also worth mentioning is functional cervical factor infertility, which occurs when a woman’s cervical mucus does not favorably interact with sperm. These are other causes of infertility are listed below. |Form of infertility||Cause of infertility||Prevalence| |Pipe (tubal factor)||obstruction or absence of the fallopian tubes||30-35%| |Peritoneal (tubal-peritoneal factor)||adhesions in the pelvic cavity||20-25%| |Fallopian (uterine factor)||pathology of the uterus, uterine malformations, uterine hyperplasia||2-3%| |Endocrine (endocrine factor)||disruption of ovulation and implantation||30-35%| |Infertility, explained endometriosis||adhesions in the pelvic cavity toxicity, preventing implantation||8-10%| While infertility is a common ailment, modern treatments, such as those provided by Dr Morice, have helped many couples with fertility problems achieve pregnancy. Atchafalaya Gynecology & Obstetrics is an advanced tubal reversal surgery and infertility center. We provide you with extensive information on the causes of infertility and help you choose the best treatment to pursue. Our clinic and treatments use the world’s best technology with proven success. It is our goal to provide the world’s best obstetrics and gynecology services to help you accomplish your dream of having a healthy baby. For appointments and questions, please call us at(985)-702-BABY (2229)or email our nurses at [email protected]. Our dedicated staff is always happy to help you.

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Bui Thi Hong’s baby is protected from hepatitis B thanks to a birth dose of vaccine. Photo: PATH/Pham Trung. Protecting newborns from hepatitis B Before she became pregnant, Bui Thi Hong had never heard of hepatitis B. The insidious infection hides in the liver for decades. When it finally manifests, it can be deadly—one in four people infected during childhood die from virus-related conditions like cirrhosis or liver cancer. In Vietnam’s Hoa Binh Province, where Hong lives, childhood infection rates are high, while prevention—the only recourse—has been dismally low. But with support from PATH and partners, Vietnam’s national immunization program has made tremendous strides in increasing coverage of the lifesaving hepatitis B vaccine. Babies like Hong’s are getting the prevention they need. A disease spread from mother to child More than 8 percent of the population of Vietnam is chronically infected with the hepatitis B virus, though most don’t realize it. As in many other endemic countries, mothers commonly pass the virus to their infants during childbirth. It’s possible to prevent this mother-to-child transmission by giving a dose of vaccine to newborns within 24 hours after birth. The challenge is reaching infants quickly—especially in rural areas where mothers give birth at home or in small health centers that lack refrigeration for storing vaccine. We address this issue from all angles—influencing national policy, training health workers, and supporting awareness-raising efforts. By working hand-in-hand with local health ministries, we’ve succeeded in expanding birth-dose coverage in Cambodia, India, and Indonesia. But the situation was especially challenging in Vietnam. In 2006, suspicions that the vaccine was responsible for a number of infant deaths were widely publicized. While an investigation found no link, confidence in the vaccine was lost. Rebuilding confidence after a scare In order to get Vietnam back on track with hepatitis B birth-dose vaccination, we worked with national and international partners to restore confidence in the vaccine. We helped Vietnam’s National Expanded Program on Immunization develop a national action plan and technical guidelines for vaccine use. And we educated stakeholders—from government officials to health workers to community members. Next we piloted our approach in a province with some of the lowest coverage rates in the country. The project trained nearly 1,000 health workers on vaccine use, including safety and storage. We also taught them how to counsel pregnant women, and we broadcast messages through local media to raise awareness of the need for vaccination. In just five months, the vaccination rate jumped from only 20 percent to remarkable 92 percent. We took the lessons learned from the pilot project and adapted the model for two more remote provinces, including Hoa Binh, where Hong lives. Given the mountainous terrain and the fact that many women give birth at home, getting the message out was difficult. But Hong heard it and knew how to protect her baby. Shortly after she gave birth to her daughter, May, she asked her birth attendant to vaccinate the infant. Protecting the child and the community With training provided through the project, health workers are now more confident about explaining the benefits of the birth-dose vaccine and administering it. For Nurse Mai Phuong Thuy, the training was personal as well as professional—her sister has hepatitis B. When Thuy learned that the disease could be passed to infants during childbirth, she encouraged her sister to vaccinate her children and to get yearly health exams. Thuy realizes that her work is protecting both today’s children and the children of the future, since 90 percent of infants who are born to infected mothers go on to become hepatitis B carriers themselves. “Not only does the vaccination of infants help prevent mother-to-child transmission of hepatitis B,” she said, “it also helps to reduce the transmission rate in the community overall.” Almost half of the 600,000 hepatitis B-related deaths worldwide every year take place in Asia—but now millions of children in Vietnam and other countries where PATH works are protected from a life sentence with hepatitis B.

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(NOTE: This study has received a lot of press and coverage today but read on to gain new insights into important details of the study that may have influenced the results and interpretation) The usefulness of folic acid supplication to reduce the risk of neural tube defects is well known. A new study from Norway published in JAMA, however, now suggests that autistic spectrum disorders (ASDs) may be another group of neurodevelopmental conditions whose risk can be reduced with folic acid, if taken at the right time. Since 1998, the Norwegian government has recommended that women planning on becoming pregnant take 400 micrograms of folic acid supplement prior to conception and through the first trimester of pregnancy. Data for this study comes from the Mother and Child Cohort Study that examined over 85,000 children born between 2002 and 2008. The Children were between ages 3 and 10 at the time of the study. Folic acid use between 4 weeks prior to conception to 8 weeks into pregnancy was assessed through questionnaires mother competed at 18 and 22 weeks of pregnancy. Mothers were not asked about specific doses but were asked to provide the specific names of their supplements. The specific time period focused upon in this study was due to the authors’ hypothesis based on available information about nervous system development. Mothers were placed in the folic acid group if they had taken the supplement all or part of the interval. A diagnosis of autism was determined through questionnaires, referral information, and a patient registry, and half were assessed directly in a related study. The study divided autistic spectrum disorders into autistic disorder, Asperger syndrome, and PDD NOS, and the authors did not group them together for their analyses. Reduction in autism risk was calculated using odds ratios and logistic regressions that controlled for a few other variables such as maternal education, parity, and year of birth (all of which were found to be significant in the odds ratio calculations). Nearly 72% (check) of mothers took folic acid supplements around their pregnancy. The overall rate of any autistic spectrum disorder was found to be 0.32%. The rate of specific autistic disorder among women who took folic acid was 0.1% and significant lower than the 0.2% found in offspring whose mothers did not take folic acid. The adjusted odds ratio for autistic disorder related to folic acid use was 0.6 representing a 40% reduction in risk. This significant reduction was not found for taking folic acid later in pregnancy or for Asperger syndrome and PDD-NOS. The authors also examined fish oil supplements and did not find a significant decrease in risk. The authors concluded that folic acid supplementation before conception and during early pregnancy was significantly related to a lower risk of autistic disorder in children. While promising, some potentially important difficulties with the study need to be mentioned. The overall rate of an autistic spectrum disorder was 0.3% which is well below approximate 1% rate often quoted these days. The authors noted that some of this difference may be due to mothers of more severely affected children not participating in the study. In addition, it is puzzling why the association with folic acid was not found for Asperger syndrome or PDD-NOS. The authors commented about a lack of power, yet they chose not to combine the ASD diagnoses which would have maximized their power (but perhaps given them a different overall conclusion?). It is also possible the folic acid is a proxy for other unmeasured variables that may have decreased autism risk. Some of these potential confounds were examined, however, and the lack of association with fish oil or for folic acid taken later in pregnancy lessen this concern somewhat. The way positive folic acid use was “counted” also leaves quite a bit of uncertainty regarding the dose and timing needed to produce maximum benefit. Despite these questions and limitations, the study offers some important data about a relatively simple step that can be taken that may reduce the rate of autism. Suren P, et al. Association Between Maternal Useof Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children. JAMA 2013; 309:570-577.

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Keratosis pilaris is a common skin condition in which a protein in the skin called keratin forms hard plugs within hair follicles. Causes, incidence, and risk factors Keratosis pilaris is harmless (benign), does not get worse over time, and often disappears with age. It is more common in patients who have very dry skin, or who have atopic dermatitis (eczema). It seems to run in families. In mild cases, small bumps, similar in appearance to "goose bumps," are found on the backs of the upper arms. The texture is that of very coarse sandpaper. Bumps may also appear on the buttocks and thighs. Less commonly, bumps appear on the face and may be mistaken for acne. Individual bumps are small, skin-colored papules that form within hair openings (follicles). The condition is generally worse in winter and often clears in the summer. - Fine, bumpy texture to skin over the outer upper arm and thigh or elsewhere - Skin-colored bumps the size of a grain of sand - Slight pinkness may be seen around some bumps Signs and tests Physical examination is usually all that is needed for your health care provider to make this diagnosis. Testing is usually not necessary. Moisturizing lotions are often soothing and may help the appearance of the skin. Skin creams with medications containing urea, lactic acid, glycolic acid, salicylic acid, tretinoin, or vitamin D may be recommended by your physician. However, improvement often takes months and the bumps are likely to come back. Keratosis pilaris may fade slowly with age. Calling your health care provider Call for an appointment with your health care provider (or discuss the condition during a routine visit) if you suspect that you have keratosis pilaris and the condition does not respond to use of over-the-counter moisturizing lotions. Reviewed By: Michael Lehrer, MD, Department of Dermatology, University of Pennsylvania Medical Center, Philadelphia, PA. Review provided by VeriMed Healthcare Network; Linda Vorvick, MD, Medical Director, MEDEX Northwest Division of Physician Assistant Studies, University of Washington School of Medicine. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

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Hepatitis is a syndrome, not a single infectious agent. Characterized by inflammation of the liver. At least 4 types of viral hepatitis: Type A - infectious Type B - serum Type C - transfusion Type D - delta, NANB- nonA nonB (no viral agents have been identified) Outcome of infection with one of these agents is extremely variable, varying from completely asymptomatic to fatal. Can be divided into 4 outcomes: 1. Typical, acute icteric (jaundice) hepatitis 2. Subclinical, anicteric - most common 3. Fulminant hepatitis - relatively rare 4. Chronic hepatitis - hepatic inflammation and necrosis lasting for at least 6 months. 10% type B 10 - 60 of C and D. Does not occur with type A. Acute viral hepatitis: course of infection separated into 4 stages (Figure 1): 1. Incubation period - average (range) A - 25 (15 - 45) B - 75 (40 - 1 80) D - (30 - 50) NANB - 50 (15 - 150) 2. Pre-icteric phase Non - specific symptoms before the onset of topical hepatitis. Most common complaint is malaise. Usually see anorexia, often followed by nausea, vomiting. Weight loss of 2 - 10 lbs is common. Right upper quadrant (RUQ) abdominal pain is a common complaint but is usually not severe. About 10 - 15% develop a serum-sickness-like syndrome in the early phase, characterized by low-grade fever, rash and arthritis. 3. Icteric phase Dark urine and/or jaundice due to increased levels of bilirubin Disease is usually diagnosed during this period. Biochemical tests: look for marked elevation of serum levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In acute hepatitis, these are almost always elevated 10-fold and can be as high as 100-fold. Enzymes levels increase during late incubation period and are always elevated once symptoms appear. Prothrombin time is usually normal or only slightly prolonged, marked prolongation indicates ervere, possibly fulminant disease. Blood counts are usually normal except in fulminant cases. 4. Convalescent phase Begins with the disappearance of juandice and other symptoms. Enzyme levels will fall but will remain slightly elevated for some time after symptoms disappear. Serolocial tests can be used at this stage to identify the viral agent responsible. NANB usually diagnosed by exclusion. Type A (Figure 2): HAV is a small, 27-nm RNA virus that belongs to the picornavirus family. Evidence indicates that it is a simple nonenveloped virus with a nuclocapsid designated the hepatitis A antigen (HA Ag). The viral capsid consists of 32 capsomeres arranged in an icosahedral conformation. Each capsid is composed of four polypeptides (VPI - VP4). Inside the capsid is a single molecule of ssRNA approximately 8,100 nucleotides in length. + strand virus (positive polarity - proteins are translated directly off the RNA). The 3' end of the RNA is polyadenylated and the 5' end has a small protein, the "viral protein, genomic" (YPg) which may aid in attaching the RNA to cell ribosomes. Virus can be grown in tissue culture - replicates in the cytoplasm and is noncytopathic. Virus is related to polio virus and has a similar epidemiology: Spread by fecal - oral route Spread is usually associated with overcrowding and poor hygiene Contaminated food and water are the usual modes of transmission Can occur as outbreaks or epidemics but also occurs sporadically in industrialized nations - accounts for ~20% of viral hepatitis in adults in the U.S. Course of hepatitis A - (Figure 3) Incubation period is relatively short Shedding of antigen (i.e. virus) in feces is maximal just before appearance of symptoms - very important in terms of spread Shares some properties in common with polio: children more often asymptomatic in areas of poor sanitation, virus tends to be endemic, children infected early possibly while still partially protected by maternal antibody and outcome less severe Where children escaped early exposure - more likely to be symptomatic when infection does occur Hepatitis A virus is usually not detected in serum. Antibody to HAV is detected with the onset of symptoms. IgM detected early and falls off in titer after symptoms resolve. IgG rises later and persists for life. Diagnosis of HAV usually depends on finding anti HAV IgM in the serum during the acute phase. Disease can be severe and prolonged but only rarely fatal (0.1% of icteric cases) and does not lead to chronic carriage. With g globulin - antibody fraction from pooled normal human serum. significance of the protective effect: indicates large proportion of the population has had, and developed antibody against HAV. HBY is a complex, 42 nm DNA virus - unrelated to the other hepatitis viruses Structure: (Figure 4) Intact virus is referred to as the "Dane particle" Composed of an outer surface component - HBsAg and an inner, core component - HBcAg inside the core is the genome - single molecule of partially double stranded DNA - single stranded region comprises 10 - 50 % of the DNA The complete strand is ~3600 nucleotides and is nicked. This strand contains all the genetic information for producing HBsAg and HBcAg. Core contains a DNA-dependent DNApolymerase - can fill in gap. Unusual DNA structure may enhance integration of the DNA into host DNA. (Figure 5) Serum of infected person contains HBsAg - most not Dane particles - Serum contains both 20 nm spheres and 20 nm diameter tubules (50 - 250 nm in length). These structures consists entirely of HBsAg, no HBcAg or polymerase or DNA. Concentration up to 10^13 particles/ml = 100 - 500 mg/ml average concentration. The production of large amounts of circulating antigen is a unique feature of HBV not observed with other hepatitis viruses. Another Ag - HBeAg, is thought to be associated with the HBV core, circulates as a soluble serum protein, either free 19k daltons (smal e) or associated with serum immunoglobulin 300k (large e) HBeAg is the most reliable marker for infectivity. While HBsAg positive individuals should be considered potentially infectious, correlation between HBsAg and infectivity is not uniform HBSAg+ who are also HBeAg+ are usually highly infectious. Those without HBeAg or who have antibody to HBeAg (anti-HBe) usually have little or no circulating virus and are at less risk for spreading the disease RIA or ELISA for HB-PAG There are other markers for infectivity but these are more complicated assays: 1. look for Dane particles in EM 2. test for DNA polymerase by incorporation of tritiated thymidine 3. test for specific HBV DNA by molecular hybridization Spread parenterally or by direct contact - virus is found in biological fluids, esp blood, and semen, lower in saliva. Epidemiology similar to HIV but HBV has higher infectivity. Parenteral spread - blood products, contaminated needles (particularly among drug abusers), dialysis patients medical personnel treating high risk groups often infected by inapparent parenteral spread e.g. contamination of small breaks in the skin with blood or saliva. Close contact - often sexually transmitted esp. among male homosexuals. Course of disease - (Figure 6) Incubation period: 40 - 180 days, length inversely proportional to dose. First serologic marker to be detected is HBsAg and it persists the longest. Peaks with onset of elevated enzyme levels. Seroconversion from HBeAg to anti-HBeAg usually associated with peak in clinical symptoms. Failure to seroconvert during acute stage is associated with progression to chronic form of the disease Free HBcAg is not found in the serum but antibody to HBcAg appears shortly before the onset of symptoms. Ab is indicative of either ongoing or previous infection. Persistent Ab is IgG rather than IgM, which is found only during the acute phase Ab to HBsAg differs from the other Ab's in that it appears during convalescence rather than during the acute phase. This is probably the major protective Ab - marker for recovery and immunity. HBV immune globulin (HBIG, hyperimmune globulin) is so named becuase it contains high titers of anti HBs. Much more effective in preventing hepatitis B than is gamma globulin. Most frequent response to HBV infection is asymptomatic infection. Usually develop high titers of HBsAg antibody, sometimes in the absence of detectable HBsAg. Lasting immunity results. 1-3% of adult acute cases progress to fulminate, fatal hepatitis. Develop signs of hepatic encephalopathy: changes in behavior and sleep patterns early, Later, lethargy and finally coma ensues. Usually a decrease in hepatic size, high fever, confusion. Hepatic failure. Usually no seroconversion to anti HBeAg or HBsAg. (1) HBs isolated and purified from human serum (2) recombinant vaccine 5 - 10 of acute cases develop a chronic HBs-AG carrier state - probably persists for life. HBe and polymerase appear in the serum at the some time as HBs. Persistence of high levels of HBeAg during the acute phase is suggestive of development of the chronic state. Highest levels of HBcAg antibody are found in the chronic carriers but little or no HBsAg antibody As in acute hepatitis, seroconversion to anti-HBeAg is associated with a favorable prognosis. Complications of chronic state - immune complex disease e.g. arthritis, glomerulonephritis Also associated with primary hepatocellular carcinoma.

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Sexually Transmitted Diseases, 2009 Active surveillance for gonorrhea and chlamydia involves cross-checking laboratory-reported cases against cases reported by clinicians. Although both laboratories and clinical facilities are required to report STDs independently of each other, an episode of STD is not considered a case for surveillance purposes until a corresponding case report is submitted by a clinical facility. Case reports contain demographic and clinical information that is not available from laboratory reports. When a laboratory report is received but no corresponding case report is received within 45 days, MDH mails a reminder letter and case report form to the corresponding clinical facility. Active surveillance for syphilis involves immediate follow-up with the clinician upon receipt of a positive laboratory report. Cases of chancroid are monitored through a mostly passive surveillance system. Herpes simplex virus and human papillomavirus infections are not reportable. Although overall incidence rates for STDs in Minnesota are lower than those in many other areas of the United States, certain population subgroups in Minnesota have very high STD rates. Specifically, STDs disproportionately affect adolescents, young adults, and persons of color. Chlamydia trachomatis infection is the most commonly reported infectious disease in Minnesota. In 2009, 14,186 chlamydia cases (288 per 100,000 population) were reported, representing a 1% decrease from 2008 (Table 3). Adolescents and young adults are at highest risk for acquiring chlamydial infection (Table 4). The chlamydia rate is highest among 20 to 24-year-olds (1,652 per 100,000), with the next highest rate among 15 to 19-year-olds (1,196 per 100,000). The incidence of chlamydia among adults 25 to 29 years of age (731 per 100,000) is considerably lower but has increased in recent years. The chlamydia rate among females (410 per 100,000) is more than twice the rate among males (164 per 100,000), a difference most likely due to more frequent screening among women. The incidence of chlamydia infection is highest in communities of color (Table 4). The rate among blacks (2,038 per 100,000) is over 15 times higher than the rate among whites (132 per 100,000). Although blacks comprise approximately 4% of Minnesota’s population, they account for 29% of reported chlamydia cases. Rates among Asian/Pacific Islanders (324 per 100,000), American Indians (511 per 100,000), and Hispanics (633 per 100,000) are over two to six times higher than the rate among whites. Chlamydia infections occur throughout the state, with the highest reported rates in Minneapolis (741 per 100,000) and St. Paul (687 per 100,000). While there was an overall decrease of 1% across the state in 2009 the greatest decrease for chlamydia was seen in the Minneapolis with a decrease of 6% compared to only 1% in each of the remaining geographic regions shown in Table 4. Gonorrhea, caused by Neisseria gonorrhoeae, is the second most commonly reported STD in Minnesota. In 2009, 2,302 cases (42 per 100,000 population) were reported, representing a 24% decrease from 2008 (Table 3). Adolescents and young adults are at greatest risk for gonorrhea (Table 4), with incidence rates of 163 per 100,000 among 15 to 19-year-olds, 237 per 100,000 among 20 to 24-year olds, and 134 per 100,000 among 25 to 29-year-olds. Gonorrhea rates for males (42 per 100,000) and females (51 per 100,000) are comparable. Communities of color are disproportionately affected by gonorrhea, with nearly one half of cases reported among blacks. The incidence of gonorrhea among blacks (546 per 100,000) is 36 times higher than the rate among whites (15 per 100,000). Rates among Asian/Pacific Islanders (15 per 100,000), American Indians (80 per 100,000), and Hispanics (58 per 100,000) are up to five times higher than among whites. Gonorrhea rates are highest in the cities of Minneapolis and St. Paul (Table 4). The incidence in Minneapolis (188 per 100,000) is 33% higher than the rate in St. Paul (141 per 100,000), nearly six times higher than the rate in the suburban metropolitan area (32 per 100,000), and over nine times higher than the rate in Greater Minnesota (20 per 100,000). Geographically in 2009, Minneapolis and Greater Minnesota saw the greatest drop in cases with 32% and 31% respectively, with St. Paul and the suburban area posting decreases of 17% and 13% respectively. The prevalence of quinolone-resistant N. gonorrhoeae (QRNG) continues to be an issue in Minnesota as well as nationally. In 2007, the MDH recommended that fluoroquinolones (eg, ciprofloxacin) no longer be used for the treatment of gonorrhea in Minnesota. The incidence of primary/secondary syphilis in Minnesota is lower than that of chlamydia or gonorrhea (Table 3), but has remained elevated since an outbreak was observed in 2002 among men who have sex with men (MSM). In 2009, there were 71 cases of primary/secondary syphilis in Minnesota (1.4 cases per 100,000 persons). This represents a decrease of 39% compared to the 116 cases (2.4 per 100,000 population) reported in 2008. Primary and Secondary Syphilis The incidence of primary/secondary syphilis in Minnesota is lower than that of chlamydia or gonorrhea (Table 3), but has remained elevated since an outbreak was observed in 2002 among men who have sex with men (MSM). This sustained outbreak reached a new level in 2008, with 116 cases of primary/secondary syphilis (2.4 per 100,000 population) being reported compared to 59 (1.2 per 100,000) cases in 2007. In 2009, the number of early syphilis cases decreased by 28%, with 117 cases occurring compared to 163 cases in 2008. The incidence remains highly concentrated among MSM. Of the early syphilis cases in 2009, 106 (91%) occurred among men; 96 (91%) of these men reported having sex with other men; 53% of the MSM diagnosed with early syphilis were co-infected with HIV. No cases were reported in 2009. The last case was reported in 1999. - For up to date information see>> Sexually Transmitted Diseases (STDs) - Full issue>> Annual Summary of Communicable Diseases Reported to the Minnesota Department of Health, 2009

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|1.1||Migraine without aura||G43.0| |Previously used terms||Common migraine, hemicrania simplex| Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea and/or photophobia and phonophobia - At least 5 attacks1 fulfilling criteria B-D - Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)2;3;4 - Headache has at least two of the following characteristics: - unilateral location5;6 - pulsating quality7 - moderate or severe pain intensity - aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) - During headache at least one of the following: - nausea and/or vomiting - photophobia and phonophobia8 - Not attributed to another disorder9 - Differentiating between 1.1 Migraine without aura and 2.1 Infrequent episodic tension-type headache may be difficult. Therefore at least 5 attacks are required. Individuals who otherwise meet criteria for 1.1 Migraine without aura but have had fewer than 5 attacks should be coded 1.6.1 Probable migraine without aura. - When the patient falls asleep during migraine and wakes up without it, duration of the attack is reckoned until the time of awakening. - In children, attacks may last 1-72 hours (although the evidence for untreated durations of less than 2 hours in children requires corroboration by prospective diary studies). - When attacks occur on ≥15 days/month for >3 months, code as 1.1 Migraine without aura and as 1.5.1 Chronic migraine. - Migraine headache is commonly bilateral in young children; an adult pattern of unilateral pain usually emerges in late adolescence or early adult life. - Migraine headache is usually frontotemporal. Occipital headache in children, whether unilateral or bilateral, is rare and calls for diagnostic caution; many cases are attributable to structural lesions. - Pulsating means throbbing or varying with the heartbeat. - In young children, photophobia and phonophobia may be inferred from their behaviour. - 9. History and physical and neurological examinations do not suggest any of the disorders listed in groups 5-12, or history and/or physical and/or neurological examinations do suggest such disorder but it is ruled out by appropriate investigations, or such disorder is present but attacks do not occur for the first time in close temporal relation to the disorder. 1.1 Migraine without aura is the commonest subtype of migraine. It has a higher average attack frequency and is usually more disabling than 1.2 Migraine with aura. Migraine without aura often has a strict menstrual relationship. In contrast to the first edition of The International Classification of Headache Disorders, this edition gives criteria for A1.1.1 Pure menstrual migraine and A1.1.2 Menstrually-related migraine, but in the appendix because of uncertainty over whether they should be regarded as separate entities. Very frequent migraine attacks are now distinguished as 1.5.1 Chronic migraine provided that there is no medication overuse. Migraine without aura is the disease most prone to accelerate with frequent use of symptomatic medication, resulting in a new headache which is coded as 8.2 Medication-overuse headache. Regional cerebral blood flow shows no changes suggestive of cortical spreading depression during attacks of migraine without aura although blood flow changes in the brainstem may occur, as may cortical changes secondary to pain activation. This contrasts with the pathognomonic spreading oligaemia of migraine with aura. In all likelihood spreading depression is therefore not involved in migraine without aura. On the other hand the messenger molecules nitric oxide (NO) and calcitonin-gene-related peptide (CGRP) are clearly involved. While the disease was previously regarded as primarily vascular, the importance of sensitisation of perivascular nerve terminals, and the possibility that attacks may originate in the central nervous system, have gained increasing attention over the last decades. At the same time the circuitry of migraine pain and several aspects of neurotransmission in this system have been recognised. A significant contribution has been made by the advent of the triptans, 5HT1B/D receptor agonists. These drugs have remarkable efficacy in acute attacks and, in view of their high receptor-specificity, their mechanism of action provides new insight into migraine mechanisms. It is now clear that migraine without aura is a neurobiological disorder and clinical as well as basic neuroscience currently advances our knowledge of migraine mechanisms at an increasing speed.

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Meconium ileus (also know as distal intestinal obstructive syndrome (DIOS)) is defined as an intestinal obstruction due to inspissated meconium within terminal ileum. It comes from the abnormal composition of the fetal meconium in cystic fibrosis. The most common cause of intestinal blockage without prior surgery in Caucasian children is DIOS. DIOS is described as protein rich, inspissated meconium causing obstruction of the distal ileum, and extremely viscid. DIOS may even be an early indication of a much more severe phenotype of Cystic Fibrosis. Abnormalities of exocrine mucous secretion caused the meconium in DIOS differs from normal meconium with less water, lower level of sucrase, lower level of lactase, decrease of pancreatic enzymes, and increased albumin. All of the above causes a more viscous intestinal mucous making the meconium thick and dehydrated, obstructing the intestine. Pediatric surgeons often evaluate newborns for suspected bowel obstruction, and in such cases DIOS should be considered in the differential diagnosis. Sonographic characteristics of DIOS are hyperbolic, intra-abdominal mass of inspissated meconium, non-visualization of the gallbladder, and dilated bowel. Simple Meconium Ileus: newborns with uncomplicated DIOS appear healthy immediately after birth. Since DIOS is much like many types of neonatal small bowl obstruction, the clinician should consider and evaluate for malrotation, volvulus, meconium plug syndrome, small left colon syndrome, duodenal atresia, small bowel atresia, colonic atresia, Hirshsprung disease, anal stenosis, and rectal atresia. Failure to pass meconium (stool) may lead to bilious vomiting and abdominal distention. Complicated Meconium Ileus Half of all DIOS patients have complications, which may consist of volvulus, intestinal necrosis, intestinal atresia, meconium peritonitis, or bowel perforation. Complications can occur in utero (perforation or bowel compromise), immediately after birth or later after birth. Prenatal perforation may result in sign of peritonitis that don’t show up until after bacterial colonization. Abdominal distension can be severe enough to respiratory distress. A pseudocyst formation caused by bowel perforation, is suggested by a palpable mass in the newborn. The neonate is often in extremis and needs immediate resuscitation and surgical exploration. Volvulus (twisted bowel) used to be the most common complication of DIOS. It can lead to loss of mesenteric blood flow which will lead to segmental necrosis and intestinal atresia associated with mesenteric defect. Some authors describe 4 types of meconium peritonitis: Adhesive meconium peritonitis Giant cystic meconium peritonitis Infected meconium peritonitis Bowel perforation is a common etiology in all four of the peritonitis forms. Most DIOS patients can be treated nonoperatively with water-soluble enemas or. Textbook criteria for the enema cleanout is as follows: 1. The infant shows signs of no complications. 2. An initial diagnostic contrast enema must exclude other causes of neonatal distal intestinal obstruction. 3. The infant should be well prepared for enema. 4. The enema has to be done under fluoroscopic control. 5. Intraveneous antibiotics should be administered. 6. Close surgical supervision from initial evaluation throughout hospital course. For complicated DIOS (see above), an operative approach is generally required. In highly selected cases at tertiary care hospitals, Golytely via nasogastric tube at a low rate with close monitoring may be offered in consultation with pediatric gastrointestinal or pediatric surgical specialists. T-tube ileostomy involes placing a surgical T-tube in the bowel to allow for further washouts. Other surgical options include a distal chimney enterostomy, also known as a Bishop-Koop. This procedure involves resection of the segment of ileum containing the mass of meconium. The distal ileum is brought out as an irrigating and decompressive ileosotomy. Nestled between the side of the distal segment of bowel just within the abdominal cavity and end of the proximal segment an anastomosis is created. This procedure allows normal gastrointestinal transit while managing distal obstruction through ileostomy, if needed. The advantage to using this method, in the absence of a distal obstruction, is that the stoma output isn’t difficult to manage. Successful resection of the anastomosis depends on the resection of compromised bowel, complete proximal distal evacuation of meconium, and the preservation of adequate blood supply of the anastomosis. Mikulicz double barrel enterostomy is also described, and preferred by some centers. In surgical treatment, intraoperative instillation of Gastrophin may facilitate the evacuation of inspissated meconium. Tenacious meconium has to often be removed directly through enteronomy.

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Mice born to mothers who are fed a diet supplemented with B vitamins are less likely to develop intestinal tumors, report scientists at the Jean Mayer USDA Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University. Previous research in humans and mice suggests that B vitamins, particularly folate, play a role in the prevention of colorectal cancer. Using a mouse model of naturally occurring colorectal cancer, the USDA HNRCA scientists examined whether a mothers' B vitamin intake impacts her offspring's cancer risk. Mothers were fed diets containing supplemental, adequate or mildly deficient quantities of vitamins B2, B6, B12 and folate prior to conception through weaning after which all of the offspring received the same adequate diet. "We saw, by far, the fewest intestinal tumors in the offspring of mothers consuming the supplemented diet," says Jimmy Crott, PhD, senior author and a scientist in the Vitamins and Carcinogenesis Laboratory at the USDA HNRCA. "Although the tumor incidence was similar between offspring of deficient and adequate mothers, 54% of tumors in the deficient offspring were advanced and had invaded surrounding tissue while only 18% of tumors in the offspring of adequate mothers displayed these aggressive properties." The results were published online June 9 in the journal Gut. Crott and colleagues associated the tumor suppression seen in the offspring of supplemented mothers with a protection against disruptions to the Wnt signaling pathway, a network of genes commonly altered in colorectal cancer. "The strongest expression of tumor-suppressing genes in the Wnt pathway was in the offspring of supplemented mothers and the weakest was in the offspring of the mildly deficient mothers," says first author Eric Ciappio, a PhD candidate at the Friedman School of Nutrition Science and Policy at Tufts. "We attribute these differences in gene expression to epigenetics, modifications of DNA which are sensitive to environmental factors such as diet," Ciappio continues. "In this case, changing maternal B vitamin intake had lasting epigenetic effects in offspring and may explain the differences in tumor incidence and aggressiveness we observed." It remains unclear whether maternal consumption of the four B vitamins could impact tumor development in humans. ""While evidence is beginning to accumulate to suggest that maternal consumption of supplements containing folate may afford some protection against childhood cancers in offspring, we don't yet have the ability to determine whether the same holds true for cancers that normally present in the mid to late decades of life," explains Crott, who is also an assistant professor at the Friedman School. Crott adds, "Aside from the known protective effect of maternal folate against neural tube defects such as spina bifida, our results suggest that mothers consuming supplemental quantities of these B vitamins may also be protecting her children against colorectal cancer." This study was funded by a cooperative agreement with the Agricultural Research Service (ARS) of the United States Department of Agriculture (USDA). - Eric D Ciappio, Zhenhua Liu, Ryan S Brooks, Joel B Mason, Roderick T Bronson, Jimmy W Crott. Maternal B vitamin supplementation from preconception through weaning suppresses intestinal tumorigenesis in Apc1638N mouse offspring. Gut, 9 June 2011 DOI: 10.1136/gut.2011.240291 Cite This Page:

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Blepharitis, defined as inflammation of the eyelids, is a common eye condition and affects both children and adults. Blepharitis can be categorized in several different ways. First, categorization is based on the length of disease process: acute or chronic blepharitis. Second, categorization is based on the anatomical location of disease: anterior, or front of the eye (e.g. staphylococcal and seborrheic blepharitis), and posterior, or back of the eye (e.g. meibomian gland dysfunction (MGD)). This review focuses on chronic blepharitis and stratifies anterior and posterior blepharitis. There were 34 studies (2169 participants with blepharitis) included in the review, 20 of which included participants with anterior blepharitis and 14 of which included participants with posterior blepharitis. For anterior blepharitis, topical antibiotics provided some symptomatic relief and were effective in clearing bacteria from the eyelid margins. There was no difference between the types of topical antibiotics used. Topical steroids also provided some symptomatic relief; however, they were ineffective in eliminating bacteria. Lid hygiene, including warm compresses and lid scrubs, showed some symptomatic relief in both anterior and posterior blepharitis. Overall, there was no strong evidence for any of the treatments in terms of curing chronic blepharitis. Further research should be done to evaluate the effectiveness of treatments for blepharitis, with particular attention paid to adequate diagnosis and classification of the disease. Interventions for blepharitis 16 May 2012

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The finding of a monoclonal protein or MGUS means that there is an abnormal protein that has been detected in your blood tests. Typically this protein is found during a routine physical examination and is identified using a screening blood test called “protein electrophoresis.” This protein by definition is not associated with more serious problems that are typically associated with protein abnormalities such as multiple myeloma. The source of this protein is a small population of plasma cells in the bone marrow. Plasma cells are present in the bone marrow of all normal adults and represent approximately 1% of all of the bone marrow cells. Plasma cells’ normal function is to produce antibody proteins that help protect your body against infection. On mass screening, the finding of an abnormal protein in the blood is not rare. In fact, 2% of adults over the age of 50 will have this as an incidental finding during screening examinations. However, the frequency with which these proteins are found rises as we age. At age 70 the incidence is from 3 to 4%. The finding of this abnormal protein will occur in both sexes and in all races and is not limited based on occupation or background. The finding of an abnormal protein in the blood (MGUS) will not produce any symptoms. Detecting an abnormal protein is generally not a concern and extensive testing is generally not required unless there are symptoms that warrant a greater index of suspicion on the part of your physician. Follow-up is required for all patients indefinitely, and your physician will monitor protein levels regularly. The protein noted above is found on a serum protein electrophoresis test; when this test is performed, the blood protein is separated into five component proteins. The monoclonal protein graphically will look like a peak or spike. Physicians often refer to this as a blood spike and, again, this finding may not require any additional testing if there are no other pertinent physical findings or symptoms. Treatment for monoclonal gammopathy is not required, although research protocols are in existence for patients at centers that specialize in the treatment of monoclonal gammopathy and multiple myeloma. The reason why these proteins are a concern is that patients who have them have a higher risk of developing a more serious blood or bone marrow problem such as multiple myeloma. Fully 80% of patients with a protein abnormality will never develop any problems related to it. However, because 20% of patients might go on to develop problems, careful follow-up is required. This may only require an annual blood test. This blood test, protein electrophoresis, can be done in virtually any hospital laboratory. For most individuals, a bone marrow examination is not required. More in-depth testing may be done if the protein level has changed or if symptoms develop. It must be kept in mind that a monoclonal gammopathy does not represent cancer. However, because patients with monoclonal proteins are at risk of developing multiple myeloma or related disorders, lifelong monitoring is required. The presence of the protein, since it is derived from bone marrow plasma cells, is not impacted by your diet or the amount of protein you consume, since dietary protein and the production of monoclonal proteins are unrelated. There is no increased risk of monoclonal gammopathies in first-degree family members; therefore, your siblings and children do not need to be screened for the presence of an abnormal protein. In summary, the finding of a monoclonal gammopathy is not an indication for treatment, generally does not require invasive testing, and is not a cause for overt concern. One must be prudent, however, since there is a risk, albeit small, that patients with monoclonal proteins could develop more serious disorders. Close monitoring will allow your physician to intervene before problems occur. Therefore, annual testing is appropriate.

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smallpox cowpox lymph vaccinated jenner disease matter infection ceely skin VACCINATION (from Lat. yucca, a cow), the name given in France to the Jennerian practice of cowpoxing, • shortly after the practice began in England (1799). The procedure was based almost exactly on the earlier practice of inoculating the smallpox, the matter being inserted under the skin of the arm by a lancet point ; also the continuance of the same stock from arm to arm through a series of cases was an idea taken from some of the more adroit variolators. To replace smallpox inoculation by cowpox inoculation under certain specified circumstances was Jenner's tentative project. The history of the introduction of cowpoxing, given in the article JENNER (VOL xiii. p. 623), is here supplemented from the point of view of historical criticism. It is right to say that the views expressed in the present article diverge in many points from the opinions generally received among medical men, and must be regarded not as the exposition of established and undisputed doctrine, but as the outcome of an independent and laborious research. Jenner's originality consisted in boldly designating cowpox as ?widee vaccinx or smallpox of the cow, and in tracing cowpox itself back to the grease of the horse's hocks. The latter contention was at length set aside by practical men as a crude fancy ; the former designation is just as arbitrary and untenable. It was elaborately shown by Pearson in 1802, and has often been confirmed by subsequent writers, that the vesicle of inoculated cowpox, even while it remains a vesicle, is quite unlike a single pustule of smallpox. But it is only for the vesicular stage of cowpox that there is even an allegation of likeness to variola ; the vesicle of natural or unmodified cowpox is only the stage of the disease before it becomes an ulcer, either inflammatory or indurated. Inoculated horse grease has the same vesicular stage ; and so also has the venereal pox when it is inoculated experimentally on the skin.1 These three very different infections have the same kind of vesicle, in every case unlike a smallpox pustule, and the same natural termination in a phagedenic or indurated sore. Jenner's originality in starting vaccination in practice is for the most part misunderstood. When he published his Inquiry in June 1798, he had twice succeeded in raising vaccine vesicles by experiment, - the first time in 1796 with matter from a milker's accidental sore, and the second time in March 1798 with matter direct from the cow. The first experiment was not carried beyond one remove from the cow ; the second was carried to the fifth remove, when the succession failed. A third experiment, in the summer of 1798, failed from the outset ; and his fourth and last experiment, in November-December 1798, led to nothing but extensive phagedenic ulceration in two cases out of six vaccinated. The so-called calf lymph is as remote from the cow as ordinary humanized lymph ; it differs from the latter or eighth, and are almost unattended by areolar redness calf, and are attended by areola, &c. Under the influence of theory, "vaccine" lymph has been got from two sources that have absolutely nothing to do with cowpox ; and, oddly enough, the matter from these sources has been so managed as to produce correct vesicles on the child's arm. One source is the grease of the horse's hocks and the other is smallpox itself. The grease of the horse was known to produce vesicles and subsequent ulcers on the hands almost indistinguishable from those of accidental cowpox. There was also the tradition (which breaks down when tested by facts) that accidental infection with the grease protected from smallpox. Jenner held that all "genuine " cowpox came from horse-grease ; and, after he had raised vaccine vesicles on the arms of children by matter from the cow's teats, he proceeded to try whether he could not raise the same kind of vesicle experimentally by matter once removed from the horse's hocks. The experiment succeeded, just as the accident had done. The vesicle (represented in plate 2 of the Inquiry) ulcerated, and the boy died of what is vaguely termed a "fever" in one place and a "contagious fever" in another. The same kind of inconsequent logic suggested the experiment of inoculating the matter of horse-groose upon the skin of the cow's teats, the object being to prove the identity of cowpox with the grease. That too succeeded in the hands of Loy of Whitby. Loy also inoculated children with the same matter, and raised vesicles on their arms, which were, of course, the same as the accidental vesicles (compared to the blister raised by a burn). Sacco of Milan actually used the equine matter on a large scale, instead of cowpox matter ; and De Carro of Vienna " equinated" many persons in that city with lymph sent him by Sacco. Baron prints a memorandum of Jenner, dated 23d July 1813, relating to "equine virus which I have been using from arm to arm for these two months past, without Observing the smallest deviation in the progress and appearance of the pustules from those produced by vaccine," and a second note, dated 17th Nay 1817, in which Jenner says he "took matter from Jane King (equine direct) for the National Vaccine Establishment. The pustules beautifully correct" This is not the place to enter upon the pathology of horse-grease ; and, as a matter of fact, equination has not been much practised on the whole. According to Jenuer's own data, it was an occasional constitutional disease of the horse's hocks in wet seasons, which was communicable to the hands of men in the form of large whitish vesicles, ending in corroding and painful open sores (see the case reported to him by Fewster, op. cit., ed. 1800, p. 96). The other anomalous source of "vaccine" is human smallpox. Jenner having succeeded in passing off his doctrine that cowpox is smallpox of the cow, it occurred to some persons about forty years after to prove the doctrine by experiment, the proof being to variolate the cow on the udder. This was accomplished in 1833, after munch trouble, by Thiele in Kazan (Russia), who inoculated several thousands of persons with the variolous matter "passed through the system of the cow." Within a few months of that experiment, the same thing was attempted by Ceely of Aylesbury, who succeeded, after many failures, in raising a large variolons pock, not on the udder of the cow, but on the mucous membrane of the vulva. The first experiment with the matter of this pock was midesigned ; his assistant pricked his hand with the lancet which had just been dipped into the large pustule, and in due course had an attack of smallpox. Ceely persevered with his experiments (having meanwhile variolated another heifer at five places on the vulva), and in due time so " managed " his matter as to produce vesicles on the human arm (without general eruption on the skin), which were regarded at Cheltenham and other places as Histori- In this posture of affairs Woodville of the inoculation cal hospital, London, succeeded in January 1799 in starting sources a succession of arm-to-arm vaccinations from a London cow, which were exceptionally free from the ulcerative lymph. termination. From that source Jenner himself was supplied with lymph in February, while more than two hundred practitioners both at home and abroad were supplied some three weeks later. There was a quarrel with Woodville in due course, and an attempt to set up an authentic Jennerian lymph independent of the London stock. But the merits of this claim (which otherwise rests on the vague evidence of Marshall) may be judged of by the fact that Ring's application to Jenner in September 1799 for genuine lymph was answered by the latter with a supply of matter which was none other than Woodville's own stock, after six months' use in the country. Woodville's stock was used all over the world down to 1836. By that time there were numerous complaints that the lymph was degenerating, and a widespread feeling that it was necessary to "go back to the cow." Apart from the numerous original cases of cowpox alleged to have been found in Wfirtemberg, the first new authentic source was the Passy cow of 1836. From the accidental vesicles on the milker's hand Bousquet, the director of vaccination in Paris, started a new stock, which partly superseded Woodville's lymph hitherto in use in France. In 1838 Estlin of Bristol, after several years' vain endeavours, heard of original cowpox in Jenner's own parish of Berkeley (Gloucestershire), where the disease was so far forgotten that the milkers were for several days unaware that the vesicles on their hands had been contracted from cows. Estlin's new geniture is one of the most fully recorded in the history of vaccination. In the same year, and the two following years (1838-41), Ceely of Aylesbury found some half-dozen distinct occurrences of cowpox in the dairy-farms of his district, and cultivated lymph from them. His account of the natural history of cowpox in the cow, and of the effects of primary lymph when inoculated on the human arm, is by far the most comprehensive and candid that has ever been given ; without it we should hardly have understood the real nature of cowpox. I3ousquet, Estlin, and Ceely are the chief writers who have authentically described the establishment of new stocks of cowpox lymph since Woodville's original report of 1799. There are numerous other references, less detailed, to original cowpox in the cow, and to vaccinations therefrom, in England, on the Continent, and in the United States ; some of these came to light in the inquiry of the Epidemiological Society in 1852. One of the best-known cases of comparatively recent times is the Beaugency cow of 1866, which has been the source of much of the calf-lymph of the Dutch, Belgian, and other vaccine "farms." Another French case occurred in the Gironde in November 1881, and is described in the Bulletin of the Academy of Medicine (p. 17, 1882). In England the editors of the Veter1,n(crian inserted a notice in the number for August 1879, making a request to their readers for lymph "from vesicles on the teats of cows in cases of so-called natural cowpox." The only answer to it hitherto has been an intimation in June 1880 that there was a case of cowpox at Halstead in Essex, which was visited by Ceely and others and pronounced by the former to be of the nature of eczema. In 1876 the disease was found at a farm near Reykjavik in Iceland, where it had never been seen before ; it was of the old type, producing sores on the milkers' hands, and causing much alarm by its unfamiliar character.1 on the whole better than the cowpox vesicle of the period. But the real practical application of this idea was reserved for Badeock, a dispensing chemist at Brighton. It does not appear that any authentic or fully detailed account of Badeock's experiments has been published ;I but he thus summarized the results some forty years later (Pall Mall Gazette, Jan. 23, 1880): - " By careful and repeated experiments I produced, by the inoculation of the cow with smallpox, a benign lymph of a non -infections and highly protective character. My lymph has now been in use at Brighton for forty years, and is at the present time the principal stock of lymph employed there, being that exclusively used by the public vaccinators." At Boston, U.S., the same kind of lymph was raised and put in use in 1852. But at Attleborough, Mass., the same experiment had in 1836 led to disaster. Smallpox was inoculated on a cow's udder, and the product used to vaccinate about fifty persons. The result was an epidemic of smallpox, a panic, and the suspension of business.2 On the face of it this method was simply variolating the cow (on a mucous membrane if the hairless or shaven skin failed) and inoculating the human subject with that curiously disguised smallpox matter. However, it was thought necessary to hold an experimental inquiry upon it, and in 1865 a commission of the Lyons Society of Medicine reported that, "in vaccinating according to the method of Thiele and Ceely, we are merely practising the old inoculation, rendered uniformly benign, it may be, by the care taken to inoculate only the first product (l'aecident primitif), but preserving for certain all its risks in respect to contagion."3 A negative result was come to by Klein in 1879, in an inquiry for the Local Government Board, wherein he had Ceely's cooperation. In 1879 the Irish Local Government Board prevented the use of similar variolous lymph by threatening to prosecute under the Act making the inoculation of smallpox penal. Notwithstanding the common sense of the case, and these experimental proofs, the official view taken by the medical department in 1857, that Thiele, Ceely, and Badcock had established the correctness of Jenner's doctrine of variohe vaccine, is still held very tenaciously by the profession. It is too simple and attractive to be soongiven up ; but perhaps the best way to get rid of it is to state in plain terms what cowpox itself really is. Although there is no difficulty in drawing up a complete natural history of cowpox, thanks to the laborious and exact studies of Ceely, yet the attention has been so much diverted to side issues that the facts to be stated in this section will come before most readers with the aspect of novelty. The other original authorities besides Ceely are Jenner himself, Pearson (who collected information by circular in the months following Jenner's Inquiry), Bousqua (1836), Estlin (1838), and Crookshank (1888). The Wiirtemberg inquiry, published by Hering (Stuttgart, 1839), is made up of very indifferently authenticated or incomplete statements, which have not the same value as the rest, and are at variance with them on the most essential points. Cowpox as an infective disease arises in cow-houses here and there, and at wide intervals of time, out of a common physiological or constitutional eruption of some particular cow, usually a heifer in her first milk, very often in the spring season or at some other crisis of the year or of the animal's life-history. It never arises except in milch cows ; it occurs nowhere in the cow but on the teats, or, by infection, on adjoining parts of the udder. All the characters by which we know it distinctively as cowpox are associated with the fact of milking, or with the inevitable traction on teats that are the subject of an otherwise unimportant eruption. The primary disorder, as Ceely describes it, is an eruption of a few pimples, the size of a vetch or larger, hard and solid at first, but at length slightly vesiculated on the summit. It is only rarely that a series of events ensues on this basis which constitute cowpox as we know it ; they ensue in some one animal out of many in the same byre, and years may elapse before the event happens again. The pimples on the teats are made to bleed by what Ceely calls "the merciless manipulations of the milkers "; the blood forms crusts, which are dislodged every six hours ; and indurated ulcers form on the sites of the original pimples. The process being thus made inveterate owing to the in- I cessant interference of the milker's hands, it becomes cons-c municable to the other cows. The milkers can usually t point out some one cow in which the disease began ; and it spreads slowly through a by-re, taking sometimes as long as three months to go the round of all the animals. An animal already infected at one or more places on its teats may become infected at other places on the teats and body of the udder, either by the traction of milking or by the contact of parts when the cow is lying down. The ulcers heal sometimes slowly, sometimes more quickly ; they may heal under crusts, or as open sores ; induration and rounding of the edges are distinctive, along with much thickening of the base. The scars are also indurated, rounded arid elevated at the edges, and smooth or puckered on the surface ; they are often as large as a walnut. It is not easy to see a vesicular stage of the disease even in the cows infected from the initial spontaneous case ; and Ceely had for the most part to be content with the coagulated matter of crusts to vaccinate with. The process is, in fact, bound up from first to last in the most intimate and essential manner with the operation of milking. Cowpox "undisturbed by the milker's hands" has no existence in the originating cow ; it is the persistent irritation that makes it a pox. It is communicable, also, to the hands of the milkers themselves, and by their filthy hands to their faces. Jenner mentions a good many such cases ; Pearson has collected several ; and Ceely gives three in very full detail. As in the inoculated venereal pox, the infection proceeds for a time under the skin, making a bluish-white vesicle ; it eats away the tissues round the margin, where the fluid makes the skin bulge out into the characteristic tumid ring. After the fourteenth day the vesicle will have become an eschar, the average size of a sixpenny piece, which comes away and leaves a sore. The open sore is a regular part of the infection in the milker's hand. Various regions of the face get infected by contact from the hands : Jenner mentions the case of "a poor girl who produced an ulceration on her lip by frequently holding her finger to her mouth to cool the raging of a cowpox sore by blowing upon it "; another of Jenner's cases had the sore on the wing of the nose ; one of Ceely's cases had an ulcer on the temple three-quarters of an inch long ; in a case observed by Crookshank there was a very large vesicle and subsequent sore over the left cheek-bone. The local infection is accompanied by constitutional disturbance, more or less severe, including headache, pains in the loins, vomiting, and sometimes delirium. The axillary glands become painful, usually about the fourth day, and remain hard for some time. Eruptions occurred, but there is very little said about them. As might have been expected, the effects of experimental infection with cowpox matter were the same as the accidental. They are spoken of as the effects of " primary lymph," that is to say, lymph direct from the cow's teats or from the milker's sore hand, or in the earlier removes from these sources.• Jenner's experience of primary lymph was very much the same as Bousquct's, Estlin's, and Ceely's forty years later. Woodville's, on the other hand, was exceptionally reassuring ;4 had it not been so, it is not likely that cowpoxing on the large scale would ever have survived the initial discon•agements entailed by the use of primary lymph. The process on the child's arm was on the whole the same as on the milker's hand, allowing for the more deliberate mode of inoculation and for different texture of the skin. The vesicle grew to a great size up to the fourteenth day, and often became an ulcer, either excavated under the crust or absolutely open. Estlin did not entirely get rid of ulceration until after the twenty-ninth remove from the cow. The constitutional disturbance was often severe in infants : axillary tenderness and swelling were somewhat constant, and eruptions were especially frequent about the second to the fourth week, including macular roseola, lichen, and pemphigoid bullet. At each successive remove from the cow the cycle of the process became more contracted, and the constitutional disturbance, exteris paribus, became less. Bousquet gives a plate which shows by parallel series of figures the differences between the vesicles of the old lymph (Woodville's, nearly forty years old) and the lymph from the Passy cow. The new lymph induced a process more protracted at every stage : the vesicle continued to enlarge at the periphery for several days after the common vaccine vesicle of the period would have ceased to extend. It was not at its maximum until about the end of the second week, and it then became an eschar and a sore. Bousquet confesses that he first understood " les frayeurs de Jenner" when he saw the ulcerative and other effects of primary lymph. After a certain number of removes from the cow the cycle became so contracted that the vesicle was full at the eighth or ninth day ; the abbreviation of its life-history enabled it to heal without ulcerating. It thus becomes the ordinary vaccine vesicle as we know it, which heals under a scab, and leaves the peculiar punctated scar of subcrustaceous repair. The abbreviation or mitigation is effected by taking lymph from each successive vaccinifer at as early a period as it can be got, until the golden mean of safe vaccination, namely, maturity at the eighth day, is reached. That corresponds to Jenner's rule of taking the matter for vaccination before the areola appears ; if the vesicle be emptied after that period, the lymph from it is apt to cause ulceration, or, as Ceely puts it, we have "all the inconveniences of primary lymph." It is thus clear that humanized cowpox might he easily cultivated back to its original type ; and, as a matter of fact, it has sometimes been so cultivated back by misadventure, with serious consequences to the vaccinated. The risks of vaccination may be divided into the risks inherent in the cowpox infection and the risks contingent to the puncture of the skin. Of the latter nothing special requires to be said ; the former will be discussed under the five heads of (1) erysipelas, (2) jaundice, (3) skin eruptions, (4) vaccinal ulcers, and (5) so-called vaccinal syphilis. (1) A slight degree of erysipelas was recognized by Jenner himself, and even postulated by him, as part of the natural history of cowpox in man ; and it is so recognized by the more unbiased writers of recent date.' The usual time for it corresponds to the appearance of the areola (eighth or ninth day), that efflorescence round the pock being normally a slight erysipelas. It may start, however, from the puncture or scratch in the skin, after a day or two's interval; but that form of it (the "early erysipelas" of German writers) is much rarer than the erysipelas of the arcola, or "late erysipelas." Primary lymph, or lymph in the first removes, is most apt to excite an extensive and spreading areolar redness. In the ordinary course of vaccination remote from the cow the intensity of the superficial redness and deep infiltration would seem to depend mostly on the child's constitution, or on whatever concurrence of circumstances serves to recall the " inconveniences of primary lymph." The registrar-general's tables of mortality for England and Wales have contained an entry of "erysipelas after vaccination " from 1855 down to 1881, when the entry was changed to "cowpox and other effects of vaccination," the numbers at the same time nearly doubling. The fatal cases of erysipelas in infants under one year referred to vaccination are but a small fraction of the whole mortality from erysipelas at that age, a mortality which le far greater than at any other period of life. It is quite certain that in foundling hospitals, such as that of St Petersburg, the erysipelas of vaccination has been the starting-point of disastrous epidemics of erysipelas affecting the inmates generally. There is DP means of knowing whether the same has been the case among the population at large. In Table I. the column of deaths from erysipelas in general, among infants of the first year in England and Wales, is given side by side with the column of deaths from erysipelas after vaccination. The post-vaccinal inflammation sometimes takes the form of phlegmon ; but there is no separate entry for that as a special sequel of vaccination. Many of the alleged deaths from erysipelas after vaccination have been the subject of coroner's inquests ; the verdict is often an open one, and even such cases as those near Gainsborough in 1876 and at Norwich in 1882 were found to have been returned (all but one) by the certifying medical practitioners as due to erysipelas merely. It may be assumed that "after vaccination" is not certified unless the case has left no doubt in the minds of the jury or of the certifying medical attendant. The increase in the first column from 0 in 1855 to 32 in 18110 is probably in appearance only, and due to more correct diagnosis. It is only within the last few years that jaundice has been recognized as a post-vaccinal effect ; and at present there is only one accepted instance of it on the large scale. This was the epidemic among re-vaccinated adults in a large shipyard at Bremen from October 1883 to April 1884. Owing to an alarm of smallpox, 1289 workmen were re-vaccinated between the 13th August and 1st September with the same humanized lymph preserved in glycerin ; of these 191 had jaundice at various intervals down to the month of April following. Circumstantial evidence (agreement and difference) clearly traced the epidemic to the vaccination.3 In future an outlook will be kept for this effect of vaccination ; at present it has no intelligible theory. It may be noted that the lymph which caused the Bremen epidemic was mixed with glycerin. The eruptions that follow vaccination are proper to cowpox infection. Although little .is said about them in the accidental infection of milkers, they were very common in the practice of Estlin, Ceely, and others with primary lymph. The eruption is a kind of exanthem, or " secondary " of the local infection, and does not ordinarily appear before the second week. One of its commonest forms is a patchy rose-rash, or macular roseola, not easily distinguishable from the macular roseola of syphilis.' Another form is lichen or dry papules, apt to scale ; it may also occur as a vesicular eruption, and in the form of pemphigoid bullm or blebs. In one of Ceely's cases the eruption extended to the whole mucous membrane of the mouth and throat. A peculiarity of the exanthem is that it may conic and go several times before it finally disappears ; and, like other skin eruptions, specific or non-specific, it may become inveterate. The widespread belief that much of the eczema of childhood dates from vaccination is not by any means to be dismissed as a mere fancy. The skin-disorders that followed vaccination in the first years of the practice were declared by Birch and others to be new in type. At present the vaccinal eruption, especially on the scalp, is sometimes distinguished by the size and form of the crusts, and by scars remaining for a time. Ulceration of the vaccine vesicle, or of the site of it, is one of the commoner forms of "bad arm." It is a return to the native or untamed characters of cowpox on the cow's teats, or on the milker's hands or face, or in the child's arm after experimental inoculation with primary lymph. It crops out not unfrequently in everyday practice, and is probably dependent for the most part on the lateness at which the lymph was taken for vaccination, or on retardation of the process in the vaccinifer, or on emptying the latter's vesicles too much ; however, it may result from picking the scab or otherwise dislodging it. The ulceration usually proceeds to some depth in the form of a crater under the crust, and is attended with induration and rounding of the edges and induration of the base. According to Bohn (op. cit., p. 166), it may alarm practitioners by its resemblance to syphilis. In other cases the crust is wanting and the ulceration has the distinct type of phagedena. The destruction of tissue in either case may be very extensive, going "down to the bone " and having as much as an inch or more of superficial area. Healing is frequently an affair of weeks, and may be aided by mercurial treatment. There are no statistics of this sequel of vaccination ; but the frequency or infrequency of it may be learned in conversation with any intelligent chemist whose shop is resorted to by the poor, or with a medical practitioner of average experience. (5) It has been proved by many experiments, undesigned or otherwise, in Paris (1831 and 1839), Vienna (1854), and elsewhere, that an infant with congenital syphilis develops correct vaccinal vesicles, provided its skin be clear of eruption and the lymph have been taken at the usual time ; also that the lymph taken from the correct vesicles of a syphilitic child produces correct vesicles in its turn, but does not produce syphilis in the vaccinated child. The congenital taint is, in fact, irrelevant to the course of cowpox infection. So far as experiment and casual experience can prove anything, that has been proved ; the recent attempt to disprove it by an officer of the Local Government Board (Report for 1882, p. 46) is vitiated by fallacies, and has no value against the overwhelming testimony collected thirty or forty years ago. What, then, is the meaning of the numerous outbreaks of syphilis in groups of children or adults vaccinated or re-vaccinated with lymph from one source ? A careful examination of these cases shows that syphilis at the source of the vaccine matter was in all eases an after-thought, that in most of the cases there was no evidence for it, and that in the remaining cases the evidence was so far-fetched as to be unlikely (apart from the known a priori improbability), or that the traces of constitutional infection found in the vaccinifer were subsequent to vaccination, and therefore capable of being explained as an effect concurrent with the more obvious symptoms in those vaccinated therefrom. The effects, however, were very much the same as in the venereal pox. The vaccine vesicle either became an indurated or phagedenic sore, as described in the foregoing section on vaccinal ulcers, or the scar opened into an indurated sore after the usual sub-crustaceous healing was complete, or became indurated without opening. The axillary and cervical glands were often indurated. In most of the epidemics there were a certain number of cases in which the effects were purely local, or confined to one only of the seats of puncture ; if these had not occurred along with others in a group, they would have been counted as ordinary vaccinal ulcers. But there were often secondary symptoms as well, including the roseolar, lichenous, or (rarely) pemphigoid eruption, and not 'infrequently condylomata circa anion ct genitalia. In some epidemics (but not in all) there were, in a small minority of the cases, mucous patches on the tonsils, tongue, or lips, tending to ulcerate ; and in some of the Italian outbreaks the infection spread among the mothers and other members of the households in the form of specific sores of the nipples, with or without constitutional symptoms. Affections of the bones and viscera do not seem to have followed ; fatalities were not very common. It will be hard to persuade medical authorities that these secondary effects are not the result exclusively of the venereal pox. The evidence, however, does not allow us to assume any other specific infection than that of cowpox, which, as we know, has its proper secondary exanthem in the form of macular roseola, lichen, or pemphigus ; the eruption has even been known to affect the mouth and throat. The evidence from epidemics of vaccinal sore arms teaches us that condylomata, mucous patches of the tonsils, tongue, and lips, and even iritis, are also possible, although far from invariable, among the " secondaries " of the primary vaccinal ulcer. The most general fact that comes out in these epidemics is that the lymph was taken late from the vaccinifer, or that the vesicles of the vaccinifer were drained dry to vaccinate a large number, or that the same vacciuifcr was used for arm-to-arm inoculation on two successive days. It is not difficult to see how, in those circumstances, the abbreviated cycle of humanized cowpox may be departed from and the native or untamed characters of cowpox infection reverted to. Cowpox, indeed, is parallel with the venereal pox, both in the circumstances of its becoming an infective ulceration (indurated or suppurating) and in its secondary or constitutional manifestations as an infection in man. lint the " bad " lymph has hardly ever been used beyond the second remove ; and there the parallel fails. The following is a list of the so-called syphilitic epidemics after vaccination, including those that have been considered spurious, because they were either anomalous in type from the point of view of syphilitic infection or had no obvious causal Connexion with that disease. Torre de' Busi near Bergamo, 1862 (see Depaul, lee. cit.). United States (troops on both sides in the Civil War), 1861A5 (Jones, Circular II., Louisiana Board of Health, Baton Rouge, 1684). Argenta near Ferrara, 1866 (Gainlyerini, in Gee. des Ilopitaux, 1870, p. 505). Morbihan (neighbourhood of Vannes and Auray), 1866 (Depaul, Dull. de Acad. de Med., xxxii., 1866437, p. 201 ; Bodelio, ibid., p. 1033). Cardaillac (Lot) 1868 (Bull. de Acad. de Mid., 28th February 1867). Sehleinitz (Styria), 1870 (Kochevar, Allgem. Wiener Med. Leg., 1870, Yes. 21 and 24 ; abstract in Arch. fur Dermatologie and Syph., 1870). London (two series), 1871 (flutchinson, Med. Chir. Trusts., liv., 1871). Switzerland, 1878 (Bull. de la Soc. de la Suisse Romantic). Algiers, 1860-81 (fount. Hygiene, 25th August 1881). Lyck (East Prussia), June 187S (Pincus' Vierteljhschr. f gericht. Med., 1875, p. 193). Asprieres (Aveyron), March 1885 (P. 13rouardel, Rapport, Paris, 1886). Attention was drawn to these cases because they occurred in groups varying in number from 10 to 100 or more, which made considerable stir, especially in country districts. It is unlikely that all cases have been reported. In the third Report of the clinical hospital of Manchester, Whitehead states the results of his inquiries on post-vaccinal illness in children. Setting aside most of the cases of illness vaguely alleged by the mothers to have been the consequence of vaccination, he admits as truly post-vaccinal 34 eases of syphilis or pseudo-syphilis ; of tl ese he enumerates only 14 in his table of 63 eases of children's syphilis of all kinds, the other 20 cases being omitted, it would appear, not because there was any doubt of their being post-vaccinal, but because they were not of the perfect type of infantine syphilis. Such was the experience of a competent observer at a single hospital during a period of 20 months. White-head's Report was published in 1859 ; but, when Hutchinson published his first series of London cases in 1871, the subject was considered to be quite new. Here again it was the concurrence of some ten cases in a group that helped the reluctant assent of the profession. The first group of London cases had hardly begun to be talked of when one of Hutchinson's colleagues was led by two cases of skin disease at a hospital to follow up the traces of another group, the very existence of which was unsuspected by the public vaccinator or general practitioners in whose district the eleven patients with vaecinal ulcers and occasional secondaries resided. In the registrar-general's tables of mortality for England and Wales about one-half of the deaths from "cowpox and other effects of vaccination," or nearly thirty per annum, may be put down to effects of vaccination other than erysipelas ; but there is nothing to show that these were fatal cases of vaccinal ulcers with constitutional symptoms or marasmus. On the other hand, the table of deaths from syphilis shows an enormous and steady increase in the number of deaths of infants under the age of one. In the first year of compulsory vaccination (1854) the deaths suddenly increased by one-half, and the increase has gone on steadily since then (see Table H.) The interpretation of the fact is by no means easy or free from fallacies. There are doubtless other and better reasons for the increase besides vaccination ; and it is significant that the tables for Scotland show the mortality to be chiefly in the first three months of life, whereas the statutory limit for vaccination in that country is six mouths. In the polemical writings of anti-vaccinists, such diseases as scrofula, tubercle, hooping-cough, diarrhcea, and other , common causes of infantine mortality are alleged to have increased owing to vaccination. There is 'little or lio I reason, in theory or in experience, to suspect that tuberculous or scrofulous infection is ever communicated by vaccine lymph. As regards the above and other infantine maladies, vaccination may predispose the child to fall into them, in so far as it produces, or ought in theory to produce, a considerable constitutional disturbance and presumably a loss, for a brief period, of the natural power to resist the various noxious influences by which the age of infancy, especially among the poor, is beset. The value of cowpox as a protection against smallpox may now be judged of apart from the fanciful doctrine of variolie vaccince by which it was originally recommended. It has been put to a test extending over eighty years ; and in some circumstances it has been possible to apply the logical methods of agreement and differ- ence with a good deal of cogency. The besetting fallacy of all vaccination logic is that of post hoe ergo propter hoe ; and the only way to escape it is to hold intelligent views of the history, the natural history, and the epidemiology of smallpox. This will necessitate a brief excursus. Smallpox, which is really a tropical skin disease of the nature of lichen turned pustular, or of ecthyma, must be judged according to what we know of foreign pestilences in general. Perhaps we are safest to take a line through the behaviour of the plague. Plague in western Europe had the start of smallpox by a good many years, if we speak only of prevalence on the large scale. "Throughout the 16th century," says Hirsch, "the plague was a permanent form of disease on the continent of Europe. . . . During the first two-thirds of the 17th century we still meet with it over an equally wide area and equally often. But in the last thirty years of that century the plague was observed to be retreating gradually from the soil of Europe." It was not only in London after the fire of 1666 but also in Denmark and Sweden, in Italy, in Holland and Belgium, in Switzerland, in France, in western Germany, and in Spain that the years 1660-1680 saw the last of plague ; it lingered only in the Levant, in Poland, and in other parts of north-eastern Europe, with occasional epidemic visits, such as those of Messina and Marseilles. Now it has left the Levant and Egypt, has abandoned even Mesopotamia and Arabia, and retreated to a few poor villages on the Perso-Armenian frontier. Or, take the example of leprosy, which owed its existence rather to the widespread or national concurrence of the same causes in various countries than to the travelling of an infection : Italy had it first and lost it first, and nearly every other country in Europe saw its rise, its general prevalence, its decline, and its extinction, the northern countries keeping it longest. Again, typhus fever was a standing disease so long as Europe was the theatre of protracted wars and all their consequences ; hut, like other infections, typhus gradually declined and has almost disappeared since the conditions on which it depended ceased. Leaving these parallels and coming to the facts of smallpox itself, it rose to prominence in western Europe in the 16th century, and in England hi the 17th.' From the early part of the 18th century a remission was noted ; but the latter half of that century saw a considerable extension of the area of the disease, for which the practice of inoculation has been blamed. It is a mistake to suppose that smallpox has shown a tendency towards a universal infection ; for all its chances it has kept within moderate limits of age and place, and extended only by repeated provocation. Thus, Hirsch says of the western hemisphere, "A still more terrible source for America was the importation of Negro slaves, so much so that hi after years, particularly in South America and the West Indies, not only the first appearances of smallpox, but every fresh outbreak of it, could be traced to importation from Africa," - the African continent being then, as now and always, one of its principal native seats. III Europe it has been peculiarly a disease of infancy and of the most crowded parts of cities. It has had victims among the upper classes, just as cholera has had ; but, like that disease, its habitat is among the crowded poor ; and it would have touched the wellto-do-classes less in former times if there bad always been spacious west-end quarters in cities or the modern "passion for clean linen," personal ablutions, and fresh air. Tenement houses and ill-ventilated courts or alleys have been the natural harbourage of smallpox ; in proportion as these have been demolished the disease has disappeared or been circumscribed in its area. It is fallacious to estimate its prevalence now in ratio of the whole population ; for a just comparison of one period with another, we have to take into account, not the death-rate per million living, but the death-rate per million still living under the old-world conditions. From the earliest period of its history in Europe, the disease has had its seasons of quickening or revival, with long intervals of quiescence ; only in the most crowded parts of Western cities has it ever been endemic from year to year. These epidemic outbursts have varied much in intensity and in area, the conditions of variation being mostly unknown. In that respect, it need hardly be said, smallpox is like other epidemic diseases. During the early years of the 19th century there was a marked remission of the epidemic outbursts of the disease in most parts of Europe. The amount of vaccination during those years was inconsiderable ; in particular it hardly touched the poor. Thus, at the time of the Norwich epidemic of 1819, it was estimated (by Cross) that only one-fourth of the inhabitants were vaccinated, and these almost exclusively the well-to-do. At the same time the practice of inoculating smallpox, which was with good reason blamed for keeping the contagion generally diffused and active among the non-inoculated, began to be discontinued and soon ceased altogether. Undoubtedly there was a marked decline in smallpox during the first fifteen years of the century, but the associated circumstances are as complex as the fact itself is simple. We have to bear in mind the old law of periodic exacerbation and dormancy, the cessation of a practice (inoculation) which almost certainly interfered with the natural tendency of smallpox as a foreign pestilence to die out, and the unusual prevalence of typhus fever (on the Continent), and other displacing or substitutive factors in the death-rate. To what extent vaccination was a factor will have to be decided by the experience of a period when the practice was much more generally in vogue. For that purpose we may here restrict the inquiry to England and Wales, premising that the experience of other European countries where vaccination has been equally practised is not different. The following table (III.) begins with the year 1847 ; the registration reports go back to 1838, but there is a break in the tables for five years near the beginning. In the first years of the table the deaths from smallpox of children under five were to those of all other ages in the ratio of 3 to 1 or of 5 to 2 (at Norwich in 1819 there were 530 deaths, of which half were in infants under two, and all the rest save ten were in children under ten years); disproportion lessened gradually, until about 1864 it was neary 4 to 3 ; in 1870 the proportion was nearly equal ; and from that time onward the preponderance leaves the age of infancy and childhood, so that in 7884 the deaths under five were three times fewer than those at all other ages. The great epidemic of 1871.72 brought out that remarkable change of incidence most decidedly. Taking the mortality of 1871 as an instance, the significance of the changed incidence on the periods of life is that the 7770 deaths under the age of five would, in pre-compulsion times, have had a complement of no more than 2500 deaths in the later periods of life, or that the actual mortality of 15,356 above the age of five would have had a complement of some 40,000 or 45,000 deaths below that age. (In British India in 1884 of 333,000 deaths 72 per cent. were of children under 12 in Bengal, and 64 per cent. in Madras.) Apart from the changed incidence of smallpox, Table III. shows merely the caprices of the disease as an epidemic. After every epidemic outburst the disease declines and sometimes looks as if it were about to die out altogether. The alarm attending each severe epidemic has induced the legislature to make the vaccination law more stringent and vaccinators to insert more of the virus, so that the periodic subsidence has corresponded to, and has seemed to be owing to, the better enforcement of the practice ; but there have always been alternating periods of quiescence and exacerbation, irrespective of any prophylactic. Moreover, smallpox being a foreign contagious skin disease lurking in congenial haunts, it would be quite according to precedent that it should one day cease absolutely in a community where sanitary progress had advanced so far as to take the ground from under the feet of the pestilence ; such absolute cessation would have no more necessary connexion with almost universal vaccination than the alternating quiescence and recrudescence of epidemics have been connected with each new Act of Parliament. The epidemic of 1871-72 was one of the worst in the whole history of European smallpox ; and it may be that it was one of the last flickers of a slowly expiring flame. The universal practice of cowpoxing, however, is based upon the assumption that this contagious skin disease imported from the tropics is a thing that Europe must reckon with for an indefinite time. On the other hand, the teaching of epidemiology is that a foreign pestilence never stays unless it finds quarters suited to its existence, and that it may even take its departure capriciously, as in the ease of the plague, after it has had a certain career, or on being displaced by some congener such as typhus. Vaccination is considered to have turned smallpox in great part aside from the early years of life and thrown it more than ever upon the later ages, while measles and other maladies proper to childhood have at the same time increased.' Thus far as regards the utility of vaccination to the state ; we have now to consider its utility to the individual. Do the vaccinated escape in an epidemic ? or, if they do not escape an attack of smallpox, do they escape death from it ? In answer to the first question, apart from the familiar negative experience of everyone, we have the statistics of smallpox hospitals, which relate to the poorer class and probably do full justice to the fact of non-vaccination, inasmuch as the unvaccinated residue is mostly to be found in those slums and tenements of the poor where smallpox (now as always) is apt to linger. At the Eastern Metropolitan Hospital (Homerton) from its opening early in 1871 to the end of 1878 there were 6533 admissions for smallpox, of which 4283 had vaccination marks, 793 had no marks although vaccinated, and 1477 were unvaccinated, giving a proportion of 0.29 unvaccinated. .In the epidemic hospitals of Liverpool, Glasgow, and Dublin the proportion was 0.25 during the same period. For some of the German states the proportion of unvaccinated cases comes out a good deal less than one-fourth ; thus, in Bavaria in 1871 of 30,742 cases 29,429 were in vaccinated persons, or 95.7 per cent., and 1313 in the unvaccinated, or 4.3 per cent.' In some of the small local outbreaks of recent years the victims have been nearly all vaccinated (e.g., at Bromley in 1881, a total of 43 cases, including sixteen confluent, all vaccinated).3 In the army and navy, where vaccination and re-vaccination are absolutely without exception, the proportion is accordingly 0. It would thus appear that the rather excessive proportion of cases among the small residue of unvaccinated in the civil population must have other associated circumstances besides non-vaccination ; and these are not far to seek. The next question is the death-rate among the vaccinated and unvaccinated respectively. The total death-rate from smallpox in modern times is almost the same as it was in the 18th century ; large aggregates collected by Jurin and others in pre-vaccination times show a mortality of 18.8 per cent., and corresponding aggregates in English and American hospitals, mostly since 1870, show a mortality of 18.5 per cent. It has, however, to be borne ill mind that the division Into discrete, confluent, and malignant smallpox is an old one ; that a mild type was quite common in the 17th and 18t11 centuries, and was now and then characteristic of whole epidemics, just as in the case of scarlatina ; and that the vaccinated are at present liable to be attacked by the confluent and malignant disease as well as by the discrete. But are the vaccinated liable ro the fatal forms of smallpox in the same proportion as the unvaccinated ? It is only since 1879 that the registrar-general's tables for England and Wales have attempted to supply data bearing on this ; and it will be seen from the following abstracts (Tables IV.-VII.) that the data are still far from being sufficient: - These figures may be made to prove anything, according to the bias of the individual ; the column of " not stated " commands the situation. The official figures' for Bavaria in 1871 are more precise: among the 29,429 cases of smallpox ill vaccinated persons there were 3994 deaths, while among the 1313 unvaccinated cases there were 790 deaths ; of the latter no fewer than 743 deaths were of infants in their first year. The mortality among both the vaccinated and the unvaccinated is always excessive for infancy. Feeble health, as well as non-vaccination, is a factor in the very excessive smallpox mortality at that tender age. The returns from special smallpox hospitals make out a very-small death-rate (6 per cent.) among the vaccinated and a very large death-rate (40 to 60 per cent.) among the unvaccinated. The result is doubtful qua vaccination, for the reason that in pre-vaccination times the death-rate (18'8 per cent.) was almost the same as it is now in the vaccinated and unvaccinated together (18-5). At the Homerton Hospital from 1871 to 1878 there were admitted 793 cases in which. "vaccination is stated to have been performed, but without any evidence of its performance"; the deaths in that important contingent were 216, or 27.2 per cent., but they are not permitted to swell the mortality among the "‘ vaccinated."' Again, the explanatory remarks of the medical officer for Birkenhead in 1877 reveal to us the rather surprising fact that his column of "unvaccinated" contained, not only cases that were admittedly not vaccinated, but also those that were "without the faintest mark "; of the 72 cases in that column no fewer than 53 died. His column of "unknown" contained 80 per cent. of patients who protested that they had been vaccinated (28 deaths in 220 cases or 12.7 per cent.). Those who passed muster as veritably vaccinated were 233, of whom 12 died (5.1 per cent.). With reference to this question of the marks, it has to be said that cowpox scars may be temporary, that their "goodness" or "badness" depends chiefly on the texture of the individual's skin and the thickness or thinness of the original crust, and that the aspect of the scar, or even its total absence some years or even months after, may be altogether misleading as to the size and correctness in other respects of the vaccine vesicle, and of the degree of constitutional disturbance that attended it. This was candidly recognized by Ceely,5 and will not he seriously disputed by anyone who knows something of cowpox and of how it has been mitigated, and of the various ways in which the tissues of individuals may react to an inoculated infection. In confluent cases the marks on the arm would be less easily seen. The following statistical table (VIII.) shows death from smallpox to be comparatively rare where the marks are many and "good." The practice of re-vaccination was first recommended in England by G. Gregory, and in Germany for the army by Heim (1829). It has been more or less the law in Prussia since 1835 :7 " re-vaceina. tion of school pupils at the age of twelve is an integral part of the vaccination law." Notwithstanding the fact that Prussia was the best re-vaccinated country ill Europe, its mortality from smallpox in the epidemic of 1871 was higher (69,839) than in any other northern state. The efficacy of re-vaccination is sometimes sought to be proved by the immunity of nurses in smallpox hospitals. The experiment of not re-vaccinating the nurses was tried at the smallpox hospital of the South Dublin Union in 1871-72 ; 29 out of the 36 attendants had not been re-vaccinated. and these all escaped smallpox as well as the other seven." But nurses are not rarely chosen from among those who have had smallpox, and cases of smallpox in re-vacemated nurses are not unknown." The evidence as to re-vaceination on a large scale comes from the army. According to a competent statistician (A. Vogt), the death-rate from smallpox in the German army, in which all recruits are re-vaccinated, was 60 per cent. more than among the civil population of the same age ; it was ten times greater among the infantry than among the cavalry, and sixty times more among the Hessians than among the Wiirtembergers. The Bavarian contingent, which was re-vaccinated without exception, had five times the death-rate from smallpox in the epidemic of 1870-71 that the Bavarian civil population of the same ages had, although re-vaccination is not obligatory among the latter. The susceptibility to cowpox infection diminishes with age ; among the pupils of twelve years in Prussian schools it fails in about one-fourth of the attempts, and at later periods of life the proportion of failures is still greater. It is often alleged that the unvaccinated are so much inflammable material in the midst of the community, and that smallpox begins among them and gathers force so that it sweeps even the vaccinated before it. Inquiry into the facts has shown that at Cologne in 1870 the first unvaccinated person attacked by smallpox was the 174th in order of time, at Bonn the same year the 42d, and at Liegnitz in 1871 the 225th. State-supported facilities for vaccination began in England in 1808 with the National Vaccine Establishment. In 1840 vaccination fees were made payable out of the rates. The first compulsory Act was passed in 1853, the guardians of the poor being intrusted with the carrying out of the law ; in 1854 the public vaccinations under one year of age were 408,824, as against an average of 180,960 for several years before. In 1867 a new Act was passed, rather to remove some technical difficulties than to enlarge the scope of the former Act ; and in 1871 the Act was passed which compelled the boards of guardians to appoint vaccination officers. The guardians also appoint a public vaccinator, who must be duly qualified to practise medicine, and whose duty it is to vaccinate (for a fee of one shilling and sixpence) any child resident within his district brought to him for that purpose, to examine the same a week after, to give a certificate, and to certify to the vaccination officer the fact of vaccination or of insusceptibility. The Local Government Board awards a considerable sum in premiums for totals of successful vaccination, at a higher scale of one shilling for each case, and a lower scale of sixpence. The vaccination officer sees that all infants are vaccinated, either publicly or privately, before they are three months old (in Scotland six months), unless there is reason for postponing the operation. He acts also as registrar of vaccinations. Parents refusing to obey the summons taken out by the vaccination officer are liable to a penalty of twenty shillings for each offence. In 1880 the president of the Local Government Board brought in a bill to repeal the part of the Act relating to cumulative penalties ; but the bill was withdrawn owing to protests from the medical profession. In a number of populous unions of England a majority of the guardians are decided not to prosecute under the Vaccination . Act ; other unions prosecutions are not unfrequent, the convictions having amounted in 1885 to upwards of two thousand, and having usually led to distraint of goods (rarely to imprisonment) in default of paying the fine. In England about two-thirds of all infants are vaccinated at the public expense. Vaccination was made compulsory in Bavaria in 1807, and subsequently in the following countries : - Demnark (1810), Sweden (1814), Wiirtemberg, Hesse, and other German states (1818), Prussia (1835), Roumania (1874), Hungary (1876), and Servia (1881). It is compulsory by cantonal law in ten out of the twenty-two Swiss cantons ; an attempt to pass a federal compulsory law was defeated by a plebiscite in 1881. In the following countries there is no compulsory law, but Governmental facilities and compulsion on various classes more or less directly under Governmental control, such as soldiers, state employes, apprentices, school pupils, Stc.: - France, Italy, Spain, Portugal, Belgium, Norway, Austria, Turkey. In only is few States or cities of the American Union is there a vaccination statute ; in Canada there is none. Vaccination has been compulsory in South Australia since 1872, in Victoria since 1874, and in Western Australia since 1878. In Tasmania a compulsory Act was passed in 1882. In New South Wales there is no compulsion, but free facilities for vaccination. Compulsion was adopted at Calcutta in 1880 and since then at eighty other towns of Bengal, at Madras in 1884, and at Bombay and elsewhere in the presidency a few years earlier. Re-vaccination was made compulsory in Denmark in 1871 and in Roumania in 1874 ; in Holland it was enacted for all school pupils in 1872. The various laws and administrative orders which had been for many years iir force as to vaccination and re-vaccination in the several German states were consolidated in an imperial statute of 1874. Anthoritics. - Jenner, Inquiry, London, 1798, and Further Observations, 1799 ; G. Pearson, Inquiry concerning the History of Cowpox, London, 1798 ; Woodville, Reports of a Series of Inoculations for the Variolte Vaccinee or Cowpox, London, 1799 ; Baron, Life of Edward Jenner, M.D., 2 vols., London, 1838; Bousquet, Sur le Cow-pox, decouvert a I'assy, Paris, 1836 ; Fstlin, in Land. Med. Casette, 1838-39 ; Ceely, Trans. Prow. Ned. and Surg. Assoc., viii. (1840) and x. (1842); Hering, Ueber Kuhpocken an laihen, Stuttgart, 1839 ; Viennois and others, in

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Date of this Version Prasher (42) cloned a cDNA for the green fluorescent protein (GFP) gene from the jellyfish Aequorea victoria in 1992. Shortly thereafter, to the amazement of many investigators, this gene or derivatives thereof were successfully expressed and conferred fluorescence to bacteria and Caenorhabditis elegans cells in culture (10, 31), followed by yeast (24, 39), mammals (40), Drosophila (66), Dictyostelium (23, 30), plants (28, 49), and filamentous fungi (54). The tremendous success of GFP as a reporter can be attributed to unique qualities of this 238- amino-acid, 27-kDa protein which absorbs light at maxima of 395 and 475 nm and emits light at a maximum of 508 nm. The fluorescence of GFP requires only UV or blue light and oxygen, and therefore, unlike the case with other reporters (β-glucuronidase, β-galacturonidase, chloramphenicol acetyltransferase, and firefly luciferase) that rely on cofactors or substrates for activity, in vivo observation of gfp expression is possible with individual cells, with cell populations, or in whole organisms interacting with symbionts or environments in real time. Complications caused by destructive sampling, cell permeablization for substrates, or leakage of products do not occur. Furthermore, the GFP protein is extremely stable in vivo and has been fused to the C or N terminus of many cellular and extracellular proteins without a loss of activity, thereby permitting the tagging of proteins for gene regulation analysis, protein localization, or specific organelle labeling. The mature protein resists many proteases and is stable up to 65°C and at pH 5 to 11, in 1% sodium dodecyl sulfate or 6 M guanidinium chloride (reviewed in references 17 and 67), and in tissue fixed with formaldehyde, methanol, or glutaraldehyde. However, GFP loses fluorescence in methanol-acetic acid (3:1) and can be masked by autofluorescent aldehyde groups in tissue fixed with glutaraldehyde. Fluorescence is optimal at pH 7.2 to 8.0 (67).

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Cranial Ultrasound/Head Ultrasound - What is cranial ultrasound? - What are some common uses of the procedure? - How should I prepare? - What does the equipment look like? - How does the procedure work? - How is the procedure performed? - What will I experience during and after the procedure? - Who interprets the results and how do I get them? - What are the benefits vs. risks? - What are the limitations of cranial ultrasound? What is cranial ultrasound? A head ultrasound examination produces images of the brain and the cerebrospinal fluid that flows and is contained within its ventricles, the fluid filled cavities located in the deep portion of the brain. Since ultrasound waves do not pass through bone easily, this exam is most commonly performed on infants, whose skulls have not completely formed. The gaps between those skull bones provide a "window," allowing the ultrasound beam to freely pass into and back from the brain. The ultrasound probe and some gel are placed on the outside of the head in one of those regions without bone. A transcranial Doppler (TCD) ultrasound evaluates both the direction and velocity of the blood flow in the major cerebral arteries of the brain. This type of ultrasound exam is also used during surgical procedures to monitor blood flow in the brain. TCD may be used alone or with other diagnostic exams such as magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) and computed tomography (CT) scans. Ultrasound is safe and painless, and produces pictures of the inside of the body using sound waves. Ultrasound imaging, also called ultrasound scanning or sonography, involves the use of a small transducer (probe) and ultrasound gel placed directly on the skin. High-frequency sound waves are transmitted from the probe through the gel into the body. The transducer collects the sounds that bounce back and a computer then uses those sound waves to create an image. Ultrasound examinations do not use ionizing radiation (as used in x-rays), thus there is no radiation exposure to the patient. Because ultrasound images are captured in real-time, they can show the structure and movement of the body's internal organs, as well as blood flowing through blood vessels. Ultrasound imaging is a noninvasive medical test that helps physicians diagnose and treat medical conditions. What are some common uses of the procedure? Head ultrasound is a routine exam for infants who were born prematurely. The procedure is used to screen for brain conditions associated with prematurity, such as bleeding or brain tissue damage as described below. If detected, follow-up ultrasound exams will be performed. In infants, head ultrasound is used to: - evaluate for hydrocephalus, or an enlargement of the ventricles, a condition that can have a number of causes. - detect bleeding within the brain tissue or the ventricles. The latter condition is called intraventricular hemorrhage (IVH). - assess whether there is damage to the white matter brain tissue surrounding the edges of the ventricles, a condition known as periventricular leukomalacia (PVL). - evaluate for congenital abnormalities. - locate the site of an infection or tumor. In adults, head ultrasound is used to locate and evaluate tumor masses during brain surgery, facilitating their safe removal. Transcranial Doppler ultrasound is used to assess the risk of stroke in adults and children with sickle cell disease. It is also used to measure conditions affecting blood flow to and within the brain, such as: - Stenosis: a narrowing of a segment of a vessel, most commonly due to atherosclerosis (hardening of the arteries). - Vasospasm: a temporary narrowing of a vessel, usually a reaction to blood being present in the spinal fluid spaces surrounding the brain. This condition is known as subarachnoid hemorrhage (SAH). How should I prepare? No special preparation is required prior to head or transcranial Doppler ultrasound exams. However, the patient should wear comfortable, loose-fitting clothing Adults may be asked to stop using nicotine-based products 30 minutes to two hours prior to a transcranial Doppler ultrasound exam. Products with nicotine may cause blood vessels to constrict and give inaccurate results. Your doctor will provide specific instructions for you or your child prior to the exam. What does the equipment look like? Ultrasound scanners consist of a console containing a computer and electronics, a video display screen and a transducer that is used to do the scanning. The transducer is a small hand-held device that resembles a microphone, attached to the scanner by a cord. The transducer sends out inaudible high frequency sound waves into the body and then listens for the returning echoes from the tissues in the body. The principles are similar to sonar used by boats and submarines. The ultrasound image is immediately visible on a video display screen that looks like a computer or television monitor. The image is created based on the amplitude (loudness), frequency (pitch) and time it takes for the ultrasound signal to return from the area of the patient being examined to the transducer (the device used to examine the patient), as well as the type of body structure and composition of body tissue through which the sound travels. A small amount of gel is put on the skin to allow the sound waves to travel back and forth from the transducer. How does the procedure work? Ultrasound imaging is based on the same principles involved in the sonar used by bats, ships and fishermen. When a sound wave strikes an object, it bounces back, or echoes. By measuring these echo waves, it is possible to determine how far away the object is as well as the object's size, shape and consistency (whether the object is solid or filled with fluid). In medicine, ultrasound is used to detect changes in appearance, size or contour of organs, tissues, and vessels or detect abnormal masses, such as tumors. In an ultrasound examination, a transducer both sends the sound waves and receives the echoing waves. When the transducer is pressed against the skin, it directs small pulses of inaudible, high-frequency sound waves into the body. As the sound waves bounce off internal organs, fluids and tissues, the sensitive microphone in the transducer records tiny changes in the sound's pitch and direction. These signature waves are instantly measured and displayed by a computer, which in turn creates a real-time picture on the monitor. One or more frames of the moving pictures are typically captured as still images. Small loops of the moving “real time” images may also be saved. Doppler ultrasound, a special application of ultrasound, measures the direction and speed of blood cells as they move through vessels. The movement of blood cells causes a change in pitch of the reflected sound waves (called the Doppler effect). A computer collects and processes the sounds and creates graphs or color pictures that represent the flow of blood through the blood vessels. How is the procedure performed? A head ultrasound is performed in the neonatal intensive care unit (NICU) at the infant's bedside. The infant is positioned lying face-up. A clear, water-based gel is applied to the transducer to help the transducer make secure contact with the body and eliminate air pockets that can block the sound waves from passing into the body. The sonographer (ultrasound technologist) or radiologist then gently presses the transducer against the fontanelle (soft spot of the infant's head, which has no bone to block the passage of the sound waves). If head ultrasound is used during brain surgery, a portion of the skull will be removed and the exposed brain examined for brain masses with the use of a transducer. During a transcranial Doppler ultrasound, the patient is either positioned on his or her back on an examination table or seated upright in an examination chair. A clear water-based gel is applied on the back of the neck, above and lateral to the cheek bone, in front of the ear or over the eyelid, as these are sites for blood vessels that supply the brain. The transducer is gently pressed over one of these areas to measure the direction and speed of the flowing blood. The patient will need to remain still during the examination, which may take up to 35 minutes. However, if the patient needs to adjust his or her position on the examination table, there is usually no problem in pausing for that time. If the examination is being performed on an infant, a nurse or radiologic technologist may assist with keeping the infant still to ensure the best imaging quality. What will I experience during and after the procedure? Ultrasound examinations are painless and easily tolerated by most patients. There may be minimal discomfort from pressure, as the transducer is pressed against the area being examined. If the gel is not warmed prior to contact with the skin, it could produce a cold sensation. If a Doppler ultrasound study is performed, you may actually hear pulse-like sounds that change in pitch as the blood flow is monitored and measured. Once the imaging is complete, the clear ultrasound gel will be wiped off your skin. Any portions that are not wiped off will dry to a powder. The ultrasound gel does not stain or discolor clothing. After an ultrasound examination, you should be able to resume your normal activities immediately. Who interprets the results and how do I get them? A radiologist, a physician specifically trained to supervise and interpret radiology examinations, will analyze the images and send a signed report to your primary care physician, or to the physician or other healthcare provider who requested the exam, and he/she will share the results with you. In some cases the radiologist may discuss results with you at the conclusion of your examination. Follow-up examinations may be necessary, and your doctor will explain the exact reason why another exam is requested. Sometimes a follow-up exam is done because a suspicious or questionable finding needs clarification with additional views or a special imaging technique. A follow-up examination may also be necessary so that any change in a known abnormality can be monitored over time. Follow-up examinations are sometimes the best way to see if treatment is working or if an abnormality is stable over time. What are the benefits vs. risks? - Most ultrasound scanning is noninvasive (no needles or injections). - Occasionally, an ultrasound exam may be temporarily uncomfortable, but it is almost never painful. - Ultrasound is widely available, easy-to-use and less expensive than other imaging methods. - Ultrasound imaging is extremely safe and does not use any ionizing radiation. - Ultrasound scanning gives a clear picture of soft tissues that do not show up well on x-ray images. - For standard diagnostic ultrasound, there are no known harmful effects on humans. What are the limitations of cranial ultrasound? Ultrasound examinations are very sensitive to motion, and an active or crying child will slow the examination process. Large patients are more difficult to image by ultrasound, because greater amounts of tissue weaken the sound waves as they pass deeper into the body. Exam results could be altered, due to: - an open wound or recent surgical incision near the area being imaged. - changes in blood flow pattern as a result of heart disease or irregular heart rhythms. Locate an ACR-accredited provider: To locate a medical imaging or radiation oncology provider in your community, you can search the ACR-accredited facilities database. This website does not provide costs for exams. The costs for specific medical imaging tests and treatments vary widely across geographic regions. Many—but not all—imaging procedures are covered by insurance. Discuss the fees associated with your medical imaging procedure with your doctor and/or the medical facility staff to get a better understanding of the portions covered by insurance and the possible charges that you will incur. Web page review process: This Web page is reviewed regularly by a physician with expertise in the medical area presented and is further reviewed by committees from the American College of Radiology (ACR) and the Radiological Society of North America (RSNA), comprising physicians with expertise in several radiologic areas. Outside links: For the convenience of our users, RadiologyInfo.org provides links to relevant websites. RadiologyInfo.org, ACR and RSNA are not responsible for the content contained on the web pages found at these links. This page was reviewed on June 23, 2014

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SOLID ALVEOLAR-TYPE RHABDOMYOSARCOMA Rhabdomyosarcoma (RMS) is the most common malignant neoplasm of the soft tissues in infants and children. RMS comprises 2-4% of all malignant tumors in children less than 15 years of age. The annual incidence of RMS is 4.5 cases per million in U.S. children less that 15 years old. 1 The incidence rate is lower in African-American and Oriental children. The median age at diagnosis is approximately 4 years, with a male : female ratio of 1.4 : 1. RMS arises from embryonic mesenchymal cells with the potential for differentiating into striated muscle. The conventional classification system proposed by Horn and Enterline2 consists of four histologic subtypes of RMS: embryonal, alveolar, pleomorphic and mixed. The embryonal subtype is the most common histology found in children, and is the most common histology of the head and neck and RMSs. Sarcoma botryoides is a subtype of the embryonal RMS, with a gross appearance that resembles a cluster of grapes. These polypoid masses most commonly develops in the walls of hollow, mucosal-lined structures, such as the nasopharynx, common bile duct, bladder, and vagina. The alveolar subtype is uncommon and is most often found in the extremities and trunks of young adults and teenagers. Pleomorphic RMS is rare and usually occurs in adults. The mixed cell subtype comprises tumors made up of more than one of the above histologic subtypes. The alveolar type of rhabdomyosarcoma is composed largely of ill-defined aggregates of poorly differentiated round or oval tumor cells that frequently show central loss of cellular cohesion and formation of irregular "alveolar" spaces. The individual cellular aggregates are separated and surrounded by frameworks of dense, frequently hyalinized fibrous septa that surround dilated vascular channels.3 Not infrequently, portions of the tumor lack an alveolar pattern entirely and are composed only of solidly packed groups or masses of tumor cells, as is seen in this case. These are presumably the same neoplasms that Tsokos et al.4 singled out as "solid variants of rhabdomyosarcoma". Furthermore, the strong nuclear staining with myogenin correlates with alveolar rhabdomyosarcoma, solid-variant.5-6 Alveolar rhabdomyosarcoma has been consistently shown to be associated with a specific translocation, t(2;13)(q37;q14) or its variant t(1;13)(p36;q14). 7 Barr et al.8 showed that the PAX3 gene in 2q35 is disrupted by the t(2;13). PAX3 encodes a developmentally regulated transcription factor with a 5' DNA-binding domain (paired box and homeodomain); the breaks in the rearrangement seem to cluster to an intron downstream of this domain. The translocation leads to the formation of a chimeric gene in which the 5' portion of PAX3 is fused to the remains of a locus on chromosome 13. The latter is the site of the gene FKHR that encodes a transcription factor identified by Galili et al9 as a member of the fork head domain family. Combined RNA and protein analyses demonstrated that the t(2;13) results in the formation of a consistent and presumably tumorigenic chimeric transcription-regulating protein consisting of an intact PAX3 DNA-binding domain, a truncated fork head DNA-binding domain, and C-terminal FKHR regions. The variant translocation t(1;13)(p36;q14) fuses the PAX7 gene on chromosome 1 with the FKHR on chromosome 13. The chimeric transcript consists of 5' PAX7 and 3' FKHR, in parallel with the generation of the 5' PAX3-3' FKHR formed by the t(2;13). In some alveolar rhabdomyosarcomas,the fusion genes are amplified,10-11 and extra copies of chromosomes 2, 8, 9, 11,12,13 and 20 can be typically seen.12 The combination of histology, immunohistochemistry, chromosome analysis, and molecular cytogenetics played an important role in the diagnosis of this tumor. Refinement of soft tissue tumor classification and a better understanding of tumor pathophysiology is becoming possible as molecular cytogenetics becomes increasingly useful in the diagnosis, characterization and classification of soft tissue tumors. Contributed by J. Thomas Molina, M.D., Ph.D., Burhan Gharaibeh, Ph.D. , Ronald Jaffe, M.B., B.Ch., Urvashi Surti, Ph.D.

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Overview of Neurodiagnostic Tests Neurodiagnostic tests, also called neurodiagnostics, are done when a patient's illness or condition is thought to be based in the central nervous system (brain and spinal cord). Signs of nervous system disorders include the following: - Chronic headaches - Hearing and vision changes - Numbness and tingling There are two types of neurodiagnostic testing: imaging tests or scans (e.g., x-ray, CT scan, MRI scan, PET scan) and electrical impulse detection (e.g., EEG, EMG). Neurodiagnostic testing may be conducted as part of a neurological exam. Computerized tomography (CT scan) uses x-ray technology to produce multiple cross-section images. In addition to providing images of the brain and nervous system, they can be used to identify broken bones, tumors, blood clots, heart disease, and internal bleeding. Magnetic resonance imaging (MRI scan) uses a powerful magnet combined with radio waves to examine organs, soft tissues, and skeletal structures. MRI scans are especially valuable in finding brain and spinal cord abnormalities. They may also be used to help diagnose torn ligaments, tumors, circulation (blood flow) problems, inflammation (e.g., arthritis), and infection. Positron emission tomography (PET scan or PET imagery) uses radiation from the emission of positrons (extremely small particles discharged from a radioactive substance) to create images that can help detect and evaluate cancer and the effects of cancer therapy. This test also can be used to diagnose a variety of neurological conditions, including memory disorders, tumors, and seizure disorders. In a PET scan, a small amount of a radioactive substance is combined with a natural body compound (e.g., glucose, water, or ammonia) and is injected into the patient. Once the substance has had time to circulate through the body and accumulate in the tissues (generally 30 to 90 minutes), a PET scanner is used to detect the various levels of energy given off by the positrons and produce images. Different colors or levels of brightness indicate different levels of organ and tissue function. Cancer tissue, for example, uses more glucose than normal tissue and shows up brighter on the PET scan. PET Scan Preparation PET scans are outpatient procedures that generally take 1 to 2 1/2 hours to perform. Patients are advised to wear loose, comfortable clothing; avoid eating for 4 hours prior to the appointment; and drink water before the appointment. Because the PET scan relies on glucose level activity, patients who have diabetes should consult a physician about how to control glucose levels during the procedure to avoid false test results. It is important to arrive on time for PET scan appointments. The radioactive substance that is used has a short lifespan and it must be prepared immediately before the procedure to remain effective during the scan. Once the substance is injected, patients are advised to rest and avoid significant movement, so that the radioactive material can be properly localized in the tissue. Scanning usually begins after 30-90 minutes. PET Scan Procedure The PET scanner is a large machine that is shaped like a doughnut. Inside the hole in the middle are several rings of detectors that record energy emission and send the information to computers, where the images are displayed. The patient lies on a padded examination table and is moved into the hole. The scan takes approximately 3045 minutes. During this time, the patient must remain as still as possible. Most people do not experience discomfort during a PET scan. However, patients who are claustrophobic or uncomfortable holding still for a long period of time may experience anxiety. The radioactive substance does not cause any physical sensations. After the procedure, patients should drink plenty of fluids to flush out the radioactive substance. There are no restrictions on activity following a PET scan. Benefits & Risks of PET Scan The primary benefit of positron emission tomography is that it can detect minor changes in biochemical levels, even before these changes show up as tumors or other abnormalities. In addition, the radiation exposure is lower than x-rays or CT scans. There are some risks, however, primarily to women who are pregnant or nursing, due to the injection of the radioactive substance into the body. The potential risks to the fetus must be weighed against the benefits of the PET scan. Women who may be pregnant should inform the PET technicians before the procedure. An electroencephalogram (EEG or brain wave test) is a noninvasive procedure used to detect and record brain cell activity. Because normal brain waves have recognizable frequencies and amplitudes, variations or abnormalities in brain waves may suggest the following: - Attention deficit disorders (e.g., ADHD) - Seizure disorders (e.g., epilepsy) - Tumors or abscesses in the brain - Head injury - Encephalitis and other inflammatory diseases - Cerebral hemorrhages - Cerebral infarct (stroke) - Sleep disorders - Alcohol or drug abuse - Migraines (in some cases) - Syncope (loss of consciousness) An EEG also is used to confirm brain death in a patient who is comatose. This neurodiagnostic test is not used to measure intelligence or diagnose mental illness. Patients usually are advised to wash their hair the night before the procedure, using no oils, sprays, or conditioners. Patients also should avoid caffeine for at least 8 hours prior to an EEG. If the test will be used to measure brain activity while sleeping, the patient way be asked to reduce or even eliminate their sleep time the night before. Some patients are advised to stop the use of medications before an EEG, but it is important not to do so unless directed by a physician. In an electroencephalogram, small metal disks (electrodes) are attached to the scalp to detect and record brain wave activity. These disks are attached by wires to a machine that records and converts electrical signals from the brain into wavy lines on a moving sheet of graph paper. Before the procedure begins, an EEG technician attaches 16 to 25 disks to the scalp using a sticky paste while the patient lies still on a table or reclining chair. In some cases, the patient is asked to perform a function, such as breathing deeply and rapidly, or looking at a blinking light. Generally, there is no discomfort associated with an EEG, although some patients may be bothered by the feeling of the disks. This neurodiagnostic test normally lasts 1 to 2 hours and is performed on an outpatient basis. However, patients who have suspected or known seizure disorders may be given a 24-hour EEG. In this procedure, the electrodes are attached to a portable lightweight recording box that is worn over the shoulder with a strap. During the test period, the patient or a family member pushes an event button every time a seizure occurs. After 24 hours, the box is returned to the EEG center for evaluation of the test results. In some cases, patients are admitted to a hospital for extended EEG testing. Risks of EEG In general, there are no risks associated with an EEG. However, in patients who have seizure disorders, a seizure may be triggered by the use of flashing lights or by a request to hyperventilate. Electromyography (EMG, myogram, or nerve conduction test) is a neurodiagnostic test used to assess the health and function of the muscles and the nerves that control the muscles. It can be used to determine whether muscle weakness and loss of muscle strength are caused by a muscle injury or by an underlying neurological disorder. EMG can be used to detect many disorders and conditions, including the following: - Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) - Carpal tunnel syndrome - Guillain-Barre syndrome - Muscular dystrophy - Myasthenia gravis - Sciatic nerve dysfunction There is no special preparation required for an EMG. Patients may be advised to avoid the use of creams and lotions on the day of the test. EMG ProcedureWhen a muscle is at rest, it is electrically "silent." When a muscle is contracted, it generates a variety of signals known as “action potential.” An EMG measures this action potential. During an EMG, a needle electrode is inserted through the skin into the muscle being tested and the patient is asked to contract the muscle in some way. The electrical activity produced during the test is displayed as waves on an oscilloscope, and may be heard on a speaker as loud pops. The presence, size, and shape of the waves indicate the ability of the muscle to respond to nerve stimulation and can help diagnose nerve or muscle damage. The test normally takes 30 to 60 minutes to perform. During the test, there may be some discomfort when the needle is inserted into the muscle. Following an EMG, the area may feel tender or sore for a few days.

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Aspergillosis is the collective term used to describe all disease entities caused by any one of ~35 pathogenic and allergenic species of Aspergillosis. Only those species that grow at 37°C can cause invasive infection, although some species without this capability can cause allergic syndromes. A. fumigatus is responsible for most cases of invasive aspergillosis, almost all cases of chronic aspergillosis, and most allergic syndromes. A. flavus is more prevalent in some hospitals and causes a higher proportion of cases of sinus and cutaneous infections and keratitis than A. fumigatus. A. niger can cause invasive infection but more commonly colonizes the respiratory tract and causes external otitis. A. terreus causes only invasive disease, usually with a poor prognosis. A. nidulans occasionally causes invasive infection, primarily in patients with chronic granulomatous disease. Aspergillus has a worldwide distribution, most commonly growing in decomposing plant materials (i.e., compost) and in bedding. This hyaline (nonpigmented), septate, branching mold produces vast numbers of conidia (spores) on stalks above the surface of mycelial growth. Aspergilli are found in indoor and outdoor air, on surfaces, and in water from surface reservoirs. Daily exposures vary from a few to many millions of conidia; the latter high numbers of conidia are encountered in hay barns and other very dusty environments. The required size of the infecting inoculum is uncertain; however, only intense exposures (e.g., during construction work, handling of moldy bark or hay, or composting) are sufficient to cause disease in healthy immunocompetent individuals. Allergic syndromes may be exacerbated by continuous antigenic exposure arising from sinus or airway colonization or from nail infection. High-efficiency particulate air (HEPA) filtration is often protective against infection; thus HEPA filters should be installed and monitored for efficiency in operating rooms and in hospital environments that house high-risk patients. The incubation period of invasive aspergillosis after exposure is highly variable, extending in documented cases from 2 to 90 days. Thus community-acquired acquisition of an infecting strain frequently manifests as invasive infection during hospitalization, although nosocomial acquisition is also common. Outbreaks usually are directly related to a contaminated air source in the hospital. Risk Factors and Pathogenesis The primary risk factors for invasive aspergillosis are profound neutropenia and glucocorticoid use; risk increases with longer duration of these conditions. Higher doses of glucocorticoids increase the risk of both acquisition of invasive aspergillosis and death from the infection. Neutrophil and/or phagocyte dysfunction is also an important risk factor, as evidenced by aspergillosis in chronic granulomatous disease, advanced HIV infection, and relapsed leukemia. An increasing incidence of invasive aspergillosis in medical intensive care units suggests that, in patients who are not immunocompromised, temporary abrogation of protective responses as a result of glucocorticoid use or a general anti-inflammatory state is a significant risk factor. Many patients have some evidence of prior pulmonary disease—typically, a history of pneumonia or chronic obstructive pulmonary disease. Glucocorticoid use does ...

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Contacts: Eileen Quinn, 202.631.9294, [email protected]; Deborah Phillips, 206.788.2449, [email protected] Gaithersburg, MD, February 20, 2008—The US Advisory Committee on Vaccines and Related Biological Products issued a positive recommendation today on the use of rotavirus vaccines, potentially bringing greater protection to children in the United States from this common and sometimes fatal cause of severe diarrhea. After reviewing data from clinical trials on the safety and efficacy of Rotarix®, manufactured by GlaxoSmithKline Biologicals (GSK), the committee recommended that the US Food and Drug Administration (FDA) approve the company’s application for licensure. The FDA should make its ultimate decision on Rotarix® licensure in the United States within the coming weeks. Another rotavirus vaccine, RotaTeq® manufactured by Merck & Co., Inc., received FDA approval in 2006. Globally, rotavirus accounts for more than 500,000 deaths and two million hospitalizations annually. Ready access to good medical care means that children in industrialized countries rarely die from rotavirus infection. Children in the poorest countries, however, suffer the greatest burden: more than 90 percent of deaths due to rotavirus occur in the developing world, where access to simple, lifesaving treatment is severely limited. “Vaccines against rotavirus remain the most effective way to prevent this deadly disease,” notes Dr. John Wecker, director of PATH’s Rotavirus Vaccine Program. “Making rotavirus vaccines available to the children in poor countries who face the greatest risk of dying must be a high priority.” Every child in the world will contract rotavirus at least once before the age of three, regardless of income level or geographic location. Because vaccination is the only way to prevent hospitalizations from severe rotavirus infection in industrialized countries and the mortality it causes in low-resource settings, the World Health Organization (WHO) strongly recommends the inclusion of rotavirus vaccination into the national immunization programs of countries where clinical trials have shown rotavirus vaccines to be safe and effective. In January 2007, WHO granted “prequalification” to Rotarix®, allowing it to be purchased through United Nations procurement systems. Because rotavirus vaccines represent the best hope to save thousands of children’s lives in poor countries, PATH’s Rotavirus Vaccine Program is working in partnership with Merck and GSK to conduct large-scale clinical trials of their vaccines in Africa and Asia. These data will provide valuable information for developing countries considering the use of rotavirus vaccines to reduce rotavirus mortality.

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The tilt table test determines how your body reacts to changes in position. This test is used if you have had syncope or fainting spells. During the test, you lie on a table that can be moved from a flat, horizontal position to an upright, vertical position. While the table is moved, your heart rate, blood pressure and symptoms are monitored. Syncope is a fainting spell or sudden, brief loss of consciousness. This can happen when the brain does not receive enough blood flow and oxygen. The most common type is called vasovagal syncope or neurocardiogenic syncope. In this case, the nerves that control the action between the heart and blood vessels have malfunctioned. The heart slows down and the blood pressure drops. As a result, the person loses consciousness. The tilt table test is designed to cause syncope in the patient under controlled conditions. It is useful for diagnosing vasovagal syncope. During the test, the upright position causes blood to collect in the lower part of the body, especially the legs. Therefore, the heart has less blood to pump and the blood pressure tends to drop. Normally, nerves increase the heart rate and tighten the blood vessels to keep the blood pressure at a certain level. These nerves do not work right in people who have a tendency to vasovagal syncope. So the person loses consciousness when the heart rate slows and the blood pressure drops. Once the person lies flat again, they regain consciousness. Do not eat or drink anything for 6 to 8 hours before the test. Make arrangements for someone to drive you home after the study. Prior to the test, check with your doctor about any medications you are taking. Some may interfere with the test. During the test, you will be asked to lie down on the tilt table. An intravenous (IV) line will be inserted into one arm and a blood pressure cuff is placed on the other arm. ECG electrodes will be placed on your chest to monitor heart rhythm. Safety straps will be placed over your chest and legs. At first you will lie flat on the tilt table. Then the table is moved so that you are almost in an upright position. You will be monitored in that position for awhile and then moved to a flat position again. If the test is normal or "negative", you may be given a medication to bring on syncope. When you are given the drug, you may feel your heart pound. At any time during the test, you may get symptoms similar to when you fainted or nearly fainted. If this happens, tell the technician or nurse in the room. If the tilting causes a loss of consciousness with low blood pressure and/or a slow heart rate, then this test is abnormal or "positive". When your family member or friend drives you home, you will want to rest for awhile. Ask you doctor about taking any medications you might have stopped taking before the test. The tilt table test is generally safe. The test may causes fainting but if this happens, the table is returned quickly to a flat position and the test is stopped. Personnel are available to handle any emergency. The tilt table test helps doctors see if you are susceptible to vasovagal syncope. This test helps your doctor to make an accurate diagnosis and develop the best treatment plan for you.

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|Classification and external resources| It is characterized by the following: - Distinctive facial appearance - Unusually sparse, brittle, curly scalp hair - A range of skin abnormalities from dermatitis to thick, scaly skin over the entire body (generalized ichthyosis) - Heart malformations (congenital or appearing later) especially an obstruction of the normal flow of blood from the lower right ventricle of the heart to the lungs (valvar pulmonary stenosis) - Delayed growth - Foot abnormalities (extra toe or fusion of two or more toes) Malformations of face and head Individuals with the disorder usually have distinctive malformations of the craniofacial area including an unusually large head (macrocephaly), prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction); The nose can be upturned and short with a low nasal bridge; and large ears that are abnormally rotated toward the back of the head. In many cases, affected individuals also have downward slanting eyelid folds, widely spaced eyes, drooping of the upper eyelids, inward deviation of the eyes, and other eye abnormalities including absent eyebrows and eyelashes. Genetic causes of CFC Costello and Noonan syndrome are similar to CFC and their phenotypic overlap may be due to the biochemical relationship of the genes mutated in each syndrome to each other. Genes that are mutated in all three of these syndromes encode proteins that function in the MAP kinase pathway. - Mutations that cause CFC are found in the KRAS, BRAF, MEK1 and MEK2 genes. - Costello syndrome is caused by mutations in HRAS. - Mutations that cause Noonan Syndrome have been found in PTPN11 and SOS1. The relative severity of CFC when compared to Noonan Syndrome may reflect the position in the biochemical pathway each gene occupies. - Shp2, the protein product of the PTPN11, appears to regulate the MAP kinase pathway at or above the level of SOS1. - SOS1 in turn regulates the activities of RAS, RAF, MEK, ERK and p90RSK. - SOS1 has been demonstrated to be a target of negative feedback by ERK and p90RSK. Thus, any activating mutation downstream of SOS1 may be subject to less regulation that may mitigate the consequence of such mutations giving rise to the phenotypic differences seen between these syndromes. - James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 550. ISBN 0-7216-2921-0. - Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). McGraw-Hill. p. 513. ISBN 0-07-138076-0. - Bentires-Alj M, Kontaridis MI, Neel BG (March 2006). "Stops along the RAS pathway in human genetic disease". Nat. Med. 12 (3): 283–5. doi:10.1038/nm0306-283. PMID 16520774. - CFC International — Support group for CFC families - CFC Syndrome at Genetics Home Reference - CFC Syndrome at WebMD - GeneReview/UW/NIH entry on CFC - A series of newspaper articles, supplemented with videos, written by the father of a boy with CFC

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- Cancer Center Home - Breast Center - - Breast Screening Guidelines - - About Mammograms - - Diagnostic Services - - Locations & Services After having a screening mammogram, approximately one out of 10 women may need a diagnostic mammogram, also called a special view. This is done so that the physician can look closer at a particular area of interest. If a woman is called back for this type of additional study, she should be prepared to stay a little while longer than for a screening mammogram. This is because the radiologist will review the films immediately in case more images are needed. Often, in addition to these extra mammogram images, an ultrasound is performed to evaluate the area from a different perspective. Ultrasound is simply another way to look at breast tissue. It uses sound waves to determine relative densities of tissue and helps to clarify whether a particular area of interest is solid or cystic (a fluid-filled pocket). Ultrasound of the breast is performed while the woman is lying down. No compression is needed for this procedure. It is very useful for denser breast tissue. The purpose of these extra images is to help the radiologist determine if any additional steps need to be taken. Often, it is determined that nothing more needs to be done other than to continue monthly breast self-exams and yearly mammograms with clinical breast exams. Sometimes, a three- or six-month repeat mammogram may be requested. Other times, a biopsy is recommended. When Biopsies Are Necessary A biopsy is recommended for tissue diagnoses of an area of concern on the imaging studies. There are several ways to perform a biopsy. The nature and location of the lesion may determine the method chosen. Several types of minimally-invasive biopsies can be done right in the Breast Center without the need for an open surgical procedure. - Image Guided Breast Biopsy: This procedure can be performed using ultrasound techniques or stereotactic mammography. The stereotactic procedure uses advanced computer imaging technology to map the precise location of the area of interest in the breast in order to obtain a reliable diagnosis with a very small amount of breast tissue. Using a specially designed mammography unit, a series of computerized mammograms are taken which allows the radiologist to identify the abnormality in three dimensions and determine the coordinates of the biopsy. The skin is cleansed and the area is anesthetized (numbed). A tiny nick is made in the skin where the biopsy device is to be inserted. Small tissue samples are removed from the abnormal area and sent to the pathologist for a diagnosis. The patient visit, including preparation, the biopsy and post-procedure care, takes about an hour. - Ultrasound Guided Core Biopsy: This procedure is used when ultrasound is the best imaging method to guide the radiologist to the area of tissue that needs to be sampled. The skin is cleansed and the area is anesthetized (numbed). The doctor can follow the path of the biopsy device on the video monitor. Tissue samples will be taken and sent for analysis by the pathologist. - Breast (Needle) Localization: When surgery is needed, a breast localization procedure may be appropriate. This is a pre-surgical procedure that uses a fine wire guided by mammography or ultrasound to locate the abnormality for the surgeon. The process begins in the Day Surgery Center, with a trip to the Breast Center before proceeding to the OR suite. First, a mammogram (or ultrasound) is performed to locate the precise location of the lesion. Then, after the skin has been cleaned and numbed, a needle with a wire is placed into the abnormal area. Once this is done, the location of the needle is verified with additional mammography views or ultrasound. Then, the needle is removed and the wire is left in place in order to guide the surgeon to the abnormality. In the operating room the surgeon will remove the abnormality along the wire, suture the incision and place a dressing over the wound. Once the patient is recovered, she may go home with instructions on how to care for the incision. Other Diagnostic Procedures - Cyst Aspiration: Breast cysts are common and are not cancerous. These fluid-filled pockets may sometimes look like something more concerning and may have to be aspirated (fluid removed) in order to make sure. The physician will place a fine needle into this pocket and remove the fluid. Sometimes, this causes the cyst to disappear completely on subsequent mammograms or ultrasounds. - Galactogram: Also called a ductogram, this diagnostic tool is used to identify a particular duct, a small opening in the nipple, where drainage has been observed. The radiologist will put a tiny catheter into the duct in order to fill it with a radiopaque (shows up on mammographic images) dye. Pictures are taken to show the outline of the duct. There are no special preparations needed prior to this procedure. However, it is important to not express any fluid for several days prior to the exam.

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- freely available Genes 2014, 5(1), 33-50; doi:10.3390/genes5010033 Published: 23 January 2014 Abstract: The centromere is the chromosomal locus essential for chromosome inheritance and genome stability. Human centromeres are located at repetitive alpha satellite DNA arrays that compose approximately 5% of the genome. Contiguous alpha satellite DNA sequence is absent from the assembled reference genome, limiting current understanding of centromere organization and function. Here, we review the progress in centromere genomics spanning the discovery of the sequence to its molecular characterization and the work done during the Human Genome Project era to elucidate alpha satellite structure and sequence variation. We discuss exciting recent advances in alpha satellite sequence assembly that have provided important insight into the abundance and complex organization of this sequence on human chromosomes. In light of these new findings, we offer perspectives for future studies of human centromere assembly and function. The centromere is the chromosomal locus that controls chromosome segregation during cell division. Visually, the centromere appears on metaphase chromosomes, at least in metazoans that have excellent cytology, as a primary constriction. This is also the site of kinetochore assembly, the multi-protein structure that forms to coordinate attachment to and movement of chromosomes along microtubules. The proteins associated with centromeres are conserved among species, consistent with the functional significance of the locus. A surprising feature of centromeres is that the DNA sequences present at the locus are dissimilar, not only among organisms but often within the same organism. However, protein components of centromeres are shared among species, suggesting an epigenetic basis for centromere assembly. Such centromere proteins (CENPs) include CENP-A, CENP-C, and CENP-T that are important for structural and functional aspects of the centromere and kinetochore. CENP-A is of particular significance since it is a histone H3 variant that contributes to specialized chromatin at centromeres. The Holliday Junction Recognition Protein HJURP and its fungal homolog Scm3 are chaperones that direct the loading of CENP-A into chromatin primed by the Mis18 complex and ensure propagation of epigenetically marked centromeric nucleosomes (reviewed by [1,2]). Despite the lack of sequence identity, many centromeres are located in regions of repetitive DNA or satellites. In humans, repetitive alpha satellite DNA defines the centromere. The sequence basis of centromere identity is widely debated, since variant centromeres have been identified in humans and other organisms. These unusual centromeres include neocentromeres, new centromeres that are formed on unique or non-centromeric DNA sequences [3,4]. Dicentric human chromosomes, those chromosomes that are formed by fusion or translocation, have two regions of centromeric DNA, but often only one is the site of kinetochore formation. In these instances, the alpha satellite DNA appears to be neither necessary nor sufficient for centromere function. Nevertheless, other evidence exists that supports the importance of DNA sequence in centromere formation in humans, particularly de novo centromere assembly. In this review, we will discuss advances in our understanding of human centromeric DNA, from the discovery of human centromeric sequences through integration of physical and genetic maps of centromeres during the Human Genome Project era to the first centromeric genome assemblies that are only now emerging. 2. Alpha Satellite DNA: Discovery, Organization, and Variation Human centromeres, and in fact most primate centromeres, are composed of alpha satellite DNA . This sequence is thought to be important for centromere function since it is present at the primary constriction of all human chromosomes. It comprises up to 5% of the genome. Alpha satellite is based on a 171 bp monomer arranged in a tandem, head-to-tail fashion. Individual monomers share 50%–70% sequence identity. An integral number of monomers give rise to a higher order repeat (HOR) unit that is itself repeated in a largely uninterrupted fashion so that within a given centromeric locus, the alpha satellite array can span from 250 to 5,000 kb. Such re-iteration of the HOR gives rise to a homogenized alpha satellite array in which the HORs differ in sequence by only a few percent (Figure 1), even though the constituent monomers show much less sequence similarity [6,7]. Some monomers within the HORs contain a 17 bp sequence called the CENP-B box, a motif that is recognized by the DNA-binding centromere protein CENP-B . Outside of the higher order arrays, monomers are randomly arranged and span the region between the homogeneous array and the chromosome arm . Variation within the alpha satellite is common and complex. Each chromosome type is defined by an alpha satellite array in which the multimers of the HOR contain a particular number of tandem monomers [7,10,11]. The homogeneity of HORs of the same monomer number makes the alpha satellite array chromosome-specific and distinguishable from related sequences at other centromeres. Certain chromosomes share greater homology of HORs based on monomer subtypes and organization, allowing them to be classified into one of three suprachromosomal families . Diverged monomeric alpha satellite falls into two additional suprachromosomal families . On a given chromosome type, the number of times the HOR is re-iterated is heterogeneous, spanning hundreds to thousands of copies. Consequently, total array size on a given chromosome varies between homologs and among individuals (Figure 2) [14,15,16,17,18]. Although array sizes can be as small as a few hundred kilobases or as large as five megabases [16,19,20], the range appears to be less extensive on a particular chromosome type . Array size polymorphisms are largely stable through meiosis since they can be efficiently tracked through multigenerational families . These polymorphisms make alpha satellite a useful centromeric marker for tracking inheritance of individual chromosomes. Additional alpha satellite variation exists at the level of the HOR. On a given chromosome, the primary HOR unit can exhibit size polymorphisms that are most likely the result of deletions caused by unequal exchange [22,23]. Human chromosome 17 is a good example of HOR polymorphism within the D17Z1 alpha satellite array. The predominant HOR on D17Z1 is a 16-monomer (16-mer) [18,22]. However, less prevalent 15-mer and 14-mer HORs are present on many D17Z1 arrays, as well as 13-mers and 12-mers [22,24]. Within this group, the 13-mer is the most abundant after the 16-mer. These size polymorphisms create centromeric haplotypes, with the 16-/15-/14-mer comprising a haplotype found on 65% of chromosome 17 s and the additional 13-mer present on 35% of chromosome 17 s [22,25]. A recent study that evaluated centromere assembly on multiple chromosome 17 s suggested that HOR variants might have different functional capacities . This possibility, however, remains to be formally tested in an independent functional assay. 3. Functional Studies that Have Defined Genomic Centromeres The strongest evidence for implicating alpha satellite DNA in human centromere function came from two lines of chromosome engineering experiments that took “bottom up” and “top down” approaches (Figure 3). In the “top down” strategy, telomere-mediated chromosomal truncation was used to modify the X chromosome or Y chromosome, some of which had been transferred to either rodent somatic cell hybrids or DT40 chicken cells (Figure 3B) [27,28]. Because DT40 cells are proficient in homologous recombination, targeted seeding of the telomere truncation constructs accelerated the deletion process. Multiple rounds of telomere truncation generated a series of deleted chromosomes, each containing less X or Y chromosome material (Figure 3B). The stability of the minichromosomes was monitored and those that maintained the least amount of the original chromosome but were still mitotically stable were concluded to contain the minimal sequence(s) necessary for centromere function. In both truncated X and Y chromosomes, minichromosomes containing alpha satellite DNA arrays DXZ1 and DYZ3, respectively, equated with the most stable linear minichromosomes. These studies strongly implicated alpha satellite DNA as the sequence that corresponds to centromere function and chromosome stability. However, it could be argued that in the top-down studies the centromere, once established on any sequence, stays at that sequence, and does not shift with truncation. At the same time, pioneering experiments were being developed by two groups to take a “bottom up” approach to define the sequences required for centromere function. In these studies, alpha satellite sequences were introduced into linear yeast artificial chromosome (YAC) or circular bacterial artificial chromosome (BAC) vectors (Figure 3A). Hunt Willard’s group created first generation artificial chromosomes from synthetic alpha satellite arrays . One higher order repeat from D17Z1 (chromosome 17) or DYZ3 (chromosome Y) was amplified through successive rounds of directional cloning to yield a 1Mb array that was inserted into a BAC vector. Introduction of these artificial chromosome assembly constructs by liposome-mediated transfection into the HT1080 cell line yielded clones that contained a microchromosome or human artificial chromosome (HAC). The HACs recruited centromere proteins and were stable in mitosis for at least 6 months. Careful analysis of the HACs showed that the D17Z1 HACs were completely derived from the input construct. However, the DYZ3-derived HAC had acquired additional alpha satellite sequences from host chromosomes. The functional significance of the inability of DYZ3 to form a functional HAC containing only Y centromere sequences was not fully appreciated at the time. Subsequent studies shed light on the correlation between DYZ3 sequence and its competence for de novo centromere assembly (see below). At the same time that the Willard group was creating HACs from synthetic alpha satellite DNA, Howard Cooke’s and Hiroshi Masumoto’s groups were collaborating to clone large alpha satellite arrays from human chromosome 21 into linear YAC vectors. In their studies, the higher order array α21-I and the unordered monomeric array α21-II were introduced into HT1080 cells and compared for de novo centromere competency . Only YACs containing the α21-I HOR array were capable of forming mitotically stable HACs that properly assembled centromere proteins. These innovative studies complemented those of the Willard group, and contributed important structure-function information that implicated HOR alpha satellite as a preferred substrate for de novo centromere assembly. In the time that has elapsed since these groundbreaking experiments, additional studies have established HACs as models for testing the genomic (and epigenetic) requirements for de novo centromere assembly and function. Circular BAC and PAC vectors, rather than linear YACs, are the most useful assembly vectors and are associated with high rates of HAC formation [31,32]. Not all alpha satellite arrays translate to HAC formation. Y chromosome alpha satellite DNA (DYZ3) lacks CENP-B boxes and is unable to efficiently form de novo centromeres on HACs [29,32]. Furthermore, arrays containing mutated CENP-B boxes cannot form de novo HACs . Thus, the presence of CENP-B binding sites is required for centromere assembly. This has been a perplexing finding, given that the Y chromosome clearly assembles a functional centromere and recruits essential centromere proteins. These findings hint at key differences between de novo versus established centromere function that are not well understood. Initial studies that tested the ability of alpha satellite to nucleate functional centromeres introduced cosmids containing human alpha satellite DNA from chromosome 17 into African green monkey (AGM) cells . These experiments did not result in supernumerary chromosomes or HACs, but instead, integration of the alpha satellite construct into AGM chromosomes (Figure 3A). Indeed, up to 60% of HAC constructs introduced into human cells integrate into the genome rather than forming an independent chromosome. While some might point out that this argues against the case for sequence-dependent centromere assembly, another interpretation is that de novo chromosome assembly and de novo centromere formation are two different processes. Indeed, some integrated alpha satellite arrays recruit centromere proteins [34,35], although they may not retain some or all of the proteins long-term. At the very least, both integrated and free-lying HAC studies suggest that alpha satellite provides sequence information for some aspects of centromere function. Contemporary studies are now using centromere-based chromosome engineering to create a new generation of HACs that contain alpha satellite in addition to tetracycline operator (tetO) sequences . The tetO sequences are bound with high affinity by the tet repressor (tetR) that can be fused to different proteins in order to manipulate the chromatin or protein composition of the HAC [37,38]. In this way, centromere assembly on the alpha satellite can be enhanced or inhibited, the long-term stability of the HAC can be monitored by tethering tetR fluorescent protein fusions, and expression of genes included on the HAC can be tested . 4. Centromere Regions in the Human Genome Project Era As the understanding of the relationship between alpha satellite DNA and centromere function emerged at the end of the 20th century, it led to a call for the identification and mapping of functional centromere sequences . However, the nature of alpha satellite, with its megabase-scale regions of higher-order repetitive structure, made it highly refractory to sequencing and assembly . As the Human Genome Project (HGP) rapidly increased the sequence information available for testing human genome function, gains were largely not seen at the pericentromeres and centromeres of most human chromosomes. A 1998 plan for the project that outlined the HGP’s goal for a 2001 working draft and a 2003 final draft acknowledged that “the small proportion of highly repeated sequence represented by the centromeres and other constitutive heterochromatic regions of the genome” might not be included in the final reference assembly . A contemporary perspective on the plan warned of the possibility that potentially important duplications and tandem repeats would be “swept under the carpet”. There was a repeated call for at least some centromeric regions to be characterized in order to confirm that their structure was as homogenous as originally claimed . But again, due to the computational complexity required to accurately assemble such highly repetitive regions, few labs attempted to close these sequence gaps [44,45,46]. A decade later, multi-megabase-sized gaps remain at the centromeres of most chromosome assemblies. This problem is not exclusive to the human genome, since centromere and pericentromere sequence gaps in other organisms such as mouse and Drosophila remain unclosed [47,48,49,50]. Only in the past year have advances in sequencing technologies and innovative computational efforts focused on elucidating alpha satellite structure helped to make a full understanding of the genome and some of its most critical elements a real possibility [51,52]. 5. Linking Physical and Genetic Maps of Human Centromeres By the late 1990s and early 2000s, several groups had pushed forward the centromere field by producing integrated physical and genetic maps of centromere regions including chromosomes X, 5, and 12 [53,54,55]. These studies used pulsed-field gel electrophoresis to estimate physical alpha satellite array sizes and either radiation hybrid or linkage analyses to estimate genetic distance across the centromere. In addition to confirming the repression of recombination across centromeres, the integrated maps that resulted allowed for the anchoring of alpha satellite regions to existing genomic maps, and sometimes identified unique pericentric sequences that had not been represented in the human genome drafts . Of the sequence assemblies around the centromere that do exist, the pericentric regions are the best characterized. Within these regions, a high proportion of segmental duplications have accumulated [44,56]. Many pericentric duplications corresponding to unmapped regions of the genome were identified using monochromosomal somatic cell hybrids and PCR or FISH with known pericentric sequences and genomic BACs that recognized paralogous sequences across the genome . Genome-wide analysis of the January 2001 draft assembly further revealed pericentromeric and subtelomeric enrichment for duplicated sequences, and showed that such sequences were frequently present in unmapped or misassembled segments . The discordance between FISH and BLAST results in these analyses was much higher than the genome-wide rate reported in the same year . Together, these studies demonstrated the importance of elucidating highly duplicated pericentric regions in order to accurately understand the Human Genome Project’s results. More recent progress was made in assembling “inaccessible” regions by using linkage disequilibrium analysis of genetically distinct (admixed) genomes to map almost 20 Mb of sequence near centromeres . As the number of admixed genomes available for analysis increases, this powerful technique is expected to reduce the gaps in the current reference assembly. 6. Correlating the Genetic and Functional Centromere In 2001, a major breakthrough in reaching beyond the boundaries of alpha satellite occurred when chromosome X short arm (Xp) genomic clones were mapped into the homogenous higher order DXZ1 array . This tour-de-force used combined in silico and high-stringency BAC clone screening to demonstrate that even in higher order alpha satellite, enough sequence variation existed to assemble a contig extending almost half a megabase from the satellite boundary towards the centromere core that is the location of the functional centromere (Figure 4). This study revealed that heterogeneity of alpha satellite DNA increased with more distance from the DXZ1 core. These studies permitted the definition of transitions between the higher order alpha satellite and flanking regions. Monomers of alpha satellite DNA that are not ordered into multi-monomer repeat units are located directly outside of the homogenous HOR domain . These monomers exhibit enough sequence variation that they can be more easily assembled and in fact represent most of the alpha satellite that exists in the human reference assembly [60,61]. The monomeric alpha satellite regions show greater sequence dissimilarity and more interspersed elements, such as L1 sequences, as they approach the chromosome arms. Currently, HSAX and HSA8 are the only human chromosomes represented in the genome assembly with contiguous sequence from higher-order alpha satellite to both arms [62,63]. Subsequent to these findings, several groups began analyzing alpha satellite at increasing sequence depth, discovering new alpha satellite polymorphisms and repeat organization. Building on the work of previous decades, targeted sequencing of several well-characterized arrays was performed. The high copy number of alpha satellite HORs on each chromosome permitted analysis of intra-homolog SNPs in addition to inter-individual variation that was paired with restriction digestion for haplotype analysis . These studies revisited the molecular basis for variation within alpha satellite by pinpointing where unequal exchange occurred to produce array homogenization. 7. The Computational Challenge of Alpha Satellite Genome Assemblies The bottleneck in generating alpha satellite assemblies has undoubtedly been the sophistication of assembly tools that are required to order distinguishable monomeric sequences within highly homogenous arrays. Several groups have developed in silico tools for analyzing higher order alpha satellite sequence available in genome assemblies [65,66]. These computational and in silico approaches are most effective when combined with experimental approaches that mapped clones by FISH to verify their location in or near the higher order array. Indeed, such dry/wet approaches were used to map the region spanning the Xp centromere-arm junction and to characterize the centromere of human chromosome 17 [60,61,67]. In the latter instance, a novel higher-order array (D17Z1-B) was discovered on chromosome 17 , emphasizing the power of this integrative approach. Another novel HOR array, localized by BLAST to HSA22 and verified by FISH to hybridize to HSA14 and 22, was found by “rescuing” unassembled alpha satellite sequence information from whole genome sequencing (WGS) repositories . These studies revealed that while challenging to assemble, repetitive satellite regions, particularly in the centromere, hold a wealth of complex genomic structure and potentially functional information. 8. Assembling Centromeres in the Present Day Previous studies utilized traditional sequencing technologies that have the potential to contain several 171-bp monomers per read. Next generation short-read sequencing technology has enabled the recent increase in whole-genome sequencing and the amount of human sequence information available overall. Nevertheless, short reads present a particular challenge for assembling alpha satellite sequence. It appears that this obstacle of aligning short-read alpha satellite sequences can be overcome to utilize functional information gleaned from chromatin immunoprecipitation with centromeric protein antibodies and Illumina sequencing of the DNA that is captured . This ChIP-sequencing (ChIP-seq) approach utilized the reference assembly as well as the HuRef genome, first by aligning the HuRef alpha satellite reads to the reference assembly. After this alignment, the reference alpha satellite was broken into sliding windows, and the alignment checked back onto the HuRef reads to determine the “mappability” of each window. This mappability information was then used for alignment of the short Illumina reads generated by ChIP-seq. It should be noted, however, that this study did not have the means to extend beyond the edges of the reference assembly into the homogenous centromere cores (see Future Perspectives). Another major discovery from the assembly annotation of this work was that many more chromosomes than previously thought contain two or more higher order alpha satellite arrays [51,61,69,70,71]. This finding has raised the complexity of centromeres to a new level and introduced the possibility that the location of centromere assembly may be quite variable in humans. This is indeed the case for human chromosome 17 on which the centromere can be assembled at either of the two higher order repeat arrays . This new information suggests that in addition to alpha satellite haplotypes, there may a number of functional centromeric genotypes. How a functional genotype might affect long-term chromosome stability is an open question. 9. Future Perspectives It is now 2014, so what can we expect from the centromere field in the next decade? Based on the foundation laid by the Human Genome Project era, the most exciting areas of centromere research are in some of the following areas. 9.1. Centromere Assemblies Clearly, the most significant frontier that remains to be explored in centromere biology is complete genomic centromere assemblies. With the recent advances in the past two years alone using long-template sequencing and advanced computational approaches that have sampled, annotated, and assembled centromere sequences in multiple genomes, centromere reference sequences are a real possibility. Just recently, ordering of monomer sequences from whole-genome shotgun reads has produced the first linear characterization of centromeric assemblies for alpha satellite arrays from chromosomes X and Y . Increasing read lengths offered by multiple platforms offer the potential to contain several multi-kilobase HORs in one read. In fact, long PacBio reads have already accelerated the discovery and mapping of centromeric tandem repeats in a variety of species . These third generation sequencing techniques should enable longer alpha satellite sequence assemblies and better understanding of centromere structure and neighboring variant HORs. Completion of even a few centromere assemblies will undoubtedly be important, but given the amount of variation in alpha satellite organization and size, the ultimate goal would be to produce centromere assemblies for each individual. These personalized maps would be useful for defining the spectrum of sequences that correlate with functional competency. In addition, they will allow identification of other features—such as genes or non-coding elements—that are present within current centromere/pericentromere gaps. These sequences may require centromeric locations for proper function, similar to heterochromatic genes in Drosophila [48,73]. Indeed, a human muscle disorder has been mapped to the gene KCNJ18 that is located in an assembly gap on 17p11.2 . It is possible that other genes or elements within centromere regions may be associated with diseases for which the molecular basis remains undefined. 9.2. Centromeric Variation and Functional Capacity The ability to confidently assemble centromeric contigs should permit identification of the full range of variability in alpha satellite, including sequence and size variants . Such variation will shed light on the molecular mechanisms that regulate alpha satellite homogenization, but also effects of fundamental processes such as DNA replication and DNA repair on alpha satellite stability. Ultimately, characterization of alpha satellite variation would reveal the range of sequences that are capable of supporting centromere function. HAC studies have taught us that not all alpha satellite sequences have the capacity to support de novo centromere assembly [29,32]. The reasons for this have been largely unexplored, and mostly attributed to the presence or absence of CENP-B boxes in alpha satellite [33,75]. One would expect that like a given complex human disease that is often associated with various SNPs, many types of sequence variation would be associated with diminished centromere function. Complete, personalized centromeric assemblies linked to functional centromere status would expedite experiments to compare efficiencies of various sequence variants in de novo centromere assembly and/or centromere maintenance. 9.3. Maps of Functional Centromeric Domains The consensus in the centromere field is that centromere identity is specified by epigenetic mechanisms. However, without detailed genomic information, this theory is not irrefutable. Centromere proteins, such as the histone H3-like protein CENP-A, are assembled onto alpha satellite DNA to create a specialized type of nucleosome within unique chromatin that distinguishes the centromere from the rest of the genome [76,77]. CENP-A and other proteins create a complicated network of protein sub-complexes that link the chromatin to the structural kinetochore that interacts with spindle microtubules . However, chromatin that contains CENP-A nucleosomes is only assembled on a portion of alpha satellite DNA [79,80]. How and why CENP-A is recruited to only a subset of alpha satellite HOR and/or monomers is unclear. Recent studies have revealed that CENP-A nucleosomes on the human X chromosome are positioned at monomers that do not contain CENP-B boxes . One could speculate that distribution of CENP-B boxes within an alpha satellite array and sequence variation that interrupts the CENP-B box motif or makes the motif non-functional (not bound by CENP-B) might impact CENP-A chromatin assembly and centromere function. Complete centromeric assemblies of many human chromosomes will be important for addressing this possibility experimentally. Since the discovery of alpha satellite DNA in the late 1970s, the field has moved from identification of centromeric sequences at every human centromere to a basic molecular understanding of the organization and structure of alpha satellite monomers into homogeneous higher order repetitive arrays (Figure 5). The Human Genome Project was essential in providing a rough and limited reference assembly for centromeres of three chromosomes (X, 8, 17). These fundamental studies of alpha satellite DNA paved the way for pioneering functional assays in which the sequence was tested in de novo centromere assembly in human artificial chromosome assays. HACs have been the gold standard for testing centromere assembly, but are now being used to explore chromosome stability and gene expression. The next challenge will be to complete genomic assemblies for all human centromeres in multiple individuals and populations and to develop the next generation of functional assays to test the role of alpha satellite variation in centromere function, chromosome stability, and disease association. We apologize to our colleagues whose work on alpha satellite DNA and human centromeres could not be cited due to space constraints. Research in the Sullivan lab is supported in part by R01 GM098500 (NIH) and Gene Discovery and Translational Research Grant #1-FY13-517 (March of Dimes Foundation). Wrote the paper: MEAM, BAS. Conflicts of interest The authors declare no conflict of interest. - Panchenko, T.; Black, B.E. The epigenetic basis for centromere identity. Prog. Mol. Subcell. Biol. 2009, 48, 1–32. [Google Scholar] [CrossRef] - Valente, L.P.; Silva, M.C.; Jansen, L.E. Temporal control of epigenetic centromere specification. Chromosome Res. 2012, 20, 481–492. [Google Scholar] [CrossRef] - Choo, K.H. Domain organization at the centromere and neocentromere. Dev. Cell 2001, 1, 165–177. [Google Scholar] [CrossRef] - Warburton, P.E. Chromosomal dynamics of human neocentromere formation. Chromosome Res. 2004, 12, 617–626. [Google Scholar] [CrossRef] - Manuelidis, L.; Wu, J.C. Homology between human and simian repeated DNA. Nature 1978, 276, 92–94. [Google Scholar] [CrossRef] - Waye, J.S.; Willard, H.F. Nucleotide sequence heterogeneity of alpha satellite repetitive DNA: A survey of alphoid sequences from different human chromosomes. Nucleic Acids Res. 1987, 15, 7549–7569. [Google Scholar] [CrossRef] - Willard, H.F. Chromosome-specific organization of human alpha satellite DNA. Am. J. Hum. Genet. 1985, 37, 524–532. [Google Scholar] - Muro, Y.; Masumoto, H.; Yoda, K.; Nozaki, N.; Ohashi, M.; Okazaki, T. Centromere protein B assembles human centromeric alpha-satellite DNA at the 17-bp sequence, CENP-B box. J. Cell Biol. 1992, 116, 585–596. [Google Scholar] [CrossRef] - Schueler, M.G.; Sullivan, B.A. Structural and functional dynamics of human centromeric chromatin. Annu. Rev. Genomics Hum. Genet. 2006, 7, 301–313. [Google Scholar] [CrossRef] - Choo, K.H.; Vissel, B.; Nagy, A.; Earle, E.; Kalitsis, P. A survey of the genomic distribution of alpha satellite DNA on all the human chromosomes, and derivation of a new consensus sequence. Nucleic Acids Res. 1991, 19, 1179–1182. [Google Scholar] [CrossRef] - Vissel, B.; Choo, K.H. Human alpha satellite DNA—Consensus sequence and conserved regions. Nucleic Acids Res. 1987, 15, 6751–6752. [Google Scholar] [CrossRef] - Alexandrov, I.A.; Mitkevich, S.P.; Yurov, Y.B. The phylogeny of human chromosome specific alpha satellites. Chromosoma 1988, 96, 443–453. [Google Scholar] [CrossRef] - Alexandrov, I.; Kazakov, A.; Tumeneva, I.; Shepelev, V.; Yurov, Y. Alpha-satellite DNA of primates: Old and new families. Chromosoma 2001, 110, 253–266. [Google Scholar] [CrossRef] - Devilee, P.; Kievits, T.; Waye, J.S.; Pearson, P.L.; Willard, H.F. Chromosome-specific alpha satellite DNA: Isolation and mapping of a polymorphic alphoid repeat from human chromosome 10. Genomics 1988, 3, 1–7. [Google Scholar] [CrossRef] - Mahtani, M.M.; Willard, H.F. Pulsed-field gel analysis of alpha-satellite DNA at the human X chromosome centromere: High-frequency polymorphisms and array size estimate. Genomics 1990, 7, 607–613. [Google Scholar] [CrossRef] - Greig, G.M.; Parikh, S.; George, J.; Powers, V.E.; Willard, H.F. Molecular cytogenetics of alpha satellite DNA from chromosome 12: Fluorescence in situ hybridization and description of DNA and array length polymorphisms. Cytogenet. Cell Genet. 1991, 56, 144–148. [Google Scholar] [CrossRef] - Wevrick, R.; Willard, H.F. Long-range organization of tandem arrays of alpha satellite DNA at the centromeres of human chromosomes: High-frequency array-length polymorphism and meiotic stability. Proc. Natl. Acad. Sci. USA 1989, 86, 9394–9398. [Google Scholar] [CrossRef] - Willard, H.F.; Waye, J.S.; Skolnick, M.H.; Schwartz, C.E.; Powers, V.E.; England, S.B. Detection of restriction fragment length polymorphisms at the centromeres of human chromosomes by using chromosome-specific alpha satellite DNA probes: Implications for development of centromere-based genetic linkage maps. Proc. Natl. Acad. Sci. USA 1986, 83, 5611–5615. [Google Scholar] [CrossRef] - Abruzzo, M.A.; Griffin, D.K.; Millie, E.A.; Sheean, L.A.; Hassold, T.J. The effect of Y-chromosome alpha-satellite array length on the rate of sex chromosome disomy in human sperm. Hum. Genet. 1996, 97, 819–823. [Google Scholar] [CrossRef] - Oakey, R.; Tyler-Smith, C. Y chromosome DNA haplotyping suggests that most European and Asian men are descended from one of two males. Genomics 1990, 7, 325–330. [Google Scholar] [CrossRef] - Willard, H.F. Evolution of alpha satellite. Curr. Opin. Genet. Dev. 1991, 1, 509–514. [Google Scholar] [CrossRef] - Waye, J.S.; Willard, H.F. Molecular analysis of a deletion polymorphism in alpha satellite of human chromosome 17: Evidence for homologous unequal crossing-over and subsequent fixation. Nucleic Acids Res. 1986, 14, 6915–6927. [Google Scholar] [CrossRef] - Waye, J.S.; Willard, H.F. Structure, organization, and sequence of alpha satellite DNA from human chromosome 17: Evidence for evolution by unequal crossing-over and an ancestral pentamer repeat shared with the human X chromosome. Mol. Cell. Biol. 1986, 6, 3156–3165. [Google Scholar] - Willard, H.F.; Greig, G.M.; Powers, V.E.; Waye, J.S. Molecular organization and haplotype analysis of centromeric DNA from human chromosome 17: Implications for linkage in neurofibromatosis. Genomics 1987, 1, 368–373. [Google Scholar] [CrossRef] - Warburton, P.E.; Willard, H.F. Interhomologue sequence variation of alpha satellite DNA from human chromosome 17: Evidence for concerted evolution along haplotypic lineages. J. Mol. Evol. 1995, 41, 1006–1015. [Google Scholar] - Maloney, K.A.; Sullivan, L.L.; Matheny, J.E.; Strome, E.D.; Merrett, S.L.; Ferris, A.; Sullivan, B.A. Functional epialleles at an endogenous human centromere. Proc. Natl. Acad. Sci. USA 2012, 109, 13704–13709. [Google Scholar] [CrossRef] - Brown, K.E.; Barnett, M.A.; Burgtorf, C.; Shaw, P.; Buckle, V.J.; Brown, W.R. Dissecting the centromere of the human Y chromosome with cloned telomeric DNA. Hum. Mol. Genet. 1994, 3, 1227–1237. [Google Scholar] [CrossRef] - Farr, C.J.; Bayne, R.A.; Kipling, D.; Mills, W.; Critcher, R.; Cooke, H.J. Generation of a human X-derived minichromosome using telomere-associated chromosome fragmentation. EMBO J. 1995, 14, 5444–5454. [Google Scholar] - Harrington, J.J.; van Bokkelen, G.; Mays, R.W.; Gustashaw, K.; Willard, H.F. Formation of de novo centromeres and construction of first-generation human artificial microchromosomes. Nat. Genet. 1997, 15, 345–355. [Google Scholar] [CrossRef] - Ikeno, M.; Grimes, B.R.; Okazaki, T.; Nakano, M.; Saitoh, K.; Hoshino, H.; McGill, N.I.; Cooke, H.; Masumoto, H. Construction of YAC-based mammalian artificial chromosomes. Nat. Biotechnol. 1998, 16, 431–439. [Google Scholar] [CrossRef] - Grimes, B.R.; Babcock, J.; Rudd, M.K.; Chadwick, B.; Willard, H.F. Assembly and characterizationof heterochromatin and euchromatin on human artificial chromosomes. Genome Biol. 2004, 5, R89. [Google Scholar] [CrossRef] - Grimes, B.R.; Rhoades, A.A.; Willard, H.F. Alpha-satellite DNA and vector composition influence rates of human artificial chromosome formation. Mol. Ther. 2002, 5, 798–805. [Google Scholar] [CrossRef] - Ohzeki, J.; Nakano, M.; Okada, T.; Masumoto, H. CENP-B box is required for de novo centromere chromatin assembly on human alphoid DNA. J. Cell Biol. 2002, 159, 765–775. [Google Scholar] [CrossRef] - Haaf, T.; Warburton, P.E.; Willard, H.F. Integration of human alpha-satellite DNA into simian chromosomes: Centromere protein binding and disruption of normal chromosome segregation. Cell 1992, 70, 681–696. [Google Scholar] [CrossRef] - Nakashima, H.; Nakano, M.; Ohnishi, R.; Hiraoka, Y.; Kaneda, Y.; Sugino, A.; Masumoto, H. Assembly of additional heterochromatin distinct from centromere-kinetochore chromatin is required for de novo formation of human artificial chromosome. J. Cell Sci. 2005, 118, 5885–5898. [Google Scholar] [CrossRef] - Nakano, M.; Cardinale, S.; Noskov, V.N.; Gassmann, R.; Vagnarelli, P.; Kandels-Lewis, S.; Larionov, V.; Earnshaw, W.C.; Masumoto, H. Inactivation of a human kinetochore by specific targeting of chromatin modifiers. Dev. Cell 2008, 14, 507–522. [Google Scholar] [CrossRef] - Bergmann, J.H.; Rodriguez, M.G.; Martins, N.M.; Kimura, H.; Kelly, D.A.; Masumoto, H.; Larionov, V.; Jansen, L.E.; Earnshaw, W.C. Epigenetic engineering shows H3K4me2 is required for HJURP targeting and CENP-A assembly on a synthetic human kinetochore. EMBO J. 2011, 30, 328–340. [Google Scholar] [CrossRef] - Cardinale, S.; Bergmann, J.H.; Kelly, D.; Nakano, M.; Valdivia, M.M.; Kimura, H.; Masumoto, H.; Larionov, V.; Earnshaw, W.C. Hierarchical inactivation of a synthetic human kinetochore by a chromatin modifier. Mol. Biol. Cell 2009, 20, 4194–4204. [Google Scholar] [CrossRef] - Kononenko, A.V.; Lee, N.C.; Earnshaw, W.C.; Kouprina, N.; Larionov, V. Re-engineering an alphoid(tetO)-HAC-based vector to enable high-throughput analyses of gene function. Nucleic Acids Res. 2013, 41, e107. [Google Scholar] [CrossRef] - Murphy, T.D.; Karpen, G.H. Centromeres take flight: Alpha satellite and the quest for the human centromere. Cell 1998, 93, 317–320. [Google Scholar] [CrossRef] - Henikoff, S. Near the edge of a chromosome’s “black hole”. Trends Genet. 2002, 18, 165–167. [Google Scholar] [CrossRef] - Collins, F.S.; Patrinos, A.; Jordan, E.; Chakravarti, A.; Gesteland, R.; Walters, L. New goals for the U.S. Human Genome Project: 1998–2003. Science 1998, 282, 682–689. [Google Scholar] [CrossRef] - Eichler, E.E. Repetitive conundrums of centromere structure and function. Hum. Mol. Genet. 1999, 8, 151–155. [Google Scholar] [CrossRef] - Horvath, J.E.; Bailey, J.A.; Locke, D.P.; Eichler, E.E. Lessons from the human genome: Transitions between euchromatin and heterochromatin. Hum. Mol. Genet. 2001, 10, 2215–2223. [Google Scholar] [CrossRef] - Horvath, J.E.; Viggiano, L.; Loftus, B.J.; Adams, M.D.; Archidiacono, N.; Rocchi, M.; Eichler, E.E. Molecular structure and evolution of an alpha satellite/non-alpha satellite junction at 16p11. Hum. Mol. Genet. 2000, 9, 113–123. [Google Scholar] [CrossRef] - She, X.; Horvath, J.E.; Jiang, Z.; Liu, G.; Furey, T.S.; Christ, L.; Clark, R.; Graves, T.; Gulden, C.L.; Alkan, C.; et al. The structure and evolution of centromeric transition regions within the human genome. Nature 2004, 430, 857–864. [Google Scholar] [CrossRef] - Hoskins, R.A.; Carlson, J.W.; Kennedy, C.; Acevedo, D.; Evans-Holm, M.; Frise, E.; Wan, K.H.; Park, S.; Mendez-Lago, M.; Rossi, F.; et al. Sequence finishing and mapping of Drosophila melanogaster heterochromatin. Science 2007, 316, 1625–1628. [Google Scholar] [CrossRef] - Smith, C.D.; Shu, S.; Mungall, C.J.; Karpen, G.H. The Release 5.1 annotation of Drosophila melanogaster heterochromatin. Science 2007, 316, 1586–1591. [Google Scholar] [CrossRef] - Kalitsis, P.; Griffiths, B.; Choo, K.H. Mouse telocentric sequences reveal a high rate of homogenization and possible role in Robertsonian translocation. Proc. Natl. Acad. Sci. USA 2006, 103, 8786–8791. [Google Scholar] [CrossRef] - Mouse Genome Sequencing Consortium; Waterston, R.H.; Lindblad-Toh, K.; Birney, E.; Rogers, J.; Abril, J.F.; Agarwal, P.; Agarwala, R.; Ainscough, R.; Alexandersson, M.; et al. Initial sequencing and comparative analysis of the mouse genome. Nature 2002, 420, 520–562. [Google Scholar] [CrossRef] - Hayden, K.E.; Strome, E.D.; Merrett, S.E.; Lee, H.R.; Rudd, M.K.; Willard, H.F. Sequences associated with centromere competency in the human genome. Mol. Cell. Biol. 2012, 33, 763–772. [Google Scholar] - Melters, D.P.; Bradnam, K.R.; Young, H.A.; Telis, N.; May, M.R.; Ruby, J.G.; Sebra, R.; Peluso, P.; Eid, J.; Rank, D.; et al. Comparative analysis of tandem repeats from hundreds of species reveals unique insights into centromere evolution. Genome Biol. 2013, 14, R10. [Google Scholar] [CrossRef] - Mahtani, M.M.; Willard, H.F. Physical and genetic mapping of the human X chromosome centromere: Repression of recombination. Genome Res. 1998, 8, 100–110. [Google Scholar] - Puechberty, J.; Laurent, A.M.; Gimenez, S.; Billault, A.; Brun-Laurent, M.E.; Calenda, A.; Marçais, B.; Prades, C.; Ioannou, P.; Yurov, Y.; et al. Genetic and physical analyses of the centromeric and pericentromeric regions of human chromosome 5: Recombination across 5cen. Genomics 1999, 56, 274–287. [Google Scholar] [CrossRef] - Vermeesch, J.R.; Duhamel, H.; Raeymaekers, P.; van Zand, K.; Verhasselt, P.; Fryns, J.P.; Marynen, P. A physical map of the chromosome 12 centromere. Cytogenet. Genome Res. 2003, 103, 63–73. [Google Scholar] [CrossRef] - Horvath, J.E.; Schwartz, S.; Eichler, E.E. The mosaic structure of human pericentromeric DNA: A strategy for characterizing complex regions of the human genome. Genome Res. 2000, 10, 839–852. [Google Scholar] [CrossRef] - Bailey, J.A.; Yavor, A.M.; Massa, H.F.; Trask, B.J.; Eichler, E.E. Segmental duplications: Organization and impact within the current human genome project assembly. Genome Res. 2001, 11, 1005–1017. [Google Scholar] [CrossRef] - Cheung, V.G.; Nowak, N.; Jang, W.; Kirsch, I.R.; Zhao, S.; Chen, X.N.; Furey, T.S.; Kim, U.J.; Kuo, W.L.; Olivier, M.; et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 2001, 409, 953–958. [Google Scholar] [CrossRef] - Genovese, G.; Handsaker, R.E.; Li, H.; Kenny, E.E.; McCarroll, S.A. Mapping the human reference genome’s missing sequence by three-way admixture in Latino genomes. Am. J. Hum. Genet. 2013, 93, 411–421. [Google Scholar] [CrossRef] - Schueler, M.G.; Higgins, A.W.; Rudd, M.K.; Gustashaw, K.; Willard, H.F. Genomic and genetic definition of a functional human centromere. Science 2001, 294, 109–115. [Google Scholar] [CrossRef] - Rudd, M.K.; Willard, H.F. Analysis of the centromeric regions of the human genome assembly. Trends Genet. 2004, 20, 529–533. [Google Scholar] [CrossRef] - Nusbaum, C.; Mikkelsen, T.S.; Zody, M.C.; Asakawa, S.; Taudien, S.; Garber, M.; Kodira, C.D.; Schueler, M.G.; Shimizu, A.; Whittaker, C.A.; et al. DNA sequence and analysis of human chromosome 8. Nature 2006, 439, 331–335. [Google Scholar] [CrossRef] - Ross, M.T.; Grafham, D.V.; Coffey, A.J.; Scherer, S.; McLay, K.; Muzny, D.; Platzer, M.; Howell, G.R.; Burrows, C.; Bird, C.P.; et al. The DNA sequence of the human X chromosome. Nature 2005, 434, 325–337. [Google Scholar] [CrossRef] - Roizes, G. Human centromeric alphoid domains are periodically homogenized so that they vary substantially between homologues. Mechanism and implications for centromere functioning. Nucleic Acids Res. 2006, 34, 1912–1924. [Google Scholar] [CrossRef] - Paar, V.; Pavin, N.; Rosandic, M.; Gluncic, M.; Basar, I.; Pezer, R.; Zinic, S.D. ColorHOR—Novel graphical algorithm for fast scan of alpha satellite higher-order repeats and HOR annotation for GenBank sequence of human genome. Bioinformatics 2005, 21, 846–852. [Google Scholar] [CrossRef] - Rosandic, M.; Paar, V.; Gluncic, M.; Basar, I.; Pavin, N. Key-string algorithm—Novel approach to computational analysis of repetitive sequences in human centromeric DNA. Croat. Med. J. 2003, 44, 386–406. [Google Scholar] - Rudd, M.K.; Schueler, M.G.; Willard, H.F. Sequence organization and functional annotation of human centromeres. Cold Spring Harb. Symp. Quant. Biol. 2003, 68, 141–149. [Google Scholar] [CrossRef] - Alkan, C.; Ventura, M.; Archidiacono, N.; Rocchi, M.; Sahinalp, S.C.; Eichler, E.E. Organization and evolution of primate centromeric DNA from whole-genome shotgun sequence data. PLoS Comput. Biol. 2007, 3, 1807–1818. [Google Scholar] - Alexandrov, I.A.; Mashkova, T.D.; Akopian, T.A.; Medvedev, L.I.; Kisselev, L.L.; Mitkevich, S.P.; Yurov, Y.B. Chromosome-specific alpha satellites: Two distinct families on human chromosome 18. Genomics 1991, 11, 15–23. [Google Scholar] [CrossRef] - Choo, K.H.; Earle, E.; Vissel, B.; Filby, R.G. Identification of two distinct subfamilies of alpha satellite DNA that are highly specific for human chromosome 15. Genomics 1990, 7, 143–151. [Google Scholar] [CrossRef] - Wevrick, R.; Willard, H.F. Physical map of the centromeric region of human chromosome 7: Relationship between two distinct alpha satellite arrays. Nucleic Acids Res. 1991, 19, 2295–2301. [Google Scholar] [CrossRef] - Miga, K.H.; Newton, Y.; Jain, M.; Altemose, N.; Willard, H.F.; Kent, W.J. Centromere reference models for human chromosomes X and Y satellite arrays. arXiv 2013. arXiv:1307.0035v3[q-bio.GN]. [Google Scholar] - Schulze, S.; Sinclair, D.A.; Silva, E.; Fitzpatrick, K.A.; Singh, M.; Lloyd, V.K.; Morin, K.A.; Kim, J.; Holm, D.G.; Kennison, J.A.; et al. Essential genes in proximal 3L heterochromatin of Drosophila melanogaster. Mol. Gen. Genet. 2001, 264, 782–789. [Google Scholar] [CrossRef] - Ryan, D.P.; da Silva, M.R.; Soong, T.W.; Fontaine, B.; Donaldson, M.R.; Kung, A.W.; Jongjaroenprasert, W.; Liang, M.C.; Khoo, D.H.; Cheah, J.S.; et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 2010, 140, 88–98. [Google Scholar] [CrossRef] - Masumoto, H.; Nakano, M.; Ohzeki, J. The role of CENP-B and alpha-satellite DNA: De novo assembly and epigenetic maintenance of human centromeres. Chromosome Res. 2004, 12, 543–556. [Google Scholar] [CrossRef] - Blower, M.D.; Sullivan, B.A.; Karpen, G.H. Conserved organization of centromeric chromatin in flies and humans. Dev. Cell 2002, 2, 319–330. [Google Scholar] [CrossRef] - Sullivan, B.A.; Karpen, G.H. Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin. Nat. Struct. Mol. Biol. 2004, 11, 1076–1083. [Google Scholar] [CrossRef] - Hori, T.; Fukagawa, T. Establishment of the vertebrate kinetochores. Chromosome Res. 2012, 20, 547–561. [Google Scholar] [CrossRef] - Spence, J.M.; Critcher, R.; Ebersole, T.A.; Valdivia, M.M.; Earnshaw, W.C.; Fukagawa, T.; Farr, C.J. Co-localization of centromere activity, proteins and topoisomerase II within a subdomain of the major human X alpha-satellite array. EMBO J. 2002, 21, 5269–5280. [Google Scholar] [CrossRef] - Sullivan, L.L.; Boivin, C.D.; Mravinac, B.; Song, I.Y.; Sullivan, B.A. Genomic size of CENP-A domain is proportional to total alpha satellite array size at human centromeres and expands in cancer cells. Chromosome Res. 2011, 19, 457–470. [Google Scholar] [CrossRef] - Hasson, D.; Panchenko, T.; Salimian, K.J.; Salman, M.U.; Sekulic, N.; Alonso, A.; Warburton, P.E.; Black, B.E. The octamer is the major form of CENP-A nucleosomes at human centromeres. Nat. Struct. Mol. Biol. 2013, 20, 687–695. [Google Scholar] [CrossRef] © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

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How the Nervous System Works?The nervous system functions as an autonomous entity in the body. The basic function of this system is to receive information from the outside world and the body itself to produce appropriate responses for the target parts. It receives impulse (the electric message or signal) via the millions of nerve cells in the body. These impulses are simultaneously processed within the nervous system to generate fast and accurate response signals so that they can be delivered to the target cells. However, if the received electric message produces low or no value response, the system automatically filters it out. The nervous system permits fast and specific communication between the brain and broadly spaced parts of the body. This communication process is done by the action of billions of dedicated nerve cells. These cells are called neurons, and they are the basic functioning cells of the nervous system. These cells not only gather and process information but also generate proper response signals to the every part of the body. Each single neuron generating many specialized connections, called synapses, with other neurons and other cells in the body. However, neurons are unable to run directly from the outer region to the brain. Synapses act as junctions for neuron cells, and they allow nerve impulses to be merged into one or divided up for neurons. They assist neuron cells by passing nerve impulses to targeted destination. Low frequency nerve impulses are also filtered out by synapses. Divisions of the Nervous SystemAnatomically, the nervous system has two subdivisions – 1. Central Nervous System (CNS) - Composed of the cerebrum and cerebellum part of the brain and the long tubular bundles of nerve tissues called as spinal cord. 2. Peripheral Nervous System (PNS) - Consists of the nervous tissues found outer part of the brain and spinal cord - the cranial and spinal nerves and their ganglia. Functionally, the nervous system is divided into two systems – 1. Somatic Nervous System 2. Autonomic (Visceral) Nervous System You might also like: What are Neurons? What is the Structure of Neurons? What are the Functions of Neurons? Resource and Further Reading: Dr. Selim Reza (2001). Nervous Tissue and Nervous System. The Essential of Gross Anatomy and Histology, 10th Edition (pp 129-170). Dhaka: Essence Publications.

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Newly discovered details might advance efforts to reverse Rett syndrome, a rare condition that prevents an infant’s brain circuitry from developing, according to a presentation called out as a “Hot Topic” by the Society for Neuroscience at its annual meeting this week. “Our results suggest that the field is on the right track in early efforts to design a treatment for a devastating condition in Rett syndrome,” said Lucas Pozzo-Miller, Ph.D., professor of neurobiology at UAB and senior author of the paper. “They also provide the latest argument that correcting for the genetic miscues behind developmental disabilities may one day reverse their effect, even if treated in adulthood.” Past studies found that mutations or changes in a single gene, MECP2, are present in 95 percent of children with Rett syndrome, called RTT, which affects one in 15,000 children. Located on the X sex chromosome, the mutated gene has different effects in boys and girls. Boys suffer severe malformation and rarely survive. Girls appear normal for a few months after birth, but then their motor skills and cognitive ability regress and they may have seizures. Previous work in Pozzo-Miller’s lab established that the nerve cells in RTT children have fewer dendritic spines, structures that branch from nerve cells to better pick up signals in the gaps, or synapses, between them. The spines can be counted as a measure of the ability of nerve cells in the hippocampus, which directs learning and memory, to relay and store information as circumstances change. The work proceeds from the revolutionary idea that experience changes the physical wiring of nerve cells. Cells become more closely wired to neighbors in the nerve pathways most often used, but dwindle when idled. Evidence also suggests that developing brains build the capacity to think and remember by changing connection strength between neurons, with the change reflected in dendritic spine density. To understand the role of MECP2 malfunction in reducing the number of dendritic spines, the team analyzed its density in mice engineered to lack the MECP2 gene. They found, as expected, that mutant mice too young to have symptoms yet had a lower dendritic spine density in hippocampal neurons than their normal counterparts. Unexpectedly though, the team also found that when mice lacking MECP2 grew old enough to become symptomatic, the mice had about the same number of spines on their dendrites as wild type mice. The finding seemed to call into question the validity of dendritic spine density as a measure for lost plasticity-related function in Rett syndrome. A closer look, however, revealed that dendritic spines in symptomatic mutant mice, while as numerous as those in control mice, were “frozen.” They no longer changed in size, number or shape over time depending on how much the nerve pathway was stimulated by known triggers like the neurotransmitter glutamate. “Perhaps the system tries to compensate for the lack of MECP2 function by increasing the number of spines formed through abnormal channels,” Pozzo-Miller said. “This dense, frozen wiring might explain why children with RTT lose cognitive ability and why they have seizures as sensitive but faulty nerve connections overload. Further study will tell.” The paper, titled “Hippocampal CA1 pyramidal neurons show impaired dendritic spine density and morphology only in presymptomatic Mecp2 mutant mice,” was presented Monday, Nov. 14, at the 2011 annual meeting of the Society for Neuroscience in Washington, D.C. Also making an important contribution was Gaston Calfa, Ph.D., a post-doctoral fellow within UAB Department of Neurobiology. The work was funded by National Institute of Neurological Disorders and Stroke and the International Rett Syndrome Foundation. “The result further validates dendritic spine density as a useful measure for the loss of plasticity in developmental disability, and potentially, of the ability of experimental treatments to restore it,” said Christopher Chapleau, Ph.D., a post-doctoral fellow in UAB’s Department of Neurobiology and first author on the paper. “Having a good model is particularly important right now because the field has identified a protein, BDNF, which drives dendritic spines to grow, and that might reverse the loss seen in Rett syndrome."

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This information is for reference purposes only. It was current when produced and may now be outdated. Archive material is no longer maintained, and some links may not work. Persons with disabilities having difficulty accessing this information should contact us at: https://info.ahrq.gov. Let us know the nature of the problem, the Web address of what you want, and your contact information. Please go to www.ahrq.gov for current information. Men, young children, and elderly people are most likely to sustain traumatic brain injury from blunt head trauma Significant traumatic brain injury (TBI), which occurs in 5 to 10 percent of all patients with blunt head trauma, can cause serious problems and death. Examples of TBIs include skull fractures, hematomas, diffuse cerebral edema, intraventricular hemorrhage, and multiple cerebral contusions. Among emergency department (ED) patients who underwent computed tomography (CT) for blunt head trauma at 21 hospital EDs, men, children younger than 10 years, and elderly people were most likely to have significant TBI. This information might help determine ED physicians' thresholds to use CT in patients of extreme ages. Anatomic factors may play a prominent role in TBI in children. Children have larger head-to-body ratios that may allow more energy from a traumatic impact to be distributed to their head. Also, certain mechanisms of injury are unique to children and may increase the risk of TBI, such as child abuse. The increased risk of TBI in the elderly may be secondary to several factors. Stretching of bridging veins as a consequence of cerebral atrophy, and being on blood thinners (common in the elderly) may increase elderly risk of serious TBI associated with even minor blunt trauma. Also, the elderly are prone to falling, which is also associated with TBIs. Age also plays a role in the type of injury sustained. For example, nearly half the children younger than 10 years with TBI had a skull fracture, but less than 20 percent of those older than 65 did. Similarly, intraparenchymal hemorrhages were exceedingly rare in children younger than 10 years. Epidural hematoma was much less common among the elderly, perhaps due to increased adherence of the dura mater to the skull with aging. Finally, men were about 30 percent more likely to suffer a TBI than women, highlighting the public health problem of trauma in the male population. The study was supported by the Agency for Healthcare Research and Quality (HS09699). See "Epidemiology of blunt head injury victims undergoing ED cranial computed tomographic scanning," by James F. Holmes, M.D., M.P.H., Gregory W. Hendey, M.D., Jennifer A. Oman, M.D., and others, in the March 2006 American Journal of Emergency Medicine 24, pp. 167-173. Return to Contents Proceed to Next Article

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Mental and behavioral disorders were found among a quarter (23%) of the children with Usher syndrome. The types of disorders observed were not uniform and included atypical autism, mental retardation, schizophrenia, and conduct disorder. The number of individuals found with schizophrenia in this study (1 child) is congruent with results reported by Nuutila [15 ] and Grøndahl and Mjøen [14 ] using samples of 133 and 89 adults with Usher syndrome, respectively. Among the children without mental and behavioral disorders around one third was found to have psychosocial difficulties. All together, 11 children (42%) faced neither mental and behavioral disorder nor psychosocial difficulties. Two major explanations for a higher incidence of mental and behavioral difficulties among children and adults with Usher syndrome can be stated. 1) Some argue that the progressive loss of vision results in severe stress and symptoms of mental and behavioral disorder. Case-studies report that mental and behavioral symptoms in patients with Usher syndrome developed simultaneously to the loss of vision. It has been suggested that they are reactive symptoms to severe stress [5 ]. In addition to stress-related responses imposed by progressive loss of vision, dual sensory loss may be associated with a higher prevalence of mental and behavioral disorders because of severe communicative difficulties [29 ]. Among adults with acquired deafblindness McDonnall [30 ] found that communication and social support was important in order to avoid the experience of depression. The communicative difficulties caused by the dual sensory loss, increase the risk of depression. Intervention by means of communication and language rehabilitation is found to be important in preventing mental and behavioral disorders and psychosocial difficulties. This rehabilitation is also important among children with hearing impairment alone [31 ] and people with deafblindness [29 2) The second possible explanation for an association between Usher syndrome and mental and behavioral disorders is that some genes are predisposed to both Usher syndrome and for example schizophrenia [8 ]. Studies of families with more than one member with Usher syndrome and schizophrenia support this hypothesis [11 ]. But until now, no specific genes or mutations have been reported as being suspected candidates. Mental and behavioral disorders may also be a consequence of brain abnormalities associated with Usher syndrome [8 ]. Schaefer and colleagues [40 ] found that the measured volume of the brain was significantly smaller compared to normal controls and Koizumi et al. [10 ] found a global degeneration of the brain in one case with Usher syndrome and schizophrenia. Similar to the surveys by Nuutila [15 ] and Grøndahl and Mjøen [14 ] this study found that only some individuals with Usher syndrome had mental and behavioral disorders and the nomenclature of disorders was not uniform. Either different Usher genes are associated with different kinds of mental and behavioral disorders, or another explanation may be the necessary. A developmental psychopathology perspective [41 ] of the dynamic interplay of physiological, genetic, social, cognitive, and cultural influences across time may be useful to understand the heterogenic picture of mental and behavioral disorders among children with Usher syndrome. Given the combination and number of disabilities (hearing, vision and balance), children with Usher syndrome may face more barriers to language, social and cognitive development compared to children with hearing loss alone. Even minor vision impairment may in combination with congenital hearing loss increase the child's difficulties developing useful language abilities. Due to the sum of barriers, children with Usher syndrome may become more vulnerable towards developing mental and behavioral disorders. More research is needed to learn more about this dynamic interplay. Several authors have asserted that there is an over-diagnosis of autism in persons with sensory impairments [42 ]. Communicative impairment in the case of individuals with dual sensory loss is similar to symptoms of autism or mental retardation [45 ]. Such symptoms among children with sensory disabilities sometimes disappear, when visual, tactile or oral communication has adequately been developed. This was the case for one of the children in this study. Assessment and support Like any other organic or somatic cause to mental and behavioral disorders (for example head trauma, tumour, drug abuse) assessing and treating the vision and hearing impairment is the first step in the case of Usher syndrome. Treatment of mental and behavioral disorders among children with Usher syndrome starts with developing the child's communication to reduce the negative impact of dual sensory loss [29 Assessing mental and behavioral disorders among children with Usher syndrome using traditional tests and diagnostic procedures is often difficult due to the children's dual sensory loss and communication deficiencies [6 ]. Monitoring of the child's development is needed from early childhood and throughout adolescence including social, cognitive and communicative functioning in addition to vision, hearing, and balance problems. In Denmark 3-4 deafblind consultants work full time supporting children with Usher syndrome, their families, and professionals at the schools where the children attend. The service is financed by the Danish government. As estimated this study only included 36% to 65% of the total population of children with Usher syndrome in Denmark, this may result in sampling error. Children with Usher type II and III, with both good vision and hearing, in mainstream schools may not be diagnosed with Usher syndrome before they reach late adolescence and are therefore not known by the national service system for children with Usher syndrome and are not included in this study. These children are probably without any serious psychological disturbances. Similarly, some children with Usher syndrome and severe mental retardation may not be assessed for vision and hearing impairment and therefore also not diagnosed or known by the national service system and thereby not included in this study. Given this possible sample error the population of this study may not be comparable with other populations. This is a first study of mental and behavior disorders among children and adolescence with Usher syndrome. More research is needed in other populations, using other assessment tools and a control group.

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Discusses the prevalence, symptoms, and possible causes of anorexia nervosa in adolescent girls. Anorexia nervosa receives a lot of press, but it is diagnosed in less than one percent of adolescents. It is a disorder in which the individual uses self-starvation in an attempt to lose weight. The condition may be rare, but the proportion of youth who are unhappy about their weight or body shape is not. For example, studies show that 70% of girls report a desire to be thinner. It should not be surprising, then, that anorexia nervosa is diagnosed ten times more often in females, than males. The primary symptoms of anorexia nervosa are major weight loss from excessive dieting and exercising, as well as a distorted sense of body image. Girls with anorexia perceive their bodies as fat, no matter how much weight they lose. Other diagnostic criteria include an intense fear of gaining weight, and the loss of menses in women. One signal that a person's weight has gotten too low is the appearance of lanugo. Lanugo is soft, downy hair that appers on the torso and body. It is the body's attempt to keep warm; people with anorexia often complain of being cold. There are many theories in the causes of anorexia nervosa, perhaps because there are many causes and influences. Most obviously, the dissatisfaction with the body may be a function of how weight is portrayed in the media and our cultural values about women's appearance. Others argue that there is a genetic or biological cause for anorexia. We do know that it is about eight times more likely in persons who have a blood relative with the disorder, but it's uncertain what the inherited factor might be (it very well could be environmental). Many theorists point to the family system as a potential cause of anorexia nervosa. The self-starvation may be a girls' attempt at asserting her autonomy in an overly controlling family system. Parents may have exceedingly high expectations that girls find difficult to live up to; teens may starve as a way of exerting control over their lives and bodies. Finally, anorexia may be a teen's way of avoiding adulthood and responsibility. Starvation stops menses, and pubertal development comes to a halt. It's uncertain whether girls realize this, though.

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Human cell types important for Hepatitis C Virus replication in vivo and in vitro. Old assertions and current evidence 1 Department of Biology, California Lutheran University, 60 W. Olsen Rd., Thousand Oaks, California, 91360 USA 2 Basic Research, California Institute of Molecular Medicine, 1879 Portola Rd., Unit J, Ventura, California, 93003 USA Virology Journal 2011, 8:346 doi:10.1186/1743-422X-8-346Published: 11 July 2011 Hepatitis C Virus (HCV) is a single stranded RNA virus which produces negative strand RNA as a replicative intermediate. We analyzed 75 RT-PCR studies that tested for negative strand HCV RNA in liver and other human tissues. 85% of the studies that investigated extrahepatic replication of HCV found one or more samples positive for replicative RNA. Studies using in situ hybridization, immunofluorescence, immunohistochemistry, and quasispecies analysis also demonstrated the presence of replicating HCV in various extrahepatic human tissues, and provide evidence that HCV replicates in macrophages, B cells, T cells, and other extrahepatic tissues. We also analyzed both short term and long term in vitro systems used to culture HCV. These systems vary in their purposes and methods, but long term culturing of HCV in B cells, T cells, and other cell types has been used to analyze replication. It is therefore now possible to study HIV-HCV co-infections and HCV replication in vitro.

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Most moms-to-be have planned everything before baby arrives: The hospital bag has been packed, the baby's nursery is in order and birthing classes have been completed. However, despite their best efforts, those first hours after birth remain a blur for most women. All babies born in the United States are checked for certain medical conditions soon after birth, according to the Centers for Disease Control and Prevention. All babies undergo this process called a newborn screening, "even if they look healthy, because some medical conditions cannot be seen by just looking at the baby. Finding these conditions soon after birth can help prevent some serious but rare problems, such as brain damage, organ damage and even death," the CDC says. According to the March of Dimes, all states require newborn screening for at least 31 health conditions (up from 26) starting in 2013, with some states checking for up to 50 or more conditions. Ask your health care provider how many conditions are checked in your state. Babies born this year will be screened for "genetic, metabolic, hormonal and/or functional conditions, including PKU (phenylketonuria) within the first hours of birth," according to a news release from the March of Dimes, which offers the following checklist for new moms: - The newborn screening starts with a blood test. Your baby's provider pricks your baby's heel to get a few drops of blood and then that sample is sent to the lab for testing. - Then, your provider will check your baby's hearing by placing a tiny soft speaker in your baby's ear to check how your baby responds to sound. - A heart screening follows with a test in which a pulse oximetry is attached to your baby's finger or foot to check the amount of oxygen in your little one's blood. This test screens for a heart condition called critical congenital heart disease (CCHD). All the medical conditions are divided into five groups: - Organic acid metabolic problems: Babies with these problems don't metabolize food correctly. - Fatty acid oxidation problems: A baby with these conditions can't change fat into energy. - Amino acid metabolism problems: Babies with these problems can't process amino acids, which help the body make protein. - Hemoglobin problems: These conditions affect red blood cells, which carry oxygen to the rest of the body. - Other problems: This category includes cystic fibrosis, hypothyroidism and severe combined immunodeficiency (SCID), among others. All states require a newborn screening to be performed on an infant, but most will allow parents to refuse for religious purposes. Some states require that babies have a newborn screening again two weeks later. If your baby is not born in a hospital, talk to your baby's provider about getting a newborn screening as soon as possible, or discuss your options with your certified midwife. For more on what to expect, check out our Navigating your Hospital Stay page for tips on how to make the most of your post-delivery experience.

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"Once upon a time, we thought hormones directed this long-term control of metabolism. Turns out, diet also plays a major role," said Dr. Kosaku "Ko" Uyeda, a UT Southwestern professor of biochemistry and research career scientist at the Dallas Veterans Affairs Medical Center. Uyeda and his UT Southwestern colleagues reported in today's issue of the Proceedings of the National Academy of Sciences that they isolated the glucose-sensitive protein, dubbed the carbohydrate response element-binding protein (ChREBP), that triggers the long-term process of transforming excess dietary carbohydrates into fat. They used rat livers in their study, but the results are believed to reflect the human body's functions. When people eat desserts, pasta, potatoes or other sugar- and starch-laden foods beyond the body's energy and nutritional needs, these carbohydrates become a flood of glucose, and the liver converts the surplus glucose to fat, Uyeda said. At some point, the glucose reaches a level that signals the ChRE-binding protein to start a chain-reaction along a series of genes that, in turn, activate the synthesis of a dozen enzymes that catalyze the transformation of the excess glucose into fat to be stored in the body, he said. "Eventually, from this line of ongoing research, it should be feasible to design a drug that will inhibit the protein's response to excess glucose and may enable us to eat all the carbohydrates we want, without getting fat," Uyeda said. "The drug would be able to slow the conversion of carbohydrates to fat, perhaps matching the body's needs. Hopefully, the body would be able to excrete or burn the excess glucose." Identifying the protein itself was a breakthrough, but Uyeda said the lab work also revealed how this protein factor binds to a specific gene's DNA and how hormones and glucose control the gene's biological activity. "Several proteins bind to the glucose-response site in the DNA. However, all but one appear to have no direct response to glucose," he said. "The newly identified protein appears to be the main factor. It may be the universal factor in activating other genes to respond to the glucose signal." Uyeda and his team worked continuous laboratory shifts for about four years to track down, isolate, identify and confirm this specialized, but illusive, protein from among many similar proteins and enzymes that operate in the liver. Three scientists at San Francisco-based Genentech also assisted on the project. After isolating the protein in rats' livers, the researchers turned to Genentech to enlist one of only two mass-spectrometer labs in the nation that could analyze the protein substances at microscopic levels, Uyeda said. His team then had to run a number of tests on the protein in the liver cells to confirm its glucose-driven response at the biochemical and genetic levels, he said. The study is an ongoing part of Uyeda's work of more than 30 years. His current goal is to explain how the body transforms and stores carbohydrates as fat. Other UT Southwestern colleagues in the project were biochemists Drs. Hiromi Yamashita, Makoto Takenoshita and Masaharu Sakurai, all of whom have returned to Japan, and Richard Bruick, a current research fellow in biochemistry. The VA and the National Institutes of Health funded the study.

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It is a life threatening medical emergency in which the heart is unable to pump oxygen rich blood to the vital organs of the body and can cause many organs to stop working. Hypovolemic shock happens due to decreased blood volume, losing about 1/5 or more of the normal amount of blood in the body causes hypovolemic shock. It is caused by: - Blood loss from bleeding, it can be bleeding from a cut, or internal bleeding. - Loss of blood plasma due to severe burns, this happens due to loss of skin and damage to the blood vessels. - Dehydration ie, diarrhea or vomiting (loss of a lot of body fluids may lead to a drop in the amount of circulatory blood). Signs and symptoms: - Anxiety or agitation. - Cold, pale skin. - General weakness. - Low blood pressure. - Rapid pulse. - Decreased or no urine output. - If severe it can lead to unconsciousness. - It is usually diagnosed based on the clinical features and physical exam, blood tests and other diagnostic methods might be needed to determine the exact cause of shock if it is not clear. - It is a medical emergency, call 911 or take the person to the emergency room. - While waiting for medical help: - Ensure that the airways are open and the person is breathing. - Place the person on his back and elevate the legs 6-12 inches unless there is a suspected back or neck injury where the person should be immobilized. - Keep the person warm. - Try to stop bleeding from an obvious bleeding site by applying direct pressure. - If the person is vomiting or there is bleeding from or around the mouth, place the person on their side or back with head turned to the side to avoid suffocation unless there is a head or neck injury. - Hypovolemic shock is treated by replacing the fluid and/or blood, usually done through an IV line, in addition to treating the cause. - The more severe the burn is, the higher the possibility that hypovolemic shock will occur. This information is not intended nor implied to be a substitute for professional medical advice; it should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. Call 911 for all medical emergencies.

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Despite optimum treatment with surgery, radiation therapy, and chemotherapy, most patients with malignant glioma have a poor prognosis. Malignant gliomas are vascular tumours that produce vascular endothelial growth factor (VEGF), which is an important mediator of angiogenesis. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of malignant glioma cells, which suggests that inhibition of angiogenesis might be an effective therapeutic strategy. Anti-angiogenic therapies that target VEGF and the VEGF receptor (VEGFR) are effective adjuncts to the treatment of solid tumours. Normalisation of dilated and leaky tumour vasculature might also enable anti-angiogenic therapy to increase the efficacy of radiation therapy and cytotoxic chemotherapy. Several studies have investigated the use of bevacizumab—a humanised monoclonal antibody against VEGF—for patients with recurrent malignant glioma. Treatment with bevacizumab is commonly combined with cytotoxic chemotherapy and results in dramatic responses seen on radiographs, prolongation of progression-free survival, and less need for corticosteroids. Similar results have been shown with small-molecule inhibitors of VEGFR, such as cediranib. Anti-angiogenic treatment is generally well tolerated but common adverse effects include hypertension and proteinuria, whereas the potentially more serious adverse effects, such as thromboembolic disease and haemorrhage, occur infrequently. At least half of patients fail to respond to anti-angiogenic treatment and the response duration is variable. Resistance to anti-angiogenic therapy might implicate alternative pro-angiogenic factors, such as basic fibroblast growth factor, stromal-derived factor-1α, the angiopoietin receptor Tie2, and placental growth factor. Anti-angiogenic therapy might also lead to mobilisation of circulating endothelial cells towards the tumour, which supports angiogenesis. Another possible mechanism of resistance of malignant glioma cells might be upregulation of pro-invasive molecules, which would result in increased infiltrative tumour growth along the blood vessels. Although anti-angiogenic therapies are promising, the duration of response with available regimens is modest. Continuing investigations will determine whether these drugs are best used for newly diagnosed or recurrent tumours and will establish the optimum combinations with radiation, cytotoxic chemotherapy, and other targeted molecular compounds. As yet, there are no effective treatments for patients on anti-angiogenic therapies whose tumours progress. Further understanding of the mechanisms of resistance to anti-angiogenic therapies and better selection of patients will be crucial to improve outcomes for patients with malignant glioma. To read this article in full you will need to login or make a payment

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What are Phase 1 Clinical Trials? Developing new drugs involves four phases of clinical testing in cancer patients, ranging from Phase 1 to Phase 4. Phase 1 trials are the first stage of clinical testing and often involve drugs that have been tested extensively in the laboratory and on animals with encouraging results, but have not yet been given to humans. Patients in Phase 1 trials are sometimes the first to try new cancer drugs. Phase 1 trials only enroll a small number of participants, usually 15 to 100 patients, most of whom have advanced cancer that has not responded to standard cancer treatments. Trial participants are divided into small groups, known as cohorts. The first cohort receives a low dose of the new drug. Doctors may collect blood or urine samples to measure drug levels in the patients. If the first cohort does not have any severe side effects, then a new cohort receives a higher dose of the same drug. The dose increases until the trial investigators find the best dose for future testing. With each increasing dose, doctors test each patient to see if he or she is responding to the treatment. If the doctors find that the treatment is safe, then it will advance to a Phase 2 trial. The objectives of Phase 1 trials include: - Understanding the side effects of new drugs - Determining how the drug affects cancer cells in patients - Observing patient response to the drug At MD Anderson, drugs used in Phase 1 trials may have been developed by pharmaceutical or biotechnology companies. Some Phase 1 trials test new uses for drugs that have already been approved by the Food and Drug Administration, or test drugs given for the first time in combination. Drugs may also be administered in different ways, such as by regional therapy (infusing the directly into the liver for patients with liver metastases). Some trials may be performed in collaboration with the National Cancer Institute (NCI) or the National Cancer Comprehensive Network (NCCN). Many trials require frequent return visits to the Clinical Center for Targeted Therapy, mainly for safety monitoring. Request an Appointment - Call Yolanda Villanueva at 713-792-1160 - Visit our Contact Us page for a checklist of information we'll need for your first appointment Phase 1 Resources Find Clinical Trials Clinical trials are research studies that test new cancer drugs, diagnostic procedures and therapies on humans.

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ARTICLE IN BRIEF Investigators reported that interictal epileptiform discharges (IEDs) on the EEGs of epilepsy patients were associated with lower scores on memory retrieval and maintenance tests. They say the the cognitive impact of IEDs in the hippocampus may be substantially more important than has been previously documented. The cognitive difficulties experienced by many epilepsy patients may be due, in part, to brief “silent” epileptic discharges in the hippocampus that occur between seizures and affect certain short-term memory processes, according to new research published online May 17 in Neurology. Researchers at Dartmouth-Hitchcock Medical Center in Lebanon, NH, and the UCL Institute of Child Health in London, UK, used intracranial electrodes to investigate whether interictal epileptiform discharges (IEDs) in the hippocampus impair specific memory processes. IEDs appear on electroencephalography (EEG) as “spikes” of various intensity and duration, and while they resemble the EEG signature of an epileptic seizure, they are much shorter and occur without any physical symptoms. Although there were no controls in the new study, in ten patients, IEDs were associated with lower scores in both memory retrieval and maintenance tests, but not in information encoding — the taking in of information — with longer EEG “spikes” associated with greater impairment, said lead author Barbara C. Jobst, MD, who directs the Dartmouth Epilepsy Program. “The cognitive impact of IEDs in the hippocampus may be substantially more important than has been previously documented,” she told Neurology Today in a telephone interview. The new study built upon earlier research by the team — published in 2010 in Annals of Neurology — in a rodent model of temporal lobe epilepsy that linked hippocampal IEDs to impairment in short-term memory retrieval, but not in memory encoding or maintenance. “This is important because it is a direct translation from an animal model to humans,” said Dr. Jobst. “The big question remains how and why is memory so badly affected, and what factors and processes are involved.” IEDs in the cortex measured using scalp EEG have been associated with transient cognitive impairment, and earlier research has found that working memory is somewhat reduced with IEDs in the medial temporal lobe. In one earlier study, discharges lasting as little as one second impaired performance in 61 percent of patients asked to perform a simple choice reaction time test. But the precise timing of the IEDs and specific components involved in memory processing have until now not been considered. EFFECTS LATERAL, NOT GLOBAL In the study, the researchers implanted electrodes in patients for preoperative seizure localization, and EEGs were recorded during 2,070 total trials of a short-term memory tasks. Memory processing was broken down into information encoding, maintenance, and retrieval; and the influence of hippocampal IEDs on each process was analyzed and adjusted for individual differences between patients. The researchers found that hippocampal IEDs during memory retrieval decreased the likelihood of a correct response when they were contralateral (p<0.05) or bilateral (p<0.001) to the seizure focus, while bilateral IEDs during the memory maintenance period had a similar effect (p<0.01), especially longer spike-wave complexes (p<0.01). “This demonstrates that IEDs are not a global brain phenomenon, but that bilateral IEDs, and IEDs originating at the opposite side of the hippocampus that cause the seizure zone, affect cognition and memory processes on the opposite side, perhaps due to a neural compensatory mechanism,” Dr. Jobst said. “For clinicians, if spikes are on the side where a seizure originates they may be clinically insignificant, but if they are occuring contralateral of the seizure onset zone, they may have an impact on memory processing. The duration of spikes is also important,” she said. “The larger and longer the spike, the more dramatic the impact on memory retrieval and maintenance tasks.” IMPLICATIONS FOR PRACTICE “I think this is something that everyone has suspected,” commented Selim Benbadis, MD, professor of neurology and director of the Comprehensive Epilepsy Program at the University of South Florida in Tampa, who was not involved with the study. “It has always been postulated that 'micro-impairment' plays some role, but it is very difficult to investigate the cognitive impact of fleeting discharges, so it is very nice to see these data.” He told Neurology Today that the findings may change the way patients' cognitive complaints are viewed and, perhaps, treated. “Interictal discharges are so brief and so localized that evaluating their effects on tasks is very tricky. This study provides a better understanding of why frequent discharges may affect cognition, especially when they are bilateral,” he said. “Maybe we should not be so complacent about these discharges. Now we can see that patients with more discharges are likely to have greater impairment that should perhaps be treated more aggressively.” “We have always questioned what to do when patients complain about memory problems,” said Orrin Devinsky, MD, professor of neurology, neurosurgery and psychiatry at New York University School of Medicine, and director of the NYU Comprehensive Epilepsy Center. “Although many patients consider medications as the sole cause, recurrent tonic-clonic seizures can impair memory, analagous to recurrent concussions,” Dr. Devinsky said. “For milder seizures and epilepsy waves, it is probable that some patients are vulnerable to their effects. This study shows that even epilepsy waves can transiently impair cognition. Future studies need to assess their cummulative effects.” He told Neurology Today that the standard has been to ignore them rather than trying to treat them. “But this study and others indicate that these discharges can affect patient function and behavior. In the hippocampi, where memory processing takes place, it turns out that IEDs do have an impact.” Future challenges will be not just monitoring IEDs, but also suppressing them somehow. “The caveat is that whether controlling them involves stimulation or pharmaceutical intervention, there are always certain risks,” he said. “Overall, medications are most effective in stopping seizures and often do not suppress all IEDs. If the goal is treating all, there is a risk of overtreating patients. You do not want to become what we call a ‘spike chaser,’” he said. “You could get a spike-free EEG, but the patient may be sleeping all the time.” And while there is a need for better medications to better control such epileptiform activity, there is an even larger issue — the tendency to think of epilepsy as simply a disorder of recurrent seizures, Dr. Devinsky noted. “This is a disorder of neurological function, and we need to think about it more broadly. Spikes affect nerve cells even when there the patient is not seizing. And in many cases, there is an impairment of neuronal function even when there are no spikes.” Further research is needed to understand memory complaints in this population and ways to address them, Drs. Devinsky and Benbadis agreed. •. Rugland AL. Neuropsychological assessment of cognitive functioning in children with epilepsy. Epilepsia. 1990;31[Suppl 4]:S41–S44. •. Kleen JK, Scott RC, Holmes GL. Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology. 2013; E-pub 2013 May 17. •. Kucewicz MT, Worrell GA, Gotman J. Pathological brain network activity: memory impairment in epilepsy. Neurology. 2013;E-pub 2013 May 17. •. Kleen JK, Scott RC, Holmes GL, Lenck-Santini PP. Hippocampal interictal spikes disrupt cognition in rats. Ann Neurol. 2010; 67:250–257. •. Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG. Lancet Neurol. 2003; 2:725–730.

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Nonalcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis when no other causes for secondary hepatic fat accumulation (eg, heavy alcohol consumption) are present. NAFLD may progress to cirrhosis and is likely an important cause of cryptogenic cirrhosis., NALFD is now the most common cause of abnormal liver biochemistry in North America and likely in the UK and is also known to be associated with some drugs, genetic defects, obesity, insulin resistance and type 2 diabetes. - NAFLD covers a spectrum ranging from simple steatosis to steato-hepatitis (NASH) and cirrhosis. Of the UK population about 33% have NAFLD, and 2-5% have NASH. - It is now the commonest cause of liver disease in the West and accounts for a growing proportion of patients undergoing liver transplantation (15-20%). Most patients commonly present in middle-age. - There is a need to increase understanding of liver disease and its many causes, to improve patient outcomes and reduce the stigma many patient’s experience. Currently there is a perception that all liver disease is due to alcohol. Yet in medicine today NAFLD is considered as the hepatic manifestation of metabolic syndrome, which is defined notably by increased waist circumference, insulin resistance and dyslipidemia. Patients with nonalcoholic fatty liver disease (NAFLD) have hepatic steatosis, with or without inflammation and fibrosis. In addition, no secondary causes of hepatic steatosis are present. NAFLD is subdivided into nonalcoholic fatty liver (NAFLD) and nonalcoholic steatohepatitis (NASH). In NAFLD, hepatic steatosis is present without evidence of significant inflammation, whereas in NASH, hepatic steatosis is associated with hepatic inflammation that may be histologically indistinguishable from alcoholic steatohepatitis., Other terms that have been used to describe NASH include pseudoalcoholic hepatitis, alcohol-like hepatitis, fatty liver hepatitis, steatonecrosis, and diabetic hepatitis. Nonalcoholic fatty liver disease (NAFLD) is seen worldwide and is the most common liver disorder in Western industrialised countries, where the major risk factors for NAFLD, central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome are common. In the United States, studies report a prevalence of NAFLD of 10 to 46 percent, with most biopsy-based studies reporting a prevalence of NASH of 3 to 5 percent., Worldwide, NAFLD has a reported prevalence of 6 to 35 percent (median 20 percent). - Systemic hypertension - Insulin resistance or overt diabetes, type 2 and 1 The pathogenesis of nonalcoholic fatty liver disease has not been fully elucidated. The most widely supported theory implicates insulin resistance as the key mechanism leading to hepatic steatosis, and perhaps also to steatohepatitis. Others have proposed that a “second hit,” or additional oxidative injury, is required to manifest the necroinflammatory component of steatohepatitis. Hepatic iron, leptin, antioxidant deficiencies, and intestinal bacteria have all been suggested as potential oxidative stressors. Most patients with nonalcoholic fatty liver disease (NAFLD) are asymptomatic, although some patients with nonalcoholic steatohepatitis (NASH) may complain of fatigue, malaise, and vague right upper abdominal discomfort. Patients are more likely to come to attention because laboratory testing revealed elevated liver aminotransferases or hepatic steatosis was detected incidentally on abdominal imaging. Patients with NAFLD may have mild or moderate elevations in the aspartate aminotransferase (AST) and alanine aminotransferase (ALT), although normal aminotransferase levels do not exclude NAFLD. The true prevalence of abnormal transaminases among patients with NAFLD is unclear, since many patients with NAFLD are diagnosed because they are noted to have abnormal aminotransferases. When elevated, the AST and ALT are typically two to five times the upper limit of normal, with an AST to ALT ratio of less than one (unlike alcoholic fatty liver disease, which typically has a ratio greater than two). The degree of aminotransferase elevation does not predict the degree of hepatic inflammation or fibrosis, and a normal alanine aminotransferase does not exclude clinically important histologic injury. Other labatory findings that may be abnormal or high end of normal include gamma γ-Glutamyl transferase (GGT)., Radiographic findings in patients with NAFLD include increased echogenicity on ultrasound, decreased hepatic attenuation on computed tomography (CT), and an increased fat signal on magnetic resonance imaging (MRI). Multiple therapies have been investigated for the treatment of nonalcoholic fatty liver disease (NAFLD). Weight loss is the only therapy with reasonable evidence suggesting it is beneficial and safe. Conventionally, the following strategies are typically employed. - Weight loss for patients who are overweight or obese. - Hepatitis A and B vaccinations should be given to patients without serologic evidence of immunity. - Treatment of risk factors for cardiovascular disease. - Pharmacological agents, such as pioglitazone, are not recommended. Numerous other drugs have been examined for the treatment of NASH. While some have shown initial promise, none has been studied sufficiently to recommend its use as a primary treatment for NASH. - Alcohol avoidance is recommended. In my opinion and experience, I have routinely screened my patients with high normal GGT levels, in isolation or in conjunction with high normal or elevated AST and/or ALT levels with a liver ultrasound and have frequently seen evidence of NASH and NAFL on the radiology report. Typically, their medical doctor, unfortunately, has brushed this off as if there was nothing to be done about it besides weight loss, if indicated. This is where nutritional and nutraceutical therapies have an enormous role to play. A diet rich in organic fruits and vegetables (the more varied the colours, the better), avoidance of refined, processed, and charred foods are beneficial. I also recommend my patients to avoid trans and saturated fats, along with nitrates/nitrates and high fructose corn syrup. Lastly, I recommend them to include a diet rich in green tea, fresh fish and liver supportive foods. The following nutrients have shown the greatest clinical efficacy in addressing and even reversing the spectrum of NAFLD. - N-acetyl-cysteine (NAC): 600 mg twice daily, best taken away from food. - Vitamin C: 500-1000 mg daily. Reference is same as above. - Omega 3 essential fatty acids: 2 grams-4 grams daily. - Vitamin E: 400 IU twice daily with food. - L-carnitine: 1 gram twice daily. - Betaine: 20 grams daily (1-6 grams/day may beneficial if used in conjunction with other therapies). - Choline: 250-1,000 mg daily. - Inositol: 500-1,500 mg daily. Other nutrients with potential benefits in the treatment of NAFLD include pantethine or pantothenic acid, taurine, magnesium, zinc with copper, vitamin B6, biotin, manganese and lysine. Younossi ZM, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011 Jun;9(6):524-530.e1; quiz e60. Epub 2011 Mar 25. View Abstract Williams CD, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124. View Abstract Vernon G, et al. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011 Aug;34(3):274-85. Epub 2011 May 30. View Abstract Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120:1640. View Abstract Charatcharoenwitthaya P, et al. The spontaneous course of liver enzymes and its correlation in nonalcoholic fatty liver disease. Dig Dis Sci. 2012 Jul;57(7):1925-31. Epub 2012 Feb 29. View Abstract Banderas DZ, et al. γ-Glutamyl transferase: a marker of nonalcoholic fatty liver disease in patients with the metabolic syndrome. Eur J Gastroenterol Hepatol. 2012 Jul;24(7):805-10. View Abstract Tetri LH, et al. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol. 2008 Nov;295(5):G987-95. View Abstract Qureshi AA, Sami SA, Salser WA, Khan FA. Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. J Nutr Biochem. 2001 June 12(6):318-329 View Abstract Malaguarnera M, et al. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis–a randomized and controlled clinical trial. Am J Gastroenterol. 2010 Jun;105(6):1338-45. View Abstract Buchman AL, et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology. 1995 Nov;22(5):1399-403. View Abstract Gaby AR. Nonalcoholic fatty liver disease in Nutritional Medicine, pg 493. 2011. Gaby AR. Nonalcoholic fatty liver disease in Nutritional Medicine, pg 494. 2011. - Dietary Treatment of Nonalcoholic Steatohepatitis (NASH) or Non Alcoholic Fatty Liver Disease (NAFLD) - Omega-3 Fatty Acids – A Promising Novel Therapy For Non-Alcoholic Fatty Liver Disease - Vitamin E Gains New Credibility - Cod Liver Oil vs TB - Omega-6 Fatty Acids and Risk for Cardiovascular Disease You can ask technical questions, be as supportive, critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Your comments will be published only after verification.

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||This article includes a list of references, but its sources remain unclear because it has insufficient inline citations. (March 2013)| |Classification and external resources| Orbital cellulitis is inflammation of eye tissues behind the orbital septum. It most commonly refers to an acute spread of infection into the eye socket from either the adjacent sinuses or through the blood. When it affects the rear of the eye, it is known as retro-orbital cellulitis. It should not be confused with periorbital cellulitis, which refers to cellulitis anterior to the septum. Signs and symptoms Common signs and symptoms of orbital cellulitis include pain with eye movement, sudden vision loss, bulging of the infected eye, and limited eye movement. Along with these symptoms, patients typically have redness and swelling of the eyelid, pain, discharge, inability to open the eye, occasional fever and lethargy. It is usually caused by a previous sinusitis. Other causes include infection of nearby structures, trauma and previous surgery. Orbital cellulitis occurs commonly from bacterial infection spread via the paranasal sinuses. Other ways in which orbital cellulitis may occur is from infection in the blood stream or from an eyelid skin infection. Upper respiratory infection, sinusitis, trauma to the eye, ocular or periocular infection and systemic infection all increase one’s risk of orbital cellulitis. - Staphylococcus aureus, is a gram-positive bacterium which is the most common cause of staphylococcal infections. Staphylococcus aureus infection can spread to the orbit from the skin. These organisms are able to produce toxins which promote their virulence which leads to the inflammatory response seen in orbital cellulitis. Staphylococcus infections are identified by a cluster arrangement on gram stain. Staphylococcus aureus forms large yellow colonies (which is distinct from other Staph infections such as Staphylococcus epidermidis which forms white colonies). - Streptococcus pneumoniae, is also a gram-positive bacterium responsible for orbital cellulitis due to its ability to infect the sinuses (sinusitis). Streptococcal bacteria are able to determine their own virulence and can invade surrounding tissues causing an inflammatory response seen in orbital cellulitis (similar to Staphyloccoccus aureus). Streptococcal infections are identified on culture by their formation of pairs or chains. Streptococcus pneumoniae produce green (alpha) hemolysis, or partial reduction of red blood cell hemoglobin. Immediate treatment is very important for someone with orbital cellulitis. Treatment typically involves intravenous (IV) antibiotics in the hospital and frequent observation (every 4-6 hours). Along with this several laboratory tests are run including a complete blood count, differential, and blood culture. - Antibiotic Therapy - Since orbital cellulitis is commonly caused by Staphylococcus and Streptococcus species both penicillins and cephalosporins are typically the best choices for IV antibiotics. However, due to the increasing rise of MRSA (methicillin-resistant Staphylococcus aureus) orbital cellulitis can also be treated with Vancomycin, Clindamycin, or Doxycycline. If improvement is noted after 48 hours of IV antibiotics, healthcare professions can then consider switching a patient to oral antibiotics (which must be used for 2-3 weeks). - Surgical Intervention - An abscess can threaten the vision or neurological status of a patient with orbital cellulitis, therefore sometimes surgical intervention is necessary. Surgery typically requires drainage of the sinuses and if a subperiosteal abscess is present in the medial orbit, drainage can be performed endoscopically. Post-operatively, patients must follow up regularly with their surgeon and remain under close observation. Although orbital cellulitis is considered an ophthalmic emergency the prognosis is good if prompt medical treatment is received. Death and blindness rates without treatment Bacterial infections of the orbit have long been associated with a risk of catastrophic local sequelae and intracranial spread. The natural course of the disease, as documented by Gamble (1933), in the pre-antibiotic era, resulted in death in 17% of patients and permanent blindness in 20%. - Nageswaran, Savithri; Woods, Charles R.; Benjamin, Daniel K.; Givner, Laurence B.; Shetty, Avinash K. (1 August 2006). "Orbital Cellulitis in Children". The Pediatric Infectious Disease Journal 25 (8): 695–699. doi:10.1097/01.inf.0000227820.36036.f1. PMID 16874168. - Howe L, Jones N (2004). "Guidelines for the management of periorbital cellulitis/abscess". Clin Otolaryngol Allied Sci 29 (6): 725–8. doi:10.1111/j.1365-2273.2004.00889.x. PMID 15533168. - Garcia GH, Harris GJ (2000). "Criteria for nonsurgical management of subperiosteal abscess of the orbit: analysis of outcomes". Ophthalmology 107 (8). doi:10.1016/S0161-6420(00)00242-6. - Ferguson MP, McNabb AA (1999). "Current treatment and outcome in orbital cellulitis". Australian and New Zealand Journal of Ophthalmology 27 (6): 375–379. doi:10.1046/j.1440-1606.1999.00242.x. PMID 10641894. - Noel LP, Clarke WN, MacDonald N (1990). "Clinical management of orbital cellulitis in children". Canadian Journal of Ophthalmology 25 (1): 11–16. PMID 2328431. - Shapiro E, Wald E, Brozanski B (1982). "Periorbital cellulitis and paranasal sinusitis: a reappraisal". Pediatric Infectious Disease 1 (2). doi:10.1097/00006454-198203000-00005. - University of Toronto - Merck Manual. - Handbook of Ocular Disease Management. - Orbital Cellulitis Photos and Medical Notes Case Study and discussion of misdiagnosis by four hospitals for the same patient. - American Academy of Ophthamology - Death Rates for Orbital Cellulitis

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Scientists Identify Major Molecular Pathway That Leads to Diabetes For immediate release: October 14, 2004 Boston, MA— Researchers from the Harvard School of Public Health have discovered what they believe is the fundamental mechanism within cells that links two fast-rising public health threats: obesity and Type 2 diabetes. In identifying a specific cell-signaling pathway through which excess fat sets in motion a series of steps culminating in diabetes, the scientists have gone farther than previous studies that provided shards of evidence but not a satisfactory whole. An article on the work appears in the October 15 issue of Science. A series of experiments in isolated cells and in mice revealed that accumulation of excess fat put unusual demands on crucial synthetic machinery of cells. In attempting to adapt to this condition, cells activate a cascade of genes and proteins that ultimately disrupt insulin function. The result is cellular stress inflammation, and diabetes. Type 2 diabetes – 90 to 95 percent of all diabetes cases – affects an estimated 18 million people in the United States, and causes some 200,000 deaths a year. Its description as “adult-onset” diabetes has been dropped, as it is now being diagnosed in younger and younger people including children and teenagers, most of whom are overweight. “What we have found is an important step toward understanding the roots of Type 2 diabetes and metabolic disease,” said Gökhan S. Hotamisligil, chair of the Department of Genetics and Complex Diseases, who headed the research team. “It is a missing piece that integrates the mechanisms of the disease at different sites in the body, including fatty tissue, liver and the pancreas.” Hotamisligil is the senior author; co-first authors are Harvard School of Public Health fellows Umut Özcan and Qiong Cao. Laurie Glimcher of the Department of Immunology and Infectious Diseases is a collaborator and provided the genetically altered mice. Until now, scientists have obtained only a sketchy picture of how the accumulation of excess calories and millions of extra fat cells in an obese person triggers a chain of events that leads to a chronic state of inflammation and insulin resistance (when cells can no longer respond to the hormone insulin, hence are unable to import sugar from the blood). Over time, these events create a high risk of heart disease and stroke, kidney disease, amputation of feet and legs, and blindness. Hotamisligil has done pioneering work on the discovery of inflammation as a cause of obesity and type 2 diabetes. He and others previously showed that fat cells are not just inert storage receptacles; instead, they play an important role in communicating with other organs to maintain proper metabolic balance. They also secrete chemical messengers that stimulate the immune system. With the goal of reaching to the deeper mechanisms, Hotamisligil tested a hypothesis that the key to the obesity-diabetes connection might be found in the endoplasmic reticulum, or ER – a system of folded membranes and tubules in the cytoplasm of cells where proteins and lipids are manufactured, processed, and shipped around the cell. When unusual demands are put on the ER’s capacity, the life of the cell is threatened and it goes into emergency mode. This condition is called ER stress. It can be triggered by a viral infection, gene mutations, exposure to toxins, or a shortage of intracellular nutrients. The cell responds with a flurry of activity aimed at survival – but which suppresses the cell’s normal responsiveness to insulin and sets off inflammation. Hotamisligil showed that turning the adaptive capacity in the ER “on or off” by regulating the levels of a gene called XBP-1 also changes insulin action. In mice, when there is less XBP-1 activity — hence susceptibility to ER stress — the animals develop insulin resistance and diabetes. The XBP-1 gene was first isolated by Glimcher. How does obesity cause ER stress to begin with? Although the details aren’t all known, Hotamisligil says that fat cells by their nature are perpetually on the verge of ER stress. “It’s a big, spherical cell that under the best of conditions uses up all its excess capacity to be able to run,” he said. “Obesity brings a huge amount of stress to a cell that has no reserve capacity to tolerate it.” With the missing link in hand, Hotamisligil said the discovery will open up many therapeutic possibilities by focusing on how to enhance the cell’s tolerance of ER stress. He cautions, however, that there is no treatment based on this concept on the immediate horizon, though he is “very excited” about the work’s rich potential for treating diabetes. The study was funded by the National Institutes of Health. For more information contact: Assistant Director, Office of Communications Harvard School of Public Health 677 Huntington Ave., Boston, MA 02115

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Picture 1. Beginning the forward roll. The doctor places his or her hands on the abdomen, moving the baby up out of the pelvic bones. If nature and natural methods do not help your baby settle into a proper pre-birth position, you have a medical option at 37 weeks. The Manual Version or External Cephalic Version (ECV) is a medical procedure (we do not do them here!) used to guide your baby from breech or other non-headfirst presentation to headfirst (vertex). The medical doctor pushes on your baby through your abdomen, either creating a forward roll like a somersault or a back flip. Whether or not to do an ECV is a personal decision that you should make with your partner and your doctor. To help you make an informed decision, we offer a brief description of the procedure below. All information should be confirmed with your medical doctor. Picture 2. The baby is turned either forward or backward ... Picture 3. ... until the baby is in the vertex (head-down) position. Since all transverse babies and most breech babies are born by cesarean, moving the baby to cephalic presentation increases the chance of having a vaginal birth. Research has shown that offering ECV to all mothers with breech babies at 37 weeks gestation decreases the cesarean rate for that group of women. The success rate for rotating a baby to headfirst position appears to be about 65%. Many factors affect your individual chances of sucess including how close you are to your due date, how much fluid is around the baby, how many pregnancies you've had, how much your baby weighs, how the placenta is positioned and how your baby is positioned. For example, the procedure is more successful in women who have had other children, since the baby can move around more easily, than it is for a first-time mom whose baby sits low in her pelvis. We suggest the Webster technique immediately prior to an ECV so that we can try to relax your pelvic bones and muscles to create more room for the maneuver. Like all procedures (including natural ones) the ECV is associated with possible negative side effects. Often the baby's heart rate will slow during or immediately after the version, especially when it is successful. The heart rate usually comes back to normal within a few moments, and there is no evidence that these short-lived heart-rate changes harm the baby in any way. In very rare situations, the heart rate stays slow long enough that practitioners will start the initial preparations for a possible emergency cesarean section. Although preparation is sometimes necessary, emergency C-sections are extremely rare under these circumstances. While it's rare to have a serious complication of ECV, it may be uncomfortable or even moderately painful. You always have the right to stop the procedure for any reason. (Remember, it's your body!) If you can keep your abdominal muscles relaxed, you might be more comfortable and the procedure may be more likely to succeed. You may feel sore for a few days. Ideally, you will want a support person with you during the version, and you'll need someone to drive you home afterward. The procedure usually is not done earlier than 37 weeks, since there is a remote possibility that the baby will need an emergency delivery as a result of the procedure--and you don't want to risk the baby being born that early if possible. Certain factors, such as premature rupture of the membranes, contraindicate the use of an ECV. Your doctor will tell you if you are a candidate for the procedure. Akthough the risk of complications is small, some doctors prefer not to try an external cephalic version. ILLUSTRATIONS BY FLOYD E. HOSMER Much of the information contained herein comes from familydoctor.org and drspock.com. Berlin Wellness Village Calendar 3D Spine Simulator Launch 3D Spine Simulator Trial of Labor Not too late to support 'Trial of Labor'

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The degree to which a person is easy-going or irritable--a personality trait thought to be one of the stable touchstones of identity--can be shifted more toward the easy-going side by a drug used to treat depression, University of California San Francisco researchers report. The evidence that drugs can act on the brain to change once-stable measures of personality is published in the March issue of the American Journal of Psychiatry by a UCSF research team led by Victor Reus, MD, and Owen Wolkowitz, MD, professors of psychiatry at UCSF, and by postdoctoral fellow Brian Knutson, PhD. Twenty-three mentally healthy men and women, average age 27, who took the anti-depressant paroxetine for four weeks as part of the study scored lower on survey questionnaires used to measure hostility and exhibited more engaging and cooperative behavior in puzzle-solving tasks with a partner than they did at the beginning of the study. In comparison, a matching group of study volunteers who took only an inactive placebo pill did not change by these measures. "Personality, a set of traits and attributes that characterize individuals and that persist throughout life, has been thought to be about fifty to sixty percent attributable to inheritance, a conclusion based in large part on studies of twins reared either together or apart," Reus explains. "Inherited aspects of personality by definition must have some biological underpinning, but this is the first controlled study of the effects of a drug on a component of personality in people who are not mentally ill," he says. "Our findings lead us to conclude that different aspects of normal personality may be altered by psychopharmaceuticals that act on distinct nerve pathways in the brain." Other researchers in previous studies found that, in psychiatric patients, low levels of a signaling molecule, the neurotransmitter serotonin, may be related to psychiatric disorders characterized by hostility and aggression, Reus Contact: UCSF News Services University of California - San Francisco

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US Pharm. 2013;38(7):69-79. ABSTRACT: Stevens-Johnson syndrome (SJS) is a rare, life-threatening mucocutaneous reaction that is often drug-induced. SJS and toxic epidermal necrolysis (TEN) are considered to be the same condition on two ends of a spectrum, differing only by the extent of epidermal detachment. Despite reports of more than 100 drugs being taken in patients who develop SJS/TEN, a few classes such as antibiotics and anticonvulsants are thought to carry the highest risk. Genetic susceptibility due to polymorphisms of the human leukocyte antigen (HLA) gene may influence the development of SJS/TEN. There is conflicting evidence on the benefit of treatment of SJS/TEN with immunomodulating therapies. Although SJS is rare, pharmacists need to be prepared to identify and manage the acute and long-term effects of this Cutaneous (skin) reactions account for a large portion of drug-induced adverse effects. These reactions can range from a mild penicillin-induced rash to life-threatening conditions involving both the skin and mucous membranes, progressing to further organ involvement. One example of a life-threatening mucocutaneous condition is Stevens-Johnson syndrome (SJS). With the broad spectrum of potential severity, it is important for clinicians to be able to recognize the differences between cutaneous reactions, identify potential causative agents, and initiate therapy if indicated. The early recognition of severe cutaneous reactions is especially important to reduce fatal SJS is a mucocutaneous immunologic reaction that is often drug-induced and can result in long-term sequelae and mortality. The incidence of SJS is estimated at 1 to 6 cases per million person-years.1 SJS itself was first described in 1922 with the publication of a case report involving two young boys. The authors described the presence of extensive cutaneous eruptions with severe mucosal and ocular involvement, and stated that the condition was “unlike anything previously observed.”2 Other than case reports, most current knowledge of SJS comes from studies conducted in other countries, especially in Europe. In 1956, a dermatologist named Alan Lyell described a mucocutaneous condition similar to but more severe than SJS, toxic epidermal necrolysis (TEN) or Lyell’s syndrome.3 Both SJS and TEN are characterized by epidermal detachment and erosive mucosal lesions. After years of debate, SJS and TEN are now considered to be the same condition but differ in severity and cutaneous involvement.4 The percentage of epidermal detachment is the primary differentiating factor between SJS and TEN, with SJS presenting with <10% epidermal detachment and TEN presenting with >30%.5 Both SJS and TEN are debatably included in the same spectrum as erythema multiforme (EM). This mucocutaneous condition has similarities in clinical presentation to SJS/TEN but has some distinct differences. TABLE 1 outlines some of the differences in the categorization of EM, SJS, and TEN.5,6 Disputes regarding the categorization of these conditions into the same spectrum revolve around the marked differences between SJS/TEN and EM in the common etiology and rate of recurrence. The most common cause of EM is the herpes simplex virus (HSV) infection, which contrasts with the medication-induced reaction in SJS/TEN.4,6 Due to the viral etiology in EM, recurrence can occur in 30% of patients; for SJS/TEN, recurrence is rare unless a patient is reexposed to the causative The appearance of the cutaneous lesions is another differentiating feature distinguishing EM from SJS/TEN. EM lesions have a target appearance with concentric rings of color and a dark center, while SJS/TEN lesions are irregularly shaped with a dark center that progressively coalesces.4-6 SJS/TEN patients normally present with flat macules (spots), which are absent in EM. Mortality is rarely seen in EM, while mortality in patients with SJS is about 10%.4-6 The typical clinical course of SJS begins within 8 weeks (usually 4 to 30 days) following the first exposure to the causative agent. Only in very rare cases where an inadvertent rechallenge occurs do symptoms appear within hours. Patients who develop SJS/TEN can have varying levels of cutaneous, extracutaneous, and mucous membrane manifestations (TABLE 2).4,7-9 About one-third of patients will present with nonspecific symptoms (e.g., fever, headache, sore throat, cough, malaise) and/or burning of the eyes followed by the appearance of mucocutaneous lesions of the eyes, mouth, genitals, and urinary tract in 1 to 3 days.4 Another third of patients will present with mucous membrane lesions (FIGURE 1), while the remainder of patients present with a diffuse rash. Following the appearance of the diffuse rash, the lesions convert to flaccid blisters, which spread with pressure and break easily, leading to extensive epidermal detachment. The detachment of the epidermis can be effortless, normally as a result of frictional trauma and on pressure points. A positive Nikolsky’s sign, which is the dislodgment of the epidermis with lateral pressure, may be present in these patients.4,7 Almost all patients with mucosal involvement develop painful hemorrhagic erosions coated by grayish white pseudo-membranes and crusts in the oral cavity and on the border of the lips.4 Involvement of the gastrointestinal (GI) tract can also affect the esophagus, small bowel, and colon, which may impact enteral nutrition and the absorption of oral medications.8 Ocular involvement is frequent, reported in up to 80% of patients, and can involve severe conjunctivitis and blepharitis along with visual disturbances and photophobia.4 Eyes can appear swollen, erythematous, and crusted as a result of ocular discharge.4, 9 Involvement of the respiratory tract epithelium may occur leading to hypoxemia, hypocapnia, and acid-base disturbances potentially requiring the need for mechanical ventilation.9 Patients who develop respiratory epithelium involvement have a higher risk of mortality. About 20% of TEN patients will develop epithelium involvement of the trachea and bronchi.9 Septicemia is another serious complication and is the most common cause of death in SJS/TEN. Normally, the epithelium provides a natural barrier to the systemic invasion of bacteria, but this barrier is compromised as large areas of the epidermis become detached. Extensive detachment can result in the collection of intravascular fluid in nontraditional body areas such as the peritoneal or pleural cavities, also known as third spacing of intravascular fluid and protein loss; this may lead to hypotension and possible organ dysfunction.8,9 The effects of SJS continue beyond the healing of the cutaneous lesions to include long-term complications such as vision loss, severe dry eye syndrome, GI/gynecological strictures, and nail disfigurement.4,7-9 Even though the cutaneous lesions rarely scar the skin, patients can exhibit hyper- and hypo-pigmentation of the affected areas.9 Low severity or lack of acute ocular symptoms is not predictive of the presence or absence of subsequent ocular sequelae.7 Survivors of this condition may display symptoms of posttraumatic stress disorder (PTSD) and have a fear of syndrome reoccurrence with exposure to a variety of medications. Pathophysiology and Genetics The specific pathophysiology of SJS and TEN is not well defined at this time. There are several theories as to the key immunologic players in their development, along with continued debate over whether it’s the parent drug or a metabolite that results in immune cell activation. The rare and seemingly random occurrence of SJS/TEN cannot be explained by medication exposure alone. Research into genetic susceptibilities has begun to elucidate the potential reasons why some individuals develop such a severe mucocutaneous reaction while others remain unaffected. Studies have shown that the presence of specific human leukocyte antigen (HLA) genotypes, which is a human version of the major histocompatibility complex (MHC), are associated with an increased risk of SJS/TEN when individuals are exposed to specific Recent studies have identified a relationship between HLA-B*1502 and the development of SJS/TEN in people given carbamazepine who were of Southeast Asian descent (e.g., Han Chinese, Malaysian).11 The presence of HLA-B*1502 in the Han Chinese confers a 7.7% predictive value that a patient could develop carbamazepine-induced SJS/TEN, whereas the absence of this allele has a negative predictive value of 100%.11 This same increase in susceptibility was not demonstrated in European populations.11 Interestingly, the majority of patients in the European study who were positive for HLA-B*1502 and developed carbamazepine-induced SJS/TEN were of Southeast Asian descent.11,12 This ethnic selectivity may be explained by the fact that Europeans have a low prevalence of this particular HLA allele, 0.1%, compared to individuals with Southeast Asian ancestry (4.8%-12.8%), making the numbers needed to detect a statistically significant difference difficult to obtain.11 As a result, genetic testing for HLA-B*1502 is only recommended in patients of Southeast Asian descent. HLA-B*5801 is another allele that has demonstrated a predictive relationship with a specific medication, allopurinol, and the development of SJS/TEN. In one study, all 51 patients who developed allopurinol-induced SJS/TEN were positive for HLA-B*5801 compared to only 15% (20/135) of allopurinol-tolerant patients.13 In Taiwan, the allopurinol labeling was recently updated to recommend genetic screening of patients prior to initiation of therapy.14 Currently, there is no FDA recommendation to test for HLA-B*5801 prior to therapy. Different from HLA-B*1502, this allele is equally distributed among ethnic groups, making genetic testing less practical.13 The development of the cutaneous lesions and epidermal necrosis are thought to occur as a result of massive apoptosis of keratinocytes. This is suspected to be a cell-mediated cytotoxic reaction. Studies have confirmed the presence of various cytotoxic cells, including natural killer T cells (NK) and drug-specific CD8+ T lymphocytes, within early cutaneous lesions.10 These cytotoxic cells are thought to lead to the amplification and release of cytokines, such as granulysin, perforin, and granzyme B, which likely play a separate role in apoptosis (FIGURE 2).4,10 Original theories proposed the interaction between Fas and Fas ligand (FasL), a member of the tumor necrosis factor (TNF) family found on the surface of activated T cells, as the main differentiating factor that leads to the extensive apoptosis of keratinocytes, cells of the epidermis, and the epidermal detachment not seen in other drug-mediated hypersensitivity reactions.8,10 The binding of FasL to Fas is known to induce activation of caspases, which are proteases that mediate apoptotic cell death, necrosis, and inflammation.4,10 This theory was challenged when recent studies identified elevated concentrations of granulysin in the blister fluid of patients with SJS/TEN.15 Unlike granulysin, the concentrations of granzyme B, perforin, and soluble Fas ligand (sFasL) in the blister fluid were insufficient to produce distinct cytotoxicity.15 Interestingly enough, the concentration levels of granulysin identified in the blisters directly correlated with the clinical severity of the symptoms; SJS lesions contained lower concentrations of granulysin compared to TEN lesions, which could explain the differences of clinical severity in these pathologically identical conditions.15 This relationship was further explored when granulysin was injected into mice and the clinical features of SJS/TEN, blistering and considerable epidermal and dermal necrosis, soon developed.15 Granulysin has a direct apoptotic effect on keratinocytes and is now thought to be a key mediator in the apoptosis of keratinocytes.7,10 Up to 60% of cases of SJS can demonstrate causality to a medication exposure, but other factors including infection (e.g., Mycoplasma pneumonia) have been implicated in the development of this mucocutaneous condition, and up to 20% of cases remain idiopathic.4 More than 100 medications have been identified as potential causative agents of SJS/TEN. Even though some drugs have been implicated in case reports, not all of these agents have demonstrated a strong association with the development of SJS (TABLE 3).4,16,17 In two large European case-control studies, fewer than a dozen medications accounted for half of the analyzed SJS/TEN cases.16,17 Some of the most notorious medications associated with the development of SJS/TEN include sulfonamide antibiotics, antiepileptics (carbamazepine, phenytoin, lamotrigine, phenobarbital), allopurinol, nevirapine, and certain oxicam nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., meloxicam, piroxicam).16 One important distinction to note is that aspirin, unlike other NSAIDs, has not been associated with the development of SJS/TEN. The presence of certain conditions, such as HIV, collagen vascular disease, and cancer can increase the risk of developing SJS.4 This is thought to be due to abnormalities of the immune system as a result of these conditions. Current evidence is limited as to how significant the risk of cross-reaction is between structurally similar medications. Avoidance of these agents may not be a viable option in certain medical conditions. Seizure disorders can be particularly challenging due to structural similarities of several of the commonly used antiepileptics. Treatment with levetiracetam may be a viable option because of a lack of structural similarity with the high-risk anticonvulsants and with no strong association to the development of SJS/TEN. In a study by Locharernkul et al, some patients who developed either carbamazepine- or phenytoin-induced SJS were noted to have been exposed, and demonstrated tolerance, to other antiepileptics (phenytoin, phenobarbital, valproic acid, carbamazepine, and/or lamotrigine).18 Nine out of 10 patients with phenytoin- or carbamazepine-induced SJS/TEN in this study were at one point treated with valproic acid without incidence. These observational findings suggest that the risk of cross-reactivity may not be as significant as once thought, but more research is needed to confirm these findings. Treatment and Management The pharmacist can be an asset in the acute- and long-term management of SJS. Outpatient pharmacists are encouraged to emphasize the importance of reporting new rash symptoms in patients who are recently started on medications more commonly associated with SJS. In the acute setting, prompt identification and removal of the highly suspected agent is vital. It is important to gather a detailed medication history in order to identify the most likely causative agent. The knee-jerk reaction to discontinue all of the patient’s medications is not appropriate and can complicate the clinical course if chronic conditions are not adequately treated. Each medication’s duration of therapy is important in implicating or excluding drugs most likely to be involved; the history should focus on those medications that were initiated within the last 8 weeks.4 If a causative agent is identified, rechallenge with that medication is not recommended, and if unintentionally done may cause a rapid recurrence of symptoms. Patients should be evaluated for future anxiety and potential PTSD symptoms when they are initiated on new medications. Prompt initiation of appropriate treatment can potentially reduce the morbidity and mortality associated with SJS. Supportive care, similar to that provided to burn victims, is a vital component in the acute management of patients with SJS. Patients will commonly have fluid and electrolyte abnormalities that require careful monitoring; a recommended equation for fluid replacement is 0.7 mL/kg per percentage of body surface area (BSA) affected.9 Fluid requirements for SJS patients are normally 66% to 75% of those required in burn patients with the same extent of BSA involved. To prevent hypoperfusion of the kidneys, urine output should be maintained at 50 to 80 mL/h.7 Nonstick dressings can be placed on denuded areas of the body, with or without a saturated anti-infective, such as 0.5% silver nitrate.19 Topical anti-infectives with a sulfa moiety (e.g., silver sulfadiazine) should be avoided, especially if the causative agent is a sulfa Mouth care with disinfecting mouthwashes (chlorhexidine) and mild ointments (white petroleum) is essential in managing the mucosal lesions of the oral cavity and lips.9,19 Every patient, whether acute ocular involvement is apparent or not, should have his or her eyes evaluated, preferably by an ophthalmologist.9 Treatment can include prophylactic ophthalmic antibiotics (e.g., bacitracin or a fluoroquinolone), preservative-free emollients, antiseptic eye drops, and/or vitamin A. Recent evidence suggests that the use of ophthalmic topical steroids (fluorometholone ointment 0.1% every 1-2 hours for about 1-2 weeks) and amniotic membranes may help to preserve visual acuity and protect against scarring.20 Routine use of oral or parenteral prophylactic antibiotics is not recommended, although patients should frequently be monitored for the signs and symptoms of an infection and sepsis. Wound debridement is not always necessary because, unlike in burn victims, the epidermis can reepithelialize if it is maintained in place.7 Removal of the activated immune cells though plasmapheresis and hemodialysis has demonstrated mixed results in studies and is currently not considered the standard of care.7,21,22 Intravenous immunoglobulin (IVIG) and corticosteroids are two therapies thought to improve clinical outcomes when used in addition to supportive care. The evidence to support the use of either IVIG or corticosteroids is conflicting and complicated by a wide variation in dosing and duration of therapy (TABLE 4).7-9,19,21-23 Whether to provide patients with high-dose pulse therapy or low-dose extended therapy is still being investigated.21 Cyclosporine is another immunomodulating therapy that has been investigated with varying results.9,23 There is currently no consensus as to what is the best medication regimen to reduce the clinical severity, complications, and occurrence of sequelae. If immunomodulating therapy is to be utilized, it should be initiated as soon as the diagnosis of SJS/TEN is determined. Currently, there are no prospective, randomized, placebo-controlled trials available to confirm whether either therapy reduces mortality or long-term sequelae. When data for 281 patients from the EuroSCAR study were retrospectively evaluated, no difference was found in mortality between IVIG and/or corticosteroids when compared to supportive care SJS is a life-threatening mucocutaneous reaction that is commonly medication induced. Symptoms can be cutaneous, extracutaneous, or involve the mucous membrane and lead to further body system involvement if not addressed. Once the acute manifestations of the condition have healed, patients can experience long-term sequelae and psychological issues. Early identification and discontinuation of the causative agent are important. Currently there is no consensus on the use of various immunomodulating therapies for acute treatment of SJS. Future studies will hopefully address the ambiguous data that are 1. Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol. 1990;126:43-47. 2. Stevens AM, Johnson F. A new eruptive fever associated with stomatitis and opthalmia: report of two cases in children. Am J Dis Child. 1922;24:526. 3. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol. 1956;68:355-361. 4. Valeyrie-Allanore L, Roujeau J. Chapter 40. Epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis). In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012. 5. Bastuji-Garin S, Rzany B, Stern RS. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92-96. 6. Roujeau J. Chapter 39. Erythema multiforme. In: L Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012. 7. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;5:1-11. 8. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review. Crit Care Med. 2011;39:1521-1532. 9. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7:803-815. 10. Chung WH, Hung SI. Recent advances in genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis. J Dermatol Sci. 2012;66:190-196. 11. Fernando SL, Broadfoot AJ. Prevention of severe cutaneous adverse drug reactions: the emerging value of pharmacogenetic screening. CMAJ. 2009;182:476-480. 12. Lonjou C, Borot N, Sekula P, et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics. 2008;18:99-107. 13. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. PNAS. 2005;102:4134-4139. 14. Hershfield MS, Callaghan JT, Tassaneeyakul W, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther. 2013;93:153-158. 15. Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14:1343-1350. 16. Roujea JC, Kell JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333:1600-1607. 17. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risk with emphasis on recently marketed drugs. The EuroSCAR study. J Invest Dermatol. 2008;128:35-44. 18. Locharernkul C, Loplumlert J, Limotai C, et al. Carbamazepine and phenytoin-induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia. 2008;49:2087-2091. 19. Fromowitz JS, Ramos-Caro FA, Flowers FP, et al. Practical guidelines for the management of toxic epidermal necrolysis and Stevens-Johnson syndrome. Int J Dermatol. 2007;46:1092-1094. 20. Shammas M, Edward C, Sarkar J, et al. Management of acute Stevens-Johnson syndrome and toxic epidermal necrolysis utilizing amniotic membrane and topical corticosteroids. Am J Ophthalmol. 2010;149:203-213. 21. Worswick S, Cotliar J. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of treatment options. Dermatol Ther. 2011;24:207-218. 22. Knowles S, Shear NH. Clinical risk management of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Dermatol Ther. 2009;22:441-451. 23. Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol. 2012;167:424-434. 24. Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective EuroSCAR study. J Am Acad Dermatol. 2008;58:33-40. To comment on this article, contact [email protected].

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For release: Monday, April 30, 2012 Two studies suggest that the sirtuin-1 (Sirt1) gene, known for its possible role in longevity, may be a therapeutic target for Huntington's disease. The studies found that boosting the levels of Sirt1 reduced the loss of brain tissue in mouse models of Huntington’s disease. "The role of sirtuins in aging and disease has been the focus of intense research. Together, these studies provide some of the strongest evidence to date that sirtuins may have a protective role in neurodegenerative disease," said Margaret Sutherland, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. The studies were funded by NINDS and published in Nature Medicine. Sirtuins were first linked to longevity in 1999, when researchers at the Massachusetts Institute of Technology found that yeast cells lived longer with increased levels, or over-expression, of a sirtuin gene. Similar results were found with roundworms and fruit flies. In another milestone, sirtuins were linked to calorie restriction. Restricting calorie intake increases lifespan and produces healthy metabolic changes in laboratory animals; there is evidence that sirtuins are needed for at least some of these effects. Sirt1 over-expression protects against brain atrophy in the mouse model of Huntington's disease (HD). In these MRI scans, the white lines represent the normal contours of the mouse brain. Left: an HD mouse. Right: an HD mouse over-expressing Sirt1. From Jiang et al., Nature Medicine 2011. Recent data, however, suggest that those early studies may have over-estimated the effects of sirtuins on lifespan. One theory is that sirtuins may influence the susceptibility to age-related diseases, not the aging process itself. Research into how sirtuins affect Huntington’s disease has its own ambiguities. Sirtuins seem to counteract Huntington's pathology in worms, but aggravate it in fruit flies. The two recent studies are the first to show that sirtuins can protect against Huntington's disease in mice. Huntington’s disease is a genetic disorder that attacks parts of the brain involved in movement and thinking. Symptoms usually appear in middle age and include involuntary movements, personality changes and mental decline. The disease worsens over time, and is usually fatal within 20 years of onset. It is caused by mutations in a gene called huntingtin. The recent studies utilized mice carrying these huntingtin mutations to investigate whether Sirt1 over-expression could protect against the disease. One study was led by Dimitri Krainc, M.D., Ph.D., who is an investigator at Massachusetts General Hospital and a professor of neurology at Harvard Medical School in Boston.* The other was led by Wenzhen Duan, M.D., Ph.D., a professor of neurobiology at The Johns Hopkins University in Baltimore, with Dr. Krainc as a co-author.** Both studies found that Sirt1 helped prevent atrophy (shrinkage) of a brain region called the striatum, which is a common feature of Huntington’s disease. Other results of the two studies diverge but still point to a protective effect. For example, Sirt1 over-expression improved survival of the mice only in Dr. Krainc’s study, and it slowed motor impairment only in Dr. Duan’s study. The researchers say some of their unique findings are likely due to differences in the overall genetic makeup of the mouse lines used and in the way that Sirt1 gene expression was controlled. In Dr. Duan’s study, the extra Sirt1 was targeted to the brain; in Dr. Krainc’s study, the gene was over-expressed in other tissues, too. “In all of the mice we examined, Sirt1 protected against brain atrophy. On that issue – which is essential in any therapeutic approach to Huntington’s disease – our studies are in complete agreement. But the differences are interesting and they should be explored,” Dr. Krainc said. Like prior research on sirtuins, Dr. Duan’s study hints at a link between sirtuins and calorie restriction. In normal mice, calorie restriction reduces the incidence of hyperglycemia (high levels of glucose in the blood) and diabetes. Some Huntington’s mice are prone to hyperglycemia. Dr. Duan found that this could be corrected either by calorie restriction or by over-expression of Sirt1. Other questions for future research include how much Sirt1 is needed, and where, for optimal protection against Huntington’s disease. "The dosage of sirtuins may be a critical factor, and could be responsible for some of the controversy in prior studies," said Dr. Duan. She is also interested in knowing which cell types must express Sirt1 in order to see its protective effects. The researchers have begun to look at the cellular changes that Sirt1 triggers to counteract Huntington’s disease. Sirt1 is an enzyme that regulates other proteins, but many of its targets are unknown. Dr. Krainc’s group found that Sirt1 can activate a gene-regulatory protein called TORC1, which in turn activates pro-survival genes. Working together, the two groups found that the mutant huntingtin protein inhibits Sirt1's enzymatic activity. Assuming that these data are confirmed in human studies, the ultimate question is whether Sirt1 and its effects against Huntington’s can be kick-started with a drug treatment. Some research has found that resveratrol, a chemical found in trace amounts in red wine, can activate sirtuins, possibly mimicking the effects of calorie restriction. As research continues to try to define these effects, pharmaceutical companies are developing sirtuin activators as potential treatments for age-related diseases. Drs. Duan and Krainc agree that for now, efforts to test such compounds against Huntington’s disease would be premature. "We are still trying to understand the role of Sirt1 in the normal brain versus its role in disease. We want to lay that groundwork before we begin evaluating therapeutic compounds," said Dr. Krainc. He also noted that currently available Sirt1 activators have non-specific effects on other proteins and do not efficiently penetrate the brain. "The development of Sirt1 activators and other novel therapeutics for Huntington's disease will require a collaborative effort involving NIH, academia, industry and foundations," Dr. Sutherland said. She noted that NINDS has partnered with the Huntington's research nonprofit CHDI, Inc. to encourage projects that will zero in on the most robust therapeutic targets. In addition to NINDS, the research received support from CHDI, Inc., and the Hereditary Disease Foundation. Dr. Krainc’s study was also supported by the Paul F. Glenn Foundation and NIH’s National Institute of Mental Health and National Center for Research Resources. Dr. Duan’s study received additional NIH support from the National Institute on Aging intramural program, the National Institute of Biomedical Imaging and Bioengineering, and the National Institute for Environmental Health Sciences. - By Daniel Stimson, Ph.D. *Jeong H et al. "Sirt1 mediates neuroprotection from mutant huntingtin by activation of TORC1 and CREB transcriptional pathway." Nature Medicine, published online December 12, 2011. **Jiang M et al. "Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets." Nature Medicine, published online December 12, 2011. Last Modified May 1, 2012

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(This article has been updated to include the contribution of Scripps Research scientist Hugh Rosen to the study). Scientists at The Scripps Research Institute have identified a cause of a deadly immune system reaction to flu infection. Moreover, they have identified how a class of drugs tested in animals stops this “cytokine storm,” which can be more damaging than the flu itself. The study was published Wednesday in the Proceedings of the National Academy of Sciences. It was led by Michael Oldstone, Hugh Rosen and John Teijaro, all of Scripps. The work builds on a 2011 study led by Oldstone and Rosen finding that cytokine storms can kill flu patients. They also discovered a compound that inhibits this out-of-control immune reaction. The new study charts the molecular paths affected by the compound, called CYM 5442, helping to explain why it’s effective. This knowledge can help guide development of new drugs to reduce flu mortality. Scientists who read the study said it may lead to new therapies for other infectious diseases characterized by immune overreaction. “We show that with this type of drug, we can quiet the storm enough to interfere with the virus-induced disease and lung injury, while still allowing the infected host to mount a sufficient immune response to eliminate the virus,” Teijaro said in a Scripps press release. Cytokine storms are believed to have caused the unusually heavy mortality of the 1918 flu, which killed an estimated 50 million to 100 million people. Most of those killed were young adults, who presumably had strong immune systems. A version of this compound has been licensed to San Diego biotech Receptos, which is now in Phase 3 testing to treat multiple sclerosis, an autoimmune disease. The compound was developed in Rosen's lab. The compound targets a receptor, or cell surface molecule, called S1P1. Receptors trigger reactions inside cells once activated. The S1P1 receptor is found in endothelial cells, which line blood vessels. These cells initiate the cytokine storm released in H1N1 flu infection. This cascade of chemicals is accompanied by infiltration of immune system cells into the lungs that can cause further damage. Activating the S1P1 receptor reduced the cytokine storm. The scientists bred mice engineered to lack certain receptors that sense influenza infection and trigger an immune response. Elimination of any individual receptor produced a modest reduction in cytokine production and immune cell infiltration into the lungs. Compounds that activated S1P1 produced a much stronger reduction. “What this shows is that our drug is working not through one selective pathway but much more broadly,” Teijara said in the release. “Many different cytokines are induced in this reaction, so just blocking one is surely not enough to reduce lung disease.” The study results are “exciting,” scientists at Sanford-Burnham Medical Research Institute and the La Jolla Institute for Allergy & Immunology said by email. “What is unknown is whether this drug is effective in humans at times late during infection when a drug like Tamiflu is not effective,” said Carl Ware, of Sanford-Burnham. “My take on John’s exciting results is a bit broader in that this class of drug may be effective in stopping damage in the lung caused by the immune system due to other infections or a virus infection in other sensitive organs, e.g., the brain.”

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ERRB Scientific Publications: HIV/AIDS: Fact Sheet What is the Public Health Problem? Acquired Immune Deficiency Syndrome (AIDS) is the leading cause of death in Sub-Saharan Africa and the fourth leading cause of death worldwide. Many complex humanitarian emergencies are in countries that face HIV/AIDS epidemics, but data on the burden of HIV/AIDS in these situations is scarce. Refugees and displaced populations may be at increased risk of contracting HIV/AIDS as a result of: - changes in societal structures, - broken family units, - economic vulnerability of women and unaccompanied minors, - a rise in transactional sex , - the presence of sexual violence and coercive sex, - untreated psychological trauma, and - the disruption of preventive and curative health services. Refugees and displaced persons with HIV/AIDS are at increased risk of infectious diseases and malnutrition which are the leading causes of morbidity and mortality in humanitarian emergencies. What has the CDC Accomplished? In 2002, CDC conducted an HIV/AIDS seroprevalence and behavioral risk factor survey in all accessible areas of Sierra Leone (representing 79% of the population). - The objective was to provide baseline data for program planning, monitoring and evaluation, and advocacy prior to implementation of the Sierra Leone HIV/AIDS Response Project (SHARP). In 2002, CDC surveyed pregnant women and patients with sexually transmitted infections (STI) in Yei County, Western Equatoria and Southern Sudan. - This was part of the pilot project, ‘Reducing HIV/AIDS Transmission and Improving Related Reproductive Health Practices in Southern Sudan’. - For the first time in a CHE situation, Rapid HIV and Syphilis tests were used. In 2005, CDC collaborated with the United Nations Department of Peacekeeping Operations (UNDPKO) to complete a comprehensive HIV/AIDS knowledge, attitudes and practices (KAP) survey among United Nations peacekeepers in Liberia. - Results were presented to the UN Security Council. In 2007, CDC completed the second comprehensive HIV/AIDS KAP survey in The UN Stabilization Mission in Haiti, in collaboration with UNDPKO. In 2007, CDC also provided technical advice to UNHCR in the analysis and editing of seroprevalence surveys among refugees in Kenyan and Ugandan camps. In 2008, CDC conducted a population based survey in Kenya and studied the effect of the election violence on access to and availability of HIV/AIDS treatment and prevention services. Most recently, CDC completed and disseminated a toolkit of protocols in HIV/STI assessment methods for organizations that support, plan or implement HIV/STI programs in humanitarian emergencies. What are the Next Steps? A follow-up comprehensive analysis of the HIV/AIDS KAP survey findings and lessons learned will be carried out. - The combination of these survey results will inform future UN deployment and training protocols and provide a standard tool and methodology for measuring HIV/AIDS indicators among UNDPKO operations globally. CDC will conduct a population-based, comprehensive HIV/AIDS behavior and awareness survey with biological indicators among refugees in Kenya and Uganda. A variety of HIV/AIDS data is being collected as part of the UNHCR Health Information System global operations. In order to evaluate the attributes of the system and the systematic collection of HIV/AIDS indicators CDC will: - monitor trends in HIV/AIDS health status and thus continually address health care priorities; - evaluate the effectiveness of interventions and service coverage; and - evaluate the quality of health interventions. CDC will continue to conduct rapid assessments, population based surveys and collect surveillance data and translate those findings into best practices which can be used to assist humanitarian agencies to prevent and mitigate HIV/AIDS and STI in complex humanitarian emergencies.

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Pericoronitis associated with the lower right third molar (wisdom tooth). |Classification and external resources| |ICD-10||K05.2 (acute), K05.3 (chronic)| Pericoronitis (from the Greek peri, "around", Latin corona "crown" and -itis, "inflammation") also known as operculitis, is inflammation of the soft tissues surrounding the crown of a partially erupted tooth, including the gingiva (gums) and the dental follicle. The soft tissue covering a partially erupted tooth is known as an operculum, an area which can be difficult to access with normal oral hygiene methods. The synonym operculitis technically refers to inflammation of the operculum alone. Pericoronitis is caused by an accumulation of bacteria and debris beneath the operculum, or by mechanical trauma (e.g. biting the operculum with the opposing tooth). Pericoronitis is often associated with partially erupted and impacted mandibular third molars (lower wisdom teeth), often occurring at the age of wisdom tooth eruption (15-24). Other common causes of similar pain from the third molar region are food impaction causing periodontal pain, pulpitis from dental caries (tooth decay), and acute myofascial pain in temporomandibular joint disorder. Pericoronitis is classified into chronic and acute. Chronic pericoronitis can present with no or only mild symptoms and long remissions between any escalations to acute pericoronitis. Acute pericoronitis is associated with a wide range of symptoms including severe pain, swelling and fever. Sometimes there is an associated pericoronal abscess (an accumulation of pus). This infection can spread to other parts of the face or neck, and occasionally can lead to airway compromise (e.g. Ludwig's angina) requiring emergency hospital treatment. The treatment of pericoronitis is through pain management and by resolving the inflammation. The inflammation can be resolved by flushing the debris or infection from the pericoronal tissues or by removing the associated tooth or operculum. Retaining the tooth requires improved oral hygiene in the area to prevent further acute pericoronitis episodes. Tooth removal is often indicated in cases of recurrent pericoronitis, extensive decay, or tooth impaction. The definition of pericoronitis is inflammation in the soft tissues surrounding the crown of a tooth. This encompasses a wide spectrum of severity, making no distinction to the extent of the inflammation into adjacent tissues or whether there is associated active infection (pericoronal infection caused by micro-organisms sometimes leading to a pus filled pericoronal abscess or cellulitis). Typically cases involve acute pericoronitis of lower third molar teeth. During "teething" in young children, pericoronitis can occur immediately preceding eruption of the deciduous teeth (baby or milk teeth). The International Classification of Diseases entry for pericoronitis lists acute and chronic forms. Acute pericoronitis (i.e. sudden onset and short lived, but significant, symptoms) is defined as "varying degrees of inflammatory involvement of the pericoronal flap and adjacent structures, as well as by systemic complications." Systemic complications refers to signs and symptoms occurring outside of the mouth, such as fever, malaise or swollen lymph nodes in the neck. Pericoronitis may also be chronic or recurrent, with repeated episodes of acute pericoronitis occurring periodically. Chronic pericoronitis may cause few if any symptoms, but some signs are usually visible when the mouth is examined. Signs and symptoms The signs and symptoms of pericoronitis depend upon the severity, and are variable: - Pain, which gets worse as the condition develops and becomes severe. The pain may be throbbing and radiate to the ear, throat, temporomandibular joint, posterior submandibular region and floor of the mouth. There may also be pain when biting. Sometimes the pain disturbs sleep. - Tenderness, erythema (redness) and Edema (swelling) of the tissues around the involved tooth, which is usually partially erupted into the mouth. The operculum is characteristically very painful when pressure is applied. - Halitosis resulting from the bacteria putrefaction of proteins in this environment releasing malodorous volatile sulfur compounds. - Bad taste in the mouth from exudation of pus. - Intra-oral halitosis. - Formation of pus, which can be seen exuding from beneath the operculum (i.e. a pericoronal abscess), especially when pressure is applied to the operculum. - Signs of trauma on the operculum, such as indentations of the cusps of the upper teeth, or ulceration. Rarely, the soft tissue around the crown of the involved tooth may show a similar appearance to necrotizing ulcerative gingivitis. - Trismus (difficulty opening the mouth). resulting from inflammation/infection of the muscles of mastication. - Dysphagia (difficulty swallowing). - Cervical lymphadenitis (inflammation and swelling of the lymph nodes in the neck), especially of the submandibular nodes. - Facial swelling, and rubor, often of the cheek that overlies the angle of the jaw. - Pyrexia (fever). - Leukocytosis (increased white blood cell count). - Malaise (general feeling of being unwell). - Loss of appetite. - The radiographic appearance of the local bone can become more radiopaque in chronic pericoronitis. Pericoronitis occurs because the operculum (the soft tissue directly overlying the partially erupted tooth) creates a "plaque stagnation area", which can accumulate food debris and micro-organisms (particularly plaque). This leads to an inflammatory response in the adjacent soft tissues. Sometimes Pericoronal infection can spread into adjacent potential spaces (including the sublingual space, submandibular space, parapharyngeal space, pterygomandibular space, infratemporal space, submasseteric space and buccal space ) to areas of the neck or face resulting in facial swelling, or even airway compromise (called Ludwig's angina). Inadequate cleaning of the operculum space allows stagnation of bacteria and any accumulated debris. This can be a result of poor access due to limited room in the case of the 3rd molars. Pericoronal infection is normally caused by a mixture of bacterial species present in the mouth, such as Streptococci and particularly various anaerobic species. This can result in abscess formation. Left untreated, the abscess can spontaneously drain into the mouth from beneath the operculum. In chronic pericoronitis, drainage may happen through an approximal sinus tract. The chronically inflamed soft tissues around the tooth may give few if any symptoms. This can suddenly become symptomatic if new debris becomes trapped or if the host immune system becomes compromised and fails to keep the chronic infection in check (e.g. during influenza or upper respiratory tract infections, or a period of stress). - When an opposing tooth bites into the operculum, it can initiate or exacerbate pericoronitis resulting in a spiraling cycle of inflammation and trauma. - Over-eruption of the opposing tooth into the unoccupied space left by the stalled eruption of a tooth is a risk factor to operculum trauma from biting. - Teeth that fail to erupt completely (commonly the lower mandibular third molars) are often the result of limited space for eruption, or a non-ideal angle of tooth eruption causing tooth impaction. - The presence of supernumerary teeth (extra teeth) makes pericoronitis more likely. |Pericoronitis||Temporomandibular joint disorder| |Swelling and tenderness of operculum and around wisdom tooth||Dull, aching pain around face, around ear, angle of jaw (masseter), and inside mouth behind upper wisdom tooth (lateral pterygoid)| |Disturbed sleep||Does not disturb sleep| |Poorly responsive to analgesics||Responds to analgesics| |Possibly limited mouth opening (trismus)||Possibly trismus, joint noises (e.g. clicking upon opening) and deviation of mandible| The presence of dental plaque or infection beneath an inflamed operculum without other obvious causes of pain will often lead to a pericoronitis diagnosis; therefore, elimination of other pain and inflammation causes is essential. For pericoronal infection to occur, the affected tooth must be exposed to the oral cavity, which can be difficult to detect if the exposure is hidden beneath thick tissue or behind an adjacent tooth. Severe swelling and restricted mouth opening may limit examination of the area. Radiographs can be used to rule out other causes of pain and to properly assess the prognosis for further eruption of the affected tooth. Sometimes a "migratory abscess" of the buccal sulcus occurs with pericoronal infection, where pus from the lower third molar region tracks forwards in the submucosal plane, between the body of the mandible and the attachment of the buccinator muscle to the mandible. In this scenario, pus may spontaneously discharge via an intra-oral sinus located over the mandibular second or first molar, or even the second premolar. Similar causes of pain, some which can occur in conjunction with pericoronitis may include: - Dental caries (tooth decay) of the wisdom tooth and of the distal surface of the second molar is common. Tooth decay may cause pulpitis (toothache) to occur in the same region, and this may cause pulp necrosis and the formation of a periapical abscess associated with either tooth. - Food can also become stuck between the wisdom tooth and the tooth in front, termed food packing, and cause acute inflammation in a periodontal pocket when the bacteria become trapped. A periodontal abscess may even form by this mechanism. - Pain associated with temporomandibular joint disorder and myofascial pain also often occurs in the same region as pericoronitis. They are easily missed diagnoses in the presence of mild and chronic pericoronitis, and the latter may not be contributing greatly to the individual's pain (see table). It is rare for pericoronitis to occur in association with both lower third molars at the same time, despite the fact that many young people will have both lower wisdom teeth partially erupted. Therefore bilateral pain from the lower third molar region is unlikely to be caused by pericoronitis and more likely to be muscular in origin. Prevention of pericoronitis can be achieved by removing impacted third molars before they erupt into the mouth, or through preemptive operculectomy. A treatment controversy exists about the necessity and timing of the removal of asymptomatic, disease-free impacted wisdom teeth which prevents pericoronitis. Proponents of early extraction cite the cumulative risk for extraction over time, the high probability that wisdom teeth will eventually decay or develop gum disease and costs of monitoring to retained wisdom teeth. Advocates for retaining wisdom teeth cite the risk and costs of unnecessary operations and the ability to monitor the disease through clinical exam and radiographs. Since pericoronitis is a result of inflammation of the pericoronal tissues of a partially erupted tooth, management can include applying pain management gels for the mouth consisting of lidocain, a numbing agent. Definitive treatment can only be through preventing the source of inflammation. This is either through improved oral hygiene or by removal of the plaque stagnation areas through tooth extraction or gingival resection. Often acute symptoms of pericoronitis are treated before the underlying cause is addressed. When possible, immediate definitive treatment of acute pericoronitis is recommended because surgical treatment has been shown to resolve the spread of the infection and pain, with a quicker return of function. Also immediate treatment avoids overuse of antibiotics (preventing antibiotic resistance). However, surgery is sometimes delayed in an area of acute infection, with the help of pain relief and antibiotics, for the following reasons: - Reduces the risk of causing an infected surgical site with delayed healing (e.g. osteomyelitis or cellulitis). - Avoids reduced efficiency of local anesthetics caused by the acidic environment of infected tissues. - Resolves the limited mouth opening, making oral surgery easier. - Patients may better cope with the dental treatment when free from pain. - Allows for adequate planning with correctly allocated procedure time. Firstly, the area underneath the operculum is gently irrigated to remove debris and inflammatory exudate. Often warm saline is used but other solutions may contain hydrogen peroxide, chlorhexidine or other antiseptics. Irrigation may be assisted in conjunction with Debridement (removal of plaque, calculus and food debris) with periodontal instruments. Irrigation may be enough to relieve any associated pericoronal abscess; otherwise a small incision can be made to allow drainage. Smoothing an opposing tooth which bites into the affected operculum can eliminate this source of trauma. Home care may involve regular use of hot salt water mouthwashes/mouth baths. Following treatment, if there are systemic signs and symptoms, such as facial or neck swelling, cervical lymphadenitis, fever or malaise, a course of oral antibiotics is often prescribed,. Common antibiotics used are from the penicillin group, clindamycin and sometimes metronidazole. If there is dysphagia or dyspnoea (difficulty swallowing or breathing), then this usually means there is a severe infection and an emergency admission to hospital is appropriate so that intravenous medications and fluids can be administered and the threat to the airway monitored. Sometimes semi-emergency surgery may be arranged to drain a swelling that is threatening the airway. If the tooth will not continue to erupt completely, definitive treatment involves either sustained oral hygiene improvements or removal of the offending tooth or operculum. The latter surgical treatment options are usually chosen in the case of impacted teeth with no further eruption potential, or in the case of recurrent episodes of acute pericoronitis despite oral hygiene instruction. In some cases, removal of the tooth may not be necessary with meticulous oral hygiene to prevent buildup of plaque in the area. Long term maintenance is needed to keep the operculum clean in order to prevent further acute episodes of inflammation. A variety of specialized oral hygiene methods are available to deal with hard to reach areas of the mouth, including small headed tooth brushes, interdental brushes, electronic irrigators and dental floss. This is a minor surgical procedure where the affected soft tissue covering and surrounding the tooth is removed. This leaves an area that is easy to keep clean, preventing plaque buildup and subsequent inflammation. Sometimes operculectomy is not an effective treatment. Typically operculectomy is done with a surgical scalpel, electrocautery, with lasers or, historically, with caustic agents (trichloracetic acid) Removal of the associated tooth will eliminate the plaque stagnation area, and thus eliminate any further episodes of pericoronitis. Removal is indicated when the involved tooth will not erupt any further due to impaction or ankylosis; if extensive work would be required to restore structural damage; or to allow improved oral hygiene. Sometimes the opposing tooth is also extracted if no longer required. Once the plaque stagnation area is removed either through further complete tooth eruption or tooth removal then pericoronitis will likely never return. A non-impacted tooth may continue to erupt, reaching a position which eliminates the operculum. A transient and mild pericoronal inflammation often continues while this tooth eruption completes. With adequate space for sustained improved oral hygiene methods, pericoronitis may never return. However, when relying on just oral hygiene for impacted and partially erupted teeth, chronic pericoronitis with occasional acute exacerbation can be expected. Dental infections such as a pericoronal abscess can develop into septicemia and be life-threatening in persons who have neutropenia. Even in people with normal immune function, pericoronitis may cause a spreading infection into the potential spaces of the head and neck. Rarely, the spread of infection from pericoronitis may compress the airway and require hospital treatment (e.g. Ludwig's angina), although the majority of cases of pericoronitis are localized to the tooth. Other potential complications of a spreading pericoronal abscess include peritonsillar abscess formation or cellulitis. Pericoronitis usually occurs in young adults, around the time when wisdom teeth are erupting into the mouth. If the individual has reached their twenties without any attack of pericoronitis, it becomes substantially less likely one will occur thereafter. - Douglass AB, Douglass JM (Feb 1, 2003). "Common dental emergencies.". American family physician 67 (3): 511–6. PMID 12588073. - Fragiskos, Fragiskos D. (2007). Oral surgery. Berlin: Springer. p. 122. ISBN 978-3-540-25184-2. - Laskaris, George (2003). Color Atlas of Oral Diseases. Thieme. p. 176. ISBN 1-58890-138-6. Retrieved 2008-05-31. - Newman MG, Takei HH, Klokkevold PR, Carranza FA (2012). Carranza's clinical periodontology (11th ed.). St. Louis, Mo.: Elsevier/Saunders. pp. 103, 133, 331–333, 440, 447. ISBN 978-1-4377-0416-7. - CA Bartzokas and GW Smith, ed. (1998). Managing Infections: Decision-making Options in Clinical Practice. Informa Health Care. p. 157. ISBN 1-85996-171-1. Retrieved 2008-05-31. - Nguyen DH, Martin, JT (Mar 15, 2008). "Common dental infections in the primary care setting.". American family physician 77 (6): 797–802. PMID 18386594. - Moloney J, Stassen, LFA (June–July 2009). "Pericoronitis: treatment and a clinical dilemma". Journal of the Irish Dental Association 55 (4): 190–192. - Neville BW, Damm DD, Allen CA, Bouquot JE. (2002). Oral & maxillofacial pathology (2nd ed.). Philadelphia: W.B. Saunders. pp. 73,129,133,153,154,590,608. ISBN 0721690033. - Wray D, Stenhouse D, Lee D, Clark AJE (2003). Textbook of general and oral surgery. Edinburgh [etc.]: Churchill Livingstone. pp. 220–222. ISBN 0443070830. - Soames JV, Southam JC (1999). Oral pathology (3rd ed.). Oxford: Oxford Univ. Press. p. 114. ISBN 0192628941. - Cawson RA, Odell EW (2002). Cawson's essentials of oral pathology and oral medicine (7th ed.). Edinburgh: Churchill Livingstone. pp. 82,166. ISBN 9780443071058. - Odell EW (2010). Clinical problem solving in dentistry (3rd ed.). Edinburgh: Churchill Livingstone. pp. 151–153. ISBN 9780443067846. - Hupp JR, Ellis E, Tucker MR (2008). Contemporary oral and maxillofacial surgery (5th ed.). St. Louis, Mo.: Mosby Elsevier. ISBN 9780323049030. - Dodson TB (Sep 2012). "The management of the asymptomatic, disease-free wisdom tooth: removal versus retention. (review)". Atlas Oral Maxillofac Surg clin North Am 20 (2): 169–76. doi:10.1016/j.cxom.2012.06.005. PMID 23021394. - "TA1: Guidance on the Extraction of Wisdom Teeth". National Institute of Clinical Excellence. Retrieved 3 April 2013. - Johri, A; Piecuch, JF (November 2011). "Should teeth be extracted immediately in the presence of acute infection?". Oral and maxillofacial surgery clinics of North America 23 (4): 507–11, v. doi:10.1016/j.coms.2011.07.003. PMID 21982602. - Samaranayake, Lakshman P. (2009). Essential microbiology for dentistry. Elseveier. p. 71. ISBN 978-0702041679. - Kravitz, ND; Kusnoto, B (April 2008). "Soft-tissue lasers in orthodontics: an overview.". American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics 133 (4 Suppl): S110–4. doi:10.1016/j.ajodo.2007.01.026. PMID 18407017.

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The field of vaccine development is getting a boost from new research that has identified a promising vaccine delivery approach, which in animal studies produced long-term immune protection after just one immunization. University of Pittsburgh researchers, who report their findings in the journal Immunity, say the method has particular relevance for efforts aimed at preventing or controlling infectious diseases, such as HIV or influenza, or stopping the growth of cancer. In one set of studies using this delivery approach, a single immunization halted the progression of melanoma and significantly extended survival in a mouse model. The approach makes use of an inactivated retrovirus, in this case, a modified lentiviral vector more commonly known for its ability to carry functional genes in certain types of gene therapy. Viral vectors in general have been of practical interest to vaccine researchers for their potential to deliver antigens from disease-causing microbes, or even cancer, in order to efficiently build immune defenses against such intruders. To date, the lentivirus has been overlooked in vaccine research. But, according to Pitt investigators, it has distinct advantages that make it a more promising approach for vaccine development than other viral vector or DNA-based vaccine approaches previously studied. According to results of their studies, a single injection of the lentivector containing either a hepatitis B virus antigen, a melanoma tumor antigen, or a commonly studied model antigen induced a more potent and notably, long-lasting immune response compared to other immunization approaches. A population of specialized immune cells that reside within the top layers of the skin is due much of the credit, say the authors. "Skin dendritic cells have long been considered the immune system's first line of defense," explains Louis D. Falo, Jr., M.D., Ph.D., professor and chairman of the department of dermatology, University of Pittsburgh School of Medicine, and the study's senior author. "But recent studies that looked at different viral vectors, including the most commonly studied vaccinia vector, have challenged this notion, suggesting that skin dendritic cells are not as important as the classical paradigm maintained. We find that with the lentivirus, it's precisely these skin dendritic cells that are responsible for the vector's more potent immune induction and sustained protection." Because they exist on the surface of the skin, these cells are the first to recognize the presence of a foreign body, or antigen. Although no longer an active virus, the lentivector is cause enough for alarm, so the dendritic cells capture their prey and then journey to the lymph nodes with their captured invaders -- the vector, and the antigens in the vector as stowaway passengers. In the lymph nodes, the dendritic cells present their bounty to the waiting T cells and program them to attack the foreign invader, subsequently generating the appropriate immune response. As the other studies have found, and the Pitt team confirms, skin-derived dendritic cells play a lesser role when other vectors are used, merely serving as the transport system to the lymph nodes, where another population of dendritic cells takes over and presents the antigen to the T cells. Importantly, the investigators found that despite being a foreign intruder itself, the lentivirus seemed to escape the notice of the immune system, even when introduced a second time, suggesting that it could be used repeatedly in the same patients. "You might say the other viral vectors are a one-shot deal because the immune system recognizes the virus and responds against it the second time around," suggests Dr. Falo. "With lentivirus, it seems feasible to use the immunization approach multiple times in the same patient, such as for annual flu vaccination, or in preventing multiple different infections or cancers in the same patient or in the general population." Taken together, the investigators say their findings have implications for the development of vaccines that involve cell-mediated immunity, including viral and bacterial infections, and cancer. In the next three-to-five years, they expect to initiate a clinical trial of the approach, most likely for patients with melanoma. In addition to Dr. Falo, other authors of the study are Yukai He, M.D., Ph.D., of the departments of dermatology and immunology, and Jiying Zhang, Ph.D., and Cara Donahue, of the department of dermatology. The research was supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institute of Allergy and Infectious Diseases and the National Cancer Institute, all of the National Institutes of Health. Cite This Page:

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APRN and PA Overview From the patient perspective, the roles of the APRN and PA within a sleep center can be quite similar; their educational programs prepare them to provide clinical assessment, diagnosis, and treatment of patients. However, the scope of practice of the NP versus PA in the clinical setting may be affected by differences in educational backgrounds, state licensure, physician oversight, prescriptive authority, and reimbursement issues. The term, APRN, refers to nurses with specialized training for providing direct care to individuals at an advanced level.9 APRNs are categorized into 4 groups, the clinical nurse specialist (CNS), certified registered nurse anesthetist (CRNA), certified nurse midwife (CNM), and nurse practitioner (NP). NPs are the most common sub-group of APRNs.4 Although the terms, NP and APRN, often are used interchangeably, this use is incorrect; all NPs are APRNs, but not all APRNs are NPs. There is some historical overlap, however variations exist between CNSs and NPs, particularly related to education and training in pharmacology, diagnosis, and treatment. Because of these differences, NPs generally have prescriptive authority while CNSs do not. Specialties for NPs often are determined by population (eg: adults) or work environment (eg: acute care).10 Examples of specialties that may be seen within sleep practices include Acute Care NP (ACNP), Adult NP (ANP), Family Practice NP (FNP), Pediatric NP (PNP), and Psychiatric/Mental Health NP (PMHNP).10 National efforts are underway to standardize APRN educational requirements, professional titles, areas of clinical practice, and state regulation.9 NP programs generally focus on a specific population (eg: pediatrics or adults), with the exception of training for FNPs which covers the lifespan. The NP clinical setting is determined by the area of specialty and may either focus on one setting (eg: outpatient) or multiple settings. PA educational programs include various clinical environments in both inpatient and outpatient settings for all age ranges. Educational programs for APRNs are typically a blend of nursing and medical models, while PA programs are based exclusively on a medical model. The undergraduate education for APRNs prepares them for licensure as a registered nurse while the undergraduate education for PAs is typically in a health-related field. In general, NPs and PAs can perform health histories and physical examinations, order and interpret appropriate testing for further assessment and develop a treatment plan for patients with common health problems. Basic tests, such as laboratory testing, can be interpreted by a PA or NP. In certain clinical settings, other testing such as electrocardiography or x-rays may also may be reviewed or interpreted by a NP or PA. Additionally, any testing, which includes a physician review and interpretation, may be utilized in their assessments (eg: sleep studies). APRNs and PAs can prescribe therapeutics including pharmacologic agents and durable medical equipment. The extent of APRN and PA formal education in pharmacology and prescribing can affect state legislation regarding the degree of prescriptive authority. Within the sleep specialty, controlled-substance prescribing is a commonly encountered prescriptive limitation resulting from either state- or federal-level regulation relating to the scheduled classification of the medication.11 Any drug that utilizes a central pharmacy (eg: sodium oxybate) must adhere to prescribing and dispensing rules for the state in which the central pharmacy is located, affecting prescribing by a provider when practicing in other states if the rules differ. APRN organizations and the American Association of Colleges of Nursing have recommended that the doctoral degree (either a Doctorate in Philosophy [PhD] or Doctorate of Nursing Practice [DNP]) be the minimum level of education required for certification by 2015.9,12 The PhD provides preparation with a focus on research while the DNP provides a clinically focused doctoral degree, focusing on evidence-based advanced nursing practice. PA programs have a target date of 2020 to award a master's degree as the minimum level of education to maintain national program accreditation.13 The American Academy of Nurse Practitioners (AANP) estimates that 98% of their members surveyed have a graduate degree and 14.6% have a doctoral degree (AANP personal communication).14 The American Academy of Physician Assistants estimates that 72% of clinically practicing PAs have a master's degree, 5% have a doctoral degree or a graduate certificate, and 20% have a bachelor's degree.15 Many factors besides educational background influence the scope of practice for APRNs and PAs.9,16 State “licensure” is probably the most obvious determinant with wide variation; some states choose to narrowly define scope of practice, while others approach it broadly. In some states, the authorization to practice does not come through licensure, but rather through other regulatory processes referred to as recognition, registration, or certification.9,16 In general, PA oversight is through the state medical board17 while APRN oversight is by the board of nursing.9 State oversight may include medication prescribing, restricted geographic location, and physician supervision or collaboration with APRN and PA practice.9,16 Additionally, state educational requirements ultimately determine what the minimum degree is for practice recognition within a state. APRN practice models can vary from independent practices to physician-collaborative practices while PA practices require physician supervision. State and federal regulatory agencies also can influence APRN and PA practices through their policies on controlled-substances prescribing, ordering therapeutic devices such as durable medical equipment and reimbursement of services.11,18,19 Employer or healthcare facilities further can influence the APRN or PA scopes of practice through internal policies. As part of the licensure process, each state board determines the minimum standard for formal educational preparation and whether or not national certification is required to practice within the state. For APRNs, the majority of states require graduate- level education and/or national certification to practice20,21 while a small number of states require master's-level education as a minimum requirement for practice as a PA.22 Both APRNs and PAs have national organizations that determine standards for competency and educational preparation.13,23 PAs have one examination,24 whereas, NPs take specialty-specific certification examinations.10 Both disciplines require maintenance of a clinical practice and the completion of continuing education and professional-development activities for recertification. PAs and APRNs are allowed to use physician-level credits to meet their continuing education requirements; although, APRNs may need a portion of their credits to be earned from approved nursing organizations at an advanced practice level.10,25 There are a growing number of post-graduation PA-residency training programs, primarily in emergency medicine and surgery, and PAs can take optional specialty certification exams offered by the National Commission on Certification of Physician Assistants.25 In addition, both APRNs and PAs may be eligible for subspecialty certifications that reflect advanced levels of preparation (eg: advanced diabetes management certification)26 or more general levels of preparation (eg: asthma educator)27 administered by multidisciplinary professional organizations. No formal training or certification in sleep medicine currently exists for APRNs or PAs. As the push towards formal education and greater specialty training increases, having specialty certifications in sleep for APRNs and PAs may become desirable; anecdotal reports suggest that some state boards are requesting additional proof of knowledge (continuing education) and competency in cases in which APRNs and PAs hold positions that exceed the education and training obtained during their initial formal education (eg: a family nurse practitioner working in a sleep center). Finally, the terminology used to refer to these professional groups can be confusing to other disciplines. For example, there are a number of terms used to identify APRNs and PAs as one group. The Drug Enforcement Agency (DEA) uses the term mid-level provider (MLP), The Centers for Medicare and Medicaid (CMS) uses the term non-physician practitioner (NPP), but there is no term that has been defined and supported by both APRN and PA professional organizations. Although the term Advanced Practice Nurse (APN) has been used by some healthcare professionals to refer to an APRN, Advance Practice Registered Nurse is the term endorsed by the APRN consensus statement9 and the recent Institute of Medicine report.28

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Living Will / Advanced Directive More than ever before, people with cancer or other serious illness and their families are being asked to take part in decisions about end-of-life care. Yet, most people still do not discuss end-of-life care at all, even if they are seriously ill. This fact sheet provides patients with an outline for thinking about these issues and some guidelines for discussion with their doctors, families, and loved ones. This fact sheet is also designed to help patients understand the medical, legal, and personal choices they may face in the future. What rights do patients have regarding their medical treatment? Patients are entitled to complete information about their illness and how it may affect their lives, and they have the right to share or withhold that information from others. People with cancer should also be informed about any procedures and treatments that are planned, the benefits and risks, and any alternatives that may be available. Patients may be asked to sign an "informed consent" form, which includes this information. Before signing such a form, patients should read it carefully and ask the doctor any questions they might have. Patients have the right to make decisions about their own treatment. These decisions may change over time. In the face of worsening disease, some patients may want to try every available drug or treatment in the hope that something will be effective. Other patients may choose to forgo aggressive medical treatment. Many patients turn to family members, friends, or caregivers for advice. But it is the patient's decision how much or how little treatment to have. Sometimes a patient is unable to make this decision, due to severe illness or a change in mental condition. That is why it is important for people with cancer to make their wishes known in advance. What is end-of-life care? What are advance directives? End-of-life care is a general term that refers to the medical and psychosocial care given in the advanced or terminal stages of illness. Advance directives are the legal documents, such as the living will, durable power of attorney and health care proxy, which allow people to convey their decisions about end-of-life care ahead of time. Advance directives provide a way for patients to communicate their wishes to family, friends, and health care professionals and to avoid confusion later on, should they become unable to do so. Ideally, the process of discussing and writing advance directives should be ongoing, rather than a single event. Advance directives can be modified as a patient's situation changes. Even after advance directives have been signed, patients can change their minds at any time. Why are advance directives important? Complex choices about end-of-life care are difficult even when people are well. If a person is seriously ill, these decisions can seem overwhelming. But patients should keep in mind that avoiding these decisions when they are well will only place a heavier burden on them and their loved ones later on. Communicating wishes about end-of-life care will ensure that people with cancer face the end of their lives with dignity and with the same values by which they have lived. Why is it important to write a will? A will is important so that patients can give instructions about distribution of their money and property when they die. Patients can name a trusted family member, friend, or professional to handle their personal affairs (also known as an Executor). It is advisable to seek the expert advice of a lawyer in drawing up a will so that the decisions made about taxes, beneficiaries, and asset distribution will be legally binding. This process can relieve a patient's family and friends of an enormous burden in case of disputes or questions about allocation of the patient's assets. What is a living will? A living will is a set of instructions documenting a person's wishes about medical care intended to sustain life. It is used if a patient becomes terminally ill, incapacitated, or unable to communicate or make decisions. Everyone has the right to accept or refuse medical care. A living will protects the patient's rights and removes the burden for making decisions from family, friends, and physicians. There are many types of life-sustaining care that should be taken into consideration when drafting a living will. These include: - the use of life-sustaining equipment (dialysis machines, ventilators, and respirators); - "do not resuscitate" orders; that is, instructions not to use CPR if breathing or heartbeat stops; - artificial hydration and nutrition (tube feeding); - withholding of food and fluids; - palliative/comfort care; and - organ and tissue donation. It is also important to understand that a decision not to receive "aggressive medical treatment" is not the same as withholding all medical care. A patient can still receive antibiotics, nutrition, pain medication, radiation therapy, and other interventions when the goal of treatment becomes comfort rather than cure. This is called palliative care, and its primary focus is helping the patient remain as comfortable as possible. Patients can change their minds and ask to resume more aggressive treatment. If the type of treatment a patient would like to receive changes, however, it is important to be aware that such a decision may raise insurance issues that will need to be explored with the patient's health care plan. Any changes in the type of treatment a patient wants to receive should be reflected in the patient's living will. Once a living will has been drawn up, patients may want to talk about their decisions with the people who matter most to them, explaining the values underlying their decisions. Most states require that the document be witnessed. Then it is advisable to make copies of the document, place the original in a safe, accessible place, and give copies to the patient's doctor, hospital, and next of kin. Patients may also want to consider keeping a card in their wallet declaring that they have a living will and where it can be found. What is a health care proxy and durable power of attorney for health care? A health care proxy is an agent (a person) appointed to make a patient's medical decisions if the patient is unable to do so. Generally, people assign someone they know well and trust to represent their preferences when they can no longer do so. Patients should be sure to ask this person for agreement to act as their agent. An agent may have to exercise judgment in the event of a medical decision for which the patient's wishes are not known. The durable power of attorney for health care is the legal document that names a patient's health care proxy. Once written, it should be signed, dated, witnessed, notarized, copied, distributed, and incorporated into the patient's medical record. Patients may also want to appoint someone to manage their financial affairs if they cannot. This is called a durable power of attorney for finances, and is a separate legal document from the durable power of attorney for health care. Patients may choose the same person or someone different from their health care proxy to act as their agent in financial matters. Where can people with cancer get assistance with their advance directives? If patients need help making the decisions discussed in this fact sheet, they should not hesitate to call upon family, friends, and other loved ones. Patients can also call an organization such as Cancer Care, Inc., for help with this process. Cancer Care, Inc., provides free, professional assistance to people with any type of cancer, at any stage of illness, and to their families. Patients and their families may write to Cancer Care, Inc., 275 Seventh Avenue, New York, NY 10001; call 1-800-813-HOPE (1-800-813-4673); or visit their Web site at http://www.cancercare.org on the Internet. Although a lawyer is not needed to complete advance directives, it is important to be aware that each state has its own laws for creating advance directives. Because these laws can vary in important details, special care should be taken to adhere to the laws of the state a patient lives in or is treated in. It is possible that a living will or durable power of attorney signed in one state may not be recognized in another. Appropriate forms can be obtained from health care providers, legal offices, Offices on Aging, and state health departments.

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Male Contraception Research Male contraception, or birth control, keeps sperm from coming into contact with an egg to avoid pregnancy. There are two approaches currently available to do this: - Blocking the sperm from entering the vagina (as with condoms) - Keeping the sperm from coming out of the penis (vasectomy/sterilization) - Keeping the male from producing the sperm (hormonal contraception) - Keeping the sperm from swimming (inhibiting sperm motility) - Preventing the sperm from fertilizing an egg (interfering with membrane integrity. Researchers have conducted studies on two types of systemic birth control for men: hormonal male contraception and immunocontraception. Hormonal male contraception uses hormones (injected, implanted, or taken orally) to stop sperm production, but this would reverse when the contraception is no longer used. Immunocontraception is a birth control method that uses the body's immune system response to prevent pregnancy. Although this is a viable option for many animal species, scientific interest in use by human subjects has recently declined because research does not show a reliable decrease in fertility among male subjects. - Different Types of Male Contraception - Differences From Female Birth Control - How Advanced Is The Research? - Does It Protect Against STIs? - Does It Protect Against Pregnancy? Different Types of Male Contraception At least four types of hormonal male contraception are currently being tested: testosterone, androgen/progestin combination, testosterone/GnRH combination, and selective androgen and progestin receptor modulators. All four methods of hormonal birth control try to stop or slow sperm production by interfering with some step in the sperm growth cycle. This creates a low sperm count, which could be reversed when the male stops using the contraceptive. Androgen – a type male sex hormone that influences the male reproductive system – inhibits sperm production by suppressing the pituitary gland's secretion of hormones. These pituitary hormones (LH and FSH) are the signals required for normal sperm production. Without them, sperm do not form properly. The androgen/progestin combination indirectly increases testosterone levels. (Testosterone is a male sex hormone that controls sperm development.) Increasing the testosterone slows the sperm production by suppressing the LH and FSH released from the pituitary gland. GnRH also suppresses pituitary hormones, and thus, reduces sperm count. Finally, androgen and progestin receptor modulators slow sperm production by changing the shape of the molecular receptors that bind androgen and progestin so that the male reproductive cells will not correctly produce sperm. Back to top Differences From Female Birth Control Obviously, male and female reproductive systems are very different. Many birth control methods available to women do not work for men. For example, men cannot use intrauterine devices, also known as IUDs, because they do not have uteruses in which to implant the IUD. Currently, most female contraceptives are oral medications. The majority of male birth control options presently being researched are injections. Many of these medications must be taken often as weekly injections. Although Depo-Provera is an injectable birth control option for women, it is only needed once every three months. Back to top How Advanced Is The Research? Currently, the most promising approach to hormonal male contraception is the combination of testosterone and progestin. There is ongoing research to test the drug's effectiveness, evaluate its safety, and monitor the side effects in 1,000 men in China. Many researchers believe a daily male birth control pill could be on the American market within five to seven years. Injectable or implantable male contraception may be available even sooner. Back to top Does It Protect Against STIs? Does It Protect Against Pregnancy? Yes. When used correctly, this type of contraception is meant to lower sperm count to the point where it is nearly impossible to become pregnant. Since all hormonal male birth control methods are currently in the testing phase, there is no comprehensive data on the efficacy of these methods. However, in one androgen-only study, pregnancy rates were 0/250 person-years for men with no sperm in the ejaculate, and 4/50 person-years for men with a very low sperm count. This means that only four out of 300 men, or 1.3 percent, were able to get a woman pregnant while using male birth control. Back to top Leigha Winters, college student writer Reviewed By: Nancy Brown, Ph.D. Last Reviewed: October 2013 Below are links PAMF accessed when researching this topic. PAMF does not sponsor or endorse any of these sites, nor does PAMF guarantee the accuracy of the information contained on them. Amory, J. K. (2005). Male hormonal contraceptives: current status and future prospects. Treat Endrocrinol, 4(6), 333-41. Summary available at PubMed. Vogelsong, Kirsten M. (2007). Male contraception. Vogelsong, Kirsten M. (n.d.). Immunocontraception. Vogelsong, Kirsten M. (n.d.). Male contraception. Weber, R. F. A. &: Dohle, G. R. (2004). Male contraception: mechanical, hormonal and non-hormonal methods. World Journal of Urology, 21(5), 338-40. Summary available at PubMed.

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LIG4 syndrome is a hereditary disorder associated with impaired DNA double-strand break repair mechanisms and characterized by microcephaly, unusual facial features, growth and developmental delay, skin anomalies, and pancytopenia, which is associated with combined immunodeficiency (CID). Prevalence is unknown. To date, at least 12 patients have been reported. LIG4 syndrome presents in childhood with microcephaly, unusual facial features that have been described as ''bird-like'' (beak-like nose and micrognathia), growth and developmental delay, skin anomalies including photosensitivity and psoriatic-like lesions, and pancytopenia. The disease is associated with immunodeficiency. Some patients have been reported as having telangiectasias, leukemia, lymphoma, bone marrow abnormalities, and type 2 diabetes. One patient presented with features of Omenn syndrome (see this term). LIG4 syndrome is caused by mutations in the LIG4 gene (13q22-q34). The resulting defect of DNA ligase IV, a component of the classical non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair. Diagnosis is based on evidence of the characteristic clinical signs of LIG4 syndrome, particularly the ''bird-like'' facial features, and low T and B cells. Diagnosis is confirmed on the basis of molecular genetic analysis and the evidence of radiosensitivity of cell lines. Chromosome 7/14 translocations are also common. Differential diagnoses include other rare DNA damage response diseases such as Seckel syndrome, Nijmegen breakage syndrome (NBS), Cernunnos-XLF deficiency and Fanconi anemia (see these terms). Prenatal diagnosis can be performed by chorionic villus sampling in families with previously affected members. Transmission is autosomal recessive. Supportive treatment is with prophylactic antibiotics and anti-virals. Hematopoietic stem cell transplantation may be indicated in some patients using modified conditioning regimens without radiotherapy. Lifespan is generally limited with an increased incidence of leukemia or lymphoma. Last update: July 2012

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Hemochromotosis is a disorder characterized by iron overload. The body absorbs and stores too much iron. Our bodies do not have a mechanism to get rid of extra iron. Iron plays a major role in developing mature red blood cells. Patients with hemochromatosis have normal iron intake levels, but abnormal regulation of iron absorption. This results in increased iron absorption and leads to overload. Iron overload first occurs in the liver where most of the iron is stored. The extra iron builds up in organs and damages them. Without treatment, the disease can cause organs to fail. Hemochromotosis is often a genetic disorder passed on from a parent. The parent passes on a defective gene called HFE, which is responsible for regulating the amount of iron the body absorbs. Patients who are transfusion dependent are also at risk for hemochromatosis. Red blood cell transfusions contain iron which builds up in the body and can affect organs. What are symptoms of hemochromatosis? Joint pain is the most common complaint of people with hemochromatosis. Other symptoms include fatigue, abdominal pain, changes in the color of the skin (bronze color), shortness of breath, swelling, increased thirst, loss of sex drive, and heart problems. Signs and symptoms are related to accumulation of iron in the body’s organs. How is hemochromatosis diagnosed? Hemochromatosis can generally be diagnosed by using blood tests. What is the treatment for hemochromotosis? In patients with genetic hemochromotosis, therapeutic phlebotomy (removal of a unit of blood) will generally manage the disease. In transfusion dependent patients, therapeutic phlebotomy is not feasible. Iron chelation therapy may be used. A medication is given by IV or injection which binds to the excess iron and allows it to be removed by the kidneys. The drug is usually given using a portable infusion pump. Patients should limit the amount of dietary iron they consume. Multivitamins with iron and iron supplements should be avoided.

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In the U.S. population aged 6–59 years, 56.3% of current asthma cases were attributable to atopy, as measured by a positive skin test response to any of 10 allergens. The PAR was significantly greater among males than females, among persons in the highest education category than in lower education categories, and among persons living in highly populated metropolitan areas than in all other areas. The PAR estimate for the U.S. population is higher than the PAR reported in several studies. In the meta-analysis by Pearce et al. , the mean PAR was 38% across studies of children and 37% across studies of adults.7 Among 4-year-old children on the Isle of Wight, Arshad et al. found that atopy (skin prick test positivity to any of 12 allergens) attributed to 35% of asthma cases.1 In a study of adults in the Pirkanmaa District of Southern Finland, Jaakkola et al. reported a PAR (defined by total and specific IgE) of 30%.13 Among Australian children aged 8–10 years, Ponsonby et al. found that atopy (defined as skin test positivity to any of 10 aeroallergens) attributed to 33% of asthma cases, although the percentage was 54% for past hospital attendance for asthma.14 And, in the European Community Respiratory Heath Study, a 36-center study of adults in 16 countries, the mean PAR across centers (atopy was defined as specific serum IgE > 0.35 kU/L to any of 5 allergens) was 30%.15 However, the U.S. estimate fell within the range of center-specific PARs (4% to 61%). Centers with a PAR similar to the U.S. estimate were Huelva, Spain (61%); Groningen, the Netherlands (58%); Antwerp, Belgium (55%); Bordeaux, France (55%); Wellington, New Zealand (52%); and Umea, Sweden (50%). The variation in PARs across the studies could reflect differences in environmental exposures and genetics between the populations as well as differences in study methodologies, such as the assessments of atopy and asthma and subject selection. In the U.S. population, the PAR differed significantly by sex, education, and urbanization categories. Across categories of those characteristics, the atopy-asthma odds ratios differed significantly. Undoubtedly, there are cofactors associated with these characteristics that strengthen or weaken the effects of atopy on asthma. One possible cofactor—and there are likely to be many—is allergen exposure, which was not measured in NHANES III. Data from the National Survey of Lead and Allergens in Housing have shown that people in the above high school education category have a higher mean level of cat allergen in their homes than people in the lower education categories whereas people living in highly populated metropolitan areas are more likely to have elevated levels of cockroach allergen in their homes than people living in other areas.16, 17 In addition, studies from rural areas in Europe have consistently shown that children growing up on farms are less likely to develop atopy and allergic disease,18 the presumption being that certain microbial exposures in early childhood may be beneficial. However, in NHANES III, the urbanization category “all other areas” consists only partially of rural or farm families, so it is not known whether any differences in the PAR by urbanization can be attributed to a protective effect of rural or farm exposures. Whereas females are more likely than males to have asthma, this study found that males are more likely to have atopic asthma. Why the etiology of asthma would differ between males and females is not known, but the difference suggests that reproductive hormones may play a role. If reproductive hormones suppressed atopic asthma or promoted non-atopic asthma in females, or if testosterone suppressed non-atopic asthma in males, a difference in the asthma-atopy association by sex would occur. Leptin, a hormone associated with obesity, might also play a role in the observed difference. A recent study indicated that serum concentrations of leptin was a stronger risk factor for asthma in females than males, and the same study found that BMI was associated with asthma in females but not males.19 However, the authors of that study did not indicate whether leptin or BMI influenced asthma through atopic or non-atopic pathways. Besides hormones, differences in environmental exposures, such as tobacco smoke, alcohol, diet, and occupations, are potential explanations for the differences in PAR by sex. Of the ten allergens included in the skin test panel, only cat, Alternaria , and white oak showed significant, positive associations with asthma after adjustment by the subject characteristics and all other allergens. Cat allergen had the largest fully-adjusted odds ratio, and a positive test to cat allergen accounted for the highest percentage of asthma cases (29.3%). Whereas some studies have shown that exposure to cats may be protective for development of allergic sensitization and disease,20 sensitization to cat appears to be a strong risk factor for asthma. In the European Community Respiratory Heath Survey, sensitization to cat allergen had the highest odds ratio for asthma, although sensitization to house dust mite and Timothy grass accounted for more cases of asthma (PARs were 18.2% for dust mite, 17.1% for Timothy grass, and 14.1% for cat).15 In a study of Swedish adults, Plaschke et al. reported that skin prick test positivity to cats and dogs had the strongest associations with asthma, while associations with dust mites and grass were less pronounced.21 Why did most of the allergen-specific skin tests lose statistical significance with asthma after adjustment by all the allergen-specific tests? One potential explanation is that some allergens were associated with asthma before adjustment not because they were independently associated with asthma but because they often occurred with one or more allergens that were. The mean number of positive skin test responses among persons with at least one positive response was 3.5. Thus, for any given allergen, a positive test to that allergen usually occurred with a positive response to other allergens, perhaps other allergens that were more strongly associated with asthma. For example, on average, people who tested positive to dust mite allergen tested positive to 4.9 allergens (). Unadjusted, the odds ratio for dust mite was 2.5 (); however, as a solitary response () or as a response fully adjusted by all the allergens (), the odds ratio was 1.3. Because the allergen-specific results represent averages across the U.S. population, some caution must be used in interpreting them when considering an individual. For a given individual, or among individuals within specific regions or subpopulations of the U.S., some of the allergen-specific sensitizations may play a more or less predominant role in asthma. The most important limitation to the study is that the data is cross-sectional, a limitation common to many of the published papers that have examined the percentage of asthma cases attributable to atopy. The estimation of population attributable risk assumes that the exposure was present before the disease—a criterion for causality. However, because asthma and skin test responses were assessed at the same point in time, the temporal relationship between the two variables cannot be established. If the onset of asthma occurred prior to the onset of allergic sensitization in a significant percentage of asthma cases, then this study has overestimated the contribution of atopy to asthma. The estimation of PAR also assumes that the relative risk estimate is unconfounded.11 Because adjustment by the 9 subject characteristics had little effect on the atopy-asthma association (unadjusted OR = 3.3 and adjusted OR = 3.5), confounding was likely well controlled in the analyses of atopy. However, for the allergen-specific skin tests, the odds ratios changed dramatically with adjustment by other allergens. Because many allergens were not skin tested, it is possible that the fully-adjusted allergen-specific odds ratios reported in were confounded. Other important limitations were that the assessment of atopy was limited to the skin testing of only 10 allergens, neither total nor allergen-specific serum IgE was measured, and neither subjects younger than 6 years nor older than 59 years were skin tested in NHANES III. Without a larger panel of allergens or the availability of serum IgE measurements, this study may have underestimated the prevalence of atopy, which would cause the PARs to be underestimated. In an attempt to address this limitation, atopy was redefined in a secondary analysis as either hay fever or a positive skin test response. The inclusion of hay fever into the definition only increased the prevalence of atopy in the total population from 54.2% to 56.0%, which suggests that the 10-allergen skin test panel included allergens to which most hay fever cases would respond. With the PAR peaking in the middle category (), it is possible that there would have been an age effect if all ages had been included. In NHANES 2005–2006, total IgE and specific IgE to 19 allergens was measured on all subjects aged 1 year and older. Those data, when made available, will allow for a more precise estimate of atopy and a broader assessment of age effects. The results of this study have two implications. First, the population attributable risk conveys a sense of how much disease can be prevented by eliminating the exposure or blocking its effects.22 Therefore, if atopy could be prevented, reversed, or blocked, then a large percentage of current asthma cases could be prevented. Atopy, by definition, is the result of gene-environment interactions; therefore, at least in theory, intervention at either the genetic or environmental level could prevent atopy. However, intervention at the genetic level is not yet possible and intervention at the environmental level by altering allergen and other exposures has had mixed results, perhaps because of our limited understanding of the environmental exposures that influence atopy and how to modify those exposures. Blocking the pathway between atopy and asthma through immunotherapy, medication, or reduction in allergen and other environmental exposures should also lead to a large reduction in asthma cases. Second, this study’s results highlight the need for research into the non-atopic causes of asthma since one-third to one-half of the asthma cases apparently have a non-atopic etiology. Pearce et al. have suggested that atopic asthma research has been at the expense of non-atopic asthma research;7 however, for the burden of asthma in the population to be significantly reduced, asthma research needs to address the causes of and interventions for both atopic and non-atopic asthma.

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Volume 17, Number 11—November 2011 CHOLERA IN HAITI Cholera—Modern Pandemic Disease of Ancient Lineage On This Page Cholera has affected humans for at least a millennium and persists as a major cause of illness and death worldwide, with recent epidemics in Zimbabwe (2008–2009) and Haiti (2010). Clinically, evidence exists of increasing severity of disease linked with emergence of atypical Vibrio cholerae organisms that have incorporated genetic material from classical biotype strains into an El Tor biotype background. A key element in transmission may be a recently recognized hyperinfectious phase, which persists for hours after passage in diarrheal feces. We propose a model of transmission in which environmental triggers (such as temperature) lead to increases in V. cholerae in environmental reservoirs, with spillover into human populations. However, once the microorganism is introduced into a human population, transmission occurs primary by “fast” transmission from person to person (taking advantage of the hyperinfectious state), without returning to the aquatic environment. Cholera has been an unwanted companion among human civilizations for at least a millennium, with suggestions that it has existed in India “since immemorial times” (1). Its impact in Bengal society was sufficient to have resulted in recognition of a goddess of cholera, Oladevi (or Oola Beebee), who required propitiation to protect villages from the disease (2). Global pandemic spread of cholera from its ancestral home in Bengal was first documented in 1817 (1), the beginning of what has been designated as the first pandemic. In the intervening 2 centuries, cholera has continued to ebb and flow from southern Asia to other parts of the known world, with 6 additional pandemics identified. During the third pandemic, which ravaged London in 1854, John Snow conducted his pioneering epidemiologic studies (and gained fame for removal of a pump handle). We are currently in the throes of the seventh pandemic (caused by V. cholerae of the El Tor biotype), which originated almost 50 years ago in the Celebes. In contrast to the earlier 6 pandemics, at no time in these past 50 years has cholera retreated to its southern Asian home. It has instead established endemicity at multiple sites around the globe and continues to trigger major localized epidemics, including the epidemics in Zimbabwe during 2008–2009 (3) and Haiti during 2010. In 2009, the most recent year for which data are available, 221,226 cholera cases were reported to the World Health Organization (WHO) from 45 countries (4). This number includes 4,946 deaths, for a case-fatality rate of 2.24%. Although the disease was reported from all continents, 98% of cases reported during 2009 were from Africa, driven in part by large numbers from the latter part of the 2008–2009 Zimbabwe epidemic. However, these numbers should be interpreted with caution because of well-recognized problems with underreporting in the WHO system, particularly because cholera is no longer a notifiable disease and countries can choose whether to report cases. In 2 examples, no cholera cases were included in the annual WHO cholera summary report for 2009 (4) from India or Bangladesh, despite anecdotal evidence to the contrary. Cholera today takes advantage of breakdowns in sanitation and health infrastructure, often in the setting of natural and complex disasters. More notably, cholera has survived the transition from ancient to modern world, with the establishment of endemic foci in virtually every continent. We have learned a great deal about cholera during the past few decades. Major advances have been made in therapy, which has decreased expected case-fatality rates to <0.5%. However, we are just coming to appreciate the evolutionary capabilities of the microorganism and the complexity of transmission pathways, an understanding of which is essential to ultimate control of the disease. Clinically, cholera is a simple disease. Its manifestations result almost entirely from action of cholera toxin, a protein enterotoxin excreted by the bacterial cell. The A subunit of cholera toxin activates adenylate cyclase, causing increased Cl– secretion by intestinal crypt cells and decreased NaCl-coupled absorption by villus cells and resulting in a net movement of electrolytes (and water) into the lumen of the intestine (5). All manifestations of the disease can be reproduced by administration of cholera toxin: in studies conducted in the 1970s at the University of Maryland (Baltimore, MD, USA), volunteers given 25 μg of pure cholera toxin had >20 L of rice-water feces; ingestion of as little as 5 μg of purified toxin resulted in 1–6 L of diarrhea in 5 of 6 volunteers (6). Severity of illness varies widely. In the most severe form of the disease, cholera gravis, patients can pass >1 L of diarrheal feces per hour. Feces are passed effortlessly, with the diarrhea assuming a rice-water appearance. If volumes are not repleted, this diarrhea can result, in as little as 6–8 hours, in circulatory collapse, shock, and death. Shock, even if adequately treated, may precipitate acute renal failure. Severe acidosis results from fecal loss of bicarbonate, exacerbated by hypotension-related lactic acidosis and renal failure. Although cholera gravis is a devastating disease, studies in the early 1970s suggested that such severe cases accounted for only 11% of total infections among persons infected with strains of the classical biotype (responsible for the sixth cholera pandemic); 59% of infections were asymptomatic or inapparent, and the remainder represented illness of mild to moderate severity. In studies during that same period, only 2% infected with seventh pandemic biotype El Tor strains had severe disease, and 75% of infected persons were asymptomatic (7). Although the El Tor biotype has persisted, its relative lack of virulence has not; recent studies have noted substantial increases in the percentage of patients with severe dehydration (8), and the percentage of asymptomatic infected patients appears to be much smaller (<50%, in a recent study by Harris et al. ). As described below, these observations coincide with the appearance of new atypical V. cholerae strains that include classical biotype genetic material within an El Tor background (10,11). The cornerstone of therapy is replacement of lost fluid. With an infrastructure able to provide adequate rehydration therapy, case-fatality rates should be <1%, ideally <0.5%. In mild to moderate cases, rehydration can generally be successfully accomplished with oral rehydration solution. In patients who are severely dehydrated (loss of 10% of body weight) intravenous rehydration is almost always necessary; limited anecdotal reports suggest that use of intravenous therapy is becoming more frequent in areas where cholera is endemic and epidemic, consistent with concerns about increasing severity of illness. In early placebo-controlled studies, tetracycline reduced duration of diarrhea, total volume of diarrhea, and days of excretion of V. cholerae by >50%; more recent studies demonstrated equivalent or better results with ciprofloxacin and azithromycin. However, antimicrobial drug use is also clearly associated with development of resistance, leading to current WHO recommendations that antimicrobial agents be limited to use in patients with severe dehydration. As recently suggested by Nelson et al. (12), extending use of antimicrobial drugs to a larger patient group may be reasonable, particularly in light of increasing awareness of direct transmission of the microorganism from person to person, as discussed below. Zinc supplementation also has been recognized as a potentially useful adjunct to therapy; recent studies among children in Bangladesh have shown that its administration resulted in a 12% reduction in duration of diarrhea and 11% reduction in fecal volume in patients compared with controls (13). V. cholerae is a diverse species and a natural (and common) inhabitant of estuarine environments around the world. Distribution depends on water temperature (optimal growth at water temperatures >20°C) and salinity (14). In contrast to most other Vibrio species, it is able to grow in fresh water and is often present in inland rivers and lakes in regions where it is endemic. In areas with seasonal variations in water temperatures, the microorganism shows clear seasonality: environmental counts increase during warmer periods and decline (or become nondetectable) during cold weather. In studies in Peru (15), V. cholerae counts in the Rimac River (at a site above Lima where sewage contamination was minimal) spiked ≈2 months after an initial summer rise in water temperature but then returned to a nondetectable level within 1–2 months (Technical Appendix [PDF - 79 KB - 1 page]). The reason for the sharp drop in counts after the initial spike (a pattern also seen in some ponds in Bangladesh ) is not clear. One hypothesis is that it is related to rapid increases in the number of V. cholerae–specific lytic bacteriophages in the local aquatic environment (17,18), providing natural predation as a countermeasure to the initial rapid increase in numbers of the microorganism. V. cholerae can assume a variety of survival forms, including a shift to what has been termed a viable but nonculturable form, which is often associated with biofilms. Strains can also assume a rugose phenotype (identifiable on culture by a characteristic rough/wrinkled appearance), in which the microorganism produces large quantities of an amorphous exopolysaccharide, leading to formation of a biofilm that is resistant to chlorine, UV light, and other standard disinfectants (19). V. cholerae has been closely linked with copepods (binding to chitin through the action of a specific chitinase) and with zooplankton (14). It has also been found in association with chironomid egg masses and water hyacinth and can be carried by gulls, other birds, and mammals. Although V. cholerae as a species is ubiquitous in the environment, strains responsible for the disease cholera are restricted to a fairly tight subset of strains, as reflected in clustering seen by multilocus sequence typing and sequence analysis. The key gene clusters responsible for the manifestations of cholera are associated with production of cholera toxin located within the ctx element (which is part of a filiamentous phage capable of movement among strains ) and the vibrio pathogenicity island, which includes the TCP (toxin-coregulated pilus) gene, essential for binding of the microorganism to the intestinal mucosa. Other genes common to strains with an epidemic phenotype also have been identified; however, the role of many of these genes in the pathogenesis of cholera remains to be determined (21,22). Even though virtually all strains that cause cholera produce cholera toxin and have the vibrio pathogenicity island, not all V. cholerae that carry 1 or both of these gene complexes cause cholera; several studies have noted the isolation of 1 or both from environmental strains that appear to lack other components of the genetic background essential for virulence in humans and epidemic spread (22,23). The V. cholerae genome readily undergoes change, with extensive genetic recombination through lateral gene transfer, resulting in what have been termed shifts and drifts in the genome sequence (21). This genetic plasticity is reflected in the observation that feces from a single infected patient in an area where cholera is endemic almost always show evidence of infection with multiple genetically distinct V. cholerae strains, as defined by variable-number tandem-repeat analysis (24). Variability also can be seen in serotype. Traditionally, epidemic disease was thought to be confined to cholera toxin-producing strains in V. cholerae O group 1. However, in 1992, a new serotype, O139, was recognized as the cause of a major cholera epidemic on the Indian subcontinent (25); emergence was linked to replacement of the O group 1 biosynthesis cassette with a biosynthesis cassette for the O139 antigen (which also encoded material for formation of a capsule). O group 1 strains continue to predominate among epidemic isolates, but serotype clearly does not directly predict virulence; cholera-like illness (albeit without epidemic spread) is now associated with several different serotypes in addition to O1 and O139. These serotypes include O141 and O75 in the United States and O37, O10, O12, O6, and O14 in other parts of the world (23,26). Changes in serotype, in turn, appear to result from lateral transfer of the gene cassettes responsible for O-antigen biosynthesis (23,26). Recent changes or recombinational events also have been seen in the ctx gene cluster, with introduction of the classical biotype ctx gene into an El Tor background and the appearance of strains containing multiple recombinational events that have modifications in ctx as well as other changes that result in loss of traditional El Tor biotype characteristics (10,11,27). Although nomenclature remains in flux (11), these new atypical strains have, at this point, entirely supplanted traditional seventh pandemic El Tor strains at a global level (including, most recently, the strain responsible for the Haiti epidemic ). As discussed above, these strains also appear to have major increases in virulence (potentially because of increased levels of cholera toxin production ), comparable with (or in excess of) clinical characteristics of the sixth pandemic classical biotype strains. V. cholerae strains associated with epidemic disease can respond to changes in their immediate environment as they move from environmental reservoirs to humans and back. Of particular relevance, it has been shown that V. cholerae passed in human rice-water feces are in a “hyperinfectious” state (17,30); in animal studies, an infectious dose is 1–2 orders of magnitude lower than that for strains grown by using traditional in vitro methods. The hyperinfectious state lasts at least 5 hours after passage of the microorganism from patients. The physiologic basis for this effect is unclear but appears to be associated, at least in part, with changes that include down-regulation of chemotaxis genes (31). V. cholerae as it is passed from the body also up-regulates a series of genes that are not required for infection but are needed for survival in the environment. Twenty-four hours after the microorganism reaches the aquatic environment, these shifts, potentially combined with lytic phage, result in a dramatic decrease in the ability of V. cholerae to cause infection (18). During the 1960s, the scientific consensus was that cholera was transmitted from person to person; a great deal of attention was given to the role of convalescent and chronic carriage in transmission. During the following decades, attention shifted sharply from human carriage to environmental reservoirs, with a focus on the role of environmental factors in persistence of the disease and triggering of epidemics. However, with the advent of increasingly sensitive molecular techniques—and mathematical modeling approaches—there has been movement back toward a transmission model that recognizes the role of environmental reservoirs and direct (human-to-human) transmission. In this context, we propose the transmission model shown in the Figure. The aquatic environmental reservoir is critical to long-term maintenance of epidemic V. cholerae. These reservoirs constitute complex biological systems, with modulation of V. cholerae populations by environmental conditions (the local microenvironment [15,16] as well as global macroenvironmental factors, such as the El Niño/Southern Oscillation ); by predatory bacteriophage populations (18); and by fluctuations in populations of copepods and zooplankton (which can, in turn, be driven by predation by fish), binding to chironomid egg masses, water hyacinth, carriage by birds and mammals, and a host of other variables. At the same time, our data from Lima (Technical Appendix [PDF - 79 KB - 1 page]) and from Bangladesh show a significant association between a spike in numbers of ctx-positive V. cholerae in the environment and subsequent occurrence of cholera in the community (15,16), consistent with the concept of spillover of the microorganism from the environment to human populations. On the basis of our studies in Lima and Bangladesh, peak environmental counts of ctx-positive V. cholerae from pristine areas range from 101 to 102 CFU/mL (15,16). The infectious dose for V. cholerae (classical biotype) ingested by healthy North American volunteers is in the range of 108 to 1011 CFU/mL, which drops to 104–108 when the inoculum is given with bicarbonate or food (5,33). Assuming consumption of a large enough volume of contaminated material; mixing with food (with the potential for further growth in food before consumption [34,35]); and possible underlying host factors, such as mild hypochlorhydria (which can be associated with Helicobacter pylori infection, endemic to many developing countries) and malnutrition, transmission from environmental sources that are not heavily fecally contaminated becomes plausible. However, this infectious dose still would be at the low end of the curve, and the percentage of exposed persons becoming infected at these low levels is likely to be relatively small. The picture changes once the microorganism is introduced into human populations. Rice-water feces contain 107–109 V. cholerae microorganisms per mL. Immediately after passage, these microorganisms are in a hyperinfectious state (further dropping the infectious dose by 1 or 2 logs), generating the opportunity for “fast” transmission of V. cholerae to other persons either by direct contact with feces or direct contamination of food or water within the immediate household environment. Microorganisms from feces can also reenter environmental reservoirs by fecal contamination. However, one then has to deal with dilutional effects within the environment and the striking drop in infectivity (noted above) that can occur as the microorganism adjusts to an environmental habitat (18). In our studies in Lima at the peak of a cholera epidemic, we found environmental counts of toxigenic V. cholerae of ≈105/mL in areas with heavy sewage contamination, so the potential for infection from environmental sources clearly increases in settings of poor sanitation during epidemics. Nonetheless, looking at the relative counts from different sources of exposure, these observations are consistent with the hypothesis that a major transmission pathway for V. cholerae during an epidemic (particularly at the beginning of an epidemic) is through a “fast” pathway, taking advantage of the short-lived hyperinfectious state to move from person to person, without an intervening “slow” transmission step through the environment. Data from a variety of sources support this hypothesis. In studies in Bangladesh that used variable-number tandem-repeat analysis (36), we found minimal overlap between clinical strain populations circulating in human populations and the ctx-positive V. cholerae strains that were circulating concurrently in environmental reservoirs. If the environmental reservoir was playing a major role in the ongoing epidemic, one would have expected to see the same genetic types appearing in strains from the environment and strains from patients. In mathematical models, inclusion of a fast (presumed person-to-person or person-to–household environment–to-person) transmission pathway that incorporates the short-lived hyperinfectious state results in a much better match with outbreak data than models that rely solely on a “slow” human-to–aquatic environment–to-human pathway (37). In subsequent work we have applied our models to data from the 2008–2009 Zimbabwe epidemic (3). When calculated by province, the reproductive number (R0) for the epidemic ranged from 1.1 to 2.7; our calculations suggest that 47%–94% of this value, dependent on province, was accounted for by fast (hyperinfectious/presumed person-to-person) transmission. These observations underscore the need to focus prevention efforts on the short window of time after passage of feces when strains are in a hyperinfectious state. This observation translates into the need for an emphasis on households (and, in particular, an emphasis on households with index cases), where exposure to recently excreted microorganisms is most likely. This finding fits with those from earlier epidemiologic studies from Bangladesh, where risk for illness was linked with the presence of an infected person in the household, not with whether the household used clean tube well water versus potentially contaminated surface water for drinking (38). It is also in agreement with work by Deb et al. in Kolkata, India, which highlighted the influence of household transmission during epidemic periods and the associated need to focus on minimizing risk for contamination of water and food sources within the household (39). V. cholerae is a wily opponent. It can live indefinitely in aquatic reservoirs, making eradication difficult, if not impossible; readily undergoes genetic modification, permitting response to changing environmental (and human) conditions; and shifts patterns of gene expression as it moves from one local environment to another (including a shift to a hyperinfectious state immediately after passage in feces). Several mathematical models (including models developed by the Emerging Pathogens Institute, University of Florida [Gainesville, FL, USA] ) support the potential value of vaccines for disease control and have outlined potential strategies for their utilization (40). Although the environment remains a critical component of transmission, interventions focused increasingly on the household and on blocking transmission immediately after passage of feces are acutely needed. Ultimately, good sanitation (as part of a strong public health infrastructure) is the key to disease control. However, until sanitation is widespread (and the impact of natural and human-made disasters is minimized), ways in which this age-old pathogen causes disease—and ways in which it can be controlled—need to continue to be explored. Dr Morris is professor and director of the Emerging Pathogens Institute at University of Florida and serves as an associate editor of Emerging Infectious Diseases. His research interests include cholera in Haiti and in the Indian subcontinent. - Pollitzer R. Cholera. Geneva: World Health Organization. 1959. - Bray RS. Armies of pestilence: the impact of disease on history. New York: Lutterworth Press; 1997. - Mukandavire Z, Liao S, Wang J, Gaff H, Smith DL, Morris JG Jr. Estimating the reproductive numbers for the 2008–2009 cholera outbreaks in Zimbabwe. Proc Natl Acad Sci U S A. 2011;108:8767–72. - World Health Organization. Cholera 2009. Wkly Epidemiol Rec. 2010;85:293–308. - Kaper JB, Morris JG Jr, Levine MM. Cholera. Microbiol Rev 1995;48–86. - Levine MM, Kaper JB, Black RE, Clements ML. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development [erratum in: Clin Microbiol Rev 1995;8:316]. Clin Microbiol Rev. 1995;8:48–86. - Gangarosa EJ, Mosley WH. Epidemiology and surveillance of cholera. In: Barua D, Burrows W, editors. Cholera. Philadelphia: W.B. Saunders; 1974. p. 381–403. - Siddique AK, Nair GB, Alam M, Sack DA, Huq A, Nizam A, El Tor cholera with severe disease: a new threat to Asia and beyond. Epidemiol Infect. 2010;138:347–52. - Harris JB, LaRocque RC, Chowdhury F, Khan AI, Logvinenko T, Faruque ASG, Susceptibility to Vibrio cholerae infection in a cohort of household contacts of patients with cholera in Bangladesh. PLoS Negl Trop Dis. 2008;2:e221. - Nair GB, Faruque SM, Bhuniyan NA, Kamaruzzaman M, Siddque AK, Sack DA. New variants of Vibrio cholerae O1 biotype El Tor with attributes of the classical biotype from hospitalized patients with acute diarrhea in Bangladesh. J Clin Microbiol. 2002;40:3296–9. - Safa A, Nair GB, Kong RYC. Evolution of new variants of Vibrio cholerae O1. Trends Microbiol. 2010;18:46–54. - Nelson EJ, Nelson DS, Salam MA, Sack DA. Antibiotics for both moderate and severe cholera. N Engl J Med. 2011;364:5–7. - Roy SK, Hossain MJ, Khatun W, Chakraborty B, Chowdhury S, Begum A, Zinc supplementation in children with cholera in Bangladesh: randomized controlled trial. BMJ. 2008;336:266–8. - Martinelli Filho JE, Lopes RM, Rivera ING, Colwell RR. Vibrio cholerae O1 detection in estuarine and coastal zooplankton. J Plankton Res. 2011;33:51–62. - Franco AA, Fix AD, Prada A, Paredes E, Palomino JC, Wright AC, Cholera in Lima, Peru, correlates with prior isolation of Vibrio cholerae from the environment. Am J Epidemiol. 1997;146:1067–75. - Huq A, Sack RB, Nizam A, Longini IM, Nair GB, Ali A, Critical factors influencing the occurrence of Vibrio cholerae in the environment in Bangladesh. Appl Environ Microbiol. 2005;71:4645–54. - Nelson EJ, Harris JB, Morris JG Jr, Calderwood SB, Camilli A. Cholera transmission: the host, pathogen, and bacteriophage dynamic. Nat Rev Microbiol. 2009;7:693–702. - Nelson EJ, Chowdhury A, Flynn J, Schild S, Bourassa L, Shao Y, Transmission of Vibrio cholerae is antagonized by lytic phage and entry into the aquatic environment. PLoS Pathog. 2008;4:e1000187. - Morris JG Jr, Sztein MB, Rice EW, Nataro JP, Losonsky GA, Panigrahi P, Vibrio cholerae can assume a chlorine-resistant rugose survival form which is virulent for humans. J Infect Dis. 1996;174:1364–8. - Waldor MK, Mekalanos JJ. Lysogenic conversion by a filamentous phage encoding cholera toxin. Science. 1996;272:1910–4. - Chun J, Grim CJ, Hasan NA, Lee JH, Choi SY, Haley BJ, Comparative genomics reveals mechanism for short-term and long-term clonal transitions in pandemic Vibrio cholerae. Proc Natl Acad Sci U S A. 2009;106:15442–7. - Faruque SM, Chowdhury N, Kamruzzaman M, Dziejman M, Rahman MH, Sack DA, Genetic diversity and virulence potential of environmental Vibrio cholerae population in a cholera-endemic area. Proc Natl Acad Sci U S A. 2004;101:2123–8. - Li M, Shimada T, Morris JG Jr, Sulakvelidze A, Sozhamannan S. Evidence for the emergence of non-O1 and non-O139 Vibrio cholerae strains with pathogenic potential by exchange of O-antigen biosynthesis regions. Infect Immun. 2002;70:2441–53. - Kendall EA, Chowdhury F, Begum Y, Khan AI, Li S, Thierer JH, Relatedness of Vibrio cholerae O1/O139 isolates from patients and their household contacts, determined by multilocus variable-number tandem repeat analysis. J Bacteriol. 2010;192:4367–76. - Nair GB, Ramamurthy T, Bhattacharya SK, Mukhopadhyay AK, Garg S, Bhattacharya MK, Spread of Vibrio cholerae O139 Bengal in India. J Infect Dis. 1994;169:1029–34. - Aydanian A, Tang L, Morris JG, Johnson JA, Stine OC. Genetic diversity of O-antigen biosynthesis regions in Vibrio cholerae. Appl Environ Microbiol. 2011;77:2247–53. - Alam M, Nusrin S, Islam A, Bhuiyan NA, Rahim N, Delgado G, Cholera between 1991 and 1997 in Mexico was associated with infection by classical, El Tor, and El Tor variants of Vibrio cholerae. J Clin Microbiol. 2010;48:3666–74. - Chin C-S, Sorenson J, Harris JB, Robins WP, Charles RC, Jean-Charles RR, The origin of the Haitian cholera outbreak strain. N Engl J Med. 2011;364:33–42. - Ghosh-Banerjee J, Senoh M, Takahashi T, Hamabata T, Barman S, Koley H, Cholera toxin production by the El Tor variant of Vibrio cholerae O1 compared to prototype El Tor and classical biotypes. J Clin Microbiol. 2010;48:4283–6. - Merrell DS, Butler SM, Qadri F, Dolganov NA, Alam A, Cohen MB, Host-induced epidemic spread of the cholera bacterium. Nature. 2002;417:642–5. - Butler SM, Nelson EJ, Chowdhury N, Faruque SM, Calderwood SB, Camilli A. Cholera stool bacteria repress chemotaxis to increase infectivity. Mol Microbiol. 2006;60:417–26. - Rodo X, Pascual M, Fuchs G, Faruque AS. ENSO and cholera: a nonstationary link related to climate change? Proc Natl Acad Sci U S A. 2002;99:12901–6. - Cash RA, Music SI, Libonati JP, Snyder MJ, Wenzel RP, Hornick RB. Response of man to infection with Vibrio cholerae. 1. Clinical, serologic, and bacteriologic responses to a known inoculum. J Infect Dis. 1974;129:45–52. - Kolvin JL, Roberts D. Studies on the growth of Vibrio cholerae biotype El Tor and biotype classical in foods. J Hyg (Lond). 1982;89:243–52. - St Louis ME, Porter JD, Helal A, Drame K, Hargrett-Bean N, Wells JG, Epidemic cholera in West Africa: the role of food handling and high-risk foods. Am J Epidemiol. 1990;131:719–28. - Stine OC, Alam M, Tang L, Nair GB, Siddique AK, Faruque SM, Cholera epidemics in rural Bangladesh are the result of multiple small outbreaks. Emerg Infect Dis. 2008;14:831–3. - Hartley DM, Morris JG Jr, Smith DL. Hyperinfectivity: a critical element in the ability of V. cholerae to cause epidemics? PLoS Med. 2006;3:e7. - Spira WM, Khan MU, Saeed YA, Sattar MA. Microbiological surveillance of intra-neighbourhood El Tor cholera transmission in rural Bangladesh. Bull World Health Organ. 1980;58:731–40. - Deb BC, Sircar BK, Sengupta PG, De SP, Mondal SK, Gupta DN, Studies on interventions to prevent El Tor cholera in urban slums. Bull World Health Organ. 1986;64:127–31. - Longini IM, Nizam A, Ali M, Yunus M, Shenvi N, Clemens JD. Controlling endemic cholera with oral vaccines. PLoS Med. 2007;4:e336. Suggested citation for this article: Morris JG Jr. Cholera—modern pandemic disease of ancient lineage. Emerg Infect Dis [serial on the Internet]. 2011 Nov [date cited]. http://dx.doi.org/10.3201/eid1711.111109 Comments to the Authors Comments to the EID Editors Please contact the EID Editors via our Contact Form. - Page created: October 27, 2011 - Page last updated: October 27, 2011 - Page last reviewed: October 27, 2011 - Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) Office of the Director (OD)

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Journal of Translational Medicine and Developmental Disorders. 2014, 1(1), 1-11DOI: Abstract: Patients with psychiatric disorders or problems need specialists to correctly diagnose and treat their psychiatric issues. However, a lot of psychiatric patients, especially the patients living rural and remote communities, cannot get timely effective treatment or they lack appropriate care because they cannot access to quality mental health treatment. Telepsychiatry is an effective means of delivering quality psychiatric care and services. Telepsychiatry patients benefit from reduced travel, less lost work time, shorter waiting time for specialist referrals, and reduced costs. Telepsychiatry has gained high levels of satisfaction in all age groups, including the elderly. It is especially useful in rural areas where access to quality psychiatric care is limited or non-existent. Telepsychiatry often uses two-way, real time, interactive and video based services on the network to deliver psychiatric care. This paper introduces several telepsychiatry service delivery models, advantages and applications of telepsychiatry, and the technology such as videoconferencing and variables such as bandwidth used in telepsychiatry treatment sessions. Some technology progress such as mobile telepsychiatry, telepsychiatry based on cloud computing, and telepsychiatry information security based on cryptographic technology or biometrics is presented in this paper. Issues about cultures and languages in telepsychiatry, and limitations and challenges of telepsychiatry in technology and services, ethical and legal considerations of the telepsychiatry, syndromes and patients groups at significantly increased risk in telepsychiatry, patient-psychiatrist relationship in telepsychiatry, and future or further research in telepsychiatry are also discussed.

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Ewing sarcoma is a malignant (cancerous) bone tumor that affects children. Ewing family of tumors; Primitive neuroectodermal tumors (PNET) Ewing sarcoma can occur anytime during childhood and young adulthood. But it usually develops during puberty, when bones are growing rapidly. It is 10 times as common in Caucasian children as in African American, African, and Asian children. may start anywhere in the body. Most often, it starts in the long bones of the arms and legs, the pelvis, or the chest. It can also develop in the skull or the flat bones of the trunk. The tumor often spreads (metastasizes) to the lungs and other bones. At the time of diagnosis, spread is seen in about one-third of children with Ewing sarcoma. In rare cases, Ewing sarcoma occurs in adults. There are few symptoms. The most common is pain and occasionally swelling at the site of the tumor. Children may also break a bone at the site of the tumor after a minor injury. Fever may also be present. Exams and Tests If a tumor is suspected, tests to locate the primary tumor and any spread (metastasis) often include: Treatment often includes a combination of: The stress of illness can be eased by joining a cancer support group . Sharing with others who have common experiences and problems can help you not feel alone. How well a patient does depends on: - The location of the tumor - If the cancer has spread The best chance for cure is with a combination of treatments that includes chemotherapy plus radiation or surgery. The treatments needed to fight this disease have many complications. Discuss these with your doctor. When to Contact a Medical Professional Call your health care provider if your child has any of the symptoms of Ewing sarcoma. An early diagnosis can increase the possibility of a favorable outcome. Anderson ME, Randall RL, Springfield DS, Gebhardt MC. Sarcomas of bone. In: Niederhuber JE, Armitage JO, Doroshow JH, et al., eds. Abeloff's Clinical Oncology. 5th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2013:chap 92. Cote GM, Choy E. Update in treatment and targets in Ewing sarcoma. Hematol Oncol Clin N Am. 2013;27:1007-1019. National Cancer Institute: PDQ Ewing Sarcoma Treatment. Bethesda, Md: National Cancer Institute. Date last modified: October 18, 2013. Available at: http://cancer.gov/cancertopics/pdq/treatment/ewings/HealthProfessional. Accessed: March 23, 2014. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bone cancer. Version 1.2014. Available at: http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Accessed March 23, 2014. Yi-Bin Chen, MD, Leukemia/Bone Marrow Transplant Program, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team.

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Young gymnasts and overhand athletes, particularly baseball pitchers and racket-sport players, are prone to an odd and troubling elbow condition. The forceful and repeated actions of these sports can strain the immature surface of the outer part of the elbow joint. The bone under the joint surface weakens and becomes injured, which damages the blood vessels going to the bone. Without blood flow, the small section of bone dies. The injured bone cracks. It may actually break off. This condition is called osteochondritis dissecans (OCD). In the past, this condition was called Little Leaguer's elbow. It got its name because it was so common in baseball pitchers between the ages of 12 and 20. Now it is known that other sports, primarily gymnastics and racket sports, put similar forces on the elbow. These sports can also lead to elbow OCD in adolescent athletes. This guide will help you understand What part of the elbow does this problem affect? The elbow is the connection of the upper arm bone (the humerus) and the two bones of the forearm (the ulna and the radius). The radius runs from the outer edge of the elbow down the forearm to the thumb-side of the wrist. The joint where the humerus meets the radius is called the humeroradial joint. This joint is formed by a knob and a shallow cup. The knob on the end of the humerus is called the capitellum. The capitellum fits into the cup-shaped end of the radius. This cup is called the head of the radius. When the head of the radius spins on the capitellum, the forearm rotates so that the palm faces up toward the ceiling (supination) or down toward the floor (pronation). The joint also hinges as the elbow bends and straightens. In the elbow joint, the ends of the bones are covered with articular cartilage. Articular cartilage is a slick, smooth material. It protects the bone ends from friction when they rub together as the elbow moves. Articular cartilage is soft enough to act as a shock absorber. It is also tough enough to last a lifetime, if it is not injured. Elbow OCD affects the articular cartilage in the capitellum. It also affects the layer of bone just below the cartilage, which is called the subchondral bone. In advanced stages of OCD, the upper end of the radius, particularly the head of the radius, is also involved. How does this problem develop? The cause of elbow OCD in adolescents is unknown. Scientists think that genetics is one possibility. This means that certain families are more likely to develop OCD. The condition often occurs among relatives, and it is sometimes seen in several generations of the same family. Another possible cause is that the tiny blood supply to the humeroradial joint is somehow blocked. Only the ends of a few small blood vessels enter the back of the humeroradial joint. If this scarce blood supply is damaged, there is no back-up. Although the exact cause of elbow OCD in adolescents is not known, most experts agree that overuse of the elbow plays a major role in its development. Pitching can lead to overuse strain and, in turn, elbow OCD. Throwing puts a lot of force on the elbow joint. When the throwing action is repeated over and over again, it can damage the immature joint surface of an adolescent's elbow. After winding up and cocking the arm back, the pitcher must quickly accelerate the arm to gain ball speed. Then, almost immediately, the pitcher has to slow the arm down and follow through. The pitcher may angle the elbow outward slightly during the acceleration phase to get more ball speed. This action jams the head of the radius against the capitellum. During the slowing and follow-through after a pitch, the forearm is fully pronated. This action puts extra pressure on the humeroradial joint. Hitting a ball with a racket can strain the elbow just like pitching a baseball. The player may angle the racket and elbow out slightly to gain ball speed. Hitting the ball with the arm and racket in this position jams the radial head against the capitellum, similar to what can happen during pitching motions. Gymnasts are also at risk for high forces on the capitellum when they repeatedly do maneuvers on their hands with their elbows locked out straight. These actions done over and over again can eventually cause an overuse injury to the humeroradial joint of adolescent athletes. Adolescents' articular cartilage is newly formed and so can't handle these types of forces. The subchondral bone (under the articular cartilage) in the capitellum takes the brunt of the stress. A portion of the bone may eventually weaken, and possibly even crack. When the bone is damaged, the tiny blood supply going to the area is somehow blocked. Without blood supply, the small area of bone dies. This type of cell death is called avascular necrosis. (Avascular means without blood, and necrosis means death.) The crack may begin to separate. Eventually, the small piece of dead bone may break loose. This produces a separation between the articular cartilage and the subchondral bone, which is the condition called OCD. If the dead piece of bone comes completely detached, it becomes a loose body. The loose body is free to float around inside the joint. Another condition, called Panner's disease, also affects the capitellum in children. It is not the same as elbow OCD in adolescents. Panner's disease affects the bone growth center (the growth plate) of the capitellum. Panner's disease generally occurs in kids (mainly boys) between five and 10. Panner's disease is a childhood condition that involves the entire capitellum and usually heals completely when bone growth is complete. Elbow OCD in adolescents is different. It occurs after growth in the capitellum has stopped, which is usually between the ages of 12 and 15. Elbow OCD in adolescents affects only a portion of the capitellum, generally along the inside and lower edges of the bony knob. Unless elbow OCD is diagnosed and treated early, the results are not as good as the results for Panner's disease. The adolescent with elbow OCD sometimes ends up with elbow arthritis by early adulthood. What does this problem feel like? Only about 20 percent of kids with elbow OCD remember hurting their elbow. The remainder usually develop symptoms over time, which is typical with overuse problems. In the absence of a specific injury, the athlete may at first feel bothersome elbow discomfort only while playing sports. The soreness generally goes away quickly when the elbow is rested. Over time, however, the elbow pain worsens, is hard to pinpoint, and may linger after using the arm. The elbow feel may feel stiff, and it may not completely straighten out. In advanced cases of elbow OCD, the patient may notice that the joint grinds (called crepitus). The elbow may catch, or even lock up occasionally. These sensations may mean that a loose body is floating around inside the elbow joint. The joint may also feel warm and swollen, and the muscles around the elbow may appear to have shrunk (atrophied). Bad cases of elbow OCD, and those that are not caught and treated early, tend to create bigger problems later in life. The joint may become arthritic early in adulthood. As a result, the patient may always have greater difficulty using the problem elbow. How do doctors identify the problem? The doctor begins by asking questions about the patient's age and sports participation. In the physical exam, the sore elbow and healthy elbow will be compared. The doctor checks for tenderness by pressing on and around the elbow. The amount of movement in each elbow is measured. The doctor checks for pain and crepitus when the forearm is rotated and when the elbow is bent and straightened. X-rays are needed to confirm the diagnosis. A front and a side view of the elbow are generally the most helpful. Early in the course of the problem, the X-rays may appear normal. As the condition worsens, the X-ray image may show changes in the capitellum. The normal shape of the bony knob may appear irregular. In bad cases of elbow OCD, the capitellum might even look like it has flattened out, suggesting that the bone has collapsed. The X-ray could show a crack in the capitellum or even a loose body. In the late stages of elbow OCD, the radial head may appear enlarged, and the humeroradial joint not be aligned as it normally should. These findings suggest early arthritis. A magnetic resonance imaging (MRI) scan may show more detail. The MRI can give an idea of the size of the affected area. It can show bone irregularities and also help detect swelling. Doctors may repeat the MRI test at various times to see if the area is healing. The doctor might order a computed tomography (CT) scan. The CT scan helps confirm the diagnosis. A CT scan clearly shows bone tissue. The doctor can compare CT scans over a period of time to monitor changes in the bones of the elbow. What treatment options are available? At first, athletes may need to stop their usual sport activities. This gives the elbow a rest so that healing can begin. The doctor may prescribe anti-inflammatory medicine to help reduce pain and swelling. Patients are shown how to apply ice to the area. When sport activities are resumed, ice treatments should be used after activity. Ice treatments are simple to do. Place a wet towel on the elbow. Then lay an ice pack or bag of ice over the elbow for 10 to 15 minutes. The doctor may also suggest working with a physical therapist. Physical therapists might use ice, heat, or ultrasound to control inflammation and pain. As symptoms ease, the physical therapist works on flexibility, strength, and muscle balance in the elbow. Therapists also work with athletes to help them improve their form in ways that reduce strain on the elbow during sports. Pitchers and racket-sport players might benefit from keeping the elbow aligned correctly, instead of angled outward, during the acceleration phase of the pitch or swing. When symptoms are especially bad, athletes may need to make changes that require less overhand activity. For example, pitchers could shift to playing first base. Gymnasts could focus on maneuvers that don't stress the sore elbow. However, if the piece of bone is loose but still attached, all sports activities must be stopped. Sports can begin again when the patient has no pain and shows full elbow movement. In severe cases, patients may need to wear a sling or a long-arm splint for several weeks before starting elbow motion exercises. As symptoms ease and elbow movement improves, a guided program of strengthening and sport training begins. Patients may need surgery if the elbow locks up, if it won't straighten out, or if pain continues even after a period of rest and physical therapy. Unfortunately, surgery isn't 100 percent successful. The various procedures don't necessarily improve athletes' chances for returning to high-level competition. Patients often lose the ability to fully straighten the elbow. And even after surgery, they are prone to elbow arthritis in early adulthood. Surgical procedures to treat elbow OCD are done from the outside edge of the elbow. The joint may be opened up to allow the surgeon to see and work on the joint. Opening up the joint is called arthrotomy. Many surgeons prefer instead to use an arthroscope. An arthroscope is a slender instrument with a TV camera on the end. The arthroscope can be inserted into a very small incision. It lets the surgeon see the area where he or she is working on a TV screen. Debridement is the most common procedure used for elbow OCD. It is especially helpful when the damaged part of the capitellum is loose but still attached. The surgeon uses a small shaver to clear away (debride) irritated tissue from the area. All the dead tissue is shaved away until the bone bleeds. This allows the defect to fill with scar tissue. Often, surgeons use a small instrument to poke holes through the damaged area and into the healthy bone just below. Bleeding from the holes promotes healing. The surgeon looks for and removes any loose fragments of bone. If the section of bone has completely detached from the capitellum, the surgeon may surgically pin the bone back in place. The spot where the bone detached is prepared. As in debridement, the bone tissue is shaved until it bleeds. Then the surgeon attempts to replace the loose piece of bone exactly in its original position. Small lengths of surgical wire are inserted through the bone fragment and into the main bone. The wires hold the piece of bone in place so that it can heal. The wires are usually left in place and not removed at a later date. Damage to a small area of the capitellum may be replaced with a graft (replacement tissue). The idea is to fill in the spot in order to reshape the knob of the capitellum. By using a piece of living tissue for the graft, it is hoped that the graft will restore the normal function of the original articular cartilage. The results of this procedure are not always optimal. The goal is that, by reshaping the capitellum, the alignment of the humeroradial joint will be improved. When it works, the joint has a better chance of lasting longer before becoming arthritic. This procedure uses an autograft, a graft of tissue from the patient's own body. The surgeon takes a small piece of bone and cartilage from a nearby area and puts it in the damaged area on the capitellum. The biggest challenge is getting the surface of the graft to match the original shape of the capitellum. What can be expected from treatment? In nonsurgical rehabilitation, the goal is to calm pain and inflammation and to protect the elbow from further harm. The doctor may prescribe anti-inflammatory medicine to help reduce pain and swelling. The elbow may need to be rested. When symptoms are especially bad, patients may need to avoid activities that make their pain worse, including sports. Even after symptoms ease up, activity may need to be restricted for another six to eight weeks. Some doctors have their patients work with a physical therapist. Treatments such as heat, ice, and ultrasound may be used to ease pain and swelling. Therapists also work with young athletes to help them improve their form and reduce strain on the elbow during sports. When the elbow starts to feel better, exercises are begun to get the elbow moving. At first, the movements are done passively, meaning that the therapist moves the arm. This is followed with active motion exercise, which means the patient's muscles help do the work of moving the arm. As elbow motion and strength improve, patients progress in more advanced strengthening exercises. A bandage or dressing is worn for a week following the procedure. The stitches are generally removed in 10 to 14 days. However, if the surgeon used sutures that dissolve, patients don't need to have the stitches taken out. Patients are shown ways to protect the elbow after surgery. Although elbow motions are avoided early on, patients are shown ways to keep motion in their shoulder, wrist, and hand. The surgeon may have the patient take part in formal physical therapy a few weeks after surgery. The first few physical therapy treatments are designed to help control the pain and swelling from the surgery. Exercises are chosen to help improve elbow motion and to get the muscles toned and active again. At first, the elbow is exercised in positions and movements that don't strain the healing cartilage. As the program evolves, more challenging exercises are chosen to safely advance the elbow's strength and function. Most patients will need to modify their activities after surgery. Most pitchers are unable to throw hard and without pain afterward. In general, most athletes with elbow OCD need to stop playing high-level sports due to lingering elbow pain and reduced elbow motion. If symptoms come back again, patients must modify their activities until symptoms subside. They'll need to avoid heavy sports activity until symptoms go away and they are able to safely begin exercising the elbow again. All materials within these pages are the sole property of Medical Multimedia Group, LLC and are used herin by permission. eOrthopod® is a registered trademark of Medical Multimedia Group, LLC.

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For several years, epilepsy practitioners have questioned the U.S. Food and Drug Administration's (FDA) definition of bioequivalence as it applies to narrow therapeutic index (NTI) drugs, such as those used for epilepsy. In response to these concerns, the FDA has sponsored 3 studies of antiepileptic drugs and also convened an advisory board to help determine which drugs are NTI. The new NTI definition and new bioequivalence guidelines and their impact will be a major point of discussion during a town hall session held with leaders from the FDA during the American Epilepsy Society's 67th annual meeting in Washington DC. Bioequivalence, a term used by the FDA to define specific criteria used to approve generic variations of brand drugs means that the versions of a drug produced by various manufacturers are expected to be used interchangeably without safety or efficacy concerns. A generic drug must produce blood levels within 80-120% of the brand drug in order to receive FDA approval. For drugs with a narrow therapeutic index, there are significant concerns among the epilepsy and neurology community that 80-120% may allow too much variability to ensure patient safety. Countless anecdotal reports suggest that manufacturer variations of antiepileptic drugs may cause changes in blood concentrations leading to loss of seizure control or other adverse effects, leading to serious mental, physical and social consequences for the person with epilepsy. "Clinicians are concerned about balancing the need to control medication costs while ensuring the safety of generic drug switches. We are grateful that the FDA has listened to concerns and funded these critical studies on generic drug safety," said Michael Privitera, MD, Director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute and Vice President for the American Epilepsy Society. In addition to the town hall session two other new studies about manufacturer variations and bioequivalence were presented at the meeting. One of the studies is part of the national FDA-funded clinical trial EQUIGEN (Equivalence Among Antiepileptic Drug Generic and Brand Products in People with Epilepsy). This particular series of experiments, led by researchers at the University of Wisconsin is an in-vitro screening of generic versions of the antiepileptic drug, lamotrigine. The goal was to find the two most different generic products to use in the human testing portion of EQUIGEN, which is using rigorous blood level testing in both single dose and multiple dose studies. The methodology identified disparate generic products for the EQUIGEN studies by demonstrating variations in dissolution time. In a separate study, a survey of retail pharmacist knowledge and attitudes about antiepileptic drugs was conducted by Cincinnati Children's Hospital Medical Center and the University of Cincinnati. The study found that most pharmacists (73%) reported reservations when switching from brand to generic manufacturers for antiepileptic drugs. Pharmacists (80%) reported trying to keep the same antiepileptic drug manufacturer in stock for patients if possible. Most pharmacists (63%) believed the range used by the FDA to determine bioequivalence to be stricter than actual requirements. Of the pharmacists surveyed, nearly a third (30%) were aware of patients that experienced breakthrough seizures or side effects associated with manufacturer change. "Pharmacists play an important role in the care of people with epilepsy," said, Lisa Garrity, PharmD, Clinical Pharmacy Specialist, Cincinnati Children's Hospital. "Our study reveals retail pharmacists share concerns surrounding manufacturer changes of antiepileptic drugs and highlights a need for additional education on issues associated with antiepileptic manufacturer changes for pharmacists. Communication between retail pharmacists, patients and epilepsy care providers is essential to safely utilize generic medications in patients with epilepsy." Cite This Page:

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This topic covers both atrial fibrillation (Afib) and atrial flutter (Aflut). - Afib: Continuous or paroxysmal arrhythmia characterized by chaotic atrial electrical activity and an irregularly irregular ventricular response - In some patients, ventricular response is rapid (>110 bpm), because AV node is bombarded with nearly continuous atrial electrical impulses. - Aflut: Continuous or paroxysmal arrhythmia with regular atrial electrical activity, typical atrial rate 250–350, manifested as sawtooth flutter waves on ECG. A 2:1 or 4:1 conduction through the AV node to the ventricle is common, so the ventricular response is frequently regular at a rate of 150 or 75 bpm. - Clinical pattern: - Persistent: Sustained >7 days, usually requiring pharmacologic or DC cardioversion to restore sinus rhythm - Paroxysmal (PAF): Self-terminating episodes, usually <7 days - Permanent: Sinus rhythm cannot be restored; cardioversion has failed or has not been attempted. - Incidence/prevalence increases with age. - Predominant gender: Male > Female - Afib: Age <40, <0.1%/year; >80, >1.5%/year, less for atrial flutter - Lifetime risk: 25% for those ≥40 years - Estimated 0.4–1% of general population <60 - ∼2–5%, 7th decade; 5–10%, 8th decade In US, hypertension/coronary disease most common. See Etiology. Familial forms rare, but do exist. Multiple culprit genes have been identified. Ethanol may trigger AF in some; so-called “holiday heart syndrome.” Adequate HTN control may prevent development of AF due to hypertensive heart disease. - In patients with PAF and no/minimal structural heart disease, triggering premature atrial beats and/or bursts of tachycardia emanate from the pulmonary venous ostia or other sites. - In patients with persistent/permanent AF and significant structural heart disease, multiple reentrant wavelets within atria may be the cause. - Cardiac: Hypertensive heart disease, valvular/rheumatic disease, CAD, acute MI, cardiomyopathy, CHF, pericarditis, infiltrative heart disease, sick sinus syndrome - Pulmonary: Pulmonary embolism, COPD, pneumonia - Ingestion: (e.g., ethanol in holiday heart), digoxin toxicity (AFlut) - Endocrine: Hyperthyroidism - Postoperative (e.g., cardiothoracic surgery) - Idiopathic: Including lone AF (<60 without clinical or electrocardiogram [EKG] evidence of cardiopulmonary disease, including HTN) Commonly Associated Conditions - Sick sinus syndrome. - Afib and Aflut are frequently associated with each other. Aflut tends to be a more unstable rhythm and tends to not last as long. - Symptoms vary from none–mild (palpitations, lightheadedness, fatigue, poor exercise capacity) to severe (angina, dyspnea, syncope). Symptoms frequently more serious in patients with structural heart disease. - In patients with Wolff-Parkinson-White syndrome and other types of bypass tracts, Afib may lead to an extremely rapid ventricular rate that may swiftly degenerate into ventricular fibrillation. - Afib: Irregularly irregular pulse, frequently tachycardic - Aflut: Regular pulse, frequently tachycardic Diagnostic Tests & Interpretation - Afib: EKG is diagnostic; low-amplitude fibrillatory waves without discrete P waves; irregularly irregular pattern of QRS complexes - Aflut: Sawtooth P-waves are the classic sign. Narrow complex QRS. Frequent tachycardia. - Holter monitor and event monitor helpful in diagnosing PAF and monitoring for recurrence. Initial lab tests TSH, CMP, cardiac enzymes, PT/INR (if anticoagulation is contemplated), consider digoxin level (if appropriate) and CBC Follow-Up & Special Considerations Occasional Holter monitoring and/or exercise stress testing to assess for adequacy of rate control - Chest x-ray (CXR) for cardiopulmonary disease - EKG for structural heart disease, signs of ischemia, heart blocks, and other arrhythmias - Spiral chest computed tomography (CT) (or other tests such as D-dimer, ventilation-perfusion scan, or pulmonary angiography) if pulmonary embolus possible etiology for new-onset disease - Transesophageal echocardiogram to detect left atrial appendage thrombus if cardioversion planned Electrophysiologic studies should be considered in patients with recurrent Aflut to map the source of the arrhythmia for possible ablation. - Atrial dilatation and fibrosis - Atrial injury (chronic or acute) - Atrial thrombus, especially in atrial appendage - Sclerosis/fibrosis of sinoatrial node - Coronary artery disease, valvular/rheumatic disease, cardiomyopathy, pulmonary embolus - Tachycardia-induced cardiomyopathy - Multifocal atrial tachycardia - Sinus tachycardia with frequent atrial premature beats - Atrial flutter/atrial fibrillation - Anticoagulation guidelines (same for Afib and Aflut): - Unless contraindicated, patients with AF with any high-risk factors for stroke (prior transient ischemic attack (TIA)/cerebrovascular accident (CVA)/thromboembolism, mitral stenosis, prosthetic valve) should receive warfarin to maintain INR of 2.0–3.0. Patients with mechanical valves should maintain INR >2.5. - CHADS2 score: Patients with ≥2 moderate risk factors (CHF, HTN, Age >75 and/or DM), should receive warfarin (INR 2.0–3.0) unless contraindicated. - Patients with 1 moderate risk factor should be treated with warfarin (INR 2.0–3.0) or aspirin (81–325 mg/d). Discuss with patient risks and benefits. - Patients at low risk of thromboembolic complications or in whom warfarin is contraindicated should receive aspirin (81–325 mg/d) or clopidogrel. - Anticoagulation recommendations are independent of AF pattern (paroxysmal, persistent, permanent). - So-called “rate control” and “rhythm control” strategies have approximately equivalent outcomes in terms of mortality. Rhythm control tends to have more adverse reactions. - Control of ventricular rate: - Nondihydropyridine calcium channel blockers: - Diltiazem (Cardizem) - Class contraindications: Hypotension, documented sensitivity, 2nd- or 3rd-degree AV block, severe CHF, sick sinus syndrome - Precautions: Use caution with CHF, left ventricular (LV) dysfunction, liver or kidney disease. Adverse reactions: Hypotension, CHF, peripheral edema, AV block. - Interactions: May increase digoxin levels; with amiodarone or beta-blockers, may severely decrease cardiac output, trigger complete heart block - Metoprolol (Lopressor) - Contraindications: Hypotension, documented sensitivity, 2nd- or 3rd-degree AV block, severe CHF, sick sinus syndrome - Precautions: Use caution with CHF, LV dysfunction, kidney disease, asthma - Interactions: Bradycardia with digoxin; with amiodarone or calcium channel blockers, may severely decrease cardiac output or trigger complete heart block - Adverse reactions: Hypotension, CHF, peripheral edema, AV block - Nondihydropyridine calcium channel blockers: - Digoxin (Lanoxin): - Indicated for CHF, hypotension - Contraindications: Documented sensitivity, sick sinus syndrome, hypertrophic cardiomyopathy - Precautions: Use caution with electrolyte abnormalities (especially hypokalemia, hypercalcemia), impaired renal function, thyroid disease, acute myocardial infarction (MI), AV block - Interactions: Unpredictable effects with many antiarrhythmics; additive bradycardia with calcium channel blockers, beta-blockers - Adverse reactions: AV block, bradycardia, mental disturbances, nausea - Rate control usually achieved in 4 hours (1). - Conversion to/maintenance of sinus rhythm: - DC cardioversion - Caution: Antiarrhythmic therapy for chemical cardioversion and maintenance of sinus rhythm following cardioversion may be proarrhythmic. - Ibutilide, an IV type III agent, for chemical cardioversion of AF and flutter of short duration (<90 days) - If duration of AF is >24–48 hours or unknown, treat with warfarin for ≥3 weeks before cardioversion. Or, once anticoagulation is established, perform transesophageal EKG. If no atrial thrombus, may cardiovert. Anticoagulation should be continued for ≥4 weeks following cardioversion. - Long-term, perhaps indefinite, anticoagulation should be considered in patients with thromboembolic risk factors with chronic or recurrent AF. - Chronic oral antiarrhythmic therapy to suppress AF recurrences: - Type IA (procainamide, disopyramide, quinidine): Generally not used - Type IC (flecainide, propafenone) in patients with structurally normal hearts or mild hypertensive heart disease. Concomitant use of β-blocker recommended. - Type III (sotalol, amiodarone, dofetilide) - Type IC drugs are contraindicated in patients with coronary artery disease, cardiomyopathy, and significant LVH. - Type IA and III drugs should not be used in patients with torsade de pointes history or long QT. The risk of torsade de pointes increases with the extent of QT interval prolongation (the QTc), so these medications should be used with great caution, if at all, in patients on medications that prolong the QT. - Precautions: Avoid hypokalemia and hypomagnesemia. - With type IC drugs, stress testing to exclude exercise-induced arrhythmia or QRS widening - With amiodarone, careful surveillance for hepatic, thyroid, pulmonary, skin, ophthalmologic adverse effects - In many patients, adequate medical therapy of AF will cause bradycardia, necessitating a permanent pacemaker. - According to a recent Cochrane Review, several class IA, IC, and III drugs are effective in maintaining sinus rhythm but increase adverse events, including pro-arrhythmia, and disopyramide and quinidine are associated with increased mortality. Any benefit on clinically relevant outcomes (embolisms, heart failure, mortality) remains to be established (1). Issues for Referral AF refractory to medical therapy (unable to achieve adequate rate control or significant bradycardia) should be considered for more definitive therapy such as pacemaker +/-AV node ablation. Antiarrhythmic therapy should be prescribed by experienced practitioners. - Current guidelines reserve catheter ablation in Afib to highly symptomatic patients who have failed at least 1 course of antiarrhythmic drug therapy [C]. It is the treatment of choice for patients who are in chronic Aflut, with a number needed to treat (NNT) of 2.2 to prevent rehospitalization, vs antiarrhythmics. - Catheter ablation success rates vary with the type of Afb (paroxysmal > persistent > permanent) and the presence of structural heart disease, particularly left atrial enlargement. May require ≥2 ablation procedures to achieve clinical success. - Cardiac surgery (e.g., the maze procedure or minimally invasive epicardial procedures) may be considered in severely symptomatic, medically refractory patients. - Permanent dual-chamber pacing may reduce incidence of new-onset AF and reduce frequency of PAF episodes in patients with sick sinus syndrome. Acute therapy for hemodynamically compromised patients: - Heparin for anticoagulation (not generally necessary; may just initiate warfarin without “bridge” therapy) - IV β- or calcium channel blocker for control of ventricular rate if blood pressure (BP) adequate - Urgent cardioversion if hemodynamically unstable: - DC cardioversion is best treatment (2)[C]. - Begin with dose of 50 J (with biphasic defibrillator) or 200 J (with monophasic defibrillator) and increase as needed (2)[C]. - Atrial overdrive pacing also effective - Inpatient if: - Significant symptoms - Extremely rapid ventricular rate - Initiating antiarrhythmic therapy - AF triggered by acute process (acute myocardial infarction, congestive heart failure [CHF], pulmonary embolus) - High risk for stroke (rheumatic heart disease, prior TIA/stroke) - Outpatient management for low-risk patients with controlled ventricular rates Adequate rate or rhythm control without symptoms. Long-term plan for anticoagulation established. There continues to be debate about whether rate or rhythm control is best for treating patients with chronic Afib/Aflut. Mortality is the same for both. Risk of stroke is higher for electrical cardioversion, but there are some measures of symptom control and quality of life that appear to be improved. Pharmacologic cardioversion is associated with more adverse events and hospitalization in elderly patients. Take into account the patient with their associated health conditions when deciding what path to take (3,4). - Monitor warfarin levels. - EKG to monitor QTc interval if on antiarrhythmic therapy Avoid potential triggers: Ethanol, caffeine, nicotine Warfarin anticoagulation reduces annual embolic stroke rate from ∼5% to 1–2%. Aspirin reduces risk to 3–4% annually. AF increases risk of morbidity and mortality, but prognosis is a function of underlying heart disease. - Embolic stroke - Peripheral arterial embolization - Bleeding with anticoagulation - Tachycardia-induced cardiomyopathy with prolonged periods of inadequate rate control 1. Lafuente-Lafuente C, Mouly S, Longas-Tejero MA, Bergmann JF, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev. 2007;CD005049. 2. Fuster, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation. 2006;114:e257–354. 3. Mead GE, Elder AT, Flapan AD, Kelman A, et al. Electrical cardioversion for atrial fibrillation and flutter. Cochrane Database Syst Rev. 2005;CD002903. 4. Cordina J, Mead G, et al. Pharmacological cardioversion for atrial fibrillation and flutter. Cochrane Database Syst Rev. 2005;CD003713. - 427.31 Atrial fibrillation - 427.32 Atrial flutter - 49436004 Atrial fibrillation (disorder) - 5370000 Atrial flutter (disorder) - There continues to be debate about whether rate or rhythm control is best for treating patients with chronic Afib/Aflut. Mortality is the same for both. When in doubt and in absence of other contraindications, rate control appears to have the best outcome data. - AF with rapid ventricular rates may be the initial presentation of tachy/brady syndrome with underlying sinus node dysfunction, particularly in the elderly. Exercise caution when initiating AV nodal-blocking agents in the elderly patient with rapid AF.

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Your glaucoma patient has long been stable on pressure-lowering therapy. So how do you now explain a sudden spike in pressure and new progression of visual field loss? Before changing the medication or blaming patient noncompliance, you might want to consider what Robert Ritch, MD, calls "overlap syndrome." Overlap gives name to the situation in which the patient with glaucoma develops a new "and different" glaucoma risk factor that can speed glaucomatous damage. Overlap can also be used to describe the coexistence of two or more frank glaucomas in one eye, each of which may have a distinct etiology, time of onset, presentation and clinical course. Recognizing overlap conditions allows for new ways of treating patients, particularly those with secondary and normal-tension glaucomas. Dr. Ritch, who is a professor of clinical ophthalmology and chief of the glaucoma service and surgery director at the New York Eye and Ear Infirmary, said, "Basically, if you have a patient with glaucoma who has been well-controlled and clicking along for some time, and then all of a sudden either the pressure goes up in one eye or a visual field destabilizes, that suggests the development of a second condition superimposed on the glaucoma." The overlap concept was first introduced in 1990, in a report of five middle-aged patients with increasingly uncontrollable IOP.1 All patients had exfoliation syndrome (XFS) and were then found to have had pigment dispersion syndrome (PDS) as well. Following that report, Dr. Ritch and colleagues conducted a retrospective chart review of records at New York Eye and Ear Infirmary, and identified an additional 26 patients who had combined PDS/XFS. 2, 3 Those two glaucomas have no known etiologic relationship. XFS is the most common identifiable disorder leading to the development of open-angle glaucoma worldwide, and it constitutes about 12 percent of glaucoma in the United States, where the combination could affect up to half a million individuals. In the context of PDS/ XFS, the overlap theory explains why patients with previous pigment dispersion syndrome who go on to develop exfoliation may be more susceptible to elevated IOP than patients with XFS who have not had PDS. The reason: preexisting damage to the trabecular meshwork. Helpful model. While there can be other overlap combinations, PDS/XFS was chosen as a paradigm for the syndrome because of the ease of diagnosis and its prevalence. "It's easy and straightforward to look at patients who have clinical evidence of PDS and pseudoexfoliation," said Raghu Mudumbai, MD, a coauthor of the overlap studies and assistant professor of ophthalmology, at the University of Washington, Seattle. Dr. Mudumbai reiterated Dr. Ritch's definition of overlap glaucomas. "In patients whose glaucoma is decompensating, and it's not an effect of the medication not working as well, or the patient not being compliant, perhaps it's a third possibility that a new comorbidity has been introduced that has exacerbated the underlying glaucoma." Not necessarily obvious. Some overlap combinations, in fact, may not be readily apparent to the ophthalmologist, Dr. Mudumbai said. For example, after developing glaucoma, a patient may develop another risk factor that may not be as self-evident as pseudoexfoliation, but which may nevertheless contribute to the decompensation of the patient's glaucoma. "Overlap syndrome is a two-hit hypothesis," he continued. "One hit is your initial glaucoma process that causes some damage and some difficulty with pressure control, for example. You've been able to manage it fairly well with medication. But now, you introduce a second problem that overwhelms the system and as a result of that, decompensation takes place." The second hit could be the appearance of XFS in patients who previously had pigmentary dispersion syndrome, or it may be a pressure-independent process. Pigment, pigment everywhere. "Overlap is a useful concept about which ophthalmologists need to be aware," said Donald S. Minckler, MD, professor of ophthalmology and pathology, University of California, Irvine. Dr. Minckler said that the PDS/XFS combination, as described by Drs. Ritch and Mudumbai, provides a very good basis for establishing the concept of overlap. "The important point is that patients with pigmentary dispersion with or without glaucoma have pseudoexfoliation-associated risks added to those of pigmentary dispersion - a double whammy - probably with a worse prognosis," he said. "Common sense dictates that the physician should watch for pseudoexfoliation to appear in pigmentary dispersion patients. Since we only see what we are looking for, being aware of the possibility is important for the small percentage of such patients whom we might encounter." Take care in the OR (and the gym). Another example, Dr. Minckler said, is a patient with open-angle glaucoma who - for various reasons, sometimes ocular surgery - develops progressive angle closure with a significant change in symptoms. "I have also rarely encountered patients without typical pigment dispersion who developed remarkable IOP rise postcataract surgery, probably provoked by intraocular manipulations and resulting in iris pigment release, with obstruction of outflow channels. Such 'pigment storms' can be confused with uveitis and can also occur in rare cases after vigorous exercise in patients with pigmentary dispersion syndrome.?" Borrowing From Beyond the Eye There's precedent for looking beyond any single etiology for a particular pathology, said Dr. Mudumbai, noting that cardiovascular disease provides an example to support the overlap syndrome. "Who ever would have thought that tooth cavities or gum disease would be related to cardiovascular disease? But it's been shown that having poor dental health can lead to inflammatory factors that can lead to cardiovascular disease." The cardiovascular example, which involves factors not typically related to heart disease, suggests that ophthalmologists who concentrate solely on IOP might not be able to control the glaucoma if they neglect to consider pressure-independent risk factors. IOP not always revealing. When he elaborated the concept for Eye M.D.s at a 1999 meeting of the American Ophthalmological Society, Dr. Ritch told colleagues, "We are entering an era in which we are becoming more aware of the existence of an ever increasing list of nonpressure-dependent risk factors for glaucomatous damage." The risk factors he cited included: atrial fibrillation, vasospastic or autoregulatory disorders, nocturnal hypertension, abnormal platelet aggregation, hemorheologic abnormalities, sleep apnea and autoimmune phenomema. The development of one of those non-IOP-dependent risk factors may cause the sudden acceleration of glaucomatous damage. "If somebody's been controlled for a long time and then goes out of control, don't just juggle the medications," Dr. Ritch said. "You have to look for a new kind of glaucoma starting up, or a non-IOP related risk factor. Look for something new that's developed." Advice to clinicians. Dr. Mudumbai agreed. The sudden decompensation should be a red flag, he said. "You should at least go through the mental process of seeing whether another problem has been introduced that's feeding into the change that's occurred." Don't doctors ordinarily do that? "They do," Dr. Mudumbai said. "But you should be more in tune for the possibility that another process may be going on that is affecting the patient's glaucoma. It's fairly easy to say, "Okay, the medications not working; I need to add another medication, as opposed to saying, "˜Maybe something else is happening. Maybe I should look again for pseudoexfoliation.'" Dr. Ritch added that a better understanding of the etiology of new risk factors is required before appropriate treatments can be devised. In the meantime, he said that thinking in terms of overlap can form the basis for "understanding the sequential appearance of various risk factors over the course of the life of a patient with glaucoma." In their 2000 Ophthalmology report, Drs. Ritch and Mudumbai expressed hope that awareness of newly arisen risk factors "will stimulate both a search for the specific causes in a particular patient workup and interdisciplinary investigations to identify these risk factors, with the goal of expanding our therapeutic armamentarium." 1 Layden, W. et al. Am J Ophthalmol 1990;109:530"“534. 2 Mudumbai, R. et al. Trans Am Ophthalmol Soc 1999;97:297"“321. 3 Ritch, R. et al. Ophthalmology 2000;107:1004"“1008.

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This information is for reference purposes only. It was current when produced and may now be outdated. Archive material is no longer maintained, and some links may not work. Persons with disabilities having difficulty accessing this information should contact us at: https://info.ahrq.gov. Let us know the nature of the problem, the Web address of what you want, and your contact information. Please go to www.ahrq.gov for current information. Programs and Tools That Improve Care for Victims Research in Action Issue 15 This report describes training programs and tools that health care providers, social workers, and facilities and their staff can use to provide better care for victims of domestic violence. Select for print version (PDF File, 940 KB). PDF Help. Introduction / Background / Impact of AHRQ Research / Ongoing Research / Conclusion / For More Information / References By Barbara L. Kass-Bartelmes, M.P.H., C.H.E.S. Up to 25 percent of U.S. women have been the victims of domestic violence, which can result in immediate injury and/or chronic health problems. When victims seek medical care, clinicians often do not screen for and identify domestic violence. In fact, the U.S. Preventive Services Task Force indicates that very few research studies exist that can help guide clinicians on how to screen for domestic violence and manage care for identified victims.1,2 Further, health care providers need to be able to refer victims to programs and counseling that will be effective in helping them end the violence in their lives. Assessing the quality and effectiveness of these programs, however, has been difficult. Research funded by the Agency for Healthcare Research and Quality (AHRQ) has: - Identified gaps in research on domestic violence indicating a need to build a stronger evidence base for screening, detecting, and treating victims. - Helped health care providers screen for and identify victims of domestic abuse. - Created tools that help providers counsel and treat victims. - Developed a tool that evaluates the quality of domestic violence programs. Return to Contents Each year in the United States, about 2 million women are physically assaulted by their intimate partners.3,4 These assaults result in injuries that lead to over 73,000 hospitalizations and 1,500 deaths.3,4 In addition to the physical injuries domestic violence causes, it is also a major risk factor for depression. For example, one study found that 61 percent of women diagnosed with depression had also experienced domestic violence—a rate two times that of the general population.5 Victims of domestic violence have more physical problems, including headaches, chronic pain, sleep problems, vaginal infections, digestive problems, sexually transmitted diseases, and urinary tract infections, and they are more likely to rate their health as only fair or poor.5,6 Even though injuries and health problems are apparent and well documented, health care providers often do not ask about domestic violence or intervene on behalf of their patients who experience it.4,7 One study found that only 6 percent of physicians ask their patients about possible domestic violence, yet 88 percent admitted that they knew they had female patients who had been abused.8 Another study indicated that 48 percent of women supported routine screening of all women, with 86 percent stating it would make it easier to get help.9 Health care providers have said that they do not screen for domestic violence because they lack the necessary training, time, tools, and resources, and they do not feel they can make a difference.4,7,8 An AHRQ-funded survey found that many primary care clinicians, nurses, physician assistants, and medical assistants lack confidence in their ability to manage and care for victims of domestic abuse.10 - Only 22 percent had attended any educational program on domestic violence within the previous year.10 - Over 25 percent of physicians and nearly 50 percent of nurses, physician assistants, and medical assistants stated that they were not at all confident in asking their patients about physical abuse.10 - Less than 20 percent of clinicians asked about domestic violence when treating their patients for high-risk conditions such as injuries, depression or anxiety, chronic pelvic pain, headache, and irritable bowel syndrome.10 - Only 23 percent of physicians, nurses, physician assistants, and medical assistants believed they had strategies that could assist victims of domestic abuse.10 Return to Contents Impact of AHRQ Research More Research Is Needed on Screening and Treating Domestic Violence Victims In an extensive review of research literature, the U.S. Preventive Services Task Force (USPSTF)a did not find enough evidence to recommend for or against routine screening for domestic violence among the general population.1,2 However, the USPSTF reinforced the necessity for health care providers to be able to identify the signs and symptoms of domestic violence, document the evidence, provide treatment for victims, and refer victims to counseling and social agencies that can provide assistance.1,2 Essentially, the USPSTF found that: - When domestic violence is suspected, health care providers need to conduct the appropriate history and examinations, offer treatment, document their findings, and refer the victim for counseling and support.1,2 - None of the research has indicated that screening patients who have no symptoms of domestic violence has reduced harm.1,2 - More research is needed to develop screening tools that are effective in the general population, along with programs that can improve health outcomes and reduce violence.1,2 - Several screening instruments have demonstrated good "internal consistency," indicating that all the items on the instrument are consistent with one another. However, the best methods to administer screening instruments in various settings have not been determined.1,2 - Definitions of abuse varied among the studies, which limited the ability to combine and compare studies in different settings. Refining these definitions, along with measurements of severity and the chronic occurrence of abuse, would allow development of standardized instruments and evaluation tools.1,2 - No research has been done to determine if there were any adverse effects of screening or interventions.1,2 a. AHRQ supports operation of the USPSTF, which was convened by the U.S. Public Health Service to rigorously evaluate clinical research in order to assess the merits of preventive measures. The USPSTF consists of an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services. Training Helps Providers Identify and Manage Victims of Domestic Violence Training sessions funded by AHRQ improved primary care providers' confidence in asking and treating victims of domestic violence. Providers who participated in the training increased their screening for domestic violence from 3.5 percent prior to the training program to 20.5 percent after training.11 Upon completion of the training sessions, participants stated they: - Felt less fear of offending patients by asking about domestic violence. - Had less fear for their own safety. - Asked patients more often about possible domestic violence. - Offered strategies to abusers to seek help. - Provided strategies so victims could change their situation. - Had better access to information on managing domestic violence. - Had methods to ask abusers about domestic violence while minimizing the risk to the victims.11 This domestic violence training program uses a systems approach, helping health care providers working in primary care settings identify and manage domestic violence. In addition, its randomized design allows assessment of outcomes and effectiveness.12 Specifically, one can measure: - Changes in providers' knowledge, attitudes, and beliefs. - How often they ask about domestic violence (documented). - Case finding. - Completeness of case management.12 An interdisciplinary team provided training for receptionists, medical assistants, nurses, physician assistants, and physicians. The team included a nurse, an epidemiologist, primary care physicians, and personnel from treatment programs, social work, and a women's shelter, as well as a former domestic violence victim and a prosecuting attorney. There were 2 4-hour training sessions. At the first training session, participants received basic information about domestic violence, including prevalence, indications, how to get information from their patients, how patients change behaviors, documentation, and patient safety. Specifically, participants were taught how to: - Ask direct questions. - Acknowledge what the patient said. - Assess the patient's safety needs. - Refer the patient to social and mental health workers as well as community and State domestic violence agencies and hotlines. - Document their findings in the patient's chart. - Arrange to have the patient follow up with them.12 The first training session also included a discussion about abusers—those who commit domestic violence.12 Participants learned: - How to identify abusers by noticing injuries to the abuser's hands, problems with alcohol, depression, employment problems, stress disorders, and problems with anger and hostility. - How to interview abusers by asking questions about what happens during disagreements with their partners and if anyone gets hurt. - The indications of increasing risk of domestic violence, including a history of escalating violence, multiple forms of violence, threats of serious harm, increased drug and alcohol use, depression, mental illness, suicide threats or attempts, jealousy, and obsession with the victim on the part of the abuser; expressions of fear for safety from victims; separation; and divorce. - Methods to help ensure their safety when meeting with abusers. - What to say to the abuser: for example, this behavior is not acceptable, violence will not go away by itself, violence has harmful effects on the family, and the abuser has a responsibility to get help. - Where to refer the abuser to get help.12 During the second training session, participants learned how to manage the care for victims of domestic violence. They participated in role playing, talked with a former victim of domestic violence, and received presentations from a prosecuting attorney and a community domestic violence agency.12 After the 2 half-day workshops, during the following year, newsletters were sent 4 times to all participants to reinforce what they had learned and were applying in practice. Additional educational sessions were held on skill improvement and community resources, and participants were told about early results of the study to encourage their efforts. Posters were placed in clinic waiting areas to allow patients to feel more comfortable about talking with providers about domestic violence. Providers also carried cue cards in their pockets to help reinforce the processes they had learned.12 Nine months after the training, when the intervention was fully in place, the participants were asked to rate the usefulness of 12 components of the training session, shown in Table 1.12 Participants stated that they felt components 1-7 were significantly more important than components 8-12.12 An Assessment Tool Helps Providers Counsel Victims The Domestic Violence Survivor Assessment (DVSA) tool helps health care providers and abused women identify issues and feelings created by domestic violence and helps guide counseling. Social workers have said that the DVSA is "easy to understand, quick to complete, and provided a valuable holistic viewpoint."13 It enabled them to see visually the various states a woman was experiencing about different issues and could help them identify areas where she was "stuck" and required counseling to be able to move forward.13 The DVSA instrument has been adopted as an outcome measure for counseling in 2 community-based and 1 hospital-based domestic violence counseling programs. It is also being piloted for possible adoption by a State for measuring outcomes of domestic violence counseling programs. Researchers funded by AHRQ collaborated with the United Family Services of Central Maryland and the House of Ruth of Baltimore, MD, to develop and implement the DVSA in order to guide interventions and measure outcomes.13 The instrument is based on the Transtheoretical Model of Change and Landenburger's Theory of Domestic Violence Recovery. It measures where a woman perceives herself regarding 11 issues commonly experienced by survivors of domestic violence. Five of these issues concern her relationship with the abuser: - Triggers of abusive incidents. - Managing partner abuse. - Attachment to the abuser. - Views of the relationship and options. - Managing loyalty to norms and her own beliefs.13 Six of the issues concern her as an individual: - Accessing help. - Self-efficacy: ability to be on her own. - Mental health. - Medical care for domestic violence injuries and stress.13 Based on interviews with the client, the clinician identifies the state the woman is in with regard to resolving each of the 11 issues. For example, when a woman denies and excuses the abuse (Figure 1, first column) or ignores her injuries (Figure 2, first column), she is still in a state of being committed to continuing the relationship. Once she is able to reject self-blame and realizes she cannot prevent her partner's abuse, she is considering change and begins looking at the abuse and her options (Figure 1, middle column), although she may delay getting medical care for her injuries (Figure 2, middle column). Finally, she makes the decision not to tolerate the abuse and either leaves the relationship or, if she stays, becomes mindful of the need for her partner to change and seeks medical treatment as needed (Figures 1 and 2, last column). The complete, updated DVSA can be obtained from: Jacqueline Dienemann, Visiting Professor University of North Carolina at Charlotte Department of Adult Health Nursing 9201 University City Boulevard Charlotte NC 28223 A Critical Pathway for Intimate Partner Violence Provides Guidance for Patient Care Researchers who developed the DVSA instrument also created a critical pathway for intimate partner violence (IPV). The critical pathway encompasses physical health, mental health, and social assessment and treatment for victims of domestic violence.14 The IPV critical pathway has been validated using the Delphi technique of gathering feedback from experts. Further research is necessary to measure processes and barriers to implementation, as well as its reliability in improving patient outcomes.14 The pathway for intervention on the first visit (initial disclosure of IPV) is shown in Figure 3. A Tool for Hospital-based Domestic Violence Programs Helps Assess Quality The Delphi Instrument for Hospital-based Domestic Violence Programs, funded by AHRQ, can be used to assess the quality of a hospital's performance in implementing a domestic violence program and can be used to create program goals, assess performance over time, and compare one program to another. Eventually, it can be linked to outcomes to determine what parts of the program create the best outcomes for victims of domestic violence. The instrument examines the physical structure of the programs, such as facilities, equipment, personnel, and organizational structure. It also examines the provider's process of care, such as chart documentation and treatment.15 The Delphi Instrument has had both local and international impact. It was used at the University of North Carolina (UNC) Chapel Hill Medical School to evaluate the domestic violence program at UNC hospitals.16 Foyle Women's Aid and the Consultancy Mentoring Works research team, based in Northern Ireland, used the Delphi Instrument in a study to investigate care for victims of domestic violence at Altnagelvin Hospital.17 The findings from that study led researchers to recommend the Delphi Instrument as an "excellent template... for any organization, agency or public body to monitor their services in respect to domestic violence."17 The tool measures 9 different categories of performance (Figure 4). A panel of 18 experts on domestic violence (researchers, program planners, and advocates) evaluated and agreed on 37 performance measures in these 9 categories that can be used to evaluate hospital-based domestic violence programs.18 Each performance measure within a category is assigned a score15 and the scores are added to obtain a total for the category. The raw scores for each category are then weighted and the weighted scores added to obtain a total score, with 100 being the best possible score.15 Guidelines, instructions, and the tool itself can be found on AHRQ's Web site at http://www.ahrq.gov/research/domesticviol/. Return to Contents AHRQ continues to fund studies that investigate domestic violence and its effects: Treatment Outcomes for Abused Women in Public Clinics. University of Texas Health Science Center, Houston, Grant No. R01 HS11079. This project is designing, implementing, and testing the effectiveness of nurse case management and group education for black, Hispanic, and white abused women attending two inner-city primary care clinics. The clinics are part of a county-wide clinic and hospital system for low-income people. In addition, the researchers are evaluating the impact of the interventions on the health, functional status, and medical use of children of abused women. Outcomes for Intimate Partner Violence: Patient and Provider Perspectives. University of California, San Francisco, Grant No. R01 HS11104. This study focuses on 125 Hispanic women at high risk for intimate partner violence who have low incomes and are receiving prenatal care from the public sector. The specific aim of this project is to determine the health care outcomes these women prefer from intimate partner violence interventions. A Randomized Controlled Trial of Computer Screening for Domestic Violence. University of Chicago, Grant No. R01 HS11096. This project is evaluating the effectiveness of a computerized assessment tool to help clinicians in emergency departments identify potential victims of domestic violence and recommend specific strategies for management. The study includes women who come to the emergency departments of two hospitals, one in the inner city and the other in the suburbs. The Cost and Benefits of Intervening: Battered Women's Mental and Physical Health Over Time. Harvard School of Public Health, Boston, MA, Grant No. R01 HS11088. This project is comparing seven existing domestic violence interventions in different hospital settings. Findings from this study will offer new information on the effectiveness and cost effectiveness of different hospital-based interventions. Cost Effectiveness of Domestic Violence Interventions. Montefiore Medical Center, Bronx, NY, Grant No. K08 HS11297. This project is investigating the effectiveness of domestic violence interventions, defining outcome measures, and developing a method for a cost-benefit analysis. The study will provide essential timely information to guide the medical community on how best to develop domestic violence interventions and investigate the cost effectiveness of domestic violence interventions in primary care. Long-term Health Care Effects of Domestic Violence. Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, WA, Grant No. R01 HS10909. This study is assessing the impact of domestic violence over an 11-year period on the health care cost and utilization of adult women and their children. For the women, the study is assessing the effects of domestic violence on health status and high-risk behaviors, such as excessive drinking. Investigators are also estimating the prevalence of domestic violence among men and the elderly of both sexes. Overall, investigators are determining the effect of domestic violence on physical and mental health status, social functioning, and health risk profiles and estimating the prevalence of domestic violence by type, duration, and frequency among women, men, and the elderly. Return to Contents AHRQ-funded research has helped to identify gaps in the research on domestic violence and areas where better tools and programs are needed to help health care providers identify and treat victims of domestic violence. Researchers supported by AHRQ have developed training programs and critical treatment pathways for clinicians and their staff, instruments to help counsel victims, and a method for hospital providers to assess the quality of their services. The Agency continues to fund research in an effort to further reduce violence and improve health outcomes. Return to Contents For More Information For further information on AHRQ's research on women and domestic violence, contact: Charlotte Mullican, B.S.W., M.P.H. Senior Advisor for Mental Health Research Center for Primary Care, Prevention, and Clinical Partnerships Agency for Healthcare Research and Quality 540 Gaither Road Rockville, MD 20850 Phone: (301) 427-1495 Return to Contents *1. Nelson HD, Nygren P, McInerney Y, et al. Screening women and elderly adults for family and intimate partner violence: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2004; 140(5):387-96. *2. U.S. Preventive Services Task Force. Screening for family and intimate partner violence: recommendation statement. Ann Intern Med 2004; 140(5):382-6. 3. Crowell NA, Burgess AW, editors. Understanding violence against women: panel on research on violence against women. 1996. National Research Council. National Academy Press, Washington, DC. http://books.nap.edu/openbook/0309054257/html/index.html. Accessed June 27, 2003. 4. Tjaden P, Thoennes N. Full report of the prevalence, incidence, and consequences of violence against women. 2002. National Institute of Justice and the Centers for Disease Control and Prevention, Washington DC. Nov 2000. Pub No. NCJ 183781. Also available online at: http://www.ncjrs.org/txtfiles1/nij/183781.txt. Accessed Oct 18, 2002. 5. Dienemann J, Boyle E, Baker D, et al. Intimate partner abuse among women diagnosed with depression. Issues Ment Health Nurs 2000; 21(5):499-513. 6. Campbell J, Jones AS, Dienemann J, et al. Intimate partner violence and physical health consequences. Arch Intern Med 2002; 162(10):1157-63. 7. Borowsky IW, Ireland M. Parental screening for intimate partner violence by pediatricians and family physicians. Pediatrics 2002; 110(3):509-16. 8. Elliott L, Nerney M, Jones T, et al. Barriers to screening for domestic violence. J Gen Intern Med 2002; 17(2):112-6. 9. Gielen AC, O'Campo PJ, Campbell JC, et al. Women's opinions about domestic violence screening and mandatory reporting. Am J Prev Med 2000 Nov; 19(4):279-85. *10. Sugg NK, Thompson RS, Thompson DC, et al. Domestic violence and primary care. Attitudes, practices, and beliefs. Arch Fam Med 1999; 8(4):301-6. *11. Thompson RS, Rivara FP, Thompson DC, et al. Identification and management of domestic violence: a randomized trial. Am J Prev Med 2000; 19(4):253-63. *12. Thompson RS, Meyer BA, Smith-DiJulio K, et al. A training program to improve domestic violence identification and management in primary care: preliminary results. Violence Vict 1998; 13(4):395-410. *13. Dienemann J, Campbell J, Landenburger K, et al. The domestic violence survivor assessment: a tool for counseling women in intimate partner violence relationships. Patient Educ Couns 2002 Mar; 46(3):221-8. *14. Dienemann J, Campbell J, Wiederhorn N, et al. A critical pathway for intimate partner violence across the continuum of care. J Obstet Gynecol Neonatal Nurs 2003; 32(5):594-603. *15. Agency for Healthcare Research and Quality. Evaluating Domestic Violence Programs. AHRQ Web site: http://www.ahrq.gov/research/domesticviol/. Accessed Oct 16, 2002. *16. Silverman J, University of North Carolina at Chapel Hill. E-mail correspondence to Barbara Kass-Bartelmes, Agency for Healthcare Research and Quality. July 9, 2003. 17. Whitehorn C, Stubbings J, Donnelly H. Domestic violence: a health emergency? 2003. Northern Ireland. *18. Coben JH. Measuring the quality of hospital-based domestic violence programs. Acad Emerg Med 2002; 9(11):1176-83. Return to Contents AHRQ Publication No. 04-0055 Current as of June 2004

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Genes mimic Facebook workings Genes interfere with each other in the same manner that the social network Facebook suggests friends, according to research published in the online version of Nature Methods. The study was funded in part by the CANCERPATHWAYS ('Developmental molecular pathways in Drosophila as a model for human cancer') project, which is backed with EUR 3 million under the Health Theme of the EU's Seventh Framework Programme (FP7). CANCERPATHWAYS brings together experts from Germany, Spain, Hungary, Austria and the UK. Scientists at the European Molecular Biology Laboratory (EMBL) and the German Cancer Research Centre (DKFZ) in Heidelberg in Germany have developed a method to uncover the combined effects of genes. The method should help scientists understand how different genes can amplify, cancel out or mask the effects of each other. If two people have many friends in common on Facebook, the odds are that those two people know each other — even if they themselves are not Facebook friends, commented lead scientists Wolfgang Huber from EMBL and Michael Boutros from DKFZ. Likewise, they said that genes that have similar genetic interaction profiles are likely to influence each other’s effects. According to Dr Huber and Professor using their new method, scientists can now suggest such ‘friends’, namely genes that are likely to affect the same cellular processes. In the long run, this could help predict patient outcomes and adapt treatments for diseases such as cancer, according to the research team. To understand the connections between genetic make—up and traits like disease susceptibility, scientists have frequently consulted genome—wide association studies, in which they compare genetic variants of people with a particular disease to those of healthy people. Such studies have linked many genes to diseases, but these links were often weak and not clear—cut, possibly because individual genes often do not act alone, said the research team. The effects of a particular gene can depend on what other genes a person carries, and the new method developed by Dr Huber and Professor Boutros at DKFZ enables scientists to uncover and measure those combined effects. As the scientists wrote in their paper in Nature Methods, ‘the analysis of synthetic genetic interaction networks can reveal how biological systems achieve a high level of complexity with a limited repertoire of components. Studies in yeast and bacteria have taken advantage of collections of deletion strains to construct matrices of quantitative interaction profiles and infer gene function. Yet comparable approaches in higher organisms have been difficult to implement in a robust manner’. In this new study, the scientists took a set of genes that are important for cell signalling and, using a technique called RNA interference (RNAi), silenced those genes two at a time, and compared the effect to what happens when only one or the other member of each pair is silenced. In so doing, they were able to identify a new component in a cell—signalling process known as the Ras pathway, which is involved in cellular proliferation, and is known to go awry in tumour cells. ‘Here we assessed the combined phenotypes of all pair¬wise RNAi treatments through eight independent measurements, including all possible combinations of two RNAi reagents for both target genes,’ they explained in their paper. ‘Different mathematical definitions have been pro¬posed for genetic interactions. We applied the most commonly used approach, deviation from multiplicativity.’ The researchers said that this approach ‘allowed us to identify sparse networks of interacting genes substantially enriched in known interaction pairs, indicating that the model is appropriate to infer biologically meaningful interactions from the observed phenotypic features’. They concluded that ‘the robust experimental design and stringent statistical analysis provides a framework for studies in other model system, including human cells’.

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Vietnam Era Twin (VET) Registry To conduct a baseline survey on cardiovascular, respiratory, and other major systemic disease and risk factors in members of the Vietnam Era Twin Registry. |Study Start Date:||April 1989| |Estimated Study Completion Date:||March 1991| The Vietnam Veteran Twin Registry, maintained by the NAS-NRC, was created with funding from the Veterans Administration. Department of Defense records were searched for subjects born between 1939-1957 and having the same last name and date of birth. Follow-up of induction records determined if the subjects were twins. The registry supplemented the older World War II Veterans Twin Registry supported by the National Heart, Lung, and Blood Institute. The new registry provided an opportunity to create a resource with Black and Hispanic twins as well as whites. The new registry also included data on greater educational, socioeconomic, and lifestyle diversity than was available in the World War II Veterans Twin Registry. During the first year a mailed questionnaire was designed which provided baseline data on family history, body size, morbidity, psychosocial characteristics, smoking, alcohol consumption, diet, physical activity, and drug use. The baseline data were used for analysis of cardiovascular, pulmonary, and blood diseases, and for follow-up. From the original survey, the Veterans Administration provided magnetic tape data on zygosity, smoking, alcohol consumption, heart, lung, and blood diseases, discharge rank, education, occupation, and family income. The questionnaire was completed by almost 8,900 individuals including over 3,000 twin pairs. No Contacts or Locations Provided

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|Classification and external resources| Helminthiasis // (alternatively spelled helminthosis; plural helminthiases) is any macroparasitic disease of humans and animals in which a part of the body is infected with parasitic worms known as helminths. These parasites are broadly classified into tapeworms, flukes, and roundworms. They often live in the gastrointestinal tract of their hosts, but may also burrow into other organs, where they induce physiological damage. They remain the major cause of wildlife diseases, economic crises in the livestock industry, and human socio-economic problems in developing countries. Major helminthiases are among the neglected tropical diseases targeted under the joint action of the world's leading pharmaceutical companies and non-governmental organizations through an ambitious project called London Declaration on Neglected Tropical Diseases which was launched on 30 January 2012. It aims to control or eradicate the diseases by 2020, by ensuring necessary supply of drugs and other intervention, and promoting sanitation and health education. - 1 Epidemiology - 2 Diseases - 3 Mode of infection - 4 Pathogenesis and symptoms - 5 Diagnosis - 6 Prevention and chemotherapy - 7 See also - 8 References - 9 External links The most serious helminth infections are prevalent in poor tropical and subtropical areas, where helminthiases are classified as neglected tropical diseases. They remain the most common parasitic infection of human in developing countries. Ascaris lumbricoides, Trichuris trichiura, Necator americanus, Ancylostoma duodenale, schistosomes, and filarial worms collectively infect more than a billion people, rivalling HIV/AIDS and malaria. Schistosomiasis alone is the second most prevalent parasitic disease of all times in humans, next only to malaria. According to current estimate, over a billion people in Subsaharan Africa, Asia, and the Americas are infected at any moment with at least one helminth species; most of them leading to severe morbidity, accompanied by persistent poverty, decreased productivity, and poor socioeconomic development. Helminthiasis can have immunomodulatory effects on the host, with implications for any coinfecting pathogens. In fact, in endemic areas, malaria, HIV, and tuberculosis are established to be exacerbated by helminthiases. In many cases, they can induce hypersensitivity leading to an acute allergy reaction called anaphylaxis. Roundworm infection (nematodiasis) - Ancylostomiasis (Ancylostoma duodenale infection) - Ascariasis (Ascaris infection) - Filariasis (Wuchereria bancrofti, Brugia malayi infection) - Onchocerciasis (Onchocerca volvulus infection) - Soil-transmitted helminthiasis (infection of Ascaris lumbricoides, Trichuris trichiura, Necator americanus, Ancylostoma duodenale) - Trichuriasis (whipworm infection) - Trichostrongyliasis (Trichostrongylus spp. infection) Tapeworm infection (cestodiasis) - Echinococcosis (Echinococcus infection) - Hymenolepiasis (Hymenolepis infection) - Taeniasis/cysticercosis (Taenia infection) Trematode infection (trematodiasis) - Amphistomiasis (amphistomes infection) - Clonorchiasis (Clonorchis sinensis infection) - Fascioliasis (Fasciola infection) - Fasciolopsiasis (Fasciolopsis buski infection) - Opisthorchiasis (Opisthorchis infection) - Schistosomiasis/bilharziasis (blood fluke infection) - Moniliformis infection Mode of infection Helminths are transmitted to the final host in several ways. The most common infection is through ingestion of contaminated vegetables, drinking water and raw or undercooked meat. The infective form can be eggs (for most nematodes] or the immature larvae. Many species of helminths require invertebrate vectors, such as insects and snails, for effective transmission, hence, for their complete life cycle. Some larvae of trematodes (specifically the cercaria of schistosomes) can directly penetrate the skin when an individual is in direct contact with an infested water body. Pathogenesis and symptoms The most obvious pathogenic effects are direct damages on tissues resulting from the blockage of internal organs or from the immense pressure exerted by the growing parasites. As the most common target organs of infections are those of alimentary tract and sometimes circulatory system, effects of infection are predominantly found in those organs and associated tissues. General symptoms are stomachache, fever, vomiting, diarrhoea, loss of appetite, haemorrhage, fatigue, and listlessness. In human population, under chronic infections, such as those in schistosomiasis, extreme morbidity is the common symptom. A severe case of taeniasis can occur when the brain is infected by accidental ingestion of cysts, a clinical condition called neurocysticercosis, which is the leading cause of acquired epilepsy. Indirect effects also associate with the disease. As pathogens, helminths induce immune reactions. Immune-mediated inflammatory changes occur in the skin, lung, liver, intestine, CNS, and eyes as they invade these tissues. Systemic changes such as eosinophilia, edema, and joint pain reflect local allergic responses to parasites. One of the major drawbacks in the control of helminthiases is the technical limitations of currently available diagnostic methods. Lack of standard clinical tests is encouraging widespread infestation and poses a hindrance to health managements. For basic diagnosis, specific helminths can be generally identified from the faeces, and their eggs microscopically examined and enumerated using the fecal egg count method. This is generally useful for most species as each has unique features, especially in veterinary investigations. However, there are certain limitations such as the inability to identify mixed infections, and on clinical practice, the technique is highly inaccurate and unreliable, such as those for schistosomes and soil-transmitted helmiths. Although the application of modern biotechnological tools to improve diagnostics for helminth infection has considerably advanced, the genuine uptake has not been practised. A range of diagnostic tools currently available is: 1) parasitological tests, where the parasite microscopically identified; 2) serological assays, where parasite-specific antibodies are detected in serum samples; 3) antigen tests, where a parasite biomarker is detected; 4) molecular diagnosis, where the parasite nucleic acid is detected; and 5) other specific tools for detection in the intermediate hosts. However, there are certain limitations such as the inability to identify mixed infections, and on clinical practice, the technique is highly inaccurate and unreliable, such as those for schistosomes and soil-transmitted helminths. Prevention and chemotherapy A large variety of chemotherapeutic drugs have been developed and commercialised. Yet all major helminthiases are classified under neglected diseases, with infestations rampant as ever. Large scale prevention and treatment remain a global crisis due to constraints on the application of these otherwise effective drugs; one of which is drug resistance and the other is poverty, which facilitates progression of the parasite population. Of the most commercially available drugs, broad-spectrum benzimidazoles (such as albendazole and mebendazole) are recommended for treatment of intestinal roundworm and tapeworm infections; while macrocyclic lactones (such as ivermectin) are effective against adult and migrating larval stages of nematode; and praziquantel is the drug of choice for schistosomiasis, taeniasis, and most types of food-borne trematodiases. In endemic regions, mass treatment is practiced, particularly among school-age children, who are the high-risk group. - London Declaration (30 January 2012). "London Declaration on Neglected Tropical Diseases". Retrieved 2013-03-26. - Lustigman S, Prichard RK, Gazzinelli A, Grant WN, Boatin BA, McCarthy JS, Basáñez MG (2012). "A research agenda for helminth diseases of humans: the problem of helminthiases". PLoS Negl Trop Dis 6 (4): e1582. doi:10.1371/journal.pntd.0001582. PMC 3335854. PMID 22545164. - Crompton DWT, Savioli L (2007). Handbook of Helminthiasis for Public Health. CRC Press, Boca Raton, Florida, US. pp. 1–362. ISBN 9781420004946. - WHO (2013). Schistosomiasis: progress report 2001 - 2011, strategic plan 2012 - 2020. WHO Press, World Health Organization, Geneva, Switzerland. pp. 1–270. ISBN 9789241503174. - WHO (2012). "Research priorities for helminth infections". World Health Organization Technical Report Series 972 (972): 1–174. PMID 23420950. - van Riet E, Hartgers FC, Yazdanbakhsh M (2007). "Chronic helminth infections induce immunomodulation: consequences and mechanisms". Immunobiology 212 (6): 475–9. doi:10.1016/j.imbio.2007.03.009. PMID 17544832. - Mkhize-Kwitshana ZL, Mabaso MH (2012). "Status of medical parasitology in South Africa: new challenges and missed opportunities". Trends in Parasitology 28 (6): 217–219. doi:10.1016/j.pt.2012.03.005. PMID 22525798. - Minciullo PL, Cascio A, David A, Pernice LM, Calapai G, Gangemi S (2012). "Anaphylaxis caused by helminths: review of the literature". Eur Rev Med Pharmacol Sci 16 (11): 1513–1518. PMID 23111963. - Baron S (1996). "87 (Helminths: Pathogenesis and Defenses by Wakelin D". Medical Microbiology (4 ed.). Galveston (TX): The University of Texas Medical Branch at Galveston. ISBN 0963117211. PMID 21413312. - Del Brutto OH (2012). "Neurocysticercosis: a review". The ScientificWorldJournal 2012: 159821. doi:10.1100/2012/159821. PMC 3261519. PMID 22312322. - Krauth SJ, Coulibaly JT, Knopp S, Traoré M, N'Goran EK, Utzinger J (2012). "An in-depth analysis of a piece of shit: distribution of Schistosoma mansoni and hookworm eggs in human stool". PLoS Negl Trop Dis 6 (12): e1969. doi:10.1371/journal.pntd.0001969. PMC 3527364. PMID 23285307. - Hunt PW, Lello J (2012). "How to make DNA count: DNA-based diagnostic tools in veterinary parasitology". Veterinary Parasitology 186 (1-2): 101–108. doi:10.1016/j.vetpar.2011.11.055. PMID 22169224. - Humphries D, Nguyen S, Boakye D, Wilson M, Cappello M (2012). "The promise and pitfalls of mass drug administration to control intestinal helminth infections". Curr Opin Infect Dis 25 (5): 584–589. doi:10.1097/QCO.0b013e328357e4cf. PMID 22903231. - WHO (2006). Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs in control interventions: a manual for health professionals and programme managers. WHO Press, World Health Organization, Geneva, Switzerland. pp. 1–61. ISBN 9241547103. - Prichard RK, Basáñez MG, Boatin BA, McCarthy JS, García HH, Yang GJ, Sripa B, Lustigman S (2012). "A research agenda for helminth diseases of humans: intervention for control and elimination". PLoS Negl Trop Dis 6 (4): e1549. doi:10.1371/journal.pntd.0001549. PMC 3335868. PMID 22545163. - Information at WHO - London Declaration Uniting to Combat NTDs - WHO Western Pacific Region - Information at Right Diagnosis - USAID's Neglected Tropical Diseases Program - Deworm the World - Global Network Neglected Tropical Diseases - Travel health information - Health Society of South Africa

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|TEM micrograph of poliovirus virions. Scale bar, 50 nm. |Group:||Group IV ((+)ssRNA)| Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is about 30 nanometres in diameter with icosahedral symmetry. Because of its short genome and its simple composition—only RNA and a non-enveloped icosahedral protein coat that encapsulates it—poliovirus is widely regarded as the simplest significant virus. Poliovirus was first isolated in 1909 by Karl Landsteiner and Erwin Popper. In 1981, the poliovirus genome was published by two different teams of researchers: by Vincent Racaniello and David Baltimore at MIT and by Naomi Kitamura and Eckard Wimmer at Stony Brook University. Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of RNA viruses. Poliovirus infects human cells by binding to an immunoglobulin-like receptor, CD155, (also known as the poliovirus receptor (PVR)) on the cell surface. Interaction of poliovirus and CD155 facilitates an irreversible conformational change of the viral particle necessary for viral entry. The precise mechanism poliovirus uses to enter the host cell has not been firmly established. Attached to the host cell membrane, entry of the viral nucleic acid was thought to occur one of two ways: via the formation of a pore in the plasma membrane through which the RNA is then “injected” into the host cell cytoplasm, or that the virus is taken up by receptor-mediated endocytosis. Recent experimental evidence supports the latter hypothesis and suggests that poliovirus binds to CD155 and is taken up via endocytosis. Immediately after internalization of the particle, the viral RNA is released. Poliovirus is a positive stranded RNA virus. Thus the genome enclosed within the viral particle can be used as messenger RNA and immediately translated by the host cell. On entry the virus hijacks the cell's translation machinery, causing inhibition of cellular protein synthesis in favor of virus–specific protein production. Unlike the host cell's mRNAs the 5' end of poliovirus RNA is extremely long—over 700 nucleotides—and highly structured. This region of the viral genome is called internal ribosome entry site (IRES) and it directs translation of the viral RNA. Genetic mutations in this region prevent viral protein production. - 3Dpol, an RNA dependent RNA polymerase whose function is to copy and multiply the viral RNA genome. - 2Apro and 3Cpro/3CDpro, proteases which cleave the viral polypeptide. - VPg (3B), a small protein that binds viral RNA and is necessary for synthesis of viral positive and negative strand RNA. - 2BC, 2B, 2C, 3AB, 3A, 3B proteins which comprise the protein complex needed for virus replication. - VP0, which is further cleaved into VP2 and VP4, VP1 and VP3 proteins of the viral capsid. The assembly of new virus particles, (i.e. the packaging of progeny genome into a capsid which can survive outside the host cell) is not fully understood. Fully assembled poliovirus leaves the confines of its host cell 4 to 6 hours following initiation of infection in cultured mammalian cells. The mechanism of viral release from the cell is unclear, but each dying cell can release up to 10,000 polio virions. Drake demonstrated that poliovirus is able to undergo multiplicity reactivation. That is, when polioviruses were irradiated with UV light and allowed to undergo multiple infections of host cells, viable progeny could be formed even at UV doses that inactivated the virus in single infections. Origin and serotypes Poliovirus is structurally similar to other human enteroviruses (coxsackieviruses, echoviruses, and rhinoviruses), which also use immunoglobulin-like molecules to recognize and enter host cells. Phylogenetic analysis of the RNA and protein sequences of poliovirus (PV) suggests that PV may have evolved from a C-cluster Coxsackie A virus ancestor, that arose through a mutation within the capsid. The distinct speciation of poliovirus probably occurred as a result of change in cellular receptor specificity from intercellular adhesion molecule-1 (ICAM-1), used by C-cluster Coxsackie A viruses, to CD155; leading to a change in pathogenicity, and allowing the virus to infect nervous tissue. The mutation rate in the virus is relatively high even for an RNA virus with a synonymous substitution rate of 1.0 x 10−2 substitutions/site/year and non synonymous substitution rate of 3.0 x 10−4 substitutions/site/year. Base distribution within the genome is non random with adenosine being less common than expected at the 5' end and higher at the 3' end. Codon use is non random with codons ending in adenosine being favoured and those ending in cytosine or guanine being avoided. Codon use differs between the three genotypes and appears to be driven by mutation rather than selection. There are three serotypes of poliovirus, PV1, PV2, and PV3; each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV1 is the most common form encountered in nature, however all three forms are extremely infectious. Wild polioviruses can be found in two continents. As of 2012, PV1 is highly localized to regions in Pakistan and Afghanistan in Asia, and Nigeria, Niger and Chad in Africa. Wild poliovirus type 2 has probably been eradicated; it was last detected in October 1999 in Uttar Pradesh, India. As of November 2014, wild PV3 has not been seen since its 2012 detection in parts of Nigeria and Pakistan. Specific strains of each serotype are used to prepare vaccines against polio. Inactive polio vaccine (IPV) is prepared by formalin inactivation of three wild, virulent reference strains, Mahoney or Brunenders (PV1), MEF-1/Lansing (PV2), and Saukett/Leon (PV3). Oral polio vaccine (OPV) contains live attenuated (weakened) strains of the three serotypes of poliovirus. Passaging the virus strains in monkey kidney epithelial cells introduces mutations in the viral IRES, and hinders (or attenuates) the ability of the virus to infect nervous tissue. Polioviruses were formerly classified as a distinct species belonging to the genus Enterovirus in the family Picornaviridae. In 2008 the Poliovirus species was eliminated from the genus Enterovirus and the three serotypes were assigned to the species Human enterovirus C (later renamed to Enterovirus C), in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to (Human) Enterovirus C. The primary determinant of infection for any virus is its ability to enter a cell and produce additional infectious particles. The presence of CD155 is thought to define the animals and tissues that can be infected by poliovirus. CD155 is found (outside of laboratories) only on the cells of humans, higher primates, and Old World monkeys. Poliovirus is however strictly a human pathogen, and does not naturally infect any other species (although chimpanzees and Old World monkeys can be experimentally infected). The CD155 gene appears to have been subject to positive selection. The protein has several domains of which domain D1 contains the polio virus binding site. Within this domain 37 amino acids are responsible for binding the virus. Poliovirus is an enterovirus. Infection occurs via the fecal–oral route, meaning that one ingests the virus and viral replication occurs in the alimentary tract. Virus is shed in the feces of infected individuals. In 95% of cases only a primary, transient presence of viremia (virus in the bloodstream) occurs, and the poliovirus infection is asymptomatic. In about 5% of cases, the virus spreads and replicates in other sites such as brown fat, reticuloendothelial tissue, and muscle. The sustained viral replication causes secondary viremia and leads to the development of minor symptoms such as fever, headache and sore throat. Paralytic poliomyelitis occurs in less than 1% of poliovirus infections. Paralytic disease occurs when the virus enters the central nervous system (CNS) and replicates in motor neurons within the spinal cord, brain stem, or motor cortex, resulting in the selective destruction of motor neurons leading to temporary or permanent paralysis. In rare cases, paralytic poliomyelitis leads to respiratory arrest and death. In cases of paralytic disease, muscle pain and spasms are frequently observed prior to onset of weakness and paralysis. Paralysis typically persists anywhere from days to weeks prior to recovery. In many respects the neurological phase of infection is thought to be an accidental diversion of the normal gastrointestinal infection. The mechanisms by which poliovirus enters the CNS are poorly understood. Three non-mutually exclusive hypotheses have been suggested to explain its entry. All theories require primary viremia. The first hypothesis predicts that virions pass directly from the blood into the central nervous system by crossing the blood–brain barrier independent of CD155. A second hypothesis suggests that the virions are transported from peripheral tissues that have been bathed in the viremic blood, for example muscle tissue, to the spinal cord through nerve pathways via retrograde axonal transport. A third hypothesis is that the virus is imported into the CNS via infected monocytes or macrophages. Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on the surface of most or all human cells. Therefore receptor expression does not explain why poliovirus preferentially infects certain tissues. This suggests that tissue tropism is determined after cellular infection. Recent work has suggested that the type I interferon response (specifically that of interferon alpha and beta) is an important factor that defines which types of cells support poliovirus replication. In mice expressing CD155 (through genetic engineering) but lacking the type I interferon receptor, poliovirus not only replicates in an expanded repertoire of tissue types, but these mice are also able to be infected orally with the virus. Immune system avoidance Poliovirus uses two key mechanisms to evade the immune system. First, it is capable of surviving the highly acidic conditions of the gastrointestinal tract, allowing the virus to infect the host and spread throughout the body via the lymphatic system. Second, because it can replicate very quickly, the virus overwhelms the host organs before an immune response can be mounted. Individuals who are exposed to poliovirus, either through infection or by immunization with polio vaccine, develop immunity. In immune individuals, antibodies against poliovirus are present in the tonsils and gastrointestinal tract (specifically IgA antibodies) and are able to block poliovirus replication; IgG and IgM antibodies against poliovirus can prevent the spread of the virus to motor neurons of the central nervous system. Infection with one serotype of poliovirus does not provide immunity against the other serotypes, however second attacks within the same individual are extremely rare. PVR transgenic mouse Although humans are the only known natural hosts of poliovirus, monkeys can be experimentally infected and they have long been used to study poliovirus. In 1990–91, a small animal model of poliomyelitis was developed by two laboratories. Mice were engineered to express a human receptor to poliovirus (hPVR). Unlike normal mice, transgenic poliovirus receptor (TgPVR) mice are susceptible to poliovirus injected intravenously or intramuscularly, and when injected directly into the spinal cord or the brain. Upon infection, TgPVR mice show signs of paralysis that resemble those of poliomyelitis in humans and monkeys, and the central nervous systems of paralyzed mice are histocytochemically similar to those of humans and monkeys. This mouse model of human poliovirus infection has proven to be an invaluable tool in understanding poliovirus biology and pathogenicity. Three distinct types of TgPVR mice have been well studied: - In TgPVR1 mice the transgene encoding the human PVR was incorporated into mouse chromosome 4. These mice express the highest levels of the transgene and the highest sensitivity to poliovirus. TgPVR1 mice are susceptible to poliovirus through the intraspinal, intracerebral, intramuscular, and intravenous pathways, but not through the oral route. - TgPVR21 mice have incorporated the human PVR at chromosome 13. These mice are less susceptible to poliovirus infection through the intracerebral route, possibly because they express decreased levels of hPVR. TgPVR21 mice have been shown to be susceptible to poliovirus infection through intranasal inoculation, and may be useful as a mucosal infection model. - In TgPVR5 mice the human transgene is located on chromosome 12. These mice exhibit the lowest levels of hPVR expression and are the least susceptible to poliovirus infection. Recently a fourth TgPVR mouse model was developed. These "cPVR" mice carry hPVR cDNA, driven by a β-actin promoter, and have proven susceptible to poliovirus through intracerebral, intramuscular, and intranasal routes. In addition, these mice are capable of developing the bulbar form of polio after intranasal inoculation. The development of the TgPVR mouse has had a profound effect on oral poliovirus vaccine (OPV) production. Previously, monitoring the safety of OPV had to be performed using monkeys, because only primates are susceptible to the virus. In 1999 the World Health Organization approved the use of the TgPVR mouse as an alternative method of assessing the effectiveness of the vaccine against poliovirus type-3. In 2000 the mouse model was approved for tests of vaccines against type-1 and type-2 poliovirus. Cloning and synthesis In 1981 Racaniello and Baltimore used recombinant DNA technology to generate the first infectious clone of an animal RNA virus, poliovirus. DNA encoding the RNA genome of poliovirus was introduced into cultured mammalian cells and infectious poliovirus was produced. Creation of the infectious clone propelled understanding of poliovirus biology, and has become a standard technology used to study many other viruses. In 2002 Eckard Wimmer's group at SUNY Stony Brook succeeded in synthesizing poliovirus from its chemical code, producing the world's first synthetic virus. Scientists first converted poliovirus's published RNA sequence, 7741 bases long, into a DNA sequence, as DNA was easier to synthesize. Short fragments of this DNA sequence were obtained by mail-order, and assembled. The complete viral genome was then assembled by a gene synthesis company. This whole painstaking process took two years. Nineteen markers were incorporated into the synthesized DNA, so that it could be distinguished from natural poliovirus. Enzymes were used to convert the DNA back into RNA, its natural state. Other enzymes were then used to translate the RNA into a polypeptide, producing functional viral particle. The newly minted synthetic virus was injected into PVR transgenic mice, to determine if the synthetic version was able to cause disease. The synthetic virus was able to replicate, infect, and cause paralysis or death in mice. However, the synthetic version was between 1,000 and 10,000 times less lethal than the original virus. - "ICTV 2009 Master Species List Version 10". International Committee on Taxonomy of Viruses. August 2011. - Ryan KJ, Ray CG, ed. (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9. - Hogle J (2002). "Poliovirus cell entry: common structural themes in viral cell entry pathways". Annu Rev Microbiol 56: 677–702. doi:10.1146/annurev.micro.56.012302.160757. PMC 1500891. PMID 12142481. - Goodsell DS (1998). The machinery of life. New York: Copernicus. ISBN 0-387-98273-6. - Paul JR (1971). A History of Poliomyelitis. (Yale studies in the history of science and medicine). New Haven, Conn: Yale University Press. ISBN 0-300-01324-8. - Racaniello and Baltimore; Baltimore, D (1981). "Molecular cloning of poliovirus cDNA and determination of the complete nucleotide sequence of the viral genome". Proc. Natl. Acad. Sci. U.S.A. 78 (8): 4887–91. doi:10.1073/pnas.78.8.4887. PMC 320284. PMID 6272282. - Kitamura N, Semler B, Rothberg P, et al. (1981). "Primary structure, gene organization and polypeptide expression of poliovirus RNA". Nature 291 (5816): 547–53. doi:10.1038/291547a0. PMID 6264310. - De Jesus NH (2007). "Epidemics to eradication: the modern history of poliomyelitis". Virol. J. 4 (1): 70. doi:10.1186/1743-422X-4-70. PMC 1947962. PMID 17623069. - Mendelsohn Cl, Wimmer E, Racaniello VR (1989). "Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobin superfamily". Cell 56 (5): 855–865. doi:10.1016/0092-8674(89)90690-9. PMID 2538245. - He Y, Mueller S, Chipman P, et al. (2003). "Complexes of poliovirus serotypes with their common cellular receptor, CD155". J Virol 77 (8): 4827–35. doi:10.1128/JVI.77.8.4827-4835.2003. PMC 152153. PMID 12663789. - Dunnebacke TH, Levinthal JD, Williams RC (1 October 1969). "Entry and release of poliovirus as observed by electron microscopy of cultured cells". J. Virol. 4 (4): 505–13. PMC 375900. PMID 4309884. - Kaplan G, Freistadt MS, Racaniello VR (1 October 1990). "Neutralization of poliovirus by cell receptors expressed in insect cells". J. Virol. 64 (10): 4697–702. PMC 247955. PMID 2168959. - Gomez Yafal A, Kaplan G, Racaniello VR, Hogle, JM (1993). "Characterization of poliovirus conformational alteration mediated by soluble cell receptors". Virology 197 (1): 501–5. doi:10.1006/viro.1993.1621. PMID 8212594. - Yin-Murphy, M.; Almond, J.W. (1996). "Ch. 53: Picornaviruses: The Enteroviruses: Polioviruses". In Samuel Baron. Baron's Medical Microbiology (4th ed.). University of Texas Medical Branch. ISBN 0-9631172-1-1. NBK7687. - Mueller S, Wimmer E, Cello J (2005). "Poliovirus and poliomyelitis: a tale of guts, brains, and an accidental event". Virus Res 111 (2): 175–93. doi:10.1016/j.virusres.2005.04.008. PMID 15885840. - Brandenburg B, Lee LY, Lakadamyali M, Rust MJ, Zhuang X, Hogle JM, (2007). "Imaging poliovirus entry in live cells". PLOS Biology 5 (7): e183. doi:10.1371/journal.pbio.0050183. PMC 1914398. PMID 17622193. - Attardi, G. and Smith, J. Virus specific protein and a ribonucleic acid associated with ribosomes in poliovirus infected HeLa cells. Cold Spring Harbor Symp. Quant. Biol. 27: 271–292. 1962 - Chen CY, Sarnow P (1995). "Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs". Science 268 (5209): 415–7. doi:10.1126/science.7536344. PMID 7536344. - Pelletier J, Sonenberg N (1988). "Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA". Nature 334 (6180): 320–5. doi:10.1038/334320a0. PMID 2839775. - Jang SK, Kräusslich HG, Nicklin MJ, Duke GM, Palmenberg AC, Wimmer E (1 August 1988). "A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation". J. Virol. 62 (8): 2636–43. PMC 253694. PMID 2839690. - Charles Chan and Roberto Neisa. "Poliomyelitis". Brown University. - Kew O, Sutter R, de Gourville E, Dowdle W, Pallansch M (2005). "Vaccine-derived polioviruses and the endgame strategy for global polio eradication". Annu Rev Microbiol 59: 587–635. doi:10.1146/annurev.micro.58.030603.123625. PMID 16153180. - DRAKE JW (August 1958). "Interference and multiplicity reactivation in polioviruses". Virology 6 (1): 244–64. doi:10.1016/0042-6822(58)90073-4. PMID 13581529. - Jiang P, Faase JA, Toyoda H, et al. (2007). "Evidence for emergence of diverse polioviruses from C-cluster Coxsackie A viruses and implications for global poliovirus eradication". Proc. Natl. Acad. Sci. U.S.A. 104 (22): 9457–62. doi:10.1073/pnas.0700451104. PMC 1874223. PMID 17517601. - Jorba J, Campagnoli R, De L, Kew O. (2008). "Calibration of multiple poliovirus molecular clocks covering an extended evolutionary range". J Virol. 82 (9): 4429–40. doi:10.1128/JVI.02354-07. PMC 2293050. PMID 18287242. - Rothberg PG, Wimmer E (1981). "Mononucleotide and dinucleotide frequencies, and codon usage in poliovirion RNA". Nucleic Acids Res. 9 (23): 6221–9. doi:10.1093/nar/9.23.6221. PMC 327599. PMID 6275352. - Zhang J, Wang M, Liu WQ, et al. (2011). "Analysis of codon usage and nucleotide composition bias in polioviruses". Virol. J. 8: 146. doi:10.1186/1743-422X-8-146. PMC 3079669. PMID 21450075. - "Transmission of wild poliovirus type 2—apparent global interruption". Wkly. Epidemiol. Rec. 76 (13): 95–7. March 2001. PMID 11315462. - "Possible Eradication of Wild Poliovirus Type 3 — Worldwide, 2012". CDC. 2014-11-14. Retrieved 2014-11-14. - Carstens, E. B.; Ball, L. A. (July 2009). "Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2008)". Archives of Virology (Springer Wien) 154 (7): 1181–8. doi:10.1007/s00705-009-0400-2. ISSN 1432-8798. PMID 19495937. - Mueller S, Wimmer E (2003). "Recruitment of nectin-3 to cell-cell junctions through trans-heterophilic interaction with CD155, a vitronectin and poliovirus receptor that localizes to alpha(v)beta3 integrin-containing membrane microdomains". J Biol Chem 278 (33): 31251–60. doi:10.1074/jbc.M304166200. PMID 12759359. - Suzuki Y (2006). "Ancient positive selection on CD155 as a possible cause for susceptibility to poliovirus infection in simians". Gene 373: 16–22. doi:10.1016/j.gene.2005.12.016. PMID 16500041. - Bodian D and Horstmann DH (1969). Polioviruse. Philadelphia, Penn: Lippincott. pp. 430–73. - Sabin A (1956). "Pathogenesis of poliomyelitis; reappraisal in the light of new data". Science 123 (3209): 1151–7. doi:10.1126/science.123.3209.1151. PMID 13337331. - Acute Poliomyelitis at eMedicine Pediatric Poliomyelitis at eMedicine - Yang W, Terasaki T, Shiroki K, et al. (1997). "Efficient delivery of circulating poliovirus to the central nervous system independently of poliovirus receptor". Virology 229 (2): 421–8. doi:10.1006/viro.1997.8450. PMID 9126254. - Ohka S. Yang WX, Terada E, Iwasaki K, Nomot A (1998). "Retrograde transport of intact poliovirus through the axon via the first transport system". Virology 250 (1): 67–75. doi:10.1006/viro.1998.9360. PMID 9770421. - Ren R, Racaniello V (1992). "Poliovirus spreads from muscle to the central nervous system by neural pathways". J Infect Dis 166 (4): 747–52. doi:10.1093/infdis/166.4.747. PMID 1326581. - Lancaster KZ, Pfeiffer JK (2010). Gale, Michael, ed. "Limited trafficking of a neurotropic virus through inefficient retrograde axonal transport and the type I interferon response". PLoS Pathog 6 (3): e1000791. doi:10.1371/journal.ppat.1000791. PMC 2832671. PMID 20221252. - Ida-Hosonuma M, Iwasaki T, Yoshikawa T, et al. (April 2005). "The alpha/beta interferon response controls tissue tropism and pathogenicity of poliovirus". J. Virol. 79 (7): 4460–9. doi:10.1128/JVI.79.7.4460-4469.2005. PMC 1061561. PMID 15767446. - Ohka S, Igarashi H, Sakai M, Koike S, Nochi T, Kiyono A, Nomoto A (2007). "Establishment of a poliovirus oral infection system in human poliovirus receptor-expressing transgenic mice that are deficient in alpha/beta interferon receptor". J. Virol. 81 (15): 7902–12. doi:10.1128/JVI.02675-06. PMC 1951287. PMID 17507470. - Ren RB, Costantini F, Gorgacz EJ, Lee JJ, Racaniello VR (1990). "Transgenic mice expressing a human poliovirus receptor: a new model for poliomyelitis". Cell 63 (2): 353–62. doi:10.1016/0092-8674(90)90168-E. PMID 2170026. - Koike S, Taya C, Kurata T, et al. (1991). "Transgenic mice susceptible to poliovirus". Proc. Natl. Acad. Sci. U.S.A. 88 (3): 951–5. doi:10.1073/pnas.88.3.951. PMC 50932. PMID 1846972. - Horie H, Koike S, Kurata T, et al. (1 February 1994). "Transgenic mice carrying the human poliovirus receptor: new animal models for study of poliovirus neurovirulence". J. Virol. 68 (2): 681–8. PMC 236503. PMID 8289371. - Ohka S, Nomoto A (2001). "Recent insights into poliovirus pathogenesis". Trends Microbiol. 9 (10): 501–6. doi:10.1016/S0966-842X(01)02200-4. PMID 11597452. - Koike S, Taya C, Aoki J, et al. (1994). "Characterization of three different transgenic mouse lines that carry human poliovirus receptor gene—influence of the transgene expression on pathogenesis". Arch. Virol. 139 (3–4): 351–63. doi:10.1007/BF01310797. PMID 7832641. - Nagata N, Iwasaki T, Ami Y, et al. (2004). "A poliomyelitis model through mucosal infection in transgenic mice bearing human poliovirus receptor, TgPVR21". Virology 321 (1): 87–100. doi:10.1016/j.virol.2003.12.008. PMID 15033568. - Dragunsky E, Nomura T, Karpinski K, et al. (2003). "Transgenic mice as an alternative to monkeys for neurovirulence testing of live oral poliovirus vaccine: validation by a WHO collaborative study". Bull. World Health Organ. 81 (4): 251–60. doi:10.1590/S0042-96862003000400006. PMC 2572431. PMID 12764491. - Racaniello V, Baltimore D (1981). "Cloned poliovirus complemenatry DNA is infectious in mammalian cells". Science 214 (453): 916–9. doi:10.1126/science.6272391. PMID 6272391. - Cello J, Paul AV, Wimmer E (2002). "Chemical synthesis of poliovirus cDNA: generation of infectious virus in the absence of natural template". Science 297 (5583): 1016–8. doi:10.1126/science.1072266. PMID 12114528. - Couzin J (2002). "Virology. Active poliovirus baked from scratch". Science 297 (5579): 174–5. doi:10.1126/science.297.5579.174b. PMID 12114601. - ICTV Master Species List 2009 Version 4 - ICTVdb virus classification 2006 - Home of Picornaviruses (latest updates of species, serotypes, & proposed changes) - Goodsell, David. "Poliovirus and Rhinovirus". August 2001 Molecule of the Month. - 3D macromolecular structures of the Poliovirus archived in the EM Data Bank(EMDB) - "Human poliovirus 1". NCBI Taxonomy Browser. 12080. - "Human poliovirus 3". NCBI Taxonomy Browser. 12086.

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Hemorrhagic Gastroenteritis (HGE) in Dogs Hemorrhagic gastroenteritis is identified by blood in the vomit and/or stool, often due to a food borne illness. Because it is a serious disorder than can be potentially fatal, immediate veterinary care is required. - Weight loss - Fluid loss - Electrolyte imbalance - Hypovolemic shock Infectious gastroenteritis is caused by pathogens (infectious agents). Some of the pathogens most commonly associated with infectious gastroenteritis include: - Bacteria (e.g., Campylobacter, Salmonella, E. coli, Clostridia) - Virus (e.g., Parvovirus, Canine distemper) - Fungi (e.g., Aspergillus, Penicillium, Fusarium) - Parasites (e.g., Roundworms, Hookworms, Tapeworms, Whipworms, Coccidia) E. coli, Salmonella and Corynebacterium are the most significant intestinal pathogens because they can be passed from animal to human or vice versa. Salmonella infections are also important due to association with reproductive disorders. Sudden dietary changes and/or dietary toxins may cause irritation and/or affect the immune system. Eosinophilic gastroenteritis, a chronic form of the illness, has been associated with allergens in dog foods. Gastroenteritis may be also observed due to irritation caused by stress, toxins, physical obstruction, ulcers, and abdominal disorders. Gastroenteritis is not specific to any breed or gender, however, small breed dogs are more prone to infectious gastroenteritis. It may be difficult to identify the cause of gastroenteritis. Therefore, invasive diagnostic procedures may be required if routine diagnostic procedures are not successful. A brief outline of diagnostic procedures: - Physical obstruction, tumors, ulcers, intestinal blockage, etc. - Information about the severity, progression and magnitude of the vomiting and diarrhea - The vaccination record may help in ruling out a parvoviral infection - A skin test to determine the presence and extent of dehydration - An abdominal palpation to check abdominal pain and/or abdominal obstruction - An examination of mucus membranes to determine hemorrhagic losses - Cardiovascular function provides information on dehydration and/or blood loss - Visual observation of the vomit and/or stool to determine if there is blood present Routine blood/biochemical tests: - Packed cell volume (hematocrit) data to confirm hemorrhagic gastroenteritis - Biochemical tests (i.e., liver, kidney, blood protein, and blood sugar) - Cultural assays to identify any potential microbiological or parasitic organisms - To locate any potentinal physical obstruction, tumor, ulcer, intestinal blockage, etc. In most of the cases, dogs recover and respond very well. The course of treatment, however, is dependent on the underlying cause of the condition. A brief outline of treatment is given below: - Fluid and electrolyte therapies are important, especially in cases of hemorrhagic gastroenteritis. - Antibiotic therapy may be restricted to animals with systemic infections. - Corticosteroid therapy is useful in cases of shock. Usually hypovolemic shock develops due to dehydration. - Medications that soothe the intestine and bind noxious agents can also be used in supportive therapy. - Parasitic infections are treated with anthelmintics. - Physical obstruction, ulcers and tumors may need surgical treatment. Living and Management An improved diet may reduce intestinal infections and other gastrointestinal disorders. The main priority should be to provide healing time for the dog's inflamed intestinal area. Thus, food and water should not be given for at least a period of 24 hours to rest the intestine. Then, provide a bland diet for three to seven days, followed by a gradual return to the dog's normal diet. Often dietary irritants (especially protein) may lead to recurrence of the problem. In these cases, a special hypoallergenic medical diet may be required. Some veterinarians have recently emphasized the importance of restoring intestinal microflora through food additives (e.g., probiotics, prebiotics, and synbiotics) in order to prevent the infection from recurring. If dog owners are using homemade diets, the ideal micro- and macro-nutrient profile, along with optimum energy density, must be the focus of formulation. These diets provide highly digestible nutrients, less fats and restricted osmolarity. Consult your veterinarian for a proper, well-balanced diet for your dog.

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By Dr. Becker Today I’d like to discuss dilated cardiomyopathy in dogs. Dilated cardiomyopathy, also called DCM, describes a diseased heart muscle that doesn’t contract or pump efficiently. As the disease progresses, the heart chambers become enlarged, heart valves may leak, and congestive heart failure can develop. Cause of Dilated Cardiomyopathy Still a Mystery The cause of DCM is unknown. Unlike heart muscle dysfunction in humans, when it happens in dogs and cats, it’s very rarely the result of chronic coronary artery disease. Nutritional deficiencies of taurine or carnitine have been linked to DCM in certain breeds. Male dogs seem to develop the condition more often than female dogs. And certain breeds, primarily large breeds, are more prone to DCM, including the Doberman pinscher, Boxer, Scottish deerhound, Irish wolfhound, Great Dane, Saint Bernard, Afghan hound, and Cocker spaniel. Once in a while, DCM-like heart muscle deficiency develops secondary to an identifiable cause like exposure to a toxin or a heart infection. Symptoms of DCM Early in the disease process there may be no obvious symptoms. Some dogs may have a reduction in exercise tolerance. Sometimes a slight heart murmur or other abnormal heart sounds or rhythms can be detected by a veterinarian during a physical exam. As the heart disease progresses, the heart’s ability to pump declines, so blood pressure in the veins behind the heart can increase. Congestion of the lungs and fluid accumulation are common. Fluid can also build up in the abdomen and around the lungs, if the right side of the heart is also involved. Congestion and fluid buildup indicate heart failure. Dogs with DCM-induced heart failure often have left-sided congestive failure. Symptoms include decreased ability to exercise, tiring quickly, increased respiration, and excessive panting and coughing. There may be recurrences of sudden episodes of weakness or fainting. Some dogs with DCM have enlarged abdomens and heavy breathing due to fluid accumulation. Sudden death can also occur from heart rhythm disturbances, even though there aren’t obvious external signs of heart disease. Advance signs of heart failure include labored breathing, reluctance to lie down, and the inability to get comfortable. A worsening cough, reduced activity level, loss of appetite, as well as collapse, can all be symptoms. Often owners of dogs with DCM feel as though their pet developed heart failure very quickly. But the underlying disease and damage to the heart muscle has actually been going on for months or even years in most cases. In addition to a physical examination, your vet will need to run medical tests to confirm a diagnosis of DCM and determine the severity of the disease. Keep in mind your vet can’t, for example, know the size of your pet’s heart by listening with a stethoscope. Sometimes a heart can sound pretty normal on auscultation (which is what vets do when they listen with a stethoscope), but there can be really significant changes going on inside the heart that are undetectable without additional tests. The proBNP test is a simple blood test with a fast turnaround time that can detect a problem very early in the disease process by measuring the amount of peptide hormone in your pet’s blood. This hormone is only released when the heart is pushed beyond its capacity. If your vet doesn’t suggest a BNP blood test, I recommend you ask for it. X-rays may also show enlargement of the heart chambers, and can also indicate the presence of fluid in the lungs. An EKG can reveal atrial fibrillation and tachycardia, which means a rapid heart rate. A heart ultrasound called an echocardiogram is also necessary for a definitive diagnosis of this disease. This test looks at the size of the heart and its ability to contract. If DCM is present, the heart chambers are enlarged and there’s compromised contraction of the muscle. The echocardiogram can also be used to detect signs of early DCM in breeds that are at higher risk for the disease. Treatment of dilated cardiomyopathy focuses on improving heart function and treating symptoms of congestive heart failure. Conventional treatment involves the use of a variety of medications. ACE inhibitors are often prescribed to slow down the progressive changes to the heart that can lead to heart failure. As the disease progresses, different drugs can be used to help the heart contract. Drugs can be administered to slow down a rapid heart rate, to manage accumulation of fluid in the lungs, or to dilate blood vessels. There are actually some drugs that can help the heart beat and pump more efficiently as well. All of these drugs require careful monitoring for side effects. And unfortunately, side effects are rampant and can include electrolyte imbalances, reduced appetite, diarrhea and vomiting, depression, a drop in blood pressure, as well as kidney disease. Veterinary cardiologists often combine medications, which makes careful monitoring of the patient that much more important. Therapy for DCM is individualized for the patient’s specific symptoms. In recent years, a small number of dogs have had defibrillators surgically implanted to manage life-threatening arrhythmias. Unfortunately, because the disease is irreversible and heart failure is typically progressive, the drugs and dosages required to manage DCM usually increase over time. Alternative therapies that can support heart function include herbs such as Hawthorne berry and cayenne. Supplements can also be very beneficial, including acetyl L-carnitine, the amino acid taurine, arginine, D-ribose, omega-3 fatty acids, and ubiquinol. Of course, feeding a fresh food diet that is rich in naturally occurring amino acids will be the very best food therapy for a dog with DCM, and can also help nourish breeds predisposed to this medical problem.

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Reiki practitioners believe that therapeutic effects of this technique are obtained from a "universal life energy" that provides strength, harmony, and balance to the body and mind. Life energy is thought to be transferred to patients when practitioners place their hands on or directly above treatment areas. This life energy is thought to vitalize organs and cells and to release trapped negative energy. Practitioners do not view themselves as the sources of life energy. Reiki practitioners believe that human energy flows through meridians (or pathways) in the body that can be sensed by trained individuals. A disturbance in the flow of this energy may be caused by physical illnesses or negative emotions. Reiki practitioners aim to channel life energy to problem areas where the patient's energy flow is sensed as being disrupted. Practitioners believe that Reiki can treat symptoms and enable patients to feel enlightened with improved mental clarity, well-being, and spirituality. Reiki is sometimes administered to patients who are dying with the goal of instilling a sense of peace. It has been proposed that Reiki can lower heart rate and blood pressure, boost the immune system and endocrine (hormonal) systems, stimulate endorphins, or affect skin temperature and blood hemoglobin levels. However, these properties have not been well-studied or clearly demonstrated in scientific studies. Reiki has been used or suggested for the management of many conditions. However, Reiki is not well studied scientifically. There are several challenges to conducting high quality research on techniques such as Reiki: there are different styles of practice with variation from practitioner to practitioner; it is challenging to design studies with "placebo" Reiki; and there is no widespread agreement on how best to measure outcomes. Better research is needed before a recommendation can be made either for or against the effectiveness of Reiki for any specific condition. These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider. Autonomic nervous system disturbances: One randomized trial suggested that Reiki may have an effect on autonomic nervous system functions such as heart rate, blood pressure, or breathing activity. Large, well-designed studies are needed before conclusions can be drawn. Reiki may contribute to reduced perception of pain, improved quality of life, and reduced fatigue in cancer patients. More studies are needed. Cognitive disorders (mild cognitive impairment): Early research suggests that Reiki therapy may improve behavioral and memory problems in patients with mild cognitive impairment or mild Alzheimer's disease. However, additional studies are needed to confirm these findings. Depression and stress: There is evidence that Reiki can reduce symptoms of distress when compared to placebo. More information is needed before a conclusion can be drawn. Reiki instruction may help HIV/AIDS patients reduce pain or anxiety, but results are unclear. Patients in a preliminary ("phase II") trial of Reiki in combination with standard pain medications (with opioids) were reported to experience improved pain control. Further research is needed to confirm these findings. In a randomized controlled trial, Reiki did not have any clinically useful effect on stroke recovery in patients receiving appropriate rehabilitation therapy. Selective positive effects on mood and energy were noted.

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Practice Guidelines: Uterine Corpus—Sarcomas Practice Guidelines: Uterine Corpus—Sarcomas Uterine sarcomas arise from the uterine muscle (leiomyosarcoma) or endometrial glands and stroma (endometrial stromal sarcoma and carcinosarcoma). They account for about 3% of all uterine malignancies and less than 1% of all gynecologic malignancies. Uterine sarcomas have differing etiologies, clinical courses, and pathologic features, which give rise to variable treatment regimens and clinical outcomes. The leiomyosarcomas and (malignant) mixed mullerian tumors (M/MMT or carcinosarcomas) have a higher rate of occurrence in black than in white females. Carcinosarcomas are unusual before the age of 40 and have rising incidence with advancing age, while leiomyosarcomas have peak incidence between ages 35 and 55 for blacks and ages 40 and 50 for whites. The development of sarcomas also appears to be increased by previous pelvic radiation, especially the carcinosarcomas and adenosarcomas. MMTs, leiomyosarcomas, and high-grade endometrial stromal sarcomas are clinically aggressive tumors. Metastases can occur by means of local extension or by lymphatic or hematogenous pathways. When spread has occurred, the survival rates are very low. Low-grade tumors of all histologic types have a better survival rate. Classification of uterine sarcomas can be simplified as follows (with % of all uterine sarcomas): - (Malignant) mixed mullerian tumor, (M)MMT, also known as carcinosarcomas (30%) - Homologous type - Heterologous type - Leiomyosarcoma (27%) - Endometrial stromal sarcoma (ESS) (26%) - Other (17%) A more detailed classification has been adopted by the International Society of Gynecologic Pathologists (Table 1). The uterine sarcomas do not lend themselves to any specific screening technique, but at times a Pap smear will be abnormal in the face of a glandular lesion. A routine pelvic examination may reveal an enlarged uterus, but due to the rarity of these lesions, no screening interventions are indicated. Abnormal bleeding with a foul discharge and/or pelvic pain from uterine distention are the most frequent symptoms. A polypoid mass or enlarged uterus is present in about 50% of patients. If there is bleeding or a foul prolapsing mass at the cervical os in a postmenopausal patient, the most likely diagnosis is an MMT. Biopsy is required to confirm the diagnosis but may be performed at the time of surgery in some instances if bleeding and symptoms dictate immediate intervention. Due to the rarity of these lesions and the lack of a landmark for depth of invasion, no International Federation of Gynecology and Obstetrics (FIGO) staging is available. A simple modification of the staging system for endometrial carcinomas is usually used: Stage I: Confined to the corpus Stage II: Confined to the corpus and cervix Stage III: Confined to the pelvis Stage IV: Spread outside of pelvis The leiomyosarcomas account for nearly a third of the uterine sarcomas. They tend to occur premenopausally. Most often the diagnosis is made retrospectively on hysterectomy specimens removed as treatment for fibroids. The establishment of the correct diagnosis of a leiomyosarcoma is based primarily on the quantitative evaluation of mitotic activity in the most undifferentiated portion of the tumor. In addition, cel-lular atypia is also important, for aneuploid tumors have a malignant course unrelated to their mitotic activity. Although pathologists may differ in their opinions of a smooth muscle tumors malignant potential, there is general agreement on the mitotic activity criteria for determining malignancy. Tumors with more than 10 mitoses/10 high power fields (hpf) are malignant; those with less than 5 mitoses/10 hpf are benign, and those with 5 to 10 mitoses/10 hpf are classified as smooth muscle tumors of uncertain malignant potential. Although nodal spread can occur, lymphadenectomy is not commonly done in these patients because the malignant nature of the tumor is usually not known at the time of surgery. Direct local spread and hematogenous spread occur frequently. Initial treatment is total abdominal hysterectomy and bilateral salpingo-oophorectomy. There is minimal clinical use for lymphadenectomy. Mixed Mullerian Tumors (Carcinosarcomas) MMTs are the most common type of uterine sarcomas and tend to behave aggressively, with frequent lymph-vascular space involvement and lymphatic spread at earlier stages than expected. Homologous MMTs are those in which the malignant elements are of cell types found in the normal uterus, such as glandular adenocarcinomas and smooth muscle tumors (leiomyosarcomas). Heterologous MMTs contain sarcomatous changes in cell types not found in the normal uterus: rhabdomyosarcomas, chondrosarcomas, osteosarcomas, and liposarcomas. Both the epithelial (carcinomas) and mesenchymal (sarcoma) components must be malignant to establish the diagnosis of MMT. Stage, depth of myometrial involvement, and tumor ploidy are the most important prognostic factors. Adjuvant chemotherapy of stage I disease because of its high recurrence rates (40% to 50%) has been utilized with minimal efficacy. Current trends favor ifosfamide (Ifex) over doxorubicin, in combination with cisplatin (Platinol) for MMTs. Radiotherapy may be important for local disease control but may not impact on overall survival. Endometrial Stromal Sarcoma (ESS) Traditionally endometrial stromal tumors have been divided into endometrial stromal nodule, endolymphatic stromal myosis, and endometrial stromal sarcoma. The stromal nodules are noninfiltrating and relatively benign with less than 3 mitoses/10 hpf. Endolymphatic stromal myosis is now considered more a low-grade form of ESS than a separate entity. With typically less than 10 mitoses/10 hpf, these tumors can have a protracted course with recurrences as late as 25 years. Progestins have an important role in the management of this type of ESS. The true endometrial stromal sarcoma is a high-grade sarcoma with an equally poor (25%) 5-year survival rate compared to the other uterine sarcomas. The mainstay of treatment for high-grade ESS is surgery, with removal of the uterus, tubes, ovaries, and selective lymphadenectomy for complete surgical staging. Low-grade ESS (stromal myosis) also calls for maximal effort to remove all gross and microscopic tumor. Many chemotherapeutic agents have been shown to have some activity in uterine sarcomas: doxorubicin, actinomycin D (dactinomycin [Cosmegan]), cyclophosphamide (Cytoxan, Neosar), vincristine, and cisplatin. One of the initial Gynecologic Oncology Group (GOG) studies of sarcomas showed no clear benefit for adjunctive chemotherapy. Radiotherapy is indicated for local-regional disease control but has not been shown to impact on overall survival. Patients need to be followed in accordance with usual gynecologic oncology protocols, with examinations every 3 to 4 months during the first 2 years and every 4 to 6 months thereafter. The chest x-ray should be part of the follow-up process every 3 to 6 months during the first 2 years because of the propensity for lung metastases. Uterine sarcomas typically recur at distant sites at a ratio of about 3:1 vs local recurrences. Focal recurrences may be treated surgically, and chemotherapy or radiation may be given selectively. Progestins are commonly used as an adjunct, although their benefit has mainly been demonstrated for the management of low-grade ESS. Barter JF, Smith EB, Szpak CA, et al: Leiomyorarcoma of the uterus: Clinicopathologic study of 21 cases. Gynecol Oncol 21:220, 1985. DeFusco PA, Gaffs TA, Malkasian GD, et al: Endometrial stromal sarcoma: Review of Mayo Clinic experience, 1945-1980. Gynecol Oncol 35:8, 1989. Disaia PJ, Creasman WT: Sarcoma of the uterus, in Clinical Gynecologic Oncology, p 178. St. Louis, CV Mosby, 1984. Harlow BL, Weiss NS, Lofton S: The epidemiology of sarcomas of the uterus. J Natl Cancer Inst 76:399, 1986. Marchese MJ, Liskow AS, Crum CP, et al: Uterine sarcomas: A clinicopathologic study, 1965-1981. Gynecol Oncol 18:299, 1984. Norris KJ, Roth E, Taylor HB: Mesenchymal tumors of the uterus: II. A clinical and pathologic study of 31 mixed mesodermal tumors. Obstet Gynecol 28:57, 1966. Norris HJ, Taylor HB: Mesenchymal tumors of the uterus: III. A clinical and pathologic study of 31 carcinorarcomas. Cancer 19:1459, 1966. Norris HJ, Taylor HB: Postirradiation sarcomas of the uterus. Obstet Gynecol 26:689, 1965. Omura GA, Blessing JA, Majors F, et al: A randomized clinical trial of adjuvant Adriamycin in uterine sarcoma: A Gynecologic Oncology Group study. J Clin Oncol 3:1240, 1985. Silverberg SG: Leiomyosarcoma of the uterus: A clinicopathological study. Obstet Gynecol 38:613, 1971. Sutton G, Blessing JA, Rosenshein N, et al: Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic Oncology Group study). Am J Obstet Gynecol 161:309, 1989. Sutton GP, Blessing JA, Barrett RJ, et al: Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: A Gynecologic Oncology Group study. Am J Obstet Gynecol 166:556, 1992. Thigpen JT, Blessing JA, Wilbanks GD: Cisplatin as second line chemotherapy in the treatment of advanced or recurrent leiomyosarcoma of the uterus. Am J Clin Oncol 9:18, 1986.

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A BYU-Harvard-Stanford research team has identified a molecule that is key to mothers’ ability to pass along immunity to intestinal infections to their babies through breast milk. The study highlights an amazing change that takes place in a mother’s body when she begins producing breast milk. For years before her pregnancy, cells that produce antibodies against intestinal infections travel around her circulatory system as if it were a highway and regularly take an “off-ramp” to her intestine. There they stand ready to defend against infections such as cholera or rotavirus. But once she begins lactating, some of these same antibody-producing cells suddenly begin taking a different “off-ramp,” so to speak, that leads to the mammary glands. That way, when her baby nurses, the antibodies go straight to his intestine and offer protection while he builds up his own immunity. This is why previous studies have shown that formula-fed infants have twice the incidence of diarrheal illness as breast-fed infants. Until now, scientists did not know how the mother’s body signaled the antibody-producing cells to take the different off-ramp. The new study identifies the molecule that gives them the green light. “Everybody hears that breastfeeding is good for the baby,” said Eric Wilson, the Brigham Young University microbiologist who is the lead author on the study. “But why is it good? One of the reasons is that mothers’ milk carries protective antibodies which shield the newborn from infection, and this study demonstrates the molecular mechanisms used by the mother’s body to get these antibody-producing cells where they need to be.” Understanding the role of the molecule, called CCR10, also has implications for potential future efforts to help mothers better protect their infants. “This tells us that this molecule is extremely important, so if we want to design a vaccine for the mother so she could effectively pass protective antibodies to the child, it would be absolutely essential to induce high levels of CCR10,” said Wilson. Speaking broadly about the long-term applications of this research, BYU undergraduate Elizabeth Nielsen Low, a co-author on the paper, said, “If we know how these cells migrate, we’ll be able to hit the right targets to get them to go where we want them.” Daniel Campbell is a researcher at the Benroya Research Institute in Seattle, a nonprofit organization that specializes in the immune system, and was not affiliated with this study. “The molecular basis for this redistribution [of the mother’s cells] has not been well characterized, but Dr. Wilson’s work has begun to crack that code and define the molecules responsible for this cellular redistribution and passive immunity,” Campbell said. “It is important work that fundamentally enhances our understanding of how immunity is provided to the [baby] via the milk. Dr. Wilson’s study will certainly form the basis for many other studies aimed at uncovering how the immune system is organized, particularly at mucosal surfaces.” To conduct their research, the team used so-called “knock-out mice” that had been genetically engineered to lack the CCR10 molecule. Whereas normal lactating mice had hundreds of thousands of antibody-producing cells in their mammary glands, the BYU team found that the knock-out mice had more than 70 times fewer such cells. Tests verified that the absence of CCR10 was responsible for the deficiency. Surprisingly, the research also showed that CCR10 does not play the same crucial role in signaling antibody-producing cells to migrate to the intestine. Another molecule is their “traffic light.” The findings will be published in the Nov. 1 issue of the Journal of Immunology. The study was supported by Wilson’s grant from the National Institutes of Health, funding which continues for another 18 months and supports his and his students’ further investigation into the cells behind transfer of immunity in breast milk. Wilson’s other students who are also co-authors on the paper are Yuetching Law, Kathryn Distelhorst and Erica D. Hill. The Harvard Medical School co-authors are Olivier Morteau, Craig Gerard, Bao Lu, Sorina Ghiran and Miriam Rits. The Stanford University School of Medicine co-authors are Raymond Kwan, Nicole H. Lazarus and Eugene C. Butcher. Cite This Page:

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both the relevance and the impact of the NIOSH program using 1–5 integer scales, and (2) providing input about emerging areas of research and recommendations for program improvement. After examining different approaches to program evaluation (see Chapter 2), the framework committee decided to define the scope and stages of the evaluation process based on the logic model (Williams et al., 2009). The resulting evaluation framework described in this chapter breaks the logic models developed by NIOSH (Figure 3-1) into discrete program components to be assessed by each evaluation committee. Criteria for evaluation of each component of the framework are detailed below. In the evaluation framework (overview provided in Figure 3-2), the assessment of strategic goals and objectives, inputs, activities, and outputs (B to E) largely define the relevance of the program, while assessment of intermediate and end outcomes (F and G) largely define the program impact. The following major components of each NIOSH program were assessed by the evaluation committees: Major occupational safety and health challenges in the program area. Goals and objectives as defined by NIOSH. Inputs (e.g., budget; staff; facilities; and input from the program’s research management, the NIOSH Board of Scientific Counselors, and stakeholders). Activities (efforts by NIOSH staff, contractors, and grantees; e.g., surveillance of injury, illness, and hazards; exposure assessment research; health-effects research; injury-risk factor research; intervention research; health services research; and technology transfer activities). Outputs (NIOSH products; e.g., publications, reports, conferences, databases, tools, methods, guidelines, recommendations, education and training, and patents). Intermediate outcomes (actions by external stakeholders in response to NIOSH products; e.g., policy change, training and education, self-reported use or repackaging of NIOSH data by stakeholders, adoption of NIOSH-developed technologies, implemented guidelines, and licenses). End outcomes (e.g., reduction in work-related injuries, illnesses, or hazardous exposures in the workplace). The framework committee understood that the efforts of any research program or the evaluation of that program will not be as linear as presented in either

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Volume 19, Number 5—May 2013 Detecting Rickettsia parkeri Infection from Eschar Swab Specimens The typical clinical presentation of several spotted fever group Rickettsia infections includes eschars. Clinical diagnosis of the condition is usually made by analysis of blood samples. We describe a more sensitive, noninvasive means of obtaining a sample for diagnosis by using an eschar swab specimen from patients infected with Rickettsia parkeri. Until 2004, all confirmed cases of tick-borne spotted fever in North, Central, and South America were attributed to 1 pathogen, Rickettsia rickettsii, the cause of Rocky Mountain spotted fever. Historically, in the Western Hemisphere, tick-borne rickettsiae other than R. rickettsii were often described as nonpathogens (1). In 2004, an otherwise healthy US serviceman living in the Tidewater region of eastern Virginia, USA, sought treatment at an acute care clinic with fever, mild headache, malaise, diffuse myalgias and arthralgias, and multiple eschars on his lower extremities. He reported frequent tick and flea exposures but could not recall a specific arthropod bite before illness. However, R. parkeri, a tick-associated Rickettsia species, was subsequently isolated from an eschar biopsy specimen, documenting the first recognized case of R. parkeri rickettsiosis (2,3). In 2006, another US serviceman visited the National Naval Medical Center with similar symptoms. He had recently returned from a vacation in the Virginia Beach area; subsequently, R. parkeri was also isolated from this patient (4). To date, >25 cases of R. parkeri infections have been diagnosed in the United States and South America (5). R. parkeri was first isolated from Gulf Coast ticks (Amblyomma maculatum) in 1937. The organism remained relatively obscure for the next several decades. R. parkeri is a member of the spotted fever group (SFG) of rickettsiae, which are gram-negative obligate intracellular rod-shaped bacteria transmitted by an arthropod vector. A. maculatum ticks, the vectors for R. parkeri in the United States, have a distribution that extends across all states bordering the Gulf of Mexico and includes several other southern, mid-Atlantic, and central states (6). R. parkeri has been detected in or isolated from A. maculatum ticks in many of these states. Generally, the clinical signs and symptoms of SFG rickettsioses begin 6–10 days after a person has been bitten by an infected arthropod and typically include fever, headache, myalgias, a characteristic inoculation eschar at the bite site (depending on Rickettsia species) (Figure), a macular or maculopapular rash, and regional lymphadenopathy (3). SFG rickettsioses in humans range from mild to life threatening. Rocky Mountain spotted fever is considered the most severe SFG rickettsiosis; mortality rate can be as high as 50% without adequate antimicrobial drug treatment (7). Death from the rickettsioses can generally be prevented if diagnosis is timely and proper treatment is given. In an ongoing, prospective study of clinical rickettsial disease in the Tidewater region of Virginia and Jacksonville, Florida, one of the primary objectives is to identify the prevalence of R. parkeri infection among persons seeking care with tick bite eschars or who have received a clinical diagnosis of rickettsial illness. One patient, a 43-year-old man, visited his primary care clinic in Virginia in early June 2011 after an eschar developed on his left knee, where he had removed an embedded tick 8 days previously. Topical mupirocin was prescribed for his condition. However, later that day, he experienced a fever of 104°F (40°C), accompanied by chills, night sweats, a diffuse maculopapular rash, headache, mylagias, neck stiffness, arthralgias, and malaise. He returned to the primary care clinic 3 days after onset of the fever and was prescribed a 2-week course of doxycycline. He fully recovered after the course of doxycycline. Whole blood specimens and a swab specimen of the unroofed eschar were collected at the time he sought treatment with the acute febrile illness before doxycycline administration. Blood was collected again 25 days later during the convalescent phase. The plasma and the buffy coat were separated from the erythrocytes after centrifugation. The eschar swab was rinsed in 300 μL of phosphate-buffered saline. DNA was extracted from the buffy coat and the swab sample rinse by using QIAamp blood mini kit (QIAGEN, Germantown, MD, USA). Three microliters of the DNA preparations were applied to the Rickettsia genus–specific quantitative real-time PCRs (qPCRs) targeting the 17-kDa antigen gene (Rick17b) (8) and gltA (9), as well as the R. parkeri species–specific qPCR (Rpark), as described (8). Positive reactions were obtained from all 3 qPCRs for the swab sample and the Rick17b assay for the buffy coat. Thus, the diagnosis of R. parkeri infection in this patient was confirmed by molecular assays. The R. rickettsia–specific qPCR (Rrick) (10) yielded negative results. Acute-phase and convalescent-phase plasma samples were tested for SFG-specific IgG and IgM by ELISA using Rickettsia conorii whole cell antigen preparation (11). The ELISA was performed side by side in 4-fold dilutions from 1:100 to 1:6,400. The SFG group–specific IgM was not detected in both samples, and the SFG group–specific IgG was also not detected in the acute sample but was detected in the convalescent-phase sample at a titer of 400. The serologic results confirmed the patient’s infection with a SFG rickettsial agent. A second patient, a 36-year-old man, sought treatment at a primary care clinic in Pensacola, Florida, in late August 2011, 10 days after he was bitten by a tick. He was otherwise healthy, but a painless eschar had developed on his left ankle ≈4 days after exposure to the tick. Over the next several days, a generalized vesicular rash developed on his torso and upper and lower extremities, along with fevers >101°F, chills, night sweats, a mild headache, and generalized lymphadenopathy. The patient was prescribed a 14-day course of doxycycline at his initial visit. His symptoms improved within 24 hours. Serum samples were collected at his initial clinic visit, before initiation of antimicrobial drug therapy. He returned to the clinic and was found to be asymptomatic after 14 days of treatment. Whole blood and a swab of his healing eschar—the crust was unroofed on sampling—were taken at his return visit. DNA was extracted from acute-phase serum and the eschar swab by using the same procedure as had been used for the first patient. Positive reactions were obtained from the swab sample by Rick17b and Rpark qPCRs, and negative by Rrick assay. The acute-phase serum sample was negative by all qPCRs mentioned above. The acute-phase serum and the convalescent-phase plasma samples were tested for SFG rickettsiae–specific IgM and IgG as was performed for the first patient. The titer of IgM for both samples was 400, whereas the IgG for the acute-phase serum and the convalescent-phase plasma samples were 1,600 and 6,400, respectively. The 4-fold raise in IgG titer between acute- and convalescent-phase samples provided the evidence for a current infection. Although R. rickettsii is reportedly the predominant pathogen causing human SFG disease in the United States, the actual prevalence of R. parkeri is unknown because most commercial serologic assays do not distinguish between SFG species. Seroprevalence studies have also demonstrated higher than expected R. rickettsii seropositivity among the general population without history of Rocky Mountain spotted fever, which suggests that they may have been infected by less pathogenic SFG rickettsiae such as R. parkeri. Recently, qPCRs have demonstrated to be effective at identifying rickettsiae specific to the species level (12). A report by Bechah et al. (12) has shown that rickettsial infection could be diagnosed from noninvasively collected cutaneous lesion swab specimens from skin eschars from guinea pigs. Using this model and our qPCR Rick17b (8), we were able to obtain positive results not only from the buffy coat sample from the Tidewater patient but also a positive reaction from a swab specimen from the eschar of the same patient. In the second patient, we were able to obtain a positive reaction from the swab specimen from the healing eschar 14 days after antimicrobial drug treatment. This finding indicates that positive reaction results may be obtained from a healing eschar 14 days after antimicrobial drug treatment and is consistent with the recent report of diagnosis of SFG from swab specimens from patients in Algeria (13). In addition, evidence is mounting that eschars can be tested for rickettsial DNA from the point of signs and symptoms all the through the convalescent phase. Dr Myers is a Public Health Service officer and the clinical laboratory director for the Naval Infectious Diseases Diagnostic Laboratory. His research interests include clinical diagnostic assay development, medical microbiology, and molecular diagnostics. This work was supported by funding from Armed Forces Health Surveillance Center (C0713_12_NM) and the Infectious Diseases Clinical Research Program (IDCRP-057). - Paddock CD. Rickettsia parkeri as a paradigm for multiple causes of tick-borne spotted fever in the Western Hemisphere. Ann N Y Acad Sci. 2005;1063:315–26. - Paddock CD, Sumner JW, Comer JA, Zaki SR, Goldsmith CS, Goddard J, Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis. 2004;38:805–11. - Paddock CD, Finley RW, Wright CS, Robinson HN, Schrodt BJ, Lane CC, Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever. Clin Infect Dis. 2008;47:1188–96. - Whitman TJ, Richards AL, Paddock CD, Tamminga CL, Sniezek PJ, Jiang J, Rickettsia parkeri infection after tick bite, Virginia. Emerg Infect Dis. 2007;13:334–6. - Romer Y, Seijo AC, Crudo F, Nicholson WL, Varela-Stokes A, Nash RR, Rickettsia parkeri rickettsiosis, Argentina. Emerg Infect Dis. 2011;17:1169–73. - Goddard J, Norment BR. Notes on the geographical distribution of the Gulf Coast tick, Amblyomma maculatum [Koch] [Acari:Ixodidae]. Entomol News. 1983;94:103–4. - Parola P, Raoult D. Tropical rickettsioses. [Review]. Clin Dermatol. 2006;24:191–200. - Jiang J, Stromdahl EY, Richards AL. Detection of Rickettsia parkeri and Candidatus Rickettsia andeanae in Amblyomma maculatum Gulf Coast ticks collected from humans in the United States. Vector Borne Zoonotic Dis. 2012;12:175–82. - Stenos J, Graves SR, Unsworth NB. A highly sensitive and specific real-time PCR assay for the detection of spotted fever and typhus group rickettsiae. Am J Trop Med Hyg. 2005;73:1083–5. - Jiang J, Blair PJ, Olson JG, Stromdahl E, Richards AL. Development of a duplex quantitative real-time PCR assay for the detection of tick-borne spotted fever group rickettsiae and Rickettsia rickettsii. Int Rev Armed Forces Med Serv. 2005;78:174. - Richards AL, Soeatmadji DW, Widodo MA, Sardjono TW, Yanuwiadi B, Hernowati TE, Seroepidemiologic evidence for murine and scrub typhus in Malang, Indonesia. Am J Trop Med Hyg. 1997;57:91–5. - Bechah Y, Socolovschi C, Raoult D. Identification of rickettsial infections by using cutaneous swab specimens and PCR. Emerg Infect Dis. 2011;17:83–6. - Mouffok N, Socolovschi C, Benabdellah A, Renvoise A, Parola P, Raoult D. Diagnosis of rickettsioses from eschar swab samples, Algeria. Emerg Infect Dis. 2011;17:1968–9. Suggested citation for this article: Myers T, Lalana T, Dent M, Jiang J, Daly PL, Maguire JD, et al. Detecting Rickettsia parkeri infection from eschar swab specimens. Emerg Infect Dis. [Internet] 2013 May [date cited]. http://dx.doi.org/10.3201/eid1905.120622

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Significance and context This paper represents the culmination of two years of work by five laboratories, making the first inroads on the problem of deciphering the sea urchin genome. These spiny ocean denizens occasionally serve as a model organism in developmental biology and are sometimes used to study gene regulation. As echinoderms, they also have a potentially informative phylogenetic relationship to chordates, and thus to the vertebrates. The California purple sea urchin, Strongylocentrotus purpuratus, was the organism selected for this genomic study. The cornerstone of the sea urchin project was the construction of a contiguous set of bacterial artificial chromosomes (BACs) spanning the entire genome. To create a genomic scaffold, BAC clones were aligned using overlapping end sequences and additional sequence-tagged sites, then checked by comparing restriction enzyme digests. Analysis of the end sequences allowed the authors to estimate that the sea urchin genome contains about 27,000 genes, consistent with the urchin's genome being about one quarter the size of a human's. In addition to the BAC map, cDNA libraries were generated from several developmental stages and from particular organs. Each library was arrayed onto filters that are now available for hybridization screening. The genome project also includes a cDNA database that will expand as data from analyzed cDNAs become available. Further information about the Sea urchin genome project is available. The good news is that a complete BAC map of the genome makes the sea urchin ready for whole-genome sequencing. Unfortunately, it is not clear if such an effort will be undertaken any time soon. As the sea urchin genome is large - about a quarter the size of the three billion bases of the human genome - determining its entire sequence would require a significant effort. So far, only widely used model organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster have received so much attention. The latest focus is on the human genome, with the mouse likely to be next. Where the sea urchin fits into these sequencing schemes is uncertain. Despite a few particular advantages as a model research organism, the urchin is now rarely used as such, and its popularity is unlikely to increase in the near future. One major feature of interest, however, is the sea urchin's phylogeny, as echinoderms are more closely related to chordates, and thus to the vertebrates, than are other invertebrate groups. Although only very distantly related, we and the sea urchin are both deuterostomes unlike protostomes such as Drosophila and Caenorhabditis. The difference between these classification groups lies in the symmetry of the embryonic divisions and the formation of the body cavity. By comparing vertebrate and echinoderm genomes, it should be possible to determine how the original gene set of an early deuterostome ancestor diverged over the course of evolution to create such different creatures. To this end, the S. purpuratus Genome Project is undertaking an in-depth, full-sequence analysis of the sea urchin's lone Hox gene cluster. The Hox genes regulate important aspects of animal development and are highly conserved between different organisms. Comparing the Hox gene clusters from sea urchins and other species is the first step in comparative genomics using these prickly little animals.

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- • A thorough sexual history, including information about the practice of rectal sex (receptive or insertive) or oral-anal sex, with or without condoms. - • Screening for rectal pathogens based on sexual - • Anoscopy in patients with symptoms of anorectal pain, tenesmus, or discharge. - • Collection of specimens for gonorrhea, chlamydia, and serologic tests for syphilis and HIV, and stool specimens for culture and ova and parasite examinations in patients with symptoms Proctitis is an inflammatory condition of the rectum that usually occurs secondary to infection introduced during sexual activity. A more extensive condition—proctocolitis—may occur after oral ingestion of a pathogen that produces colorectal inflammation. Both conditions are noted more frequently in men who have sex with men (MSM). Proctitis is commonly caused by gonorrhea, chlamydia, and herpes simplex virus (HSV) infections, and proctocolitis by enteric bacteria or parasites. The incidence of acute, sexually transmitted proctitis and proctocolitis, which decreased dramatically during the 1980s and early 1990s, began increasing again in the mid-1990s. As a consequence of successful antiretroviral therapy for HIV infection and AIDS, declining concern about HIV and AIDS, and renewed physical health, many HIV-infected men in the United States have increasingly been engaging in sexual risk behaviors associated with the spread of STDs. Consistent condom use between HIV-infected sex partners in some cities has also declined, resulting in substantial increases in rates of syphilis and rectal Sexually transmitted intestinal infections may be transmitted by direct rectal inoculation or indirectly in the course of oral-anal contact. Conventional sexually transmitted diseases (STDs) most often cause rectal infections through direct inoculation by anal intercourse, although perineal contamination by cervicovaginal secretions among women has been described. Chlamydia trachomatis and Neisseria gonorrhoeae infect columnar epithelium and infect the anorectal mucosa via oral-genital and rectal insertive intercourse. HSV, human papillomavirus, and Treponema pallidum infect stratified squamous epithelium and can be transmitted similarly to the anorectal region. Although not considered “classical” STDs, enteric pathogens, parasites, and hepatitis A and B can be transmitted during direct oral-anal contact, (anilingus) or during oral-genital contact after rectal intercourse. Exposure to as few as 10–100 organisms of Shigella, Entamoeba histolytica cysts, or Giardia lamblia cysts may precipitate Multiple partners, anonymous partners, and individual sexual practices that increase the risk of acquiring specific diseases are associated with increased risk of acquiring any STD. Individuals who engage in receptive anal intercourse or anilingus are at high risk for acquiring sexually transmitted proctitis and enteritis. Anal intercourse continues as a prevalent sexual practice in both homosexual and heterosexual populations. Studies report that up to 43% of adult women have participated in anal intercourse. Teen definitions of sexual activity may not include oral or anal sex, and the prevalence of anal sex among teens ...

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An enlarged heart (cardiomegaly) may have various causes. But it's usually the result of high blood pressure (hypertension) or coronary artery disease. An enlarged heart may not pump blood effectively, resulting in congestive heart failure. Cardiomegaly may improve over time. But most people with an enlarged heart need lifelong treatment with medications. The heart enlarges in response to damage to the heart muscle. Up to a point, enlargement permits the heart to continue to pump blood normally. As enlargement progresses, though, the heart's pumping ability declines. Dilated cardiomyopathy is the main type of cardiomegaly. In dilated cardiomyopathy, the walls of both the left and right side of the heart (ventricles) become thin and stretched. The result is an enlarged heart. In the other types of enlarged heart, the heart's muscular left ventricle becomes abnormally thick. High blood pressure usually causes left ventricular enlargement (hypertrophy), while hypertrophic cardiomyopathy is an inherited condition. Generally speaking, the heart's pumping ability is better preserved when the enlarged heart is "thick" rather than "thin." Causes of an Enlarged Heart The most common causes of an enlarged heart are blockages in the heart's blood supply (coronary artery disease) and high blood pressure. An enlarged heart can have many other causes, including: Frequently, no cause for an enlarged heart is identified. This is known as idiopathic dilated cardiomyopathy. Symptoms of an Enlarged Heart Most often, an enlarged heart causes no symptoms. If an enlarged heart becomes unable to pump blood effectively, symptoms of congestive heart failure can develop: Shortness of breath (especially with exertion or when lying flat) Increased abdominal girth Palpitations or skipped heartbeats Symptoms vary widely in people with an enlarged heart. Some may never have symptoms. Others may have mild symptoms that remain unchanged for years. And some may experience steadily worsening shortness of breath.

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Why is the incidence of stress fractures in military basic training greater for women than for men? What is the relationship of genetics and body composition to bone density and the incidence of stress fractures in women? What are the effects of diet, physical activity, contraceptive use, and other lifestyle factors (smoking and alcohol) on the accrual of peak bone mineral content, incidence of stress fractures, and development of osteoporosis in military women? How do caloric restriction and disordered eating patterns affect hormonal balance and the accrual and maintenance of peak bone mineral content? How can the military best ensure that the dietary intakes of active-duty military women in training and throughout their military careers do not contribute to an increased incidence of stress fractures and osteoporosis? In considering the questions posed by the military (and as a follow-on activity to the subcommittee's earlier report, Assessing Readiness in Military Women [IOM, 1998]), the subcommittee consulted with a liaison panel comprising military researchers and health care personnel. A workshop was held in December 1997 to bring together additional military personnel in the areas of training, physical fitness, and military nutrition, as well as civilian researchers and practitioners in the areas of physical fitness and performance, endocrinology, bone mineral assessment, and sports medicine. A focused literature review culled from workshop presentations and selected military and civilian research on the pathophysiology and epidemiology of stress fractures is included in this report. This report responds to the five task questions by evaluating the relevant information provided to the subcommittee at the workshop and subsequent deliberations in executive session, which form the basis for the subcommittee's conclusions and recommendations. Chapter 1 reviews the essential concepts of bone health, Chapter 2 reviews the risk factors for stress fracture, and Chapter 3 examines the effects of energy intake, physical activity, and hormonal factors on bone health. In Chapter 4, the subcommittee provides its responses to the task questions; these responses form the basis for the subcommittee's conclusions, recommendations, and suggestions for additional research. The appendixes contain the agenda and speakers' abstracts from the workshop Reducing Stress Fracture Among Physically Active Young Servicemembers , which was held on December 10, 1997 (Appendix A); summary tables of the most recent (1985) Military Recommended Dietary Allowances (Appendix B) and the Food and Nutrition Board's 1997 Recommended Intakes summary table for Calcium and Related Nutrients (Appendix C); and biographical sketches of the subcommittee members (Appendix D).

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Tips from Other Journals Booster Seats Prevent Injuries in Children Four to Eight Years of Age FREE PREVIEW Log in or buy this issue to read the full article. AAFP members and paid subscribers get free access to all articles. Subscribe now. FREE PREVIEW Subscribe or buy this issue. AAFP members and paid subscribers get free access to all articles. Am Fam Physician. 2010 May 1;81(9):1150-1151. Background: The American Academy of Pediatrics and the National Highway Traffic Safety Administration recommend the use of belt-positioning booster seats in children four years and older until they fit properly in the vehicle seat belt; however, many children graduate prematurely to car seat belts, increasing their risk of serious injury in a crash. Data from 1998 to 2002 showed a notable injury reduction in four- to five-year-old children who used booster seats, but data on older children were not available because most did not use booster seats at the time. Recently, many states have mandated that booster seats be used for children up to six to eight years of age, with a resulting threefold increase in booster seat use. Arbogast and colleagues reviewed more recent safety data to update the estimated effectiveness of belt-positioning booster seats versus seat belts alone in children four to eight years of age. The Study: The Partners for Child Passenger Safety project collected and analyzed data from December 1998 through November 2007. This large-scale, child-specific crash surveillance system incorporates data reported by insurance claims from the State Farm insurance company, as well as telephone surveys and onsite crash investigations. A driver telephone survey functioned as the primary source of data for this analysis. Inclusion criteria consisted of State Farm–insured vehicles built in 1990 or later that were involved in a crash that included at least one child 15 years or younger. The insurance company initially contacted the policyholders of qualifying crashes to inform them of the study and to get consent for further evaluation of crash data. A stratified group sample was designed to select and categorize vehicles based on the initial degree of medical treatment required by the child passengers (i.e., no treatment required, physician's office or emergency department only, admitted to the hospital, or death), and whether the vehicle was drivable. All child occupants of a selected vehicle were included in the survey. All selected vehicles with at least one injured child passenger and a 10 percent random sample of vehicles without child injuries were contacted for a full telephone interview. The 30-minute survey included the parents of the involved children (or the driver if he or she was not the parent). During the study, 97 percent of eligible claims were accurately identified; 80 percent of policyholders consented to participate in the study. Of those who consented, 79 percent were successfully contacted and interviewed, comprising 52 percent of all eligible persons. Injuries were categorized by severity using the Abbreviated Injury Scale (AIS). Only the more severe injuries (those with an AIS score of 2+), including concussions and more serious brain injuries, internal organ and spinal cord injuries, and extremity fractures, were included in the analyses. Only children four to eight years of age who were seated in the backseat and restrained by a booster seat or seat belt were included. Booster seats were further identified by high-back or backless models. Results: During the nine-year study, the authors interviewed a representative sample of 34,732 children involved in 21,943 crashes, and 7,151 children in 6,591 crashes met inclusion criteria. A total of 70 percent were restrained by seat belts, and 30 percent used booster seats. In both groups the ages were closely divided among the four- to eight-year range, although children in seat belts were more likely to be heavier and older than those in booster seats. The overall risk of serious injury was 1.15 percent for children in this age group. Children in booster seats had about one half the risk of those in seat belts, which persisted when adjusted for child age, weight, seating position, driver restraint and relationship to the child, crash severity, and car model year and crash year. Regardless of the type of restraint used, head injuries accounted for approximately 65 percent of all injuries; facial injuries accounted for approximately 9 percent. In children in booster seats, lower extremity injuries accounted for 8 percent of injuries, whereas abdominal injuries constituted 12 percent of injuries in those wearing seat belts. Among children with multiple injuries, there was not a significant difference in injury rates between high-back and backless styles of booster seats. Conclusion: The authors conclude that the use of belt-positioning booster seats reduces the risk of serious injury by 45 percent compared with seat belt use alone in children four to eight years of age. Physicians and health educators should continue to recommend booster seat use for children until at least eight years of age. Arbogast KB, et al. Effectiveness of belt positioning booster seats: an updated assessment. Pediatrics. November 2009;124(5):1281–1286. Copyright © 2010 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. Want to use this article elsewhere? Get Permissions

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* This is a professional Version * - Spinal Trauma - Symptoms and Signs - Key Points - Spinal Cord Injury in Children - Resources In This Article - Drugs Mentioned In This Article Trauma to the spine may cause injuries involving the spinal cord, vertebrae, or both. Occasionally, the spinal nerves are affected (see Hereditary Motor Neuropathy With Liability to Pressure Palsies (HNPP) : Symptoms and Signs). The anatomy of the spinal column is reviewed in another chapter (see Spinal Cord Disorders). During a typical year, there are about 11,000 spinal cord injuries in the US. Overall, nearly 48% occur in motor vehicle crashes, and 23% result from falls; however, falls are the most common causes in the elderly. The remainder are attributed to assault (14%), sports (9%), and work-related accidents. About 80% of patients are male. Spinal cord injuries occur when blunt physical force damages the vertebrae, ligaments, or disks of the spinal column, causing bruising, crushing, or tearing of spinal cord tissue, and when the spinal cord is penetrated (eg, by a gunshot or a knife wound). Such injuries can also cause vascular injury with resultant ischemia or hematoma (typically extradural), leading to further damage. All forms of injury can cause spinal cord edema, further decreasing blood flow and oxygenation. Damage may be mediated by excessive release of neurotransmitters from damaged cells, an inflammatory immune response with release of cytokines, accumulation of free radicals, and apoptosis. Fractures may involve the vertebral body, lamina, and pedicles as well as the spinous, articular, and transverse processes. Dislocations typically involve the facets. Subluxation may involve ligament rupture without bony injury. In the neck, fractures of the posterior elements and dislocations can damage the vertebral arteries, causing a syndrome resembling a brain stem stroke. Unstable vertebral injuries are those in which bony and ligamentous integrity is disrupted sufficiently that free movement can occur, potentially compressing the spinal cord or its vascular supply and resulting in marked pain and potential worsening of neurologic function. Such vertebral movement may occur even with a shift in patient position (eg, for ambulance transport, during initial evaluation). Stable fractures are able to resist such movement. Specific injuries typically vary with mechanism of trauma. Flexion injuries can cause wedge fractures of the vertebral body or spinous process fractures. Greater flexion force may cause bilateral facet dislocation, or if the force occurs at the level of C1 or C2, odontoid fracture, atlanto-occipital or atlantoaxial subluxation, or both fracture and subluxation. Rotational injury can cause unilateral facet dislocation. Extension injury most often causes posterior neural arch fracture. Compression injuries can cause burst fractures of vertebral bodies. The lower tip of the spinal cord (conus medullaris) is usually at the level of the L1 vertebra. Spinal nerves below this level comprise the cauda equina. Findings in spinal injuries below this level may mimic those of spinal cord injury, particularly conus medullaris syndrome. Effects of Spinal Cord Injury by Location The cardinal sign of cord injury is a discrete injury level in which neurologic function above the injury is intact, and function below the injury is absent or markedly diminished. Muscle strength is assessed using the standard 0 to 5 scale (see Muscle strength) Specific manifestations depend on the exact level (see Effects of Spinal Cord Injury by Location) and whether cord injury is complete or incomplete. Priapism may occur in the acute phase of spinal cord injury. Vertebral injury, as with other fractures and dislocations, typically is painful, but patients who are distracted by other painful injuries (eg, long bone fractures) or whose level of consciousness is altered by intoxicants or head injury may not complain of pain. Complete cord injury leads to immediate, complete, flaccid paralysis (including loss of anal sphincter tone), loss of all sensation and reflex activity, and autonomic dysfunction below the level of the injury. High cervical injury (at or above C5) affects the muscles controlling respiration, causing respiratory insufficiency; ventilator dependence may occur, especially in patients with injuries at or above C3. Autonomic dysfunction from cervical cord injury can result in bradycardia and hypotension, termed neurogenic shock; unlike inother forms of shock, the skin remains warm and dry. Arrhythmias and BP instability may develop. Pneumonia is a frequent cause of death in people with a high spinal cord injury, especially in those who are ventilator dependent. Flaccid paralysis gradually changes over hours or days to spastic paralysis with increased deep tendon reflexes due to loss of descending inhibition. Later, if the lumbosacral cord is intact, flexor muscle spasms appear and autonomic reflexes return. Incomplete motor and sensory loss occurs, and deep tendon reflexes may be hyperactive. Motor and sensory loss may be permanent or temporary depending on the etiology; function may be lost briefly due to concussion or more lastingly due to a contusion or laceration. Sometimes, however, rapid swelling of the cord results in total neurologic dysfunction resembling complete cord injury, which is termed spinal shock (not to be confused with neurogenic shock), Symptoms resolve over one to several days; residual disability often remains. Manifestations depend on which portion of the cord is involved; several discrete syndromes are recognized. Brown-Séquard syndrome results from unilateral hemisection of the cord. Patients have ipsilateral spastic paralysis and loss of position sense below the lesion, and contralateral loss of pain and temperature sensation. Anterior cord syndrome results from direct injury to the anterior spinal cord or to the anterior spinal artery. Patients lose motor and pain sensation bilaterally below the lesion. Posterior cord function (vibration, proprioception) is intact. Central cord syndrome usually occurs in patients with a narrowed spinal canal (congenital or degenerative) after a hyperextension injury. Motor function in the arms is impaired to a greater extent than that in the legs. If the posterior columns are affected, posture, vibration, and light touch are lost. If the spinothalamic tracts are affected, pain, temperature, and, often, light or deep touch are lost. Hemorrhage in the spinal cord from trauma (hematomyelia) is usually confined to the cervical central gray matter, resulting in signs of lower motor neuron damage (muscle weakness and wasting, fasciculations, and diminished tendon reflexes in the arms), which is usually permanent. Motor weakness is often proximal and accompanied by selective impairment of pain and temperature sensation. Motor or sensory loss, or both, usually partial, occurs in the distal legs. Sensation is usually diminished in the perineal region (saddle anesthesia). Bowel and bladder dysfunction, either incontinence or retention, may occur. Men may have erectile dysfunction, and women diminished sexual response. Anal sphincter tone is lax, and bulbocavernosus and anal wink reflexes are abnormal. These findings may be similar to those of conus medullaris syndrome, a spinal cord injury. Sequelae depend on the severity and level of the injury. Breathing may be impaired if the injury is at or above the C5 segment. Reduced mobility increases the risk of blood clots, UTIs, contractures, atelectasis and pneumonia, and pressure ulcers. Disabling spasticity may develop. Autonomic dysreflexia may occur in response to triggering events such as pain or pressure on the body. Chronic neurogenic pain may manifest as burning or stinging. Spinal injuries resulting from trauma are not always obvious. Injury to the spine and spinal cord must be considered in patients with injuries that involve the head, with pelvic fractures, with penetrating injuries in the area of the spine, in most motor vehicle crashes, in any kind of major blunt injury, in any injury related to falling from heights or diving into water, and, in elderly patients, sometimes after minor falls. Injury should also be considered in patients with altered sensorium, localized spinal tenderness, painful distracting injuries, or compatible neurologic deficits. Motor function is tested in all extremities. Sensation testing should involve both light touch (posterior column function), pinprick (anterior spinothalamic tract), and position sense. Identification of the sensory level is best done by testing from distal to proximal and by testing thoracic roots on the back to avoid being misled by the cervical cape. Priapism indicates spinal cord damage. Rectal tone may be decreased, and deep tendon reflexes may be exuberant or absent. When spinal cord injury is suspected, the spine is immediately immobilized. Traditionally, plain x-rays are taken of any possibly injured areas. CT is done of areas that appear abnormal on x-rays and areas at risk of injury based on clinical findings. However, CT is being used increasingly as the primary imaging study for spinal trauma because it has better diagnostic accuracy and, at many trauma centers, can be obtained rapidly. MRI helps identify the type and location of cord injury; it is the most accurate study for imaging the spinal cord and other soft tissues but may not be immediately available. Manifestations of injury may be characterized using the ASIA (American Spinal Injury Association) Impairment Scale or a similar instrument (see Spinal Injury Impairment Scale*). Spinal Injury Impairment Scale* Transected or degenerated nerves in the cord do not recover, and functional damage is permanent. Compressed nerve tissue can recover its function. Return of a movement or sensation during the first week after injury heralds a favorable recovery. Dysfunction remaining after 6 mo is likely to be permanent. An important goal is to prevent secondary injury to the spine or spinal cord. In unstable injuries, flexion or extension of the spine can contuse or transect the cord. Thus, when injured people are moved, inappropriate handling can precipitate paraplegia, quadriplegia, or even death from spinal injury. Patients who may have a spinal injury should have the spine immobilized immediately; the neck is held straight manually (in line stabilization) during endotracheal intubation. As soon as possible, the spine is fully immobilized on a firm, flat, padded backboard or similar surface to stabilize the position without excessive pressure. A rigid collar should be used to immobilize the cervical spine. Patients with thoracic or lumbar spine injuries can be carried prone or supine. Those with cervical cord damage that could induce respiratory difficulties should be carried supine, with attention to maintaining a patent airway and avoiding chest constriction. Transfer to a trauma center is desirable. Medical care should be directed at avoiding hypoxia and hypotension, both of which can further stress the injured cord. In cervical injuries higher than C5, intubation and respiratory support are usually needed. Large doses of corticosteroids, started within 8 h after spinal cord injury, may improve the outcome in blunt injuries, but this finding has not been firmly established and remains controversial. Methylprednisolone 30 mg/kg IV over 1 h, followed by 5.4 mg/kg/h for the next 23 h is the recommended regimen. Injuries are treated with rest, analgesics, and muscle-relaxing drugs with or without surgery until swelling and local pain have subsided. Additional general treatment for trauma patients is discussed elsewhere (see Approach to the Trauma Patient : Evaluation and Treatment). Unstable injuries are immobilized until bone and soft tissues have healed in proper alignment; surgery with fusion and internal fixation is sometimes needed. Patients with incomplete cord injuries can have significant neurologic improvement after decompression. In contrast, in complete injury, return of useful neurologic function below the level of the injury is unlikely. Thus, surgery aims to stabilize the spine to allow early mobilization. Early surgery allows for earlier mobilization and rehabilitation. Recent studies suggest that the optimal timing of decompression surgery for incomplete cord injuries is within 24 h of injury. For complete injuries, surgery is sometimes done in the first few days, but it is not clear that this timing affects outcome. Nursing care includes preventing urinary and pulmonary infections and pressure ulcers—eg, by turning the immobile patient every 2 h (on a Stryker frame when necessary). Deep venous thrombosis prophylaxis is required. An inferior vena cava filter could be considered in immobile patients. Drugs effectively control spasticity in some patients. Drugs such as baclofen 5 mg po tid (maximum, 80 mg during a 24-h period) and tizanidine 4 mg po tid (maximum, 36 mg during a 24-h period) are typically used for spasticity occurring after spinal cord injury. Intrathecal baclofen 50 to 100 mcg once/day may be considered in patients in whom oral drugs are ineffective. Rehabilitation is needed to help people recover as fully as possible (see Spinal cord injury). Rehabilitation, best provided through a team approach, combines physical therapies, skill-building activities, and counseling to meet social and emotional needs. The rehabilitation team is best directed by a physician with training and expertise in rehabilitation (physiatrist); it usually includes nurses, social workers, nutritionists, psychologists, physical and occupational therapists, recreational therapists, and vocational counselors (see also Rehabilitation). Physical therapy focuses on exercises for muscle strengthening, passive stretch exercises to prevent contractures, and appropriate use of assistive devices such as braces, a walker, or a wheelchair that may be needed to improve mobility. Strategies for controlling spasticity, autonomic dysreflexia, and neurogenic pain are taught. Occupational therapy focuses on redeveloping fine motor skills. Bladder and bowel management programs teach toileting techniques, which may require intermittent catheterization. A bowel regimen, involving timed stimulation with laxatives, is often needed. Vocational rehabilitation involves assessing both fine and gross motor skills, as well as cognitive capabilities, to determine the likelihood for meaningful employment. The vocational specialist then helps identify possible work sites and determines need for assistive equipment and workplace modifications. Recreation therapists use a similar approach in identifying and facilitating participation in hobbies, athletics, and other activities. Emotional care aims to combat the depersonalization and the almost unavoidable depression that occur after losing control of the body. Emotional care is fundamental to the success of all other components of rehabilitation and must be accompanied by efforts to educate the patient and encourage active involvement of family and friends. Treatments to promote nerve regeneration and minimize scar tissue formation in the injured cord are under study. Such treatments include injections of autologous, incubated macrophages; human-derived embryonic stem cell oligodendrocytes; neural stem cells; and trophic factors. Stem cell research is under study; many animal studies have shown promising results and there have been several phase I and II human clinical trials. Suspect spinal cord injuries in patients who have a high-risk injury mechanism (including minor falls in the elderly), an altered sensorium, neurologic deficits suggesting cord injury, or localized spinal tenderness. To ensure recognition of incomplete spinal cord injuries, test motor function and sensory function (including light touch, pinprick, and position sensation) and check for disproportionate weakness in the upper extremities. Immediately immobilize the spine in patients at risk. Arrange for immediate CT or, if available, MRI. Arrange for surgery within 24 h of injury if patients have incomplete cord injuries. Treat irreversible spinal cord injury with multimodal rehabilitation and drugs that control spasticity. Although children < 10 yr have the lowest rate of spinal cord injuries, such injuries are not rare. In children < 8 yr, cervical spine injuries occur most commonly above C4; in those > 8 yr, injuries at C5 to C8 are more common. Of increasing importance has been the recognition of spinal cord injury without evidence of radiologic abnormality (SCIWORA). This type of injury occurs almost exclusively in children and is related to direct spinal cord traction, spinal cord concussion, and vascular injury. Spinal cord injury should be suspected in any child that has been in a motor vehicle crash, has fallen from a height ≥ 3 m, or has had a submersion injury. SCIWORA is suspected in children who have even transient symptoms of neurologic dysfunction or lancinating pains down the spine or extremities and a mechanism of injury compatible with spinal cord injury. Treatment is similar to that in adults, with immobilization and attention to the adequacy of oxygenation, ventilation, and circulation. Treatment may also include high-dose corticosteroids (same weight-based dose as for adults). Children with significant spinal cord trauma should be transferred to a pediatric trauma center as soon as possible. Drug NameSelect Trade Was This Page Helpful? * This is a professional Version *

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6 Health Risks of Poor Sleep, and 6 Ways to Avoid Them Many sleep disorders can disrupt your night and jeopardize your health You’re in bed tossing and turning. The minutes tick by and you can’t seem to relax. Or maybe you fall asleep, only to awaken a few hours later. The next day, you’re tired, again. According to the federal Centers for Disease Control and Prevention, which calls insufficient rest a public health epidemic, approximately 70 million Americans experience sleep problems. About a third of working adults, 41 million people in all, get less than six hours of sleep a night. (MORE: Is Your Sleeping Pill Shortening Your Life?) Unfortunately, getting a good night's sleep becomes trickier with age. "As we get older, our sleep gets a little bit lighter,” says clinical psychologist Michael Breus, author of The Sleep Doctor’s Diet Plan: Losing Weight Through Better Sleep (Rodale, 2011). "You might get the same amount of sleep," he says, but its intensity in stages three and four, more commonly known as our periods of "deep sleep," tends to decline, becoming less physically and mentally restorative. As our sleep patterns shift away from deeper states, we sleep lighter and are more likely to wake up in the middle of the night. Common middle-age health issues can also contribute to the problem. “Disorders such as sleep apnea and leg movements increase with age, and are found in a majority of adults over age 70," says Dr. Donna Arand, clinical director of the Kettering Sleep Disorders Center in Dayton, Ohio. "Sleep may also be affected by medications or medical conditions, especially those associated with pain." For women experiencing menopause, she adds, "hormonal changes, including hot flashes, can disrupt sleep, while decreased estrogen and progesterone levels in post-menopausal women can cause insomnia." Stress can have a detrimental effect on our sleep, too. Caregiving, divorce, unemployment, the death of loved ones and the financial pressures of preparing for retirement can all undermine our best nighttime intentions. Most adults need about seven hours of sleep daily, Arand says, but only 20 percent of us actually get it. Yet the more we learn about the links between sleep and health, the more we realize how crucial it is to improve our rest. "At one point, sleep was viewed as what happens between 10 p.m. and 6 a.m.," says Dr. Douglas Kirsch, a clinical instructor at Harvard Medical School and the regional medical director of the SleepHealth Centers in Boston. But given the discoveries made in the past decade, he says, "Now we’re interested in how it affects your health.” 6 Health Risks of Poor Sleep Cognitive decline. Simply put, people who don’t get enough sleep (or sleep too much) are at greater risk of cognitive decline. Four separate studies presented at the recent Alzheimer’s Association International Conference found the likelihood of developing symptoms is linked to common sleep disorders like deprivation, too much or too little rest, sleep-disordered breathing (apnea) and daytime sleepiness. (MORE: Learn How to Enjoy Better Sleep) Weight gain and diabetes. When you don’t get enough sleep, you’re at greater risk for gaining weight and, potentially, contracting Type 2 diabetes. This is due in part to the poor food choices we tend to make on low sleep, Breus says, but also because of hormonal changes. Research published earlier this month in The Annals of Internal Medicine found striking differences in the way our fat cells respond to insulin depending on how much we've slept. The study of lean, healthy young adults found that after just four nights with four-and-a-half hours of sleep, fat cells responded to insulin as if they were 10 to 20 years older. The cells' increased resistance to insulin limited their ability to store lipids, which instead can leach out and enter the bloodstream, a common a precursor to Type 2 diabetes. "I was very surprised" by the results, said University of Chicago associate professor of medicine Matthew Brady, who led the study. Mood disorders. We're all grumpier when we don’t get enough sleep. According to a recent University of Michigan study, even earning an additional $60,000 more each year has less impact on happiness than averaging one additional hour of sleep each night. Scientists have long known that poor sleep puts people at greater risk for depression and that adults who already suffer from depression are much more likely to have trouble sleeping. Insomniacs are about 10 times more likely than others to be depressed and nearly 20 times more likely to have anxiety. Similarly, people with depression are five times more likely to have obstructive sleep apnea than others. The good news: Treatment of apnea has been found to reduce symptoms of depression. Heart disease. Sleeping too little, or too much, raises your risk for heart attack, stroke and congestive heart failure, according to research presented at an American College of Cardiology conference this past spring. The new study of more than 3,000 adults age 45 or over — the first "nationally representative sample to find an association between sleep duration and heart health" — found that people who sleep less than six hours a night were twice as likely to have a stroke or heart attack and 1.6 times more likely to have congestive heart failure. Those who sleep more than eight hours a night are also at risk. The study found they're twice as likely to have angina (chest pain) and also have an increased risk of developing coronary artery disease. “We now have an indication that sleep can impact heart health — and it should be a priority,” Chicago Medical School professor Rohit Arora, who led the study, said in a statement. “Based on these findings, it seems getting six to eight hours of sleep every day probably confers the least risk for cardiovascular disease over the long term.” Car accidents. Insufficient sleep can slow your reaction time and impair your judgment behind the wheel. According to the National Sleep Foundation, 60 percent of Americans have driven while feeling sleepy and 37 percent admit that they've actually fallen asleep at the wheel. Most troubling, the foundation reports, is research that finds many drivers cannot tell when sleepiness is about to overcome them. More pain. If you suffer from arthritis, fibromyalgia or back pain, you already know that less sleep equals more pain. It's not that the conditions get worse, though; it's that you're less able to cope with them: "The pain itself might not be different," Breus says, "but your perception of it is worse." The Path to Better Sleep The first step in improving your sleep is to make it a priority, something that doesn’t come easily to fiftysomething adults used to burning the candle at both ends. “Sleep is important, but we tend to value lots of things more,” Kirsch says. “On the other hand, if we slept more, we’d do better at the things we value." Following are six expert tips for sleeping better: - Stay on schedule. “The best way to improve sleep is to develop and maintain regular sleep and wake times on a daily basis,” Arand says, adding that those habits should apply on weekends as well. - Have a bedtime routine. Like children, adults need a nightly routine. Whether it's reading, listening to music or taking a bath, establish a pattern that works for you as you wind down every night. - Exercise regularly. Being physically active helps improve sleep, especially when the exercise takes place in the morning or afternoon. Limit alcohol and caffeine intake. Both can keep you awake or disturb your sleep. To avoid their impact, finish your last glass of wine at least three hours before bed and stop consuming caffeine by 2 pm. (MORE: The Risk of Becoming an 'Almost' Alcoholic) - Keep your bedroom cool, dark and quiet. A slightly cool temperature, around 68 degrees Fahrenheit, is most conducive for sleeping, says Arand, who, like most sleep experts, strongly advises against keeping TVs, computers and tablets by your bedside. All tend to prevent you from winding down successfully when it's time for sleep. - Have the right nighttime gear. Replace old, uncomfortable mattresses, make sure your pillows are comfortable and consider room-darkening shades if exterior lights or sunrise are disruptive. "Sleep is a performance activity," Breus says. "If you have the right equipment you’ll be better off." © Twin Cities Public Television — 2013. All rights reserved.

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Data sources and inclusion criteria for the Database on Iodine Deficiency Survey reports and publications reporting on goitre and/or urinary iodine are collected/requested from: - Ministries of Health through WHO regional and country offices. - National research and academic institutions. - Nongovernmental organizations. - Organizations of the United Nations system. - Regular searches of online databases, such as PubMed, Medline, Ovid, Embase, and WHO regional databases (African Index Medicus, Index Medicus for the WHO Eastern Mediterranean Region, Latin American and Caribbean Center on Health Sciences Information, Pan American Health Organization Library Institutional Memory Database, Index Medicus for South-East Asia Region). Data inclusion criteria Survey data are extracted and included in the database only from complete original survey reports and publications that provide details of the sampling methods. Data from all administrative levels and all population groups cited are included. Studies must have a population-based sample frame and must use standard UI and TGP measuring techniques1. To be included, a survey must report on at least one of the following criteria: - Goitre* prevalence investigated by palpation and classified according to WHO recommendations. - Grade 1: A goitre that is palpable but not visible when the neck is in the normal position, even when the thyroid is not visibly enlarged. Thyroid nodules in a thyroid, which is otherwise not enlarged, fall into this category. - Grade 2: A swelling in the neck that is clearly visible when the neck is in a normal position and is consistent with an enlarged thyroid when the neck is palpated. * A thyroid gland will be considered goitrous when each lateral lobe has a volume greater than the terminal phalanx of the thumbs of the subject being examined. Only TGP data measuring goitre by palpation are included. Until recently, no international reference values for thyroid size in iodine-replete populations measured by ultrasonography were available, and thus results from surveys using this technique have not yet been included2. - Urinary iodine (UI) reported by at least one of the following categories: - Distribution: The percentage of the population falling within the categories <20 µg/L, 20-49 µg/L, 50-99 µg/L, 100-299 µg/L, >300 µg/L. - Prevalence: The percentage of the population falling below the cut-off level of 100 µg/L. - Median and/or mean (µg/L, µg/g creatinine or µg/24h). When a potentially relevant survey is identified and the full report obtained, all data are checked for consistancy as part of routine quality control. When necessary, the authors are contacted for clarification or additional information. Final data are extracted and entered into a standard data form. The full archived documentation and correspondence are available to users on request. - World Health Organization, United Nation Children's Fund, International Council for Control of Iodine Deficiency Disorders. Assessment of the iodine deficiency disorders and monitoring their elimination. Geneva: World Health Organization; 2001. WHO document WHO/NHD/01.1. - Zimmermann MB, Hess SY, Molinari L, de Benoist B, Delange F, Braverman LE et al. New reference values for thyroid volume by ultrasound in iodine-sufficient schoolchildren: a World Health Organization/Nutrition for Health and Development Iodine Deficiency Study Group Report. American Journal of Clinical Nutrition 2004;79: 231-237.

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Fluorescence quenching spectrometry was applied to study the interactions between gold colloidal nanoparticles and alpha-fetoprotein (AFP). Experimental results show that the gold nanoparticles can quench the fluorescence emission of adsorbed AFP effectively. Furthermore, the intensity of fluorescence emission peak decreases monotonously with the increasing gold nanoparticles content. A mechanism based on surface plasmon resonance–induced non-radiative decay was investigated to illuminate the effect of a dielectric shell on the fluorescence quenching ability of gold nanoparticles. The calculation results show that the increasing dielectric shell thickness may improve the monochromaticity of fluorescence quenching. However, high energy transfer efficiency can be obtained within a wide wavelength band by coating a thinner dielectric shell. Keywords:Fluorescence quenching; Gold nanoparticles; Alpha-fetoprotein (AFP); Non-radiative decay; Dielectric shell Noble metal colloids, such as gold and silver nanoparticles, allow effective fluorescence quenching over a broad range of wavelengths, which is to be used across a vast spectrum of applications such as energy transfer assays for the detection of proteins [1-4]. As we know, sensitive analytical technology for quantification of protein concentration in solution is important in biological science . The application of fluorescence quenching is a powerful technique for protein measurement and analysis [6,7]. Comparing with other commonly used methods to determine protein concentration, the method based on fluorescence resonance energy transfer has a greatly improved sensitivity . For example, Pihlasalo et al. reported a new and highly sensitive method to detect protein concentrations relying on protein adsorption on gold colloids and quenching of fluorescently labeled protein. This assay allowed the determination of picogram quantities of proteins with an average variation of 4.5% in a 10-min assay. Mayilo et al. report the homogeneous sandwich immunoassay with gold nanoparticles (AuNPs) as fluorescence quenchers. A limit of detection of 0.7 ng/ml was obtained for protein cardiac troponin T (cTnT), which is the lowest value reported for a homogeneous sandwich assay for cTnT. Guan et al. utilize the “superquenching” property of AuNPs to polythiophene derivatives for detecting aspartic acid (Asp) and glutamic acid (Glu) in pure water. A sensitive method for detecting Asp and Glu is established with 32 nMand 57 nM as limit of detection for Asp and Glu, respectively. A resonance energy transfer model based on non-radiative decay provides a theoretical understanding of these observations of fluorescence quenching. The optical properties of molecules adsorbed on or enclosed in metallic and dielectric particles have been investigated both experimentally and theoretically in recent years [10-13]. When a particle has been excited and is oscillating in the incident electromagnetic field, the excited system may have a fluctuating electric dipole moment and causes the radiation . This light radiation from dipole moment provides the channel for radiative decay. On the other hand, the Joule heating and plasmon absorption caused by these fields open the non-radiative decay channels [14,15]. The competition between radiative decay and non-radiative decay energy transfer affects the fluorescence emission of the molecules located near the particle. If the non-radiative takes the dominating effect, fluorescence quenching occurs. The different distance behavior of the radiative and non-radiative rates explains why the apparent quantum yield always vanishes at short distance from a metallic nanoparticle . Alpha-fetoprotein (AFP) is an oncofetal protein, which has been widely used as a tumor marker for diagnosis and management of hepatocellular carcinoma [16-18]. Many efforts such as amperometric immunosensor , enhanced chemiluminescent (CL) immunoassay and fluoroimmunoassay have been developed to improve the sensitivity on detecting AFP level in human serum. Although the fluorescence spectral properties of AFP have already been studied , the effect of gold nanoparticles on the fluorescence emission of AFP has seldom been reported. Especially, when protein molecules such as AFP are adsorbed on the gold particle, there will be a dielectric shell. How does the dielectric shell affect the non-radiative energy transfer and fluorescence quenching is also an interesting topic. In this paper, we studied the effect of gold colloids with different concentration on the fluorescence quenching of AFP. By calculating the quantum efficiency as a function of shell thickness, we discuss in detail the quenching mechanism based on SPR-induced non-radiative decay of the dielectric shell-coated gold nanospheres. Gold colloid nanoparticles with spherical shape were synthesized by sodium citrate reduction of HAuCl4 as reported earlier [9,21]. The AFP standard samples were obtained from Biocell Biotechnology Co. Ltd (China). The solutions of AFP were prepared in ultra-pure water at room temperature by directly dissolved to prepare stock solutions of 3, 6, 9, and 40 ng/ml, respectively. When the comparison of fluorescence spectra between pure AFP (6 ng/ml) and solution containing both AFP and gold colloid was studied, the solution containing both AFP and gold colloid was obtained by mixing 1 ml gold colloid with 2 ml pure AFP solution (9 ng/ml). So AFP concentration was kept fixed at 6 ng/ml for all samples. When the fluorescence spectra of solution containing both AFP and gold colloid with different gold particle content were studied, the high AuNPs concentration sample was obtained by mixing 2 ml pure AFP (40 ng/ml) with 1.5 ml gold colloid and 0.5 ml ultra-pure water; the medium AuNPs concentration sample was obtained by mixing 2 ml pure AFP (40 ng/ml) with 1.0 ml gold colloid and 1.0 ml ultra-pure water; the low AuNPs concentration sample was obtained by mixing 2 ml pure AFP (40 ng/ml) with 0.5 ml gold colloid and 1.5 ml ultra-pure water. Fluorescence emission and excitation spectra were carried out on a Perkin–Elmer LS 55 spectrophotofluorometer. The fluorescence excitation spectra were registered in the range from 250 to 320 nm. The fluorescence emission spectra were registered in the range from 250 to 500 nm. Results and Discussion The fluorescence excitation spectrum of pure AFP with a concentration of 3 ng/ml in Fig. 1 is the scanning excited wavelength from 200 to 320 nm when the detection wavelength was located at 345 nm (the fluorescence emission peak of AFP usually takes place at the wavelength range from 320 to 350 nm ). The experimental result in Fig. 1 shows that there is a broad exciting band with two peaks at around 260 and 293 nm, respectively, which indicates that the fluorescence emission of AFP at 345 nm is sensitive to the excitation from 260 to 293 nm. Figure 1. Fluorescence excitation spectrum of pure AFP solution with a concentration of 3 ng/ml, detection wavelength is 345 nm The fluorescence emission spectrum of pure AFP with a concentration of 6 ng/ml in Fig. 2 is the scanning detection wavelength from 250 to 500 nm when the exciting wavelength was located at 293 nm. It is obvious that there is a strong fluorescence emission peak noted at 345 nm. However, when amount of gold colloids were dropped into the AFP solution (the concentration of AFP is kept at 6 ng/ml), the emission peak at 345 nm decreases distinctly, as shown in Fig. 2. This experimental result indicates that the gold nanoparticles can quench the fluorescence of AFP. Fluorescence emission spectra of solution containing both AFP and gold colloid with different gold particle content are compared in Fig. 3. In this comparison, all the samples have the same AFP concentration and the exciting wavelength was located at 260 nm. It is interesting to note that the increasing gold colloid content leads to a decrease in the fluorescence emission peak, as shown in Fig. 3. Figure 2. Comparision of fluorescence emission spectra between pure AFP and solution containing both AFP and gold colloid, exciting wavelength is 293 nm Figure 3. Fluorescence emission spectra of solution containing both AFP and gold colloid with different gold nanoparticle content, exciting wavelength is 260 nm The observed fluorescence quenching is attributed to the resonance energy transfer from AFP to gold nanoparticles. This non-radiative decay can be theoretically studied by using the Förster energy transfer theory [11,22]. When some amounts of gold colloidal nanoparticles are dropped into the solutions of AFP, AFP molecules would tend to cluster around gold particles due to physical adsorption. Increasing the AFP concentration leads to more and more molecules adsorb on the gold particles, so the gold particle will be coated by a dielectric shell. The thickness and dielectric constant of the shell are controlled by the concentration of AFP and gold colloid content. In order to find the effect of the dielectric shell on the fluorescence quenching from gold particle, we calculated the quantum efficiency of the shell-coated gold nanosphere , In Eq. 1, ΓR denotes the radiative decay rate, ΓNR denotes the non-radiative decay rate, k = 2π/λ denotes the wave number of the light, z denotes the distance from particle center to the attached molecule. In our calculation, we study the attached molecule at the outer surface of the shell. So the value of z is equal to the radius of the dielectric shell r2, which is changing from 15 to 65 nm. The polarizability α of this dielectric shell-coated gold sphere can be obtained from the quasi-static theory , In this calculation, the gold core has radius r1 = 15 nm and dielectric function ε1, the dielectric shell has a thickness r2 − r1 and dielectric constant ε2 (when ε2 = 2.0, the gold particle is coated by a shell; when ε2 = ε3 = 1.0, no dielectric shell is coated on the gold particle), the embedding medium has dielectric function ε3 = 1.0. In Drude model, this frequency-dependent complex dielectric constant of gold particle can be written as where εb(ω) is dielectric function of bulk metal which is due to inter-band transition and varies with frequency, these numerical parameters are given in . ωp = 9 eV denotes the plasmon frequency of the bulk metal , τ is the size limit relaxation time of gold nanoparticle [27,28] and ω is the frequency of electromagnetic wave. As shown in Fig. 4, the quantum efficiency at SPR frequency is calculated as a function of separation distance from the particle center to the outer surface of the dielectric shell. Increasing the separation distance leads to a non-linear increase in quantum efficiency. The changing speed is relatively weak at very short and very far distance. These results are similar to the reports of . In order to find the effect of the dielectric shell on this distance-dependent quantum efficiency, the curves corresponding to gold sphere with a dielectric shell and without a shell are compared in Fig. 4. When ε2 = ε3, the gold sphere is immersed in a dielectric environment and no shell coated on the gold sphere indeed. In this case, r2 only denotes the distance from particle center to the attached molecule. When ε2 ≠ ε3, the gold sphere is coated with a dielectric shell (the dielectric constant is ε2 = 2.0) first and then immersed in a dielectric environment (the dielectric constant is ε3 = 1.0). The calculated results show that the existence of dielectric shell reduces the quantum efficiency. This reduction begins to take effect when the shell thickness exceeds 10 nm and gets intense with the increasing shell thickness. This reduction of quantum efficiency also indicates the quenching efficiency of a shell-coated gold particle starts to decrease at a farer distance at resonance frequency. Figure 4. Quantum efficiency as a function of separation distance at SPR frequency As we know, the fluorescence wavelength is not always matching the SPR frequency of gold nanoparicle. Especially, the fluorescence wavelength of the attached molecule is fixed, whereas the SPR frequency of coated gold nanosphere is tunable by the shell thickness. In order to find the quantum efficiency at different frequency, we plotted the quantum efficiency as a function of wavelength with different shell thickness, as shown in Fig. 5. It is interesting to note that increasing the shell thickness leads to the quantum efficiency peak red shifts, attenuates and narrows down. The shift and narrow down speed is fast with thinner shell and slow with thicker shell. However, the attenuate speed is slow with thinner shell and fast with thicker shell. These results show that increasing the dielectric shell thickness may improve the monochromaticity of fluorescence quenching. High energy transfer efficiency can be obtained within a wide wavelength band when coated by a thinner shell. This conclusion is in agreement with our experimental results. Increasing the gold particle content leads to a decrease in particle separation and reduces the shell thickness. Therefore, the fluorescence emission decreases with the increasing gold colloids. Figure 5. Quantum efficiency as a function of wavelength with different dielectric shell thickness Our next goal is to find the physical origin of the quantum efficiency of dielectric shell-coated gold nanosphere. We believe the SPR absorption is the most important factor that affects the quantum efficiency of a single dipole emitter close to a gold nanoparticle. Therefore, we plotted the absorption cross-section as a function of wavelength and separation distance, as shown in Fig. 6. When ε2 = ε3, the shell has the same dielectric constant of the embedding medium, thus there is no shell coated on the gold particle indeed. However, in order to make a comparison, we still assumed that there is a shell and calculated absorption cross-section of this dielectric shell-coated gold particle on the condition of ε2 = ε3, as shown in Fig. 6a. In this case, the absorption intensity decreases rapidly with the increasing separation distance. However, when ε2 > ε3, the existence of the dielectric shell may slow down the decreasing speed of the absorption cross-section and then reduces the quantum efficiency, as shown in Fig. 6b. Therefore, the existence of dielectric shell may weaken the quantum efficiency of gold nanosphere, which is in agreement with the results in Fig. 4. Figure 6b also shows that the resonance absorption at SPR frequency is intense with thin dielectric shell and decreases as the shell gets thicker. However, the off-resonance absorption, which is far away from SPR frequency, is very weak and is not sensitive to the shell thickness. Therefore, the changing range of absorption intensity is larger for thinner shell but smaller for thicker shell, which results in the narrow down of the quantum efficiency band with the increasing shell thickness. This conclusion is in agreement with the result in Fig. 5. Figure 6. Absorption cross-section as a function of wavelength and distance from the gold particle center, a ε2 = ε3, b ε2 > ε3 Fluorescence quenching of AFP has been observed in the presence of colloidal gold nanoparticles. The quenching effect can be improved by increasing the gold nanoparticle content. Based on non-radiative energy transfer theory, we explained the observed fluorescence quenching characters by calculating the quantum efficiency as a function of dielectric shell thickness. The calculated results show that, because of the SPR-induced non-radiative decay, high energy transfer efficiency and intense fluorescence quenching can be obtained within a wide wavelength band when the gold particles are coated by a thinner dielectric shell. This work was supported by the National High-tech Research and Development Program (863 Program) of China under grant No. 2009AA04Z314 and the Fundamental Research Funds for the Central Universities under grant No. xjj20100049. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Nano Lett. 2007, 7:1941-1946. COI number [1:CAS:528:DC%2BD2sXmtlaqsb0%3D]; Bibcode number [2007NanoL...7.1941S]Publisher Full Text Anal. Chem. 2006, 78:1104. COI number [1:CAS:528:DC%2BD28XkvFGqsg%3D%3D]PubMed Abstract | Publisher Full Text Anal. Chem. 2009, 81:4995-5000. COI number [1:CAS:528:DC%2BD1MXmtVGgtb8%3D]PubMed Abstract | Publisher Full Text Biophys. Chem. 2009, 139:1-7. COI number [1:CAS:528:DC%2BD1cXhsVGgsrnI]PubMed Abstract | Publisher Full Text J. Phys. Chem. C 2009, 113:2722-2730. COI number [1:CAS:528:DC%2BD1MXhtV2ktL0%3D]Publisher Full Text Anal. Chem. 2008, 80:1497-1504. COI number [1:CAS:528:DC%2BD1cXht1Cjtr0%3D]PubMed Abstract | Publisher Full Text Science 2006, 312:217-224. COI number [1:CAS:528:DC%2BD28XjtlOjs70%3D]; Bibcode number [2006Sci...312..217G]PubMed Abstract | Publisher Full Text Mayilo S, Kloster MA, Wunderlich M, Lutich A, Klar TA, Nichtl A, Kürzinger K, Stefani FD, Feldmann J: Long-range fluorescence quenching by gold nanoparticles in a sandwich immunoassay for cardiac Troponin T. Nano Lett. 2009, 9:4558-4563. COI number [1:CAS:528:DC%2BD1MXhsValurzL]; Bibcode number [2009NanoL...9.4558M]PubMed Abstract | Publisher Full Text Talanta 2008, 77:319-324. COI number [1:CAS:528:DC%2BD1cXhtFCit7%2FJ]PubMed Abstract | Publisher Full Text J. Chem. Phys. 1981, 75:1139-1152. COI number [1:CAS:528:DyaL3MXltVGmtr4%3D]; Bibcode number [1981JChPh..75.1139G]Publisher Full Text Opt. Commun. 2006, 261:368-375. COI number [1:CAS:528:DC%2BD28Xjsl2qu7o%3D]; Bibcode number [2006OptCo.261..368C]Publisher Full Text Mater. Lett. 2005, 59:1413-1416. COI number [1:CAS:528:DC%2BD2MXitFyqtbw%3D]Publisher Full Text Nano Lett. 2007, 7:3157-3164. COI number [1:CAS:528:DC%2BD2sXhtVWisL7M]; Bibcode number [2007NanoL...7.3157P]PubMed Abstract | Publisher Full Text Dulkeith E, Morteani AC, Niedereichholz T, Klar TA, Feldmann J, Levi SA, van Veggel FCJM, Reinhoudt DN, Moller M, Gittins DI: Fluorescence quenching of dye molecules near gold nanoparticles: radiative and nonradiative effects. Phys. Rev. Lett. 2002, 89:203002. COI number [1:CAS:528:DC%2BD38XosVenur4%3D]; Bibcode number [2002PhRvL..89t3002D]PubMed Abstract | Publisher Full Text Nano Lett. 2007, 7:690-696. COI number [1:CAS:528:DC%2BD2sXhvFKqtbg%3D]; Bibcode number [2007NanoL...7..690C]PubMed Abstract | Publisher Full Text Biosens. Bioelectron. 2009, 24:2707-2711. COI number [1:CAS:528:DC%2BD1MXjvVyltb8%3D]PubMed Abstract | Publisher Full Text Sens. Actuator B Chem. 2005, 106:455-460. COI number [1:CAS:528:DC%2BD2MXjtlGiurY%3D]Publisher Full Text Biosens. Bioelectron. 2009, 24:1610-1614. COI number [1:CAS:528:DC%2BD1MXltV2rt70%3D]PubMed Abstract | Publisher Full Text Anal. Chim. Acta 2006, 561:48-54. COI number [1:CAS:528:DC%2BD28XhvFOiurw%3D]Publisher Full Text Food Bioprod. Process. 2006, 84:9-17. COI number [1:CAS:528:DC%2BD28XlvVOju7s%3D]Publisher Full Text Anal. Chem. 1995, 67:735-743. COI number [1:CAS:528:DyaK2MXjt1Sitbg%3D]Publisher Full Text Ann. Physik. 1948, 2:55-75. Publisher Full Text J. Opt. Soc. Am. B 1999, 16:1824-1832. COI number [1:CAS:528:DyaK1MXmtlOms78%3D]; Bibcode number [1999OSAJB..16.1824A]Publisher Full Text Phys. Rep. 1981, 78:173. COI number [1:CAS:528:DyaL38XmtFaktA%3D%3D]; Bibcode number [1981PhR....78..173P]Publisher Full Text Phys. Rev. B 1972, 6:4370-4379. COI number [1:CAS:528:DyaE3sXjsFKksA%3D%3D]; Bibcode number [1972PhRvB...6.4370J]Publisher Full Text J. Appl. Phys. 2006, 99:044304. COI number [1:CAS:528:DC%2BD28XitVCiur0%3D]; Bibcode number [2006JAP....99d4304B]Publisher Full Text Surf. Sci. 2005, 577:95-111. COI number [1:CAS:528:DC%2BD2MXhs1ygs7o%3D]; Bibcode number [2005SurSc.577...95C]Publisher Full Text Phys. Lett. A 2004, 323:455-459. COI number [1:CAS:528:DC%2BD2cXitVOgtLg%3D]; Bibcode number [2004PhLA..323..455Z]Publisher Full Text Phys. Rev. Lett. 2004, 93:166108. COI number [1:CAS:528:DC%2BD2cXos1Cru7o%3D]; Bibcode number [2004PhRvL..93p6108G]PubMed Abstract | Publisher Full Text

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For support and advice from others, visit our Arteriovenous Malformation (AVM) Community Arteriovenous malformations (AVMs) are defects of the circulatory system that are generally believed to arise during embryonic or fetal development or soon after birth. They are comprised of snarled tangles of arteries and veins, called lesions. How do AVMs damage the brain and spinal cord? become symptomatic only when the damage they cause to the brain or spinal cord reaches a critical level. This is one of the reasons why a relatively small fraction of people with these lesions experiences significant health problems related to the condition. AVMs damage the brain or spinal cord through three basic mechanisms: by reducing the amount of oxygen reaching neurological tissues; by causing bleeding (hemorrhage) into surrounding tissues; and by compressing or displacing parts of the brain or spinal cord. AVMs compromise oxygen delivery to the brain or spinal cord by altering normal patterns of blood flow. Arteries and veins are normally interconnected by a series of progressively smaller blood vessels that control and slow the rate of blood flow. Oxygen delivery to surrounding tissues takes place through the thin, porous walls of the smallest of these interconnecting vessels, known as capillaries, where the blood flows most slowly. The arteries and veins that make up AVMs, however, lack this intervening capillary network. Instead, arteries dump blood directly into veins through a passageway called a fistula. The flow rate is uncontrolled and extremely rapid-too rapid to allow oxygen to be dispersed to surrounding tissues. When starved of normal amounts of oxygen, the cells that make up these tissues begin to deteriorate, sometimes dying off completely. This abnormally rapid rate of blood flow frequently causes blood pressure inside the vessels located in the central portion of an AVM directly adjacent to the fistula-an area doctors refer to as the nidus, from the Latin word for nest-to rise to dangerously high levels. The arteries feeding blood into the AVM often become swollen and distorted; the veins that drain blood away from it often become abnormally constricted (a condition called stenosis). Moreover, the walls of the involved arteries and veins are often abnormally thin and weak. Aneurysms-balloon-like bulges in blood vessel walls that are susceptible to rupture-may develop in association with approximately half of all neurological AVMs due to this structural weakness. Bleeding can result from this combination of high internal pressure and vessel wall weakness. Such hemorrhages are often microscopic in size, causing limited damage and few significant symptoms. Even many nonsymptomatic AVMs show evidence of past bleeding. But massive hemorrhages can occur if the physical stresses caused by extremely high blood pressure, rapid blood flow rates, and vessel wall weakness are great enough. If a large enough volume of blood escapes from a ruptured AVM into the surrounding brain, the result can be a catastrophic stroke. AVMs account for approximately 2 percent of all hemorrhagic strokes that occur each year. Even in the absence of bleeding or significant oxygen depletion, large AVMs can damage the brain or spinal cord simply by their presence. They can range in size from a fraction of an inch to more than 2.5 inches in diameter, depending on the number and size of the blood vessels making up the lesion. The larger the lesion, the greater the amount of pressure it exerts on surrounding brain or spinal cord structures. The largest lesions may compress several inches of the spinal cord or distort the shape of an entire hemisphere of the brain. Such massive AVMs can constrict the flow of cerebrospinal fluid-a clear liquid that normally nourishes and protects the brain and spinal cord-by distorting or closing the passageways and open chambers (ventricles) inside the brain that allow this fluid to circulate freely. As cerebrospinal fluid accumulates, hydrocephalus results. This fluid buildup further increases the amount of pressure on fragile neurological structures, adding to the damage caused by the AVM itself. AVMs can form virtually anywhere in the brain or spinal cord-wherever arteries and veins exist. Some are formed from blood vessels located in the dura mater or in the pia mater, the outermost and innermost, respectively, of the three membranes surrounding the brain and spinal cord. (The third membrane, called the arachnoid, lacks blood vessels.) AVMs affecting the spinal cord are of two types, AVMs of the dura mater, which affect the function of the spinal cord by transmitting excess pressure to the venous system of the spinal cord, and AVMs of the spinal cord itself, which affect the function of the spinal cord by hemorrhage, by reducing blood flow to the spinal cord, or by causing excess venous pressure. Spinal AVMs frequently cause attacks of sudden, severe back pain, often concentrated at the roots of nerve fibers where they exit the vertebrae; the pain is similar to that caused by a slipped disk. These lesions also can cause sensory disturbances, muscle weakness, or paralysis in the parts of the body served by the spinal cord or the damaged nerve fibers. Spinal cord injury by the AVM by either of the mechanisms described above can lead to degeneration of the nerve fibers within the spinal cord below the level of the lesion, causing widespread paralysis in parts of the body controlled by those nerve fibers. Dural and pial AVMs can appear anywhere on the surface of the brain. Those located on the surface of the cerebral hemispheres-the uppermost portions of the brain-exert pressure on the cerebral cortex, the brain's "gray matter." Depending on their location, these AVMs may damage portions of the cerebral cortex involved with thinking, speaking, understanding language, hearing, taste, touch, or initiating and controlling voluntary movements. AVMs located on the frontal lobe close to the optic nerve or on the occipital lobe, the rear portion of the cerebrum where images are processed, may cause a variety of visual disturbances. AVMs also can form from blood vessels located deep inside the interior of the cerebrum. These AVMs may compromise the functions of three vital structures: the thalamus, which transmits nerve signals between the spinal cord and upper regions of the brain; the basal ganglia surrounding the thalamus, which coordinate complex movements; and the hippocampus, which plays a major role in memory. AVMs can affect other parts of the brain besides the cerebrum. The hindbrain is formed from two major structures: the cerebellum, which is nestled under the rear portion of the cerebrum, and the brainstem, which serves as the bridge linking the upper portions of the brain with the spinal cord. These structures control finely coordinated movements, maintain balance, and regulate some functions of internal organs, including those of the heart and lungs. AVM damage to these parts of the hindbrain can result in dizziness, giddiness, vomiting, a loss of the ability to coordinate complex movements such as walking, or uncontrollable muscle tremors. The greatest potential danger posed by AVMs is hemorrhage. Researchers believe that each year between 2 and 4 percent of all AVMs hemorrhage. Most episodes of bleeding remain undetected at the time they occur because they are not severe enough to cause significant neurological damage. But massive, even fatal, bleeding episodes do occur. The present state of knowledge does not permit doctors to predict whether or not any particular person with an AVM will suffer an extensive hemorrhage. The lesions can remain stable or can suddenly begin to grow. In a few cases, they have been observed to regress spontaneously. Whenever an AVM is detected, the individual should be carefully and consistently monitored for any signs of instability that may indicate an increased risk of hemorrhage. A few physical characteristics appear to indicate a greater-than-usual likelihood of clinically significant hemorrhage. Smaller AVMs have a greater likelihood of bleeding than do larger ones. Impaired drainage by unusually narrow or deeply situated veins also increases the chances of hemorrhage. Pregnancy also appears to increase the likelihood of clinically significant hemorrhage, mainly because of increases in blood pressure and blood volume. Finally, AVMs that have hemorrhaged once are about nine times more likely to bleed again during the first year after the initial hemorrhage than are lesions that have never bled. The damaging effects of a hemorrhage are related to lesion location. Bleeding from AVMs located deep inside the interior tissues, or parenchyma, of the brain typically causes more severe neurological damage than does hemorrhage by lesions that have formed in the dural or pial membranes or on the surface of the brain or spinal cord. (Deeply located bleeding is usually referred to as an intracerebral or parenchymal hemorrhage; bleeding within the membranes or on the surface of the brain is known as subdural or subarachnoid hemorrhage.) Thus, location is an important factor to consider when weighing the relative risks of surgical versus non-surgical treatment of AVMs. Besides AVMs, three other main types of vascular lesion can arise in the brain or spinal cord: cavernous malformations, capillary telangiectases, and venous malformations. These lesions may form virtually anywhere within the central nervous system, but unlike AVMs, they are not caused by high-velocity blood flow from arteries into veins. In contrast, cavernous malformations, telangiectases, and venous malformations are all low-flow lesions. Instead of a combination of arteries and veins, each one involves only one type of blood vessel. These lesions are less unstable than AVMs and do not pose the same relatively high risk of significant hemorrhage. In general, low-flow lesions tend to cause fewer troubling neurological symptoms and require less aggressive treatment than do AVMs. Source: Information provided courtesy of the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH). NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history. o Arteriovenous Malformation- Overview o Arteriovenous Malformation- Causes, detection and treatment