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pubmed23n0629_14054

Performance of FASTPlaqueTB and a modified protocol in a high HIV prevalence community in South Africa.

Modifications in the FASTPlaqueTB test protocol have resulted in an increase in the analytical limits of detection. This study investigated whether the performance of a modified prototype was able to increase the detection of smear-negative, culture-positive sputum samples as compared to the first generation FASTPlaqueTB test. Modifications to the FASTPlaqueTB did result in increased detection of smear-negative samples, but this was associated with a decrease in the specificity of the test. Before the FASTPlaqueTB can be considered as a viable replacement for smear microscopy and culture for the identification of tuberculosis, further work is required to resolve the performance issues identified in this study.

Performance of FASTPlaqueTB and a modified protocol in a high HIV prevalence community in South Africa. Modifications in the FASTPlaqueTB test protocol have resulted in an increase in the analytical limits of detection. This study investigated whether the performance of a modified prototype was able to increase the detection of smear-negative, culture-positive sputum samples as compared to the first generation FASTPlaqueTB test. Modifications to the FASTPlaqueTB did result in increased detection of smear-negative samples, but this was associated with a decrease in the specificity of the test. Before the FASTPlaqueTB can be considered as a viable replacement for smear microscopy and culture for the identification of tuberculosis, further work is required to resolve the performance issues identified in this study.

pubmed23n0738_18790

Highly sensitive biosensor based on UV-imprinted layered polymeric-inorganic composite waveguides.

An evanescent field sensor utilizing layered polymeric-inorganic composite waveguide configuration was developed in this work. The composite waveguide structure consists of a UV-imprint patterned polymer inverted rib waveguide with a Ta2O5 thin film sputter-deposited on top of the low refractive index polymer layers. The results suggest that the polymer based sensor can achieve a detection limit of 3 × 10(-7) RIU for refractive index sensing and corresponding limit of about 100 fg/mm2 for molecular adsorption detection. Besides enhancing the sensitivity significantly, the inorganic coating on the polymer layer was found to block water absorption effectively into the waveguide resulting in a stabilized sensor operation. The ability to use the developed sensor in specific molecular detection was confirmed by investigating antibody - antigen binding reactions. The results of this work demonstrate that high performance sensing capability can be obtained with the developed composite waveguide sensor.

Highly sensitive biosensor based on UV-imprinted layered polymeric-inorganic composite waveguides. An evanescent field sensor utilizing layered polymeric-inorganic composite waveguide configuration was developed in this work. The composite waveguide structure consists of a UV-imprint patterned polymer inverted rib waveguide with a Ta2O5 thin film sputter-deposited on top of the low refractive index polymer layers. The results suggest that the polymer based sensor can achieve a detection limit of 3 × 10(-7) RIU for refractive index sensing and corresponding limit of about 100 fg/mm2 for molecular adsorption detection. Besides enhancing the sensitivity significantly, the inorganic coating on the polymer layer was found to block water absorption effectively into the waveguide resulting in a stabilized sensor operation. The ability to use the developed sensor in specific molecular detection was confirmed by investigating antibody - antigen binding reactions. The results of this work demonstrate that high performance sensing capability can be obtained with the developed composite waveguide sensor.

pubmed23n0083_19333

[Physical properties of the aorta in normotensive insulin-dependent diabetic subjects. Study using Doppler echocardiography].

We studied 16 normotensive insulin-dependent diabetic patients (D) (11 males + 5 females) aged of 25-51 years old (mean = 35 +/- 6) with a good glycemic control, without microangiopathy and previous heart disease and 16 healthy control of 25 subjects (C) matched for sex age and body area. We measured: Systolic blood pressure (SBP) with a mercury sphygmomanometer, aortic diameter (AD), end diastolic left ventricular radius (r) and wall thickness (Th) by Echocardiography TM with 2 D echo control, the pulse wave delay (PWD) by measurement of time between the feet of aortic velocity tracings, recorded in the isthmus and near the diaphragm, Sternal length (L). Parameters calculated were: the ratio th/r. The pulse wave velocity PWV = L/PWD and the ratio PWV/AD which represents an indirect index of aortic characteristic impedance. (table; see text) PWV and the radio Th/r are significantly increased in diabetic patients as compared to the control group. Th/r is not significantly correlated with PWV in the 2 groups. This lack of correlation could be explained in the control group by the small rang of values of PWV (5-7.3 ms-1) and Th/r (0.26-0.38). It is not the case in the diabetic group where values are widespread (PWD 5-10 ms-1 and Th/r 0.23-0.53). in normotensive young insulin-dependent diabetic patients studied by doppler echocardiography: aortic rigidity measured by the pulse wave velocity is increased. Th/r ratio is also increased but this change of left ventricular geometry is not related to aortic rigidity in this group of patients.

[Physical properties of the aorta in normotensive insulin-dependent diabetic subjects. Study using Doppler echocardiography]. We studied 16 normotensive insulin-dependent diabetic patients (D) (11 males + 5 females) aged of 25-51 years old (mean = 35 +/- 6) with a good glycemic control, without microangiopathy and previous heart disease and 16 healthy control of 25 subjects (C) matched for sex age and body area. We measured: Systolic blood pressure (SBP) with a mercury sphygmomanometer, aortic diameter (AD), end diastolic left ventricular radius (r) and wall thickness (Th) by Echocardiography TM with 2 D echo control, the pulse wave delay (PWD) by measurement of time between the feet of aortic velocity tracings, recorded in the isthmus and near the diaphragm, Sternal length (L). Parameters calculated were: the ratio th/r. The pulse wave velocity PWV = L/PWD and the ratio PWV/AD which represents an indirect index of aortic characteristic impedance. (table; see text) PWV and the radio Th/r are significantly increased in diabetic patients as compared to the control group. Th/r is not significantly correlated with PWV in the 2 groups. This lack of correlation could be explained in the control group by the small rang of values of PWV (5-7.3 ms-1) and Th/r (0.26-0.38). It is not the case in the diabetic group where values are widespread (PWD 5-10 ms-1 and Th/r 0.23-0.53). in normotensive young insulin-dependent diabetic patients studied by doppler echocardiography: aortic rigidity measured by the pulse wave velocity is increased. Th/r ratio is also increased but this change of left ventricular geometry is not related to aortic rigidity in this group of patients.

pubmed23n1108_22746

Wearable Personal Core Body Temperature Measurement Considering Individual Differences and Dynamic Tissue Blood Perfusion.

Accurate and continuous measurement of the human core body temperature by a wearable device is of great significance for human health care and disease monitoring. The current wearable thermometers ignore the physiological differences between individuals and the role of blood perfusion in thermoregulation, resulting in insufficient accuracy and limitations in terms of the measurement sites. This study proposed a novel personal model for measuring core body temperature by taking dynamic tissue blood perfusion and individual differences into consideration. The technique facilitates possible accurate core body temperature measurements from the skin surface of the wrist and forehead. First, the personal core body temperature model was established based on the thermal equilibrium between the human body and the measurement device, in which the tissue blood perfusion changes dynamically with tissue temperature. Then, the parameters of the personal model that imply individual physiological differences were obtained based on personal data collected daily. The results show that with the developed personal model, the accuracy of the measured body temperature from the wrist is close to that of the forehead model. The wrist model and the forehead model have a mean absolute error of 0.297 (SD = 0.078)°C and 0.224 (SD = 0.071)°C, respectively, which meets the accuracy and robustness requirements of practical applications. The personal models significantly improve the accuracy compared with that of the group model, especially for the wrist model.

Wearable Personal Core Body Temperature Measurement Considering Individual Differences and Dynamic Tissue Blood Perfusion. Accurate and continuous measurement of the human core body temperature by a wearable device is of great significance for human health care and disease monitoring. The current wearable thermometers ignore the physiological differences between individuals and the role of blood perfusion in thermoregulation, resulting in insufficient accuracy and limitations in terms of the measurement sites. This study proposed a novel personal model for measuring core body temperature by taking dynamic tissue blood perfusion and individual differences into consideration. The technique facilitates possible accurate core body temperature measurements from the skin surface of the wrist and forehead. First, the personal core body temperature model was established based on the thermal equilibrium between the human body and the measurement device, in which the tissue blood perfusion changes dynamically with tissue temperature. Then, the parameters of the personal model that imply individual physiological differences were obtained based on personal data collected daily. The results show that with the developed personal model, the accuracy of the measured body temperature from the wrist is close to that of the forehead model. The wrist model and the forehead model have a mean absolute error of 0.297 (SD = 0.078)°C and 0.224 (SD = 0.071)°C, respectively, which meets the accuracy and robustness requirements of practical applications. The personal models significantly improve the accuracy compared with that of the group model, especially for the wrist model.

pubmed23n0359_22506

An evaluation of a community-based vocational rehabilitation program for adults with psychiatric disabilities.

The purpose of this research is to examine the effectiveness of a project aimed at the vocational rehabilitation of individuals suffering from chronic psychiatric disabilities. Gastown Vocational Services (GVS) is a specialized vocational rehabilitation program, under the auspices of Greater Vancouver Mental Health Service Society. The project consisted of three distinct phases and utilized a gradual, step-by-step rehabilitative approach to achieve vocational success. The first phase of the GVS project included comprehensive vocational assessment and work-readiness skill training. Participants in this phase met in small groups for three hours, three times a week for a 12-week period. The second phase involved supported work-experience placements in the community. These placements were two to five months in duration. The final phase included assistance in seeking employment, job re-training, or educational programs. Assessment measures were taken before participants began the program, immediately after the 12-week job preparation program, and at six-month follow-up. Seventy-three individuals participated in the training program over a two-year period. Their progress was compared to 18 individuals comprising a Waiting List Control group. The results showed significant improvement in the Intervention group on measures of assertiveness, work behaviour, depression, income, and employment status. No changes were evident in the Waiting List Control group.

An evaluation of a community-based vocational rehabilitation program for adults with psychiatric disabilities. The purpose of this research is to examine the effectiveness of a project aimed at the vocational rehabilitation of individuals suffering from chronic psychiatric disabilities. Gastown Vocational Services (GVS) is a specialized vocational rehabilitation program, under the auspices of Greater Vancouver Mental Health Service Society. The project consisted of three distinct phases and utilized a gradual, step-by-step rehabilitative approach to achieve vocational success. The first phase of the GVS project included comprehensive vocational assessment and work-readiness skill training. Participants in this phase met in small groups for three hours, three times a week for a 12-week period. The second phase involved supported work-experience placements in the community. These placements were two to five months in duration. The final phase included assistance in seeking employment, job re-training, or educational programs. Assessment measures were taken before participants began the program, immediately after the 12-week job preparation program, and at six-month follow-up. Seventy-three individuals participated in the training program over a two-year period. Their progress was compared to 18 individuals comprising a Waiting List Control group. The results showed significant improvement in the Intervention group on measures of assertiveness, work behaviour, depression, income, and employment status. No changes were evident in the Waiting List Control group.

pubmed23n0848_5188

A systematic review of the influence of skin pigmentation on changes in the concentrations of vitamin D and 25-hydroxyvitamin D in plasma/serum following experimental UV irradiation.

Defining whether skin pigmentation influences vitamin D photosynthesis is important for delivering accurate public health messages. Current evidence is contradictory. We undertook a systematic review of the published literature to examine the association between skin pigmentation and change in blood concentrations of vitamin D and 25-hydroxyvitamin D following experimental UV irradiation. Twelve studies fulfilled the inclusion criteria: human study in vivo with non-diseased participants; controlled artificial UV radiation; vitamin D or 25-hydroxyvitamin D measured in serum or plasma; full text in English. In seven studies, vitamin D photosynthesis was reduced in dark-skinned compared with fairer-skinned individuals. In the remaining five studies, only one of which was published after 1990, there was no difference in vitamin D photosynthesis according to skin type. The disparities in these results may be due to small sample sizes and variations in study methodology, including the source, dose and frequency of UV irradiation, phototype classification, and analysis of vitamin D and 25-hydroxyvitamin D. Of these, the spectrum emitted by the UV lamps may be significant. No study considered potential modifying factors, such as relevant genetic polymorphisms. On balance, we conclude that pigmented skin has less effective photoproduction of vitamin D and 25-hydroxyvitamin D. The quantity of sun exposure needed for dark-skinned, compared with light-skinned, people to achieve vitamin D sufficiency remains uncertain.

A systematic review of the influence of skin pigmentation on changes in the concentrations of vitamin D and 25-hydroxyvitamin D in plasma/serum following experimental UV irradiation. Defining whether skin pigmentation influences vitamin D photosynthesis is important for delivering accurate public health messages. Current evidence is contradictory. We undertook a systematic review of the published literature to examine the association between skin pigmentation and change in blood concentrations of vitamin D and 25-hydroxyvitamin D following experimental UV irradiation. Twelve studies fulfilled the inclusion criteria: human study in vivo with non-diseased participants; controlled artificial UV radiation; vitamin D or 25-hydroxyvitamin D measured in serum or plasma; full text in English. In seven studies, vitamin D photosynthesis was reduced in dark-skinned compared with fairer-skinned individuals. In the remaining five studies, only one of which was published after 1990, there was no difference in vitamin D photosynthesis according to skin type. The disparities in these results may be due to small sample sizes and variations in study methodology, including the source, dose and frequency of UV irradiation, phototype classification, and analysis of vitamin D and 25-hydroxyvitamin D. Of these, the spectrum emitted by the UV lamps may be significant. No study considered potential modifying factors, such as relevant genetic polymorphisms. On balance, we conclude that pigmented skin has less effective photoproduction of vitamin D and 25-hydroxyvitamin D. The quantity of sun exposure needed for dark-skinned, compared with light-skinned, people to achieve vitamin D sufficiency remains uncertain.

pubmed23n0045_14873

Ceftazidime and amikacin as empiric treatment of febrile episodes in neutropenic patients in Saudi Arabia.

Sixty-four consecutive febrile episodes in 50 consecutive patients with malignancy and neutropenia were empirically treated with a combination of ceftazidime and amikacin. Of 52 analysable episodes, the response rate was 59.6% overall and 26.3% of episodes with microbiologically documented infections with septicaemia. Infection-related death occurred in 10 patients (19.2% of episodes). The response rates were similar in patients with acute leukaemia or other malignancies. Poor response is attributed to increased frequency of infections with Gram-positive and fungal organisms. A modified empiric regimen including cover for Gram-positive and fungal organisms is suggested in similar patient populations.

Ceftazidime and amikacin as empiric treatment of febrile episodes in neutropenic patients in Saudi Arabia. Sixty-four consecutive febrile episodes in 50 consecutive patients with malignancy and neutropenia were empirically treated with a combination of ceftazidime and amikacin. Of 52 analysable episodes, the response rate was 59.6% overall and 26.3% of episodes with microbiologically documented infections with septicaemia. Infection-related death occurred in 10 patients (19.2% of episodes). The response rates were similar in patients with acute leukaemia or other malignancies. Poor response is attributed to increased frequency of infections with Gram-positive and fungal organisms. A modified empiric regimen including cover for Gram-positive and fungal organisms is suggested in similar patient populations.

pubmed23n0777_20584

[Clinical evaluation of leukocyte differential count in peripheral blood by five-color flow cytometry].

To explore the clinical application values of five-color flow cytometry for leukocyte differential count in peripheral blood. Leukocyte differentiation in 265 peripheral blood samples collected at Peking University First Hospital from September 2010 to December 2010 was detected by standard microscopic cytology as a reference method. Meanwhile, Beckman-Coulter LH750 hematology analyzer and FC500 flow cytometer were performed. Then the correlations were analyzed between microscopic cytology, hematology analyzer and flow cytometry. Forty blood samples collected at Peking University First Hospital, Beijing Daopei Hospital and General Hospital of Beijing Military Command from August 2010 to November 2010 were analyzed by standard microscopic cytology, Beckman-Coulter LH750 hematology analyzer and NAVIOS flow cytometer. Then the correlations between microscopy, hematology analyzer and flow cytometry were explored to analyze the clinical diagnostic efficiency of flow cytometry. Correlation of leukocyte differential count between FC500 flow cytometer and standard microscopic cytology was significant (all P < 0.01) . And it was superior in the detection of lymphocytes, neutrophils and eosinophils (r = 0.955, 0.928, 0.876). Moreover, the correlation of leukocyte differential count between NAVIOS flow cytometer via manual gate and standard microscopic cytology was significant (r > 0.700, all P < 0.01) except for basophils. And it was superior in the detection of neutrophils, lymphocytes and blasts (r = 0.950, 0.915, 0.852). When 1% was set as the cut-off value of immature granulocytes on standard microscopic cytology, the sensitivity and specificity of flow cytometry was 87% and 76% respectively. When 0.5% was set as the cut-off value of blasts on standard microscopic cytology, the sensitivity and specificity of flow cytometry stood at 100% and 92% respectively. Five-color flow cytometry is well-correlated with standard microscopic cytology for leukocyte differential count in peripheral blood with different flow cytometers, and the sensitivity of detecting blasts and immature granulocytes is very excellent.

[Clinical evaluation of leukocyte differential count in peripheral blood by five-color flow cytometry]. To explore the clinical application values of five-color flow cytometry for leukocyte differential count in peripheral blood. Leukocyte differentiation in 265 peripheral blood samples collected at Peking University First Hospital from September 2010 to December 2010 was detected by standard microscopic cytology as a reference method. Meanwhile, Beckman-Coulter LH750 hematology analyzer and FC500 flow cytometer were performed. Then the correlations were analyzed between microscopic cytology, hematology analyzer and flow cytometry. Forty blood samples collected at Peking University First Hospital, Beijing Daopei Hospital and General Hospital of Beijing Military Command from August 2010 to November 2010 were analyzed by standard microscopic cytology, Beckman-Coulter LH750 hematology analyzer and NAVIOS flow cytometer. Then the correlations between microscopy, hematology analyzer and flow cytometry were explored to analyze the clinical diagnostic efficiency of flow cytometry. Correlation of leukocyte differential count between FC500 flow cytometer and standard microscopic cytology was significant (all P < 0.01) . And it was superior in the detection of lymphocytes, neutrophils and eosinophils (r = 0.955, 0.928, 0.876). Moreover, the correlation of leukocyte differential count between NAVIOS flow cytometer via manual gate and standard microscopic cytology was significant (r > 0.700, all P < 0.01) except for basophils. And it was superior in the detection of neutrophils, lymphocytes and blasts (r = 0.950, 0.915, 0.852). When 1% was set as the cut-off value of immature granulocytes on standard microscopic cytology, the sensitivity and specificity of flow cytometry was 87% and 76% respectively. When 0.5% was set as the cut-off value of blasts on standard microscopic cytology, the sensitivity and specificity of flow cytometry stood at 100% and 92% respectively. Five-color flow cytometry is well-correlated with standard microscopic cytology for leukocyte differential count in peripheral blood with different flow cytometers, and the sensitivity of detecting blasts and immature granulocytes is very excellent.

pubmed23n0698_23441

Regulation of the urokinase receptor (uPAR) by LDL receptor-related protein-1 (LRP1).

LDL receptor-related protein (LRP1) is an endocytic receptor for multiple ligands, including proteases, growth factors, apolipoproteins, and extracellular matrix proteins. In some cell types, including neurons, neuron-like cells, and Schwann cells, ligand-binding to LRP1 triggers robust cell-signaling. This "direct" pathway by which LRP1 regulates cell-signaling promotes cell survival and cell migration. LRP1 also regulates the composition of the plasma membrane proteome. Although multiple mechanisms are involved, LRP1 and receptors in the same gene family facilitate the endocytosis of other plasma membrane proteins. When LRP1 regulates the abundance or trafficking of another cell-signaling receptor in the plasma membrane, activation of important cell-signaling pathways may be controlled "indirectly" by LRP1. The urokinase receptor (uPAR) was the first cell-signaling receptor identified as a member of the LRP1-regulated plasma membrane proteome. Because LRP1 down-regulates cell-surface uPAR by facilitating its endocytosis, under some conditions, uPAR-initiated cell-signaling may be inhibited by LRP1. However, the relationship between LRP1 and uPAR is complicated because uPAR endocytosis may be necessary for sustained uPAR-initiated cell-signaling. Certain cell-signaling factors, including ERK, phosphatidylinositol 3-kinase, and Rac1 are regulated by LRP1, directly, and indirectly through uPAR. Thus, the predominant effect of LRP1 on cell-signaling, in different cell types, may depend on the abundance of LRP1 and uPAR and on the availability of ligands for LRP1 and uPAR. Opportunities for targeting the uPAR-LRP1 system through drug discovery are discussed.

Regulation of the urokinase receptor (uPAR) by LDL receptor-related protein-1 (LRP1). LDL receptor-related protein (LRP1) is an endocytic receptor for multiple ligands, including proteases, growth factors, apolipoproteins, and extracellular matrix proteins. In some cell types, including neurons, neuron-like cells, and Schwann cells, ligand-binding to LRP1 triggers robust cell-signaling. This "direct" pathway by which LRP1 regulates cell-signaling promotes cell survival and cell migration. LRP1 also regulates the composition of the plasma membrane proteome. Although multiple mechanisms are involved, LRP1 and receptors in the same gene family facilitate the endocytosis of other plasma membrane proteins. When LRP1 regulates the abundance or trafficking of another cell-signaling receptor in the plasma membrane, activation of important cell-signaling pathways may be controlled "indirectly" by LRP1. The urokinase receptor (uPAR) was the first cell-signaling receptor identified as a member of the LRP1-regulated plasma membrane proteome. Because LRP1 down-regulates cell-surface uPAR by facilitating its endocytosis, under some conditions, uPAR-initiated cell-signaling may be inhibited by LRP1. However, the relationship between LRP1 and uPAR is complicated because uPAR endocytosis may be necessary for sustained uPAR-initiated cell-signaling. Certain cell-signaling factors, including ERK, phosphatidylinositol 3-kinase, and Rac1 are regulated by LRP1, directly, and indirectly through uPAR. Thus, the predominant effect of LRP1 on cell-signaling, in different cell types, may depend on the abundance of LRP1 and uPAR and on the availability of ligands for LRP1 and uPAR. Opportunities for targeting the uPAR-LRP1 system through drug discovery are discussed.

pubmed23n0570_11170

Re-examining medical modernization: framing the public in Finnish biomedical research policy.

Despite recent evidence that suggests that knowledge production within the medical community is increasingly based on knowledge-making coalitions or what some have called the co-production of knowledge, there remains a strong expert led policy agenda in many countries in relation to human genome research. This article reports on the role of experts in defining the scope of discussion in relation to the biomedical use of human tissue sample collections or biobanks in Finland using the case of the Genome Information Center. It is argued that the rhetorical strategies should not be understood simply as subversive tactics, but rather as ways of engaging the public within particular contexts of creating commercial expectations and visions which are easier to negotiate from a policy perspective.

Re-examining medical modernization: framing the public in Finnish biomedical research policy. Despite recent evidence that suggests that knowledge production within the medical community is increasingly based on knowledge-making coalitions or what some have called the co-production of knowledge, there remains a strong expert led policy agenda in many countries in relation to human genome research. This article reports on the role of experts in defining the scope of discussion in relation to the biomedical use of human tissue sample collections or biobanks in Finland using the case of the Genome Information Center. It is argued that the rhetorical strategies should not be understood simply as subversive tactics, but rather as ways of engaging the public within particular contexts of creating commercial expectations and visions which are easier to negotiate from a policy perspective.

pubmed23n1125_15795

Phylogeny, diversification, and biogeography of a hemiclonal hybrid system of native Australian freshwater fishes (Gobiiformes: Gobioidei: Eleotridae: Hypseleotris).

Carp gudgeons (genus Hypseleotris) are a prominent part of the Australian freshwater fish fauna, with species distributed around the western, northern, and eastern reaches of the continent. We infer a calibrated phylogeny of the genus based on nuclear ultraconserved element (UCE) sequences and using Bayesian estimation of divergence times, and use this phylogeny to investigate geographic patterns of diversification with GeoSSE. The southeastern species have hybridized to form hemiclonal lineages, and we also resolve relationships of hemiclones and compare their phylogenetic placement in the UCE phylogeny with a hypothesis based on complete mitochondrial genomes. We then use phased SNPs extracted from the UCE sequences for population structure analysis among the southeastern species and hemiclones. Hypseleotris cyprinoides, a widespread euryhaline species known from throughout the Indo-Pacific, is resolved outside the remainder of the species. Two Australian radiations comprise the bulk of Hypseleotris, one primarily in the northwestern coastal rivers and a second inhabiting the southeastern region including the Murray-Darling, Bulloo-Bancannia and Lake Eyre basins, plus coastal rivers east of the Great Dividing Range. Our phylogenetic results reveal cytonuclear discordance between the UCE and mitochondrial hypotheses, place hemiclone hybrids among their parental taxa, and indicate that the genus Kimberleyeleotris is nested within the northwestern Hypseleotris radiation along with three undescribed species. We infer a crown age for Hypseleotris of 17.3 Ma, date the radiation of Australian species at roughly 10.1 Ma, and recover the crown ages of the northwestern (excluding H. compressa) and southeastern radiations at 5.9 and 7.2 Ma, respectively. Range-dependent diversification analyses using GeoSSE indicate that speciation and extinction rates have been steady between the northwestern and southeastern Australian radiations and between smaller radiations of species in the Kimberley region and the Arnhem Plateau. Analysis of phased SNPs confirms inheritance patterns and reveals high levels of heterozygosity among the hemiclones. The northwestern species have restricted ranges and likely speciated in allopatry, while the southeastern species are known from much larger areas, consistent with peripatric speciation or allopatric speciation followed by secondary contact. Species in the northwestern Kimberley region differ in shape from those in the southeast, with the Kimberley species notably more elongate and slender than the stocky southeastern species, likely due to the different topographies and flow regimes of the rivers they inhabit.

Phylogeny, diversification, and biogeography of a hemiclonal hybrid system of native Australian freshwater fishes (Gobiiformes: Gobioidei: Eleotridae: Hypseleotris). Carp gudgeons (genus Hypseleotris) are a prominent part of the Australian freshwater fish fauna, with species distributed around the western, northern, and eastern reaches of the continent. We infer a calibrated phylogeny of the genus based on nuclear ultraconserved element (UCE) sequences and using Bayesian estimation of divergence times, and use this phylogeny to investigate geographic patterns of diversification with GeoSSE. The southeastern species have hybridized to form hemiclonal lineages, and we also resolve relationships of hemiclones and compare their phylogenetic placement in the UCE phylogeny with a hypothesis based on complete mitochondrial genomes. We then use phased SNPs extracted from the UCE sequences for population structure analysis among the southeastern species and hemiclones. Hypseleotris cyprinoides, a widespread euryhaline species known from throughout the Indo-Pacific, is resolved outside the remainder of the species. Two Australian radiations comprise the bulk of Hypseleotris, one primarily in the northwestern coastal rivers and a second inhabiting the southeastern region including the Murray-Darling, Bulloo-Bancannia and Lake Eyre basins, plus coastal rivers east of the Great Dividing Range. Our phylogenetic results reveal cytonuclear discordance between the UCE and mitochondrial hypotheses, place hemiclone hybrids among their parental taxa, and indicate that the genus Kimberleyeleotris is nested within the northwestern Hypseleotris radiation along with three undescribed species. We infer a crown age for Hypseleotris of 17.3 Ma, date the radiation of Australian species at roughly 10.1 Ma, and recover the crown ages of the northwestern (excluding H. compressa) and southeastern radiations at 5.9 and 7.2 Ma, respectively. Range-dependent diversification analyses using GeoSSE indicate that speciation and extinction rates have been steady between the northwestern and southeastern Australian radiations and between smaller radiations of species in the Kimberley region and the Arnhem Plateau. Analysis of phased SNPs confirms inheritance patterns and reveals high levels of heterozygosity among the hemiclones. The northwestern species have restricted ranges and likely speciated in allopatry, while the southeastern species are known from much larger areas, consistent with peripatric speciation or allopatric speciation followed by secondary contact. Species in the northwestern Kimberley region differ in shape from those in the southeast, with the Kimberley species notably more elongate and slender than the stocky southeastern species, likely due to the different topographies and flow regimes of the rivers they inhabit.

pubmed23n1106_16616

Association of subcortical gray-matter volumes with life-course-persistent antisocial behavior in a population-representative longitudinal birth cohort.

Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively-measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7-26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The life-course-persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions.

Association of subcortical gray-matter volumes with life-course-persistent antisocial behavior in a population-representative longitudinal birth cohort. Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively-measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7-26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The life-course-persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions.

pubmed23n1131_2295

Population Genetic Structure and Selection Signature Analysis of Beijing Black Pig.

Beijing Black pig is an excellent cultivated black pig breed in China, with desirable body shape, tender meat quality and robust disease resistance. To explore the level of admixture and selection signatures of Beijing Black pigs, a total number of 90 individuals covering nine pig breeds were used in our study, including Beijing Black pig, Large White, Landrace, Duroc, Lantang pig, Luchuan pig, Mashen pig, Huainan pig and Min pig. These animals were resequenced with 18.19 folds mapped read depth on average. Generally, we found that Beijing Black pig was genetically closer to commercial pig breeds by population genetic structure and genetic diversity analysis, and was also affected by Chinese domestic breeds Huainan pig and Min pig. These results are consistent with the cross-breeding history of Beijing Black pig. Selection signal detections were performed on three pig breeds, Beijing Black pig, Duroc and Large White, using three complementary methods (F<subST</sub, <iθπ</i, and XP-EHH). In total, 1,167 significant selected regions and 392 candidate genes were identified. Functional annotations were enriched to pathways related to immune processes and meat and lipid metabolism. Finally, potential candidate genes, influencing meat quality (<iGPHA2, EHD1</i, <iHNF1A</i, <iC12orf43</i, <iGLTP</i, <iTRPV4</i, <iMVK</i, and <iMMAB</i), reproduction (<iPPP2R5B</i and <iMAP9</i), and disease resistance (<iOASL</i, <iANKRD13A</i, and <iGIT2</i), were further detected by gene annotation analysis. Our results advanced the understanding of the genetic mechanism behind artificial selection of Beijing Black pigs, and provided theoretical basis for the subsequent breeding and genetic research of this breed.

Population Genetic Structure and Selection Signature Analysis of Beijing Black Pig. Beijing Black pig is an excellent cultivated black pig breed in China, with desirable body shape, tender meat quality and robust disease resistance. To explore the level of admixture and selection signatures of Beijing Black pigs, a total number of 90 individuals covering nine pig breeds were used in our study, including Beijing Black pig, Large White, Landrace, Duroc, Lantang pig, Luchuan pig, Mashen pig, Huainan pig and Min pig. These animals were resequenced with 18.19 folds mapped read depth on average. Generally, we found that Beijing Black pig was genetically closer to commercial pig breeds by population genetic structure and genetic diversity analysis, and was also affected by Chinese domestic breeds Huainan pig and Min pig. These results are consistent with the cross-breeding history of Beijing Black pig. Selection signal detections were performed on three pig breeds, Beijing Black pig, Duroc and Large White, using three complementary methods (F<subST</sub, <iθπ</i, and XP-EHH). In total, 1,167 significant selected regions and 392 candidate genes were identified. Functional annotations were enriched to pathways related to immune processes and meat and lipid metabolism. Finally, potential candidate genes, influencing meat quality (<iGPHA2, EHD1</i, <iHNF1A</i, <iC12orf43</i, <iGLTP</i, <iTRPV4</i, <iMVK</i, and <iMMAB</i), reproduction (<iPPP2R5B</i and <iMAP9</i), and disease resistance (<iOASL</i, <iANKRD13A</i, and <iGIT2</i), were further detected by gene annotation analysis. Our results advanced the understanding of the genetic mechanism behind artificial selection of Beijing Black pigs, and provided theoretical basis for the subsequent breeding and genetic research of this breed.

pubmed23n0380_22662

Clopidogrel: new preparation. An alternative to aspirin.

(1) Clopidogrel, an antiplatelet drug chemically similar to ticlopidine, is marketed in France for secondary prevention of thrombotic complications in patients with a history of myocardial infarction, ischaemic stroke or peripheral arterial disease. (2) Marketing authorisation was based mainly on the CAPRIE trial, a study that involved 19,815 patients. In this trial of secondary cardiovascular prevention, clopidogrel was slightly more effective than aspirin (325 mg/day) according to a statistical analysis of a combined end point (ischaemic stroke, or myocardial infarction, or death of vascular causes). The difference was more marked in the subgroup of patients with obstructive arterial disease of the lower limbs. (3) Clopidogrel was well tolerated in this trial. The only adverse effects more frequent on clopidogrel than on aspirin were rash and diarrhoea. (4) Clopidogrel showed no haematological toxicity, an adverse effect that restricts the use of ticlopidine. (5) The lack of long-term follow-up in real clinical settings prevents any meaningful estimation of the safety profile or of the risk of drug interactions.

Clopidogrel: new preparation. An alternative to aspirin. (1) Clopidogrel, an antiplatelet drug chemically similar to ticlopidine, is marketed in France for secondary prevention of thrombotic complications in patients with a history of myocardial infarction, ischaemic stroke or peripheral arterial disease. (2) Marketing authorisation was based mainly on the CAPRIE trial, a study that involved 19,815 patients. In this trial of secondary cardiovascular prevention, clopidogrel was slightly more effective than aspirin (325 mg/day) according to a statistical analysis of a combined end point (ischaemic stroke, or myocardial infarction, or death of vascular causes). The difference was more marked in the subgroup of patients with obstructive arterial disease of the lower limbs. (3) Clopidogrel was well tolerated in this trial. The only adverse effects more frequent on clopidogrel than on aspirin were rash and diarrhoea. (4) Clopidogrel showed no haematological toxicity, an adverse effect that restricts the use of ticlopidine. (5) The lack of long-term follow-up in real clinical settings prevents any meaningful estimation of the safety profile or of the risk of drug interactions.

pubmed23n0541_19409

Subcutaneous fat necrosis with hypercalcemia.

Subcutaneous fat necrosis of the newborn (SCFN) is an uncommon condition and may be complicated by hypercalcemia. A 28-day-old neonate, presenting with SCFN, hypercalcemia and nephrocalcinosis was managed with intravenous saline followed by furosemide, oral prednisolone, potassium citrate and etidronate.

Subcutaneous fat necrosis with hypercalcemia. Subcutaneous fat necrosis of the newborn (SCFN) is an uncommon condition and may be complicated by hypercalcemia. A 28-day-old neonate, presenting with SCFN, hypercalcemia and nephrocalcinosis was managed with intravenous saline followed by furosemide, oral prednisolone, potassium citrate and etidronate.

pubmed23n0962_14375

Prevalence of Low-Attenuation Homogeneous Papillary Renal Cell Carcinoma Mimicking Renal Cysts on CT.

The objective of our study was to determine the attenuation range of homogeneous papillary renal cell carcinomas (RCCs) on contrast-enhanced CT. This retrospective study was performed at two institutions from January 1, 2007, to January 1, 2017. Multiphasic CT studies with and without IV contrast material of 114 patients with pathologically proven papillary RCCs were independently reviewed by two sets of two abdominal radiologists. Seventy-two cases were excluded because of subjective lesion heterogeneity, leaving 42 homogeneous RCCs. Three ROIs were placed on all lesions for all CT phases, and the mean attenuations were calculated. Mean lesion size was 2.8 cm (range, 1.2-11.0 cm). The attenuation range for each CT phase was as follows: unenhanced, 14.7-50.7 HU; corticomedullary, 32.2-99.5 HU; portal venous, 40.8-95.1 HU; nephrographic, 17.9-90.8 HU; and excretory, 18.0-73.0 HU. Two of 114 (1.8%; 95% CI, 0.2-6.5%) RCCs were homogeneous and less than 30 HU on the portal venous or nephrographic phase. One of these RCCs was a solid hypoenhancing mass, and the other was a homogeneous cystic RCC. Of the cases with an unenhanced phase, three of 107 (2.8%; 95% CI, 0.6-8.8%) were both homogeneous and were less than 20 HU in attenuation. Papillary RCCs are rarely both subjectively homogeneous and less than 20 HU at unenhanced CT and less than 30 HU at portal venous or nephrographic phase CT.

Prevalence of Low-Attenuation Homogeneous Papillary Renal Cell Carcinoma Mimicking Renal Cysts on CT. The objective of our study was to determine the attenuation range of homogeneous papillary renal cell carcinomas (RCCs) on contrast-enhanced CT. This retrospective study was performed at two institutions from January 1, 2007, to January 1, 2017. Multiphasic CT studies with and without IV contrast material of 114 patients with pathologically proven papillary RCCs were independently reviewed by two sets of two abdominal radiologists. Seventy-two cases were excluded because of subjective lesion heterogeneity, leaving 42 homogeneous RCCs. Three ROIs were placed on all lesions for all CT phases, and the mean attenuations were calculated. Mean lesion size was 2.8 cm (range, 1.2-11.0 cm). The attenuation range for each CT phase was as follows: unenhanced, 14.7-50.7 HU; corticomedullary, 32.2-99.5 HU; portal venous, 40.8-95.1 HU; nephrographic, 17.9-90.8 HU; and excretory, 18.0-73.0 HU. Two of 114 (1.8%; 95% CI, 0.2-6.5%) RCCs were homogeneous and less than 30 HU on the portal venous or nephrographic phase. One of these RCCs was a solid hypoenhancing mass, and the other was a homogeneous cystic RCC. Of the cases with an unenhanced phase, three of 107 (2.8%; 95% CI, 0.6-8.8%) were both homogeneous and were less than 20 HU in attenuation. Papillary RCCs are rarely both subjectively homogeneous and less than 20 HU at unenhanced CT and less than 30 HU at portal venous or nephrographic phase CT.

pubmed23n0691_24245

Effect of deep brain stimulation on autonomic dysfunction in patients with Parkinson's disease.

Increasing attention is being paid to the non-motor symptoms of Parkinson's disease (PD). While deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to clearly improve motor symptoms of PD, the effects of STN DBS on autonomic symptoms have not been well studied. We examined 11 patients undergoing STN DBS for PD. Patients were administered a questionnaire by phone to evaluate pre-operative and post-operative function. Three out of the 11 patients reported marked improvement post-DBS in one or more symptoms of autonomic dysfunction (sweating, bladder, or bowel function). All three patients had early-onset PD (EOPD), whereas the eight patients reporting no significant improvement were those with late-onset PD. Thus, we found that some patients experienced marked improvement in sweating and/or bowel and bladder function after STN DBS, with a trend towards a response in patients with EOPD. Our results suggest the utility of a larger prospective study.

Effect of deep brain stimulation on autonomic dysfunction in patients with Parkinson's disease. Increasing attention is being paid to the non-motor symptoms of Parkinson's disease (PD). While deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to clearly improve motor symptoms of PD, the effects of STN DBS on autonomic symptoms have not been well studied. We examined 11 patients undergoing STN DBS for PD. Patients were administered a questionnaire by phone to evaluate pre-operative and post-operative function. Three out of the 11 patients reported marked improvement post-DBS in one or more symptoms of autonomic dysfunction (sweating, bladder, or bowel function). All three patients had early-onset PD (EOPD), whereas the eight patients reporting no significant improvement were those with late-onset PD. Thus, we found that some patients experienced marked improvement in sweating and/or bowel and bladder function after STN DBS, with a trend towards a response in patients with EOPD. Our results suggest the utility of a larger prospective study.

pubmed23n0936_12446

MicroRNAs and cancer: Key paradigms in molecular therapy.

MicroRNAs (miRNAs) are a type of small non-coding RNA molecule that performs an important role in post-transcriptional gene regulation. Since miRNAs were first identified in 1993, a number of studies have demonstrated that they act as tumor suppressors or oncogenes in human cancer, including colorectal, lung, brain, breast and liver cancer, and leukemia. Large high-throughput studies have previously revealed that miRNA profiling is critical for the diagnosis and prognosis of patients with cancer, while certain miRNAs possess the potential to be used as diagnostic and prognostic biomarkers or therapeutic targets in cancer. The present study reviews the studies and examines the roles of miRNAs in cancer diagnosis, prognosis and treatment, and discusses the potential therapeutic modality of exploiting miRNAs.

MicroRNAs and cancer: Key paradigms in molecular therapy. MicroRNAs (miRNAs) are a type of small non-coding RNA molecule that performs an important role in post-transcriptional gene regulation. Since miRNAs were first identified in 1993, a number of studies have demonstrated that they act as tumor suppressors or oncogenes in human cancer, including colorectal, lung, brain, breast and liver cancer, and leukemia. Large high-throughput studies have previously revealed that miRNA profiling is critical for the diagnosis and prognosis of patients with cancer, while certain miRNAs possess the potential to be used as diagnostic and prognostic biomarkers or therapeutic targets in cancer. The present study reviews the studies and examines the roles of miRNAs in cancer diagnosis, prognosis and treatment, and discusses the potential therapeutic modality of exploiting miRNAs.

pubmed23n0408_20652

Comparative evaluation of retrospective shading correction methods.

Because of the inherent imperfections of the image formation process, microscopical images are often corrupted by spurious intensity variations. This phenomenon, known as shading or intensity inhomogeneity, may have an adverse affect on automatic image processing, such as segmentation and registration. Shading correction methods may be prospective or retrospective. The former require an acquisition protocol tuned to shading correction, whereas the latter can be applied to any image, because they only use the information already present in an image. Nine retrospective shading correction methods were implemented, evaluated and compared on three sets of differently structured synthetic shaded and shading-free images and on three sets of real microscopical images acquired by different acquisition set-ups. The performance of a method was expressed quantitatively by the coefficient of joint variations between two different object classes. The results show that all methods, except the entropy minimization method, work well for certain images, but perform poorly for others. The entropy minimization method outperforms the other methods in terms of reduction of true intensity variations and preservation of intensity characteristics of shading-free images. The strength of the entropy minimization method is especially apparent when applied to images containing large-scale objects.

Comparative evaluation of retrospective shading correction methods. Because of the inherent imperfections of the image formation process, microscopical images are often corrupted by spurious intensity variations. This phenomenon, known as shading or intensity inhomogeneity, may have an adverse affect on automatic image processing, such as segmentation and registration. Shading correction methods may be prospective or retrospective. The former require an acquisition protocol tuned to shading correction, whereas the latter can be applied to any image, because they only use the information already present in an image. Nine retrospective shading correction methods were implemented, evaluated and compared on three sets of differently structured synthetic shaded and shading-free images and on three sets of real microscopical images acquired by different acquisition set-ups. The performance of a method was expressed quantitatively by the coefficient of joint variations between two different object classes. The results show that all methods, except the entropy minimization method, work well for certain images, but perform poorly for others. The entropy minimization method outperforms the other methods in terms of reduction of true intensity variations and preservation of intensity characteristics of shading-free images. The strength of the entropy minimization method is especially apparent when applied to images containing large-scale objects.

pubmed23n1125_2192

Personality changes after subarachnoid hemorrhage: A systematic review and meta-analysis.

Personality changes (PC) comprise a common and debilitating illness that accompanies many neurological disorders, including non-traumatic subarachnoid hemorrhage (SAH). The aim of this systematic review was to identify and critically appraise all published studies that have reported the frequency, severity, and time course of PC after SAH, the factors associated with the development of PC and the effects of PC on patients' lives after SAH. We searched the PubMed, EMBASE, PsycINFO, and Ovid Nursing databases for studies published in English that recruited at least 10 patients (&gt;18 years old) after SAH who were also diagnosed with PC. We found eight studies involving 1227 patients met the study entry criteria. The frequency of PC ranged from 32% to 59%, with a pooled frequency of 44%. The clinical course of PC after SAH was unclear. PC after SAH may be associated with the clinical features and treatment factors related to SAH and comorbid conditions. Neurological signs, disability and surgical treatment increased the risk of PC. PC reduced the study participants' chance of employment. In summary, PC commonly occurs after SAH. Further research is needed to clarify the time course of PC and identify the risk factors, neurochemical factors, and brain circuits associated with the development of post-SAH PC. Randomized controlled treatment trials targeting SAH-related PC are warranted.

Personality changes after subarachnoid hemorrhage: A systematic review and meta-analysis. Personality changes (PC) comprise a common and debilitating illness that accompanies many neurological disorders, including non-traumatic subarachnoid hemorrhage (SAH). The aim of this systematic review was to identify and critically appraise all published studies that have reported the frequency, severity, and time course of PC after SAH, the factors associated with the development of PC and the effects of PC on patients' lives after SAH. We searched the PubMed, EMBASE, PsycINFO, and Ovid Nursing databases for studies published in English that recruited at least 10 patients (&gt;18 years old) after SAH who were also diagnosed with PC. We found eight studies involving 1227 patients met the study entry criteria. The frequency of PC ranged from 32% to 59%, with a pooled frequency of 44%. The clinical course of PC after SAH was unclear. PC after SAH may be associated with the clinical features and treatment factors related to SAH and comorbid conditions. Neurological signs, disability and surgical treatment increased the risk of PC. PC reduced the study participants' chance of employment. In summary, PC commonly occurs after SAH. Further research is needed to clarify the time course of PC and identify the risk factors, neurochemical factors, and brain circuits associated with the development of post-SAH PC. Randomized controlled treatment trials targeting SAH-related PC are warranted.

pubmed23n0570_7762

[Perioperative changes of blood coagulability evaluated by thromboelastography (TEG) in patients undergoing total knee and total hip arthroplasty].

A large number of studies have examined the incidence of thromboembolic complications after orthopedic surgery of the lower extremity. We investigated the perioperative changes of coagulability following total knee arthroplasty (TKA) or total hip arthroplasty (THA) using thromboelastography (TEG), which could comprehensively assess the coagulation and fibrinolytic system. Thirty patients scheduled for TKA (n= 10), THA (n= 10) and other lower extremity orthopedic surgery (control, n= 10) were studied. TEG was analyzed with K-value, MA-value and coagulation index (CI) before induction of anesthesia and 24 hours after surgery. K-values decreased significantly after TKA and THA compared with the values before the induction of anesthesia. MA-values and CI increased significantly after TKA and THA compared with the values before the induction. There were no significant changes in K-value, MA-value and CI in the control group during the perioperative period. The results suggest that TKA and THA lead blood coagulation to hypercoagulable state at the early postoperative stage.

[Perioperative changes of blood coagulability evaluated by thromboelastography (TEG) in patients undergoing total knee and total hip arthroplasty]. A large number of studies have examined the incidence of thromboembolic complications after orthopedic surgery of the lower extremity. We investigated the perioperative changes of coagulability following total knee arthroplasty (TKA) or total hip arthroplasty (THA) using thromboelastography (TEG), which could comprehensively assess the coagulation and fibrinolytic system. Thirty patients scheduled for TKA (n= 10), THA (n= 10) and other lower extremity orthopedic surgery (control, n= 10) were studied. TEG was analyzed with K-value, MA-value and coagulation index (CI) before induction of anesthesia and 24 hours after surgery. K-values decreased significantly after TKA and THA compared with the values before the induction of anesthesia. MA-values and CI increased significantly after TKA and THA compared with the values before the induction. There were no significant changes in K-value, MA-value and CI in the control group during the perioperative period. The results suggest that TKA and THA lead blood coagulation to hypercoagulable state at the early postoperative stage.

pubmed23n0512_4528

Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis.

Hodgkin's disease (HD) is characterized by the accumulation of functionally anergic T cells in the vicinity of the malignant Hodgkin/Reed-Sternberg (H/RS) cells. To revert cellular anergy against H/RS cells, we generated an anti-CD30-antibody-interleukin-(IL)-2 and an anti-CD30-antibody-IL12 fusion protein that target IL2 and IL12, respectively, specifically to CD30+ H/RS cells. Both antibody-cytokine fusion proteins act cooperatively in the activation of resting NK cells, the induction of IFN-g gamma secretion and enhanced target cell lysis. The cooperative activity of the targeted cytokines suggests that the application of both antibody-cytokine fusion proteins may be particularly suitable for the specific immunotherapy of Hodgkin's lymphoma.

Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis. Hodgkin's disease (HD) is characterized by the accumulation of functionally anergic T cells in the vicinity of the malignant Hodgkin/Reed-Sternberg (H/RS) cells. To revert cellular anergy against H/RS cells, we generated an anti-CD30-antibody-interleukin-(IL)-2 and an anti-CD30-antibody-IL12 fusion protein that target IL2 and IL12, respectively, specifically to CD30+ H/RS cells. Both antibody-cytokine fusion proteins act cooperatively in the activation of resting NK cells, the induction of IFN-g gamma secretion and enhanced target cell lysis. The cooperative activity of the targeted cytokines suggests that the application of both antibody-cytokine fusion proteins may be particularly suitable for the specific immunotherapy of Hodgkin's lymphoma.

pubmed23n0627_6488

CXCR3 ligands are augmented during the pathogenesis of pulmonary sarcoidosis.

We and other investigators have hypothesised that the CXC chemokine receptor (CXCR)3/CXCR3 ligand biological axis is involved in the formation of sarcoid lung granulomas; however, significant discrepancies in the current literature remain. In an effort to clarify previous conflicting findings, we performed the largest observational study to date of interferon-inducible ELR(-) (lacking the sequence glutamic acid-leucine-arginine) CXC chemokines in sarcoid bronchoalveolar fluid (BALF). BALF chemokine levels from sarcoid patients (n = 72) and healthy controls (n = 8) were measured with the ELISA method. Immunohistochemical staining was performed for CXCR3 and its ligands. BALF CXC chemokine ligand (CXCL)10 levels from sarcoid patients were not significantly increased compared with controls. BALF CXCL11 levels from sarcoid patients demonstrated a trend towards elevation; subgroup analysis by stage showed significant BALF CXCL11 elevation in stage I sarcoid patients compared with controls. BALF CXCL9 levels were elevated from sarcoid patients compared with controls. CXC11, CXCL9 and CXCR3 were expressed from epithelioid histiocytes, multinucleated giant cells and other inflammatory cells forming sarcoid lung granulomas. Our data suggest that CXCL9 and CXCL11 are important mediators in recruiting CXCR3-expressing cells. Importantly, we have made the novel observation that both lymphocytes and cells of monocyte linage express CXCR3 and are involved in the formation of sarcoid lung granulomas.

CXCR3 ligands are augmented during the pathogenesis of pulmonary sarcoidosis. We and other investigators have hypothesised that the CXC chemokine receptor (CXCR)3/CXCR3 ligand biological axis is involved in the formation of sarcoid lung granulomas; however, significant discrepancies in the current literature remain. In an effort to clarify previous conflicting findings, we performed the largest observational study to date of interferon-inducible ELR(-) (lacking the sequence glutamic acid-leucine-arginine) CXC chemokines in sarcoid bronchoalveolar fluid (BALF). BALF chemokine levels from sarcoid patients (n = 72) and healthy controls (n = 8) were measured with the ELISA method. Immunohistochemical staining was performed for CXCR3 and its ligands. BALF CXC chemokine ligand (CXCL)10 levels from sarcoid patients were not significantly increased compared with controls. BALF CXCL11 levels from sarcoid patients demonstrated a trend towards elevation; subgroup analysis by stage showed significant BALF CXCL11 elevation in stage I sarcoid patients compared with controls. BALF CXCL9 levels were elevated from sarcoid patients compared with controls. CXC11, CXCL9 and CXCR3 were expressed from epithelioid histiocytes, multinucleated giant cells and other inflammatory cells forming sarcoid lung granulomas. Our data suggest that CXCL9 and CXCL11 are important mediators in recruiting CXCR3-expressing cells. Importantly, we have made the novel observation that both lymphocytes and cells of monocyte linage express CXCR3 and are involved in the formation of sarcoid lung granulomas.

pubmed23n0129_7833

[Determinants of health in nurses].

A cross-sectional survey was carried out in 1980 among 824 nurses in 10 hospitals on the occasion of the annual checkups. The purpose was to describe the relationship between demographic and occupational characteristics and health, stressing the effects of work in shifts. Using Khi-2 tests and logistic models, the negative health effects of arduous shift work appear to be less than expected. This could be a result of the high turnover in the profession, which is characterized by a low average age and a short occupational lifetime.

[Determinants of health in nurses]. A cross-sectional survey was carried out in 1980 among 824 nurses in 10 hospitals on the occasion of the annual checkups. The purpose was to describe the relationship between demographic and occupational characteristics and health, stressing the effects of work in shifts. Using Khi-2 tests and logistic models, the negative health effects of arduous shift work appear to be less than expected. This could be a result of the high turnover in the profession, which is characterized by a low average age and a short occupational lifetime.

pubmed23n0371_8056

Pesticide effects on freshwater zooplankton: an ecological perspective.

The effects of pesticides on zooplankton are reviewed and their ecological significance is discussed. Toxicity is shown to vary depending on animal species, genotype, life stage, and size at birth. Natural stresses such as food shortage, oxygen depletion and odors of potential predators can also affect toxicity. Populations in the growth phase are vulnerable to pesticides but have the potential to recover rapidly from the damage. Pesticides may affect the population dynamics by controlling individual survival and reproduction, and by altering the sex ratio. Furthermore, toxic chemicals may control predation risk by changing swimming behavior and body morphology, and this in turn influences the population dynamics. Many zooplankton display morphological and behavioral responses to predators when exposed to their odor-producing chemicals. However, pesticides induce a maladaptive response to predator odor, and this poses an ecological risk. The following patterns are recognized as effects of pesticides at the community and ecosystem levels: (1) induction of dominance by small species; (2) an increase of species richness and diversity; and (3) elongation of the food chain and reduction of energy transfer efficiency from primary producers to top predators.

Pesticide effects on freshwater zooplankton: an ecological perspective. The effects of pesticides on zooplankton are reviewed and their ecological significance is discussed. Toxicity is shown to vary depending on animal species, genotype, life stage, and size at birth. Natural stresses such as food shortage, oxygen depletion and odors of potential predators can also affect toxicity. Populations in the growth phase are vulnerable to pesticides but have the potential to recover rapidly from the damage. Pesticides may affect the population dynamics by controlling individual survival and reproduction, and by altering the sex ratio. Furthermore, toxic chemicals may control predation risk by changing swimming behavior and body morphology, and this in turn influences the population dynamics. Many zooplankton display morphological and behavioral responses to predators when exposed to their odor-producing chemicals. However, pesticides induce a maladaptive response to predator odor, and this poses an ecological risk. The following patterns are recognized as effects of pesticides at the community and ecosystem levels: (1) induction of dominance by small species; (2) an increase of species richness and diversity; and (3) elongation of the food chain and reduction of energy transfer efficiency from primary producers to top predators.

pubmed23n0530_310

Management of excessive menstrual bleeding in women with hemostatic disorders.

Because there are many important considerations for managing excessive menstrual bleeding in women who have systemic disorders of hemostasis, a multidisciplinary approach is the best model for care. Specific attention to effective treatments is highlighted, but few studies have been performed in this population.

Management of excessive menstrual bleeding in women with hemostatic disorders. Because there are many important considerations for managing excessive menstrual bleeding in women who have systemic disorders of hemostasis, a multidisciplinary approach is the best model for care. Specific attention to effective treatments is highlighted, but few studies have been performed in this population.

pubmed23n0315_14140

Active MR visualization of a vascular guidewire in vivo.

The purpose of this study was development of an actively visualized .035-inch vascular guidewire for use in MR-guided interventions. The guidewire was actively visualized by inclusion of a 6-cm-long radiofrequency coil in its tip. A high contrast outline of the distal tip of the guidewire was obtained by acquiring an image with the radiofrequency coil as the receiving antenna. The position of the guidewire relative to the surrounding anatomy was determined by overlaying the guidewire image on a previously acquired road map. The guidewire was evaluated in vivo in the abdominal vessels of a rabbit and swine at 1.5 T. The built-in radiofrequency coil delivered a high contrast signal over its full length, enabling visualization of the position and curvature of the tip of the guidewire. The ability to see the curvature of the guidewire over several centimeters significantly eased manipulation into targeted vessels and represents an important advance toward MR-guided vascular interventions.

Active MR visualization of a vascular guidewire in vivo. The purpose of this study was development of an actively visualized .035-inch vascular guidewire for use in MR-guided interventions. The guidewire was actively visualized by inclusion of a 6-cm-long radiofrequency coil in its tip. A high contrast outline of the distal tip of the guidewire was obtained by acquiring an image with the radiofrequency coil as the receiving antenna. The position of the guidewire relative to the surrounding anatomy was determined by overlaying the guidewire image on a previously acquired road map. The guidewire was evaluated in vivo in the abdominal vessels of a rabbit and swine at 1.5 T. The built-in radiofrequency coil delivered a high contrast signal over its full length, enabling visualization of the position and curvature of the tip of the guidewire. The ability to see the curvature of the guidewire over several centimeters significantly eased manipulation into targeted vessels and represents an important advance toward MR-guided vascular interventions.

pubmed23n0323_10858

Cutaneous manifestations of Paecilomyces lilacinus infection induced by a contaminated skin lotion in patients who are severely immunosuppressed.

New opportunistic fungal infections cause significant morbidity and death in patients who are severely immunocompromised. Cutaneous lesions may be the first clinical manifestation and give the clue to early diagnosis. The purpose of this study was to describe the clinical and histologic manifestations of Paecilomyces lilacinus infection in patients who are severely immunosuppressed. Within a 3-month period, we observed 5 patients with allogenic bone marrow transplantation and 4 patients with aplasia after chemotherapy for hematologic malignancies who developed skin eruptions caused by invasive P lilacinus. The skin lesions began in 7 cases during or shortly after recovery of pancytopenia. Most of the skin lesions were located on the lower extremities. The cutaneous manifestations were highly variable including erythematous macules, nodules, pustules, vesicular lesions, and necrotic crusts. In 3 biopsy specimens, histologic examination revealed hyphae in periodic acid-Schiff-stained sections. In all patients P lilacinus was isolated from skin tissue samples. P lilacinus was identified from all lesions either by skin biopsy or needle aspiration from clinically evident lesions. In 3 additional cases, the patient's hands were colonized without skin lesions. The source of the epidemic outbreak was finally traced down to several contaminated lots of a topical moisturizing agent. Two patients died; one patient had septic lesions in the eye and kidney as the result of P lilacinus. Clinical and histologic findings of P lilacinus infection with cutaneous manifestations in patients who are severely immunosuppressed are summarized. P lilacinus is resistant to all systemic antimycotics available, and in general, recovery of immunosuppression is necessary to eradicate the mold. Contaminated topical dermatologic agents should be included in the differential diagnosis as a source for severe epidemic cutaneous manifestations of fungal infection in patients who are severely immunosuppressed. This fact implies that additional safety guidelines are necessary for topical dermatologic agents used for patients who are severely immunosuppressed.

Cutaneous manifestations of Paecilomyces lilacinus infection induced by a contaminated skin lotion in patients who are severely immunosuppressed. New opportunistic fungal infections cause significant morbidity and death in patients who are severely immunocompromised. Cutaneous lesions may be the first clinical manifestation and give the clue to early diagnosis. The purpose of this study was to describe the clinical and histologic manifestations of Paecilomyces lilacinus infection in patients who are severely immunosuppressed. Within a 3-month period, we observed 5 patients with allogenic bone marrow transplantation and 4 patients with aplasia after chemotherapy for hematologic malignancies who developed skin eruptions caused by invasive P lilacinus. The skin lesions began in 7 cases during or shortly after recovery of pancytopenia. Most of the skin lesions were located on the lower extremities. The cutaneous manifestations were highly variable including erythematous macules, nodules, pustules, vesicular lesions, and necrotic crusts. In 3 biopsy specimens, histologic examination revealed hyphae in periodic acid-Schiff-stained sections. In all patients P lilacinus was isolated from skin tissue samples. P lilacinus was identified from all lesions either by skin biopsy or needle aspiration from clinically evident lesions. In 3 additional cases, the patient's hands were colonized without skin lesions. The source of the epidemic outbreak was finally traced down to several contaminated lots of a topical moisturizing agent. Two patients died; one patient had septic lesions in the eye and kidney as the result of P lilacinus. Clinical and histologic findings of P lilacinus infection with cutaneous manifestations in patients who are severely immunosuppressed are summarized. P lilacinus is resistant to all systemic antimycotics available, and in general, recovery of immunosuppression is necessary to eradicate the mold. Contaminated topical dermatologic agents should be included in the differential diagnosis as a source for severe epidemic cutaneous manifestations of fungal infection in patients who are severely immunosuppressed. This fact implies that additional safety guidelines are necessary for topical dermatologic agents used for patients who are severely immunosuppressed.

pubmed23n1095_22529

Virtual clinical trial to compare cancer detection using combinations of 2D mammography, digital breast tomosynthesis and synthetic 2D imaging.

This study was designed to compare the detection of subtle lesions (calcification clusters or masses) when using the combination of digital breast tomosynthesis (DBT) and synthetic mammography (SM) with digital mammography (DM) alone or combined with DBT. A set of 166 cases without cancer was acquired on a DBT mammography system. Realistic subtle calcification clusters and masses in the DM images and DBT planes were digitally inserted into 104 of the acquired cases. Three study arms were created: DM alone, DM with DBT and SM with DBT. Five mammographic readers located the centre of any lesion within the images that should be recalled for further investigation and graded their suspiciousness. A JAFROC figure of merit (FoM) and lesion detection fraction (LDF) were calculated for each study arm. The visibility of the lesions in the DBT images was compared with SM and DM images. For calcification clusters, there were no significant differences (p &gt; 0.075) in FoM or LDF. For masses, the FoM and LDF were significantly improved in the arms using DBT compared to DM alone (p &lt; 0.001). On average, both calcification clusters and masses were more visible on DBT than on DM and SM images. This study demonstrated that masses were detected better with DBT than with DM alone and there was no significant difference (p = 0.075) in LDF between DM&amp;DBT and SM&amp;DBT for calcifications clusters. Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses. • The detection of masses was significantly better using DBT than with digital mammography alone. • The detection of calcification clusters was not significantly different between digital mammography and synthetic 2D images combined with tomosynthesis. • Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses for the imaging technology used.

Virtual clinical trial to compare cancer detection using combinations of 2D mammography, digital breast tomosynthesis and synthetic 2D imaging. This study was designed to compare the detection of subtle lesions (calcification clusters or masses) when using the combination of digital breast tomosynthesis (DBT) and synthetic mammography (SM) with digital mammography (DM) alone or combined with DBT. A set of 166 cases without cancer was acquired on a DBT mammography system. Realistic subtle calcification clusters and masses in the DM images and DBT planes were digitally inserted into 104 of the acquired cases. Three study arms were created: DM alone, DM with DBT and SM with DBT. Five mammographic readers located the centre of any lesion within the images that should be recalled for further investigation and graded their suspiciousness. A JAFROC figure of merit (FoM) and lesion detection fraction (LDF) were calculated for each study arm. The visibility of the lesions in the DBT images was compared with SM and DM images. For calcification clusters, there were no significant differences (p &gt; 0.075) in FoM or LDF. For masses, the FoM and LDF were significantly improved in the arms using DBT compared to DM alone (p &lt; 0.001). On average, both calcification clusters and masses were more visible on DBT than on DM and SM images. This study demonstrated that masses were detected better with DBT than with DM alone and there was no significant difference (p = 0.075) in LDF between DM&amp;DBT and SM&amp;DBT for calcifications clusters. Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses. • The detection of masses was significantly better using DBT than with digital mammography alone. • The detection of calcification clusters was not significantly different between digital mammography and synthetic 2D images combined with tomosynthesis. • Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses for the imaging technology used.

pubmed23n0493_13372

Effects of lead-contaminated surface water from a trap and skeet range on frog hatching and development.

Pickerel frogs (Rana palustris) and bullfrogs (Rana catesbeiana) were exposed from the egg stage to lead-contaminated surface water from a trap and skeet range. Seven experimental treatments were employed: 25, 50, 75 and 100% range water, 100% range water plus a chelating agent (sodium citrate), control water and control water plus chelating agent. Total lead concentrations in 100% range water treatments varied from 840-3150 microg litre(-1), with the filterable form accounting for approximately 4-5% of the total. Hatching was not affected in either species (p &gt; 0.2). There were highly significant differences in mortality among treatments for R. palustris (p = 0.0001), with tadpoles exhibiting 100 and 98% mortality after 10 d of exposure to 100 and 75% range water, respectively. Mortality in the 100% range water + citrate treatment was similar to controls (p &gt; 0.05). There were no significant differences in mortality among treatments for R. catesbeiana after 10 d of exposure (p = 0.7119). Exposure to lead in the range water did not adversely affect the growth of surviving R. palustris or R. catesbeiana tadpoles after 14 weeks and 10 weeks, respectively. In both species, the intestinal mucosa in tadpoles exposed to range water was reduced in thickness. Scanning electron micrographs of R. palustris tadpoles that died in 100% range water revealed stunted tail growth, incurvation of the spine, hydropsy and generally reduced body size.

Effects of lead-contaminated surface water from a trap and skeet range on frog hatching and development. Pickerel frogs (Rana palustris) and bullfrogs (Rana catesbeiana) were exposed from the egg stage to lead-contaminated surface water from a trap and skeet range. Seven experimental treatments were employed: 25, 50, 75 and 100% range water, 100% range water plus a chelating agent (sodium citrate), control water and control water plus chelating agent. Total lead concentrations in 100% range water treatments varied from 840-3150 microg litre(-1), with the filterable form accounting for approximately 4-5% of the total. Hatching was not affected in either species (p &gt; 0.2). There were highly significant differences in mortality among treatments for R. palustris (p = 0.0001), with tadpoles exhibiting 100 and 98% mortality after 10 d of exposure to 100 and 75% range water, respectively. Mortality in the 100% range water + citrate treatment was similar to controls (p &gt; 0.05). There were no significant differences in mortality among treatments for R. catesbeiana after 10 d of exposure (p = 0.7119). Exposure to lead in the range water did not adversely affect the growth of surviving R. palustris or R. catesbeiana tadpoles after 14 weeks and 10 weeks, respectively. In both species, the intestinal mucosa in tadpoles exposed to range water was reduced in thickness. Scanning electron micrographs of R. palustris tadpoles that died in 100% range water revealed stunted tail growth, incurvation of the spine, hydropsy and generally reduced body size.

pubmed23n1097_6020

Recent Progress of Rice Husk Reinforced Polymer Composites: A Review.

Recently, because of the rising population, carbon overloading, and environmental distress, human beings have needed to increase awareness and responsibility for the reduction of agricultural waste. The utilization of agricultural waste as a filler material in reinforced polymers is a fascinating discovery. This review paper attempts to study the physical, mechanical, and thermal behavior of rice husk (RH) as a fiber for reinforcing various synthetic polymers, based on recent studies, conducted between 2017 and 2021. It also highlights that advanced modification techniques could further improve the performance of composites by tailoring the physical and chemical substances of the fiber or matrix. The thermal properties, including flame-retardance and thermal behavior, are also discussed. The characteristics of the fiber-matrix interaction between RH and the polymer matrix provide essential insights into the future-ready applications of this agricultural waste fiber. The way forward in researching RH polymer composites is finally reviewed.

Recent Progress of Rice Husk Reinforced Polymer Composites: A Review. Recently, because of the rising population, carbon overloading, and environmental distress, human beings have needed to increase awareness and responsibility for the reduction of agricultural waste. The utilization of agricultural waste as a filler material in reinforced polymers is a fascinating discovery. This review paper attempts to study the physical, mechanical, and thermal behavior of rice husk (RH) as a fiber for reinforcing various synthetic polymers, based on recent studies, conducted between 2017 and 2021. It also highlights that advanced modification techniques could further improve the performance of composites by tailoring the physical and chemical substances of the fiber or matrix. The thermal properties, including flame-retardance and thermal behavior, are also discussed. The characteristics of the fiber-matrix interaction between RH and the polymer matrix provide essential insights into the future-ready applications of this agricultural waste fiber. The way forward in researching RH polymer composites is finally reviewed.

pubmed23n0839_20954

Whole-animal mounts of Caenorhabditis elegans for 3D imaging using atomic force microscopy.

The 3D surface of Caenorhabditis elegans was imaged at nanometer resolution using atomic force microscopy (AFM). Oscillation of a medium stiffness silicon AFM cantilever at the upper second amplitude peak, typically 6 times above the fundamental frequency, vastly improved image quality on the moist, sticky, and soft worms. Whole-animal mounts of normal and double-headed mutants of the nematode worm were prepared and scanned. Well-preserved anatomical features including annuli, furrows, alae, and rows of never before seen nanometer-sized pores dotting the molted worm's outermost surface coat were resolved. Well-preserved anatomical features including annuli, furrows, alae, and rows of nanometer-sized pores or struts dotting the molted worm's outermost surface were resolved. This AFM method represents a simple and rapid new approach for nanometer-resolved 3D imaging and analysis of whole-animal specimens of C. elegans. In this interesting article the authors describe a new AFM sampling method to allow better images on whole-animal mounts such as C. elegans. This method would generate more information and in the future may be useful for differentiating even individual animals with different genetic backgrounds.

Whole-animal mounts of Caenorhabditis elegans for 3D imaging using atomic force microscopy. The 3D surface of Caenorhabditis elegans was imaged at nanometer resolution using atomic force microscopy (AFM). Oscillation of a medium stiffness silicon AFM cantilever at the upper second amplitude peak, typically 6 times above the fundamental frequency, vastly improved image quality on the moist, sticky, and soft worms. Whole-animal mounts of normal and double-headed mutants of the nematode worm were prepared and scanned. Well-preserved anatomical features including annuli, furrows, alae, and rows of never before seen nanometer-sized pores dotting the molted worm's outermost surface coat were resolved. Well-preserved anatomical features including annuli, furrows, alae, and rows of nanometer-sized pores or struts dotting the molted worm's outermost surface were resolved. This AFM method represents a simple and rapid new approach for nanometer-resolved 3D imaging and analysis of whole-animal specimens of C. elegans. In this interesting article the authors describe a new AFM sampling method to allow better images on whole-animal mounts such as C. elegans. This method would generate more information and in the future may be useful for differentiating even individual animals with different genetic backgrounds.

pubmed23n0231_4636

Phase II trail cisplatin in refractory childhood cancer: Children's Cancer Study Group Report.

A total of 114 children with solid tumors refractory to conventional therapy were evaluated for response and/or toxic effects after receiving cisplatin at doses of 3.0-4.5 mg/kg with aggressive hydration and mannitol diuresis every 3 weeks; a minimum of two courses was required for evaluation of response (110 patients). Objective responses were noted in 18 patients: rhabdomyosarcoma (three), Wilm's tumor (three), osteogenic sarcoma (three). Ewing's sarcoma (two), neuroblastoma (one), undifferentiated sarcoma (one), hepatoblastoma (one), ovarian teratoma (one), hepatocellular carcinoma (one), embryonal carcinoma of the mediastinum (one), and thymoma (one). Twenty-six patients had some evidence of renal toxicity. Asymptomatic hearing loss was commonly found when audiometry was performed (eight of 18 patients tested). Eight additional patients had symptomatic hearing problems--tinnitus or hearing loss. Myelosuppression was mild. Hypomagnesemia and/or hypocalcemia were common but only one patient had symptoms. Cisplatin, administered at a dose of 3.0 mg/kg with aggressive hydration and mannitol diuresis, is reasonably well-tolerated. Its role in the therapy for those tumors against which it shows activity remains to be determined.

Phase II trail cisplatin in refractory childhood cancer: Children's Cancer Study Group Report. A total of 114 children with solid tumors refractory to conventional therapy were evaluated for response and/or toxic effects after receiving cisplatin at doses of 3.0-4.5 mg/kg with aggressive hydration and mannitol diuresis every 3 weeks; a minimum of two courses was required for evaluation of response (110 patients). Objective responses were noted in 18 patients: rhabdomyosarcoma (three), Wilm's tumor (three), osteogenic sarcoma (three). Ewing's sarcoma (two), neuroblastoma (one), undifferentiated sarcoma (one), hepatoblastoma (one), ovarian teratoma (one), hepatocellular carcinoma (one), embryonal carcinoma of the mediastinum (one), and thymoma (one). Twenty-six patients had some evidence of renal toxicity. Asymptomatic hearing loss was commonly found when audiometry was performed (eight of 18 patients tested). Eight additional patients had symptomatic hearing problems--tinnitus or hearing loss. Myelosuppression was mild. Hypomagnesemia and/or hypocalcemia were common but only one patient had symptoms. Cisplatin, administered at a dose of 3.0 mg/kg with aggressive hydration and mannitol diuresis, is reasonably well-tolerated. Its role in the therapy for those tumors against which it shows activity remains to be determined.

pubmed23n0267_6879

[Changes in collagen type IV metabolism in diabetes].

In Diabetes Mellitus, type IV collagen biosynthesis is increased: the alpha 1(IV) procollagen specific mRNA concentration is elevated, particularly in the kidney, and the type IV collagen protein is accumulating is the thickened basement membranes. Aldose reductase inhibitors like sorbinil do prevent basement membrane thickening and type IV collagen overproduction. The latter seems related to intracellular sorbitol accumulation and also to protein kinase C activation. Autocrine or paracrine TGF beta may be involved in the type IV collagen oversecretion. The secreted type IV collagen is subject to posttranslational alterations, especially glycation which leads to advanced glycation end-products and covalent crosslinks. This decreases collagen extractability and susceptibility to collagenases and favours basement membrane thickening. Disaccharide unit-specific alpha-glucosidase activity is inhibited by glucose (Kp = 7.5 mM). Type IV collagenase activity secreted by endothelial cells cultured at high glucose concentrations appears to be diminished. Therefore type IV collagen catabolism may be decreased in Diabetes Mellitus.

[Changes in collagen type IV metabolism in diabetes]. In Diabetes Mellitus, type IV collagen biosynthesis is increased: the alpha 1(IV) procollagen specific mRNA concentration is elevated, particularly in the kidney, and the type IV collagen protein is accumulating is the thickened basement membranes. Aldose reductase inhibitors like sorbinil do prevent basement membrane thickening and type IV collagen overproduction. The latter seems related to intracellular sorbitol accumulation and also to protein kinase C activation. Autocrine or paracrine TGF beta may be involved in the type IV collagen oversecretion. The secreted type IV collagen is subject to posttranslational alterations, especially glycation which leads to advanced glycation end-products and covalent crosslinks. This decreases collagen extractability and susceptibility to collagenases and favours basement membrane thickening. Disaccharide unit-specific alpha-glucosidase activity is inhibited by glucose (Kp = 7.5 mM). Type IV collagenase activity secreted by endothelial cells cultured at high glucose concentrations appears to be diminished. Therefore type IV collagen catabolism may be decreased in Diabetes Mellitus.

pubmed23n0647_20085

Candida albicans biofilm formation on peptide functionalized polydimethylsiloxane.

In order to prevent biofilm formation by Candida albicans, several cationic peptides were covalently bound to polydimethylsiloxane (PDMS). The salivary peptide histatin 5 and two synthetic variants (Dhvar 4 and Dhvar 5) were used to prepare peptide functionalized PDMS using 4-azido-2,3,5,6-tetrafluoro-benzoic acid (AFB) as an interlinkage molecule. In addition, polylysine-, polyarginine-, and polyhistidine-PDMS surfaces were prepared. Dhvar 4 functionalized PDMS yielded the highest reduction of the number of C. albicans biofilm cells in the Modified Robbins Device. Amino acid analysis demonstrated that the amount of peptide immobilized on the modified disks was in the nanomole range. Poly-d-lysine PDMS, in particular the homopeptides with low molecular weight (2500 and 9600) showed the highest activity against C. albicans biofilms, with reductions of 93% and 91%, respectively. The results indicate that the reductions are peptide dependent.

Candida albicans biofilm formation on peptide functionalized polydimethylsiloxane. In order to prevent biofilm formation by Candida albicans, several cationic peptides were covalently bound to polydimethylsiloxane (PDMS). The salivary peptide histatin 5 and two synthetic variants (Dhvar 4 and Dhvar 5) were used to prepare peptide functionalized PDMS using 4-azido-2,3,5,6-tetrafluoro-benzoic acid (AFB) as an interlinkage molecule. In addition, polylysine-, polyarginine-, and polyhistidine-PDMS surfaces were prepared. Dhvar 4 functionalized PDMS yielded the highest reduction of the number of C. albicans biofilm cells in the Modified Robbins Device. Amino acid analysis demonstrated that the amount of peptide immobilized on the modified disks was in the nanomole range. Poly-d-lysine PDMS, in particular the homopeptides with low molecular weight (2500 and 9600) showed the highest activity against C. albicans biofilms, with reductions of 93% and 91%, respectively. The results indicate that the reductions are peptide dependent.

pubmed23n0672_15677

Acute impact of moderate-intensity and vigorous-intensity exercise bouts on daily physical activity energy expenditure in postmenopausal women.

This study determined whether performing a single moderate- or vigorous-intensity exercise bout impacts daily physical activity energy expenditure (PAEE, by accelerometer). Overweight/obese postmenopausal women underwent a 5-month caloric restriction and moderate- (n = 18) or vigorous-intensity (n = 18) center-based aerobic exercise intervention. During the last month of intervention, in women performing moderate-intensity exercise, PAEE on days with exercise (577.7 ± 219.7 kcal·d(-1)) was higher (P = .011) than on days without exercise (450.7 ± 140.5 kcal·d(-1)); however, the difference (127.0 ± 188.1 kcal·d(-1)) was much lower than the energy expended during exercise. In women performing vigorous-intensity exercise, PAEE on days with exercise (450.6 ± 153.6 kcal·d(-1)) was lower (P = .047) than on days without exercise (519.2 ± 127.4 kcal·d(-1)). Thus, women expended more energy on physical activities outside of prescribed exercise on days they did NOT perform center-based exercise, especially if the prescribed exercise was of a higher intensity.

Acute impact of moderate-intensity and vigorous-intensity exercise bouts on daily physical activity energy expenditure in postmenopausal women. This study determined whether performing a single moderate- or vigorous-intensity exercise bout impacts daily physical activity energy expenditure (PAEE, by accelerometer). Overweight/obese postmenopausal women underwent a 5-month caloric restriction and moderate- (n = 18) or vigorous-intensity (n = 18) center-based aerobic exercise intervention. During the last month of intervention, in women performing moderate-intensity exercise, PAEE on days with exercise (577.7 ± 219.7 kcal·d(-1)) was higher (P = .011) than on days without exercise (450.7 ± 140.5 kcal·d(-1)); however, the difference (127.0 ± 188.1 kcal·d(-1)) was much lower than the energy expended during exercise. In women performing vigorous-intensity exercise, PAEE on days with exercise (450.6 ± 153.6 kcal·d(-1)) was lower (P = .047) than on days without exercise (519.2 ± 127.4 kcal·d(-1)). Thus, women expended more energy on physical activities outside of prescribed exercise on days they did NOT perform center-based exercise, especially if the prescribed exercise was of a higher intensity.

pubmed23n0496_19609

Messenger RNA and protein expression analysis of voltage-gated potassium channels in the brain of Abeta(25-35)-treated rats.

Potassium channel dysfunction has been implicated in Alzheimer's disease. In the present study, the expression of voltage-gated potassium channel (Kv) subunits in rat brain was measured after a single intracerebroventricular injection of beta-amyloid peptide 25-35 (Abeta(25-35)). After injection of Abeta, the spatial memory of rats was significantly impaired in the Morris water maze. Expression of five main Kv channel subunits (Kv1.5, Kv2.1, Kv1.4, Kv4.2, and Kv4.3) in mRNA level was assessed by using reverse transcription-polymerase chain reaction (RT-PCR). The mRNA levels of Kv2.1 and Kv1.4 were increased by 72% and 67%, respectively, in hippocampus, and Kv4.2 mRNA was increased by 58% in cortex. No other significant mRNA expression changes were found in Abeta-treated rats. The protein expression of Kv2.1, Kv1.4, and Kv4.2 was detected by using Western blotting. Kv2.1 and Kv1.4 protein levels were increased by 48% and 50%, respectively, in hippocampus of Abeta-treated rats, and Kv4.2 protein was increased by 42% in cerebral cortex. This study indicates that the expression up-regulation of Kv1.4, Kv2.1, and Kv4.2 in Abeta-induced cognitive impairment might play an important role in the pathogenesis of Alzheimer's disease.

Messenger RNA and protein expression analysis of voltage-gated potassium channels in the brain of Abeta(25-35)-treated rats. Potassium channel dysfunction has been implicated in Alzheimer's disease. In the present study, the expression of voltage-gated potassium channel (Kv) subunits in rat brain was measured after a single intracerebroventricular injection of beta-amyloid peptide 25-35 (Abeta(25-35)). After injection of Abeta, the spatial memory of rats was significantly impaired in the Morris water maze. Expression of five main Kv channel subunits (Kv1.5, Kv2.1, Kv1.4, Kv4.2, and Kv4.3) in mRNA level was assessed by using reverse transcription-polymerase chain reaction (RT-PCR). The mRNA levels of Kv2.1 and Kv1.4 were increased by 72% and 67%, respectively, in hippocampus, and Kv4.2 mRNA was increased by 58% in cortex. No other significant mRNA expression changes were found in Abeta-treated rats. The protein expression of Kv2.1, Kv1.4, and Kv4.2 was detected by using Western blotting. Kv2.1 and Kv1.4 protein levels were increased by 48% and 50%, respectively, in hippocampus of Abeta-treated rats, and Kv4.2 protein was increased by 42% in cerebral cortex. This study indicates that the expression up-regulation of Kv1.4, Kv2.1, and Kv4.2 in Abeta-induced cognitive impairment might play an important role in the pathogenesis of Alzheimer's disease.

pubmed23n0707_4038

Discovering a new role for the atrial natriuretic peptide: A novel risk factor for cardiovascular diseases.

Atrial natriuretic peptide, a diuretic, natriuretic and vasorelaxant hormone, is also involved in the regulation of cardiovascular remodeling and it has been recently shown to be significantly associated with higher occurrence of cardiovascular diseases. In fact, high plasma ANP levels predict higher mortality rate for cardiovascular events. Moreover, ANP gene alterations are associated with higher risk of cardiovascular intermediate phenotypes, such as left ventricular hypertrophy, and of cardiovascular diseases, such as stroke and hypertension. Thus, the characterization of ANP plasma levels, and of ANP genotype for known mutations can be proposed as an informative component of the individual cardiovascular risk profile.

Discovering a new role for the atrial natriuretic peptide: A novel risk factor for cardiovascular diseases. Atrial natriuretic peptide, a diuretic, natriuretic and vasorelaxant hormone, is also involved in the regulation of cardiovascular remodeling and it has been recently shown to be significantly associated with higher occurrence of cardiovascular diseases. In fact, high plasma ANP levels predict higher mortality rate for cardiovascular events. Moreover, ANP gene alterations are associated with higher risk of cardiovascular intermediate phenotypes, such as left ventricular hypertrophy, and of cardiovascular diseases, such as stroke and hypertension. Thus, the characterization of ANP plasma levels, and of ANP genotype for known mutations can be proposed as an informative component of the individual cardiovascular risk profile.

pubmed23n1159_11738

Local energy transfer and dissipation in incompressible Hall magnetohydrodynamic turbulence: The coarse-graining approach.

We derive the coarse-graining (CG) equations of incompressible Hall magnetohydrodynamic (HMHD) turbulence to investigate the local (in space) energy transfer rate as a function of the filtering scale ℓ. First, the CG equations are space averaged to obtain the analytical expression of the mean cascade rate. Its application to three-dimensional simulations of (weakly compressible) HMHD shows a cascade rate consistent with the value of the mean dissipation rate in the simulations and with the classical estimates based on the "third-order" law. Furthermore, we developed an anisotropic version of CG that allows us to study the magnitude of the cascade rate along different directions with respect to the mean magnetic field. Its implementation on the numerical data with moderate background magnetic field shows a weaker cascade along the magnetic field than in the perpendicular plane, while an isotropic cascade is recovered in the absence of a background field. The strength of the CG approach is further revealed when considering the local-in-space energy transfer, which is shown theoretically and numerically to match at a given position x, when locally averaged over a neighboring region, the (quasi-)local dissipation. Prospects of exploiting this model to investigate local dissipation in spacecraft data are discussed.

Local energy transfer and dissipation in incompressible Hall magnetohydrodynamic turbulence: The coarse-graining approach. We derive the coarse-graining (CG) equations of incompressible Hall magnetohydrodynamic (HMHD) turbulence to investigate the local (in space) energy transfer rate as a function of the filtering scale ℓ. First, the CG equations are space averaged to obtain the analytical expression of the mean cascade rate. Its application to three-dimensional simulations of (weakly compressible) HMHD shows a cascade rate consistent with the value of the mean dissipation rate in the simulations and with the classical estimates based on the "third-order" law. Furthermore, we developed an anisotropic version of CG that allows us to study the magnitude of the cascade rate along different directions with respect to the mean magnetic field. Its implementation on the numerical data with moderate background magnetic field shows a weaker cascade along the magnetic field than in the perpendicular plane, while an isotropic cascade is recovered in the absence of a background field. The strength of the CG approach is further revealed when considering the local-in-space energy transfer, which is shown theoretically and numerically to match at a given position x, when locally averaged over a neighboring region, the (quasi-)local dissipation. Prospects of exploiting this model to investigate local dissipation in spacecraft data are discussed.

pubmed23n0825_166

The effect of graded glass-zirconia structure on the bond between core and veneer in layered zirconia restorations.

The aim of this study was to test the hypothesis that a graded glass-zirconia structure can strengthen the core-veneer bond in layered zirconia materials. A graded glass-zirconia structure was fabricated by infiltrating glass compositions developed in our laboratory into a presintered yttria tetrahedral zirconia polycrystal (Y-TZP) substrate by the action of capillary forces. The wettability of the infiltrated glass and Y-TZP substrate was investigated by the sessile drop technique. The microstructures of the graded glass-zirconia structure were examined by scanning electron microscopy (SEM). The phase structure characterization in the graded glass-zirconia structure were identified by X-ray diffraction (XRD) analysis. The elastic modulus and hardness of the graded glass-zirconia structure were evaluated from nanoindentations. Further, the shear bond strength (SBS) of the graded glass-zirconia structure and veneering porcelain was also evaluated. SEM images confirmed the formation of the graded glass-zirconia structure. Glass frits wet the Y-TZP substrate at 1200 °C with a contact angle of 43.2°. Only a small amount of t-m transformation was observed in as-infiltrated Y-TZP specimens. Nanoindentation studies of the glass-zirconia graded structure showed that the elastic modulus and hardness of the surface glass layer were higher than those of the dense Y-TZP layer. The mean SBS values for the graded glass-zirconia structure and veneering porcelain (24.35 ± 0.40 MPa) were statistically higher than those of zirconia and veneering porcelain (9.22 ± 0.20 MPa) (P&lt;0.05). A graded glass-zirconia structure can be fabricated by the glass infiltration/densification technique, and this structure exhibits a strong core-veneer bond.

The effect of graded glass-zirconia structure on the bond between core and veneer in layered zirconia restorations. The aim of this study was to test the hypothesis that a graded glass-zirconia structure can strengthen the core-veneer bond in layered zirconia materials. A graded glass-zirconia structure was fabricated by infiltrating glass compositions developed in our laboratory into a presintered yttria tetrahedral zirconia polycrystal (Y-TZP) substrate by the action of capillary forces. The wettability of the infiltrated glass and Y-TZP substrate was investigated by the sessile drop technique. The microstructures of the graded glass-zirconia structure were examined by scanning electron microscopy (SEM). The phase structure characterization in the graded glass-zirconia structure were identified by X-ray diffraction (XRD) analysis. The elastic modulus and hardness of the graded glass-zirconia structure were evaluated from nanoindentations. Further, the shear bond strength (SBS) of the graded glass-zirconia structure and veneering porcelain was also evaluated. SEM images confirmed the formation of the graded glass-zirconia structure. Glass frits wet the Y-TZP substrate at 1200 °C with a contact angle of 43.2°. Only a small amount of t-m transformation was observed in as-infiltrated Y-TZP specimens. Nanoindentation studies of the glass-zirconia graded structure showed that the elastic modulus and hardness of the surface glass layer were higher than those of the dense Y-TZP layer. The mean SBS values for the graded glass-zirconia structure and veneering porcelain (24.35 ± 0.40 MPa) were statistically higher than those of zirconia and veneering porcelain (9.22 ± 0.20 MPa) (P&lt;0.05). A graded glass-zirconia structure can be fabricated by the glass infiltration/densification technique, and this structure exhibits a strong core-veneer bond.

pubmed23n0636_5268

Risks of intracranial hemorrhage in patients with Parkinson's disease receiving deep brain stimulation and ablation.

This study analyzed risk factors for hemorrhage in a large series of deep brain stimulation (DBS) and ablation procedures in patients with advanced Parkinson's disease (PD). Six hundred and forty four subjects with advanced PD treated with DBS or ablation procedures between March 1999 and December 2007 were enrolled in the study. Procedures were performed by the same surgeon, and included DBS in 126 patients, ablation in 507 patients and DBS after prior unilateral ablation procedures in 11 patients. Of 796 target procedures, 207 were DBS including 202 subthalamic nucleus (STN) targets, 3 ventralis intermedius nucleus (Vim) targets and 2 globus pallidus internus (GPi) targets, and the others were 589 ablation procedures including 474 GPi targets and 115 Vim targets. Postoperative CT or MRI was performed in all patients within 24 h of lead implantation or ablation treatment. Statistical correlation analysis of risk factors for intracranial hemorrhage (ICH) was performed by stepwise logistic regression. Explanatory variables were patient age, sex, blood pressure, anatomical targets, the number of microelectrode recording (MER) penetrations and surgical modality. Postoperative symptomatic ICH occurred in 10 cases (8 pallidotomy and 2 thalamotomy) and asymptomatic ICH in 14 cases (9 pallidotomy, 4 thalamotomy and 1 DBS). Hypertension and surgical modality were significant factors contributing to hemorrhage (both P &lt; 0.05). The likelihood of hemorrhage in hypertensive patients was 2.5 times that in normotensive patients. The risk of hemorrhage during ablation was 5.4 times that in DBS. The number of MER trajectories did not significantly correlate with ICH occurrence (P = 0.07). No statistically significant difference was found in age, sex and anatomical targets. This study demonstrated that hypertension is a risk factor for ICH in PD patients. DBS is generally a safe surgical modality as compared with ablation. Increasing microelectrode trajectories seemed to increase the risk of ICH, but no statistically significant difference was found (P = 0.07).

Risks of intracranial hemorrhage in patients with Parkinson's disease receiving deep brain stimulation and ablation. This study analyzed risk factors for hemorrhage in a large series of deep brain stimulation (DBS) and ablation procedures in patients with advanced Parkinson's disease (PD). Six hundred and forty four subjects with advanced PD treated with DBS or ablation procedures between March 1999 and December 2007 were enrolled in the study. Procedures were performed by the same surgeon, and included DBS in 126 patients, ablation in 507 patients and DBS after prior unilateral ablation procedures in 11 patients. Of 796 target procedures, 207 were DBS including 202 subthalamic nucleus (STN) targets, 3 ventralis intermedius nucleus (Vim) targets and 2 globus pallidus internus (GPi) targets, and the others were 589 ablation procedures including 474 GPi targets and 115 Vim targets. Postoperative CT or MRI was performed in all patients within 24 h of lead implantation or ablation treatment. Statistical correlation analysis of risk factors for intracranial hemorrhage (ICH) was performed by stepwise logistic regression. Explanatory variables were patient age, sex, blood pressure, anatomical targets, the number of microelectrode recording (MER) penetrations and surgical modality. Postoperative symptomatic ICH occurred in 10 cases (8 pallidotomy and 2 thalamotomy) and asymptomatic ICH in 14 cases (9 pallidotomy, 4 thalamotomy and 1 DBS). Hypertension and surgical modality were significant factors contributing to hemorrhage (both P &lt; 0.05). The likelihood of hemorrhage in hypertensive patients was 2.5 times that in normotensive patients. The risk of hemorrhage during ablation was 5.4 times that in DBS. The number of MER trajectories did not significantly correlate with ICH occurrence (P = 0.07). No statistically significant difference was found in age, sex and anatomical targets. This study demonstrated that hypertension is a risk factor for ICH in PD patients. DBS is generally a safe surgical modality as compared with ablation. Increasing microelectrode trajectories seemed to increase the risk of ICH, but no statistically significant difference was found (P = 0.07).

pubmed23n1126_13735

Quantifying and reducing cross-contamination in single- and multiplex hybridization capture of ancient DNA.

The use of hybridization capture has enabled a massive upscaling in sample sizes for ancient DNA studies, allowing the analysis of hundreds of skeletal remains or sediments in single studies. Nevertheless, demands in throughput continue to grow, and hybridization capture has become a limiting step in sample preparation due to the large consumption of reagents, consumables and time. Here, we explored the possibility of improving the economics of sample preparation via multiplex capture, that is, the hybridization capture of pools of double-indexed ancient DNA libraries. We demonstrate that this strategy is feasible, at least for small genomic targets such as mitochondrial DNA, if the annealing temperature is increased and PCR cycles are limited in post-capture amplification to avoid index swapping by jumping PCR, which manifests as cross-contamination in resulting sequence data. We also show that the reamplification of double-indexed libraries to PCR plateau before or after hybridization capture can sporadically lead to small, but detectable cross-contamination even if libraries are amplified in separate reactions. We provide protocols for both manual capture and automated capture in 384-well format that are compatible with single- and multiplex capture and effectively suppress cross-contamination and artefact formation. Last, we provide a simple computational method for quantifying cross-contamination due to index swapping in double-indexed libraries, which we recommend using for routine quality checks in studies that are sensitive to cross-contamination.

Quantifying and reducing cross-contamination in single- and multiplex hybridization capture of ancient DNA. The use of hybridization capture has enabled a massive upscaling in sample sizes for ancient DNA studies, allowing the analysis of hundreds of skeletal remains or sediments in single studies. Nevertheless, demands in throughput continue to grow, and hybridization capture has become a limiting step in sample preparation due to the large consumption of reagents, consumables and time. Here, we explored the possibility of improving the economics of sample preparation via multiplex capture, that is, the hybridization capture of pools of double-indexed ancient DNA libraries. We demonstrate that this strategy is feasible, at least for small genomic targets such as mitochondrial DNA, if the annealing temperature is increased and PCR cycles are limited in post-capture amplification to avoid index swapping by jumping PCR, which manifests as cross-contamination in resulting sequence data. We also show that the reamplification of double-indexed libraries to PCR plateau before or after hybridization capture can sporadically lead to small, but detectable cross-contamination even if libraries are amplified in separate reactions. We provide protocols for both manual capture and automated capture in 384-well format that are compatible with single- and multiplex capture and effectively suppress cross-contamination and artefact formation. Last, we provide a simple computational method for quantifying cross-contamination due to index swapping in double-indexed libraries, which we recommend using for routine quality checks in studies that are sensitive to cross-contamination.

pubmed23n0112_4156

An experimental and clinical study of immunocompetence and immunostimulation in breast cancer.

Two hundred and seven patients aged from 37 to 65 years with noninflammatory breast cancer treated by surgery without radiation were studied over a ten year period with a view to forecasting the prognosis on the basis of the immune status and treatment. The immunocompetence or immune status was studied in 121 patients by in vitro and in vivo pre and post-surgical skin tests. The immunostimulation or restoration of the immune status was conducted by the P 40 immunomodulator from the Pasteur Institute: in an experimental study whose results are based on modified Huggins model and take in to account the survival rate and the evaluation of tumor growth; in a subgroup of 86 patients, demonstrating that immunostimulation is effective in low-scores, improves tolerance to chemotherapy and increases the six year survival rate in high risk low-score patients. The results are encouraging enough to propose improving the survival rate in a prospective clinical study of early breast cancer treated by local and regional means using a protocol incorporating an immunostimulation based on the existing immunocompetence with interferon-induced reconversion of the target cells in the hope of specific stimulation.

An experimental and clinical study of immunocompetence and immunostimulation in breast cancer. Two hundred and seven patients aged from 37 to 65 years with noninflammatory breast cancer treated by surgery without radiation were studied over a ten year period with a view to forecasting the prognosis on the basis of the immune status and treatment. The immunocompetence or immune status was studied in 121 patients by in vitro and in vivo pre and post-surgical skin tests. The immunostimulation or restoration of the immune status was conducted by the P 40 immunomodulator from the Pasteur Institute: in an experimental study whose results are based on modified Huggins model and take in to account the survival rate and the evaluation of tumor growth; in a subgroup of 86 patients, demonstrating that immunostimulation is effective in low-scores, improves tolerance to chemotherapy and increases the six year survival rate in high risk low-score patients. The results are encouraging enough to propose improving the survival rate in a prospective clinical study of early breast cancer treated by local and regional means using a protocol incorporating an immunostimulation based on the existing immunocompetence with interferon-induced reconversion of the target cells in the hope of specific stimulation.

pubmed23n0391_9462

Primary hyperparathyroidism in Hong Kong: an analysis of 44 cases.

Primary hyperparathyroidism is increasingly being diagnosed subsequent to the detection of hypercalcaemia using multichannel auto-analyser screening. This paper provides a local picture of the clinical presentation and management of primary hyperparathyroidism. A retrospective review was conducted of 44 patients with primary hyperparathyroidism who were treated at the Queen Elizabeth Hospital between January 1987 and July 1996. Twenty-five (56.8%) of the patients were asymptomatic. Only three (6.8%) patients gave radiograms that had features indicating primary hyperparathyroidism; seven (15.9%) had renal stones. The patients underwent one or more of the following localisation procedures: computerised tomography, ultrasonography, thallium-technetium subtraction scanning, and technetium Tc 99m sestamibi scanning. The latter method was the most sensitive (64.3%). Ten adenomas that could not be localised by any of these procedures were successfully removed during surgery. Surgery was successful in 94.4% of cases and surgical outcome was comparable to that reported in the literature.

Primary hyperparathyroidism in Hong Kong: an analysis of 44 cases. Primary hyperparathyroidism is increasingly being diagnosed subsequent to the detection of hypercalcaemia using multichannel auto-analyser screening. This paper provides a local picture of the clinical presentation and management of primary hyperparathyroidism. A retrospective review was conducted of 44 patients with primary hyperparathyroidism who were treated at the Queen Elizabeth Hospital between January 1987 and July 1996. Twenty-five (56.8%) of the patients were asymptomatic. Only three (6.8%) patients gave radiograms that had features indicating primary hyperparathyroidism; seven (15.9%) had renal stones. The patients underwent one or more of the following localisation procedures: computerised tomography, ultrasonography, thallium-technetium subtraction scanning, and technetium Tc 99m sestamibi scanning. The latter method was the most sensitive (64.3%). Ten adenomas that could not be localised by any of these procedures were successfully removed during surgery. Surgery was successful in 94.4% of cases and surgical outcome was comparable to that reported in the literature.

pubmed23n0849_12727

Volition and low back pain: When patients talk.

Our objective was to explore, describe and understand volition of chronic low back pain (LBP) patients, highlighting barriers and facilitators to practicing regular physical activity in order to develop a questionnaire assessing those volitional competencies. A content analysis of semi-structured interviews with 30 chronic LBP patients was performed. Participants were asked about their pain, motivation, physical abilities, barriers and facilitators to regular exercises and finally strategies implemented to achieve the exercise program. Patients often reported that they were motivated and that exercises had no negative effects on LBP. Many patients recognized having difficulties performing all their exercises regularly. The main barriers were: lack of time, fatigue, lack of visible results, pain and other daily priorities. The main facilitators were: group exercise, help from the therapist, strategic planning, favorable environment, pleasure associated with exercises, fear of pain recurrence and pain itself. Content analysis showed that sharing stories allowed patients to express their experience of LBP in their own words. It provides a solid ground to develop a questionnaire assessing volitional competencies in chronic LBP patients in order to identify patients who will not realize their exercises and help them be (more) active and avoid chronicity.

Volition and low back pain: When patients talk. Our objective was to explore, describe and understand volition of chronic low back pain (LBP) patients, highlighting barriers and facilitators to practicing regular physical activity in order to develop a questionnaire assessing those volitional competencies. A content analysis of semi-structured interviews with 30 chronic LBP patients was performed. Participants were asked about their pain, motivation, physical abilities, barriers and facilitators to regular exercises and finally strategies implemented to achieve the exercise program. Patients often reported that they were motivated and that exercises had no negative effects on LBP. Many patients recognized having difficulties performing all their exercises regularly. The main barriers were: lack of time, fatigue, lack of visible results, pain and other daily priorities. The main facilitators were: group exercise, help from the therapist, strategic planning, favorable environment, pleasure associated with exercises, fear of pain recurrence and pain itself. Content analysis showed that sharing stories allowed patients to express their experience of LBP in their own words. It provides a solid ground to develop a questionnaire assessing volitional competencies in chronic LBP patients in order to identify patients who will not realize their exercises and help them be (more) active and avoid chronicity.

pubmed23n0313_22057

Quantitative determination of cabergoline in human plasma using liquid chromatography combined with tandem mass spectrometry.

A liquid chromatography/mass spectrometry (LC/MS) method using electrospray ionization (ESI) is described for the quantitative determination of cabergoline (N-[3-(dimethylamino)propyl]-N-(ethylamino)-carbonyl-6-(2-propenyl)- ergoline-8 beta-carboxamide) in human plasma. The method consists of liquid-liquid extraction after addition of deuterated internal standard, and reverse-phase liquid chromatography with electrospray ionization combined with tandem mass spectrometry (MS/MS). Using selected reaction monitoring, the method provides a quantitation limit of 1.86 pg/mL. Calibration curves acquired on five different days showed good linearity (r &gt; 0.99) in the range 1.86-124 pg/mL and reproducibility of the slope (% relative standard deviation, RSD = 10.0). The intra-day precision, determined by assaying plasma containing four different concentrations of cabergoline processed in replicate, was found to range from 2.4 to 17.0% (RSD). The inter-day precision, evaluated for the same concentrations, ranged from 7.9 to 10.7% (RSD). The accuracy of the method, expressed as the percent ratio between found to added amount, was 99.1 +/- 10.2% (RSD = 10.3%, n = 78).

Quantitative determination of cabergoline in human plasma using liquid chromatography combined with tandem mass spectrometry. A liquid chromatography/mass spectrometry (LC/MS) method using electrospray ionization (ESI) is described for the quantitative determination of cabergoline (N-[3-(dimethylamino)propyl]-N-(ethylamino)-carbonyl-6-(2-propenyl)- ergoline-8 beta-carboxamide) in human plasma. The method consists of liquid-liquid extraction after addition of deuterated internal standard, and reverse-phase liquid chromatography with electrospray ionization combined with tandem mass spectrometry (MS/MS). Using selected reaction monitoring, the method provides a quantitation limit of 1.86 pg/mL. Calibration curves acquired on five different days showed good linearity (r &gt; 0.99) in the range 1.86-124 pg/mL and reproducibility of the slope (% relative standard deviation, RSD = 10.0). The intra-day precision, determined by assaying plasma containing four different concentrations of cabergoline processed in replicate, was found to range from 2.4 to 17.0% (RSD). The inter-day precision, evaluated for the same concentrations, ranged from 7.9 to 10.7% (RSD). The accuracy of the method, expressed as the percent ratio between found to added amount, was 99.1 +/- 10.2% (RSD = 10.3%, n = 78).

pubmed23n0749_23311

Diagnosis of personality disorders in adolescents: a study among psychologists.

Recent guidelines concerning the treatment of personality disorders (PDs) recommend diagnosing PDs in adolescents. However, it remains unclear whether these guidelines influence the current opinions and practices of mental health care professionals. Five hundred sixty-six psychologists completed an online survey concerning PDs in adolescents, of whom 367 professionals reported working with adolescents. The survey contained demographical questions (age, gender, profession, work setting) and specific questions related to PD in adolescence. Although a majority of psychologists working with adolescents acknowledged the existence of PDs in adolescents (57.8%), only a small minority diagnoses PDs in adolescence (8.7%) and offers a treatment specifically aimed at targeting PD pathology (6.5%). Reasons for not diagnosing PDs in adolescence mainly concerned the belief that adolescent personality problems are transient (41.2%) and that the DSM-IV-TR does not allow diagnosing PDs in adolescence (25.9%). Although practice guidelines might have influenced clinicians' opinions about PDs in adolescence, they have had little impact so far on routine clinical practice.

Diagnosis of personality disorders in adolescents: a study among psychologists. Recent guidelines concerning the treatment of personality disorders (PDs) recommend diagnosing PDs in adolescents. However, it remains unclear whether these guidelines influence the current opinions and practices of mental health care professionals. Five hundred sixty-six psychologists completed an online survey concerning PDs in adolescents, of whom 367 professionals reported working with adolescents. The survey contained demographical questions (age, gender, profession, work setting) and specific questions related to PD in adolescence. Although a majority of psychologists working with adolescents acknowledged the existence of PDs in adolescents (57.8%), only a small minority diagnoses PDs in adolescence (8.7%) and offers a treatment specifically aimed at targeting PD pathology (6.5%). Reasons for not diagnosing PDs in adolescence mainly concerned the belief that adolescent personality problems are transient (41.2%) and that the DSM-IV-TR does not allow diagnosing PDs in adolescence (25.9%). Although practice guidelines might have influenced clinicians' opinions about PDs in adolescence, they have had little impact so far on routine clinical practice.

pubmed23n0957_19359

Intimate partner violence against women in Nigeria: a multilevel study investigating the effect of women's status and community norms.

Intimate partner violence (IPV) against women has been recognised as a public health problem with far-reaching consequences for the physical, reproductive, and mental health of women. The ecological framework portrays intimate partner violence as a multifaceted phenomenon, demonstrating the interplay of factors at different levels: individual, community, and the larger society. The present study examined the effect of individual- and community-level factors on IPV in Nigeria, with a focus on women's status and community-level norms among men. A cross-sectional study based on the latest Nigerian Demographic Health Survey (2013) was conducted involving 20,802 ever-partnered women aged 15-49 years. Several multilevel logistic regression models were calibrated to assess the association of individual- and community-level factors with IPV. Both measures of association (fixed effect) and measures of variations (random effect) were reported. Almost one in four women in Nigeria reported having ever experienced intimate partner violence. Having adjusted for other relevant covariates, higher women's status reduced the odds of IPV (OR = 0.47; 95% CI = 0.32-0.71). However, community norms among men that justified IPV against women modified the observed protective effect of higher women's status against IPV and reversed the odds (OR = 1.89; 95% CI = 1.26-2.83). Besides women's status, community norms towards IPV are an important factor for the occurrence of IPV. Thus, addressing intimate partner violence against women calls for community-wide approaches aimed at changing norms among men alongside improving women's status.

Intimate partner violence against women in Nigeria: a multilevel study investigating the effect of women's status and community norms. Intimate partner violence (IPV) against women has been recognised as a public health problem with far-reaching consequences for the physical, reproductive, and mental health of women. The ecological framework portrays intimate partner violence as a multifaceted phenomenon, demonstrating the interplay of factors at different levels: individual, community, and the larger society. The present study examined the effect of individual- and community-level factors on IPV in Nigeria, with a focus on women's status and community-level norms among men. A cross-sectional study based on the latest Nigerian Demographic Health Survey (2013) was conducted involving 20,802 ever-partnered women aged 15-49 years. Several multilevel logistic regression models were calibrated to assess the association of individual- and community-level factors with IPV. Both measures of association (fixed effect) and measures of variations (random effect) were reported. Almost one in four women in Nigeria reported having ever experienced intimate partner violence. Having adjusted for other relevant covariates, higher women's status reduced the odds of IPV (OR = 0.47; 95% CI = 0.32-0.71). However, community norms among men that justified IPV against women modified the observed protective effect of higher women's status against IPV and reversed the odds (OR = 1.89; 95% CI = 1.26-2.83). Besides women's status, community norms towards IPV are an important factor for the occurrence of IPV. Thus, addressing intimate partner violence against women calls for community-wide approaches aimed at changing norms among men alongside improving women's status.

pubmed23n0319_3328

In vivo native cellular fluorescence and histological characteristics of head and neck cancer.

Native cellular fluorescence (NCF) represents the innate capacity of tissues to absorb and emit light of a specified wavelength. The ability to define the relationship of in vivo NCF with biological characteristics of neoplastic disease may allow for an improved understanding of the clinical course of disease. Head and neck cancers from 35 patients were evaluated in vivo for NCF characteristics using a xenon lamp-based spectrometer coupled to a handheld fiberoptic probe. Spectral assessment was limited to lambda 450-nm emission characteristics, in which tissues were excited at various wavelengths, ranging from lambda 290 nm to lambda 415 nm, and the intensity of lambda 450 nm emission was recorded. Each cancer was subsequently biopsied and assessed for histological differentiation by a pathologist who was blinded to NCF analysis. Considerable variation in spectral characteristics between head and neck cancers was identified, which was determined, in part, by NCF characteristics of the normal mucosa from the same patient. Poorly differentiated tumors were more likely than well- or moderately differentiated tumors to have lower excitation maxima (P &lt; 0.05 by ANOVA). Most significantly, the tumor differentiation status, as well as the probability of demonstrating recurrent disease, could also be related to the NCF characteristics of the patient's normal mucosa from the same site within the upper aerodigestive tract. NCF analysis may represent an effective tool to identify biological characteristics of head and neck tumors in vivo without the need for invasive biopsies. Results suggest the need to explore the determinants of NCF characteristics expressed by clinically normal mucosa.

In vivo native cellular fluorescence and histological characteristics of head and neck cancer. Native cellular fluorescence (NCF) represents the innate capacity of tissues to absorb and emit light of a specified wavelength. The ability to define the relationship of in vivo NCF with biological characteristics of neoplastic disease may allow for an improved understanding of the clinical course of disease. Head and neck cancers from 35 patients were evaluated in vivo for NCF characteristics using a xenon lamp-based spectrometer coupled to a handheld fiberoptic probe. Spectral assessment was limited to lambda 450-nm emission characteristics, in which tissues were excited at various wavelengths, ranging from lambda 290 nm to lambda 415 nm, and the intensity of lambda 450 nm emission was recorded. Each cancer was subsequently biopsied and assessed for histological differentiation by a pathologist who was blinded to NCF analysis. Considerable variation in spectral characteristics between head and neck cancers was identified, which was determined, in part, by NCF characteristics of the normal mucosa from the same patient. Poorly differentiated tumors were more likely than well- or moderately differentiated tumors to have lower excitation maxima (P &lt; 0.05 by ANOVA). Most significantly, the tumor differentiation status, as well as the probability of demonstrating recurrent disease, could also be related to the NCF characteristics of the patient's normal mucosa from the same site within the upper aerodigestive tract. NCF analysis may represent an effective tool to identify biological characteristics of head and neck tumors in vivo without the need for invasive biopsies. Results suggest the need to explore the determinants of NCF characteristics expressed by clinically normal mucosa.

pubmed23n0311_22635

Concurrent fluorescence in situ hybridization and immunocytochemistry for the detection of chromosome aberrations in exfoliated bronchial epithelial cells.

A procedure was developed to allow concurrent detection of chromosome aberrations and identification of bronchial epithelial cells. Fluorescence in situ hybridization for chromosome 7 and immunocytochemistry for cytokeratin were performed on exfoliated bronchial epithelial cells in a sputum sample from a cancer patient. The Spectrum Orange-labeled alpha satellite probe for chromosome 7 produced red fluorescence, nuclei were counterstained with 4,6-diamidino-2-phenylindole (blue), and cytokeratin was visualized using a fluorescein isothiocyanate (FITC)-conjugated secondary antibody (green). This procedure allowed the rapid identification of airway epithelial cells with numerical chromosome aberrations in this sample. Ultimately, this procedure could increase the sensitivity and specificity of sputum cytology as a laboratory diagnostic tool for the early detection of lung cancer.

Concurrent fluorescence in situ hybridization and immunocytochemistry for the detection of chromosome aberrations in exfoliated bronchial epithelial cells. A procedure was developed to allow concurrent detection of chromosome aberrations and identification of bronchial epithelial cells. Fluorescence in situ hybridization for chromosome 7 and immunocytochemistry for cytokeratin were performed on exfoliated bronchial epithelial cells in a sputum sample from a cancer patient. The Spectrum Orange-labeled alpha satellite probe for chromosome 7 produced red fluorescence, nuclei were counterstained with 4,6-diamidino-2-phenylindole (blue), and cytokeratin was visualized using a fluorescein isothiocyanate (FITC)-conjugated secondary antibody (green). This procedure allowed the rapid identification of airway epithelial cells with numerical chromosome aberrations in this sample. Ultimately, this procedure could increase the sensitivity and specificity of sputum cytology as a laboratory diagnostic tool for the early detection of lung cancer.

pubmed23n0860_5011

Automatic online buffer capacity (alkalinity) measurement of wastewater using an electrochemical cell.

The use of an automatic online electrochemical cell (EC) for measuring the buffer capacity of wastewater is presented. pH titration curves of different solutions (NaHCO3, Na2HPO4, real municipal wastewater, and anaerobic digester liquid) were obtained by conventional chemical titration and compared to the online EC measurements. The results show that the pH titration curves from the EC were comparable to that of the conventional chemical titration. The results show a linear relationship between the response of the online EC detection system and the titrimetric partial alkalinity and total alkalinity of all tested samples. This suggests that an EC can be used as a simple online titration device for monitoring the buffer capacity of different industrial processes including wastewater treatment and anaerobic digestion processes.

Automatic online buffer capacity (alkalinity) measurement of wastewater using an electrochemical cell. The use of an automatic online electrochemical cell (EC) for measuring the buffer capacity of wastewater is presented. pH titration curves of different solutions (NaHCO3, Na2HPO4, real municipal wastewater, and anaerobic digester liquid) were obtained by conventional chemical titration and compared to the online EC measurements. The results show that the pH titration curves from the EC were comparable to that of the conventional chemical titration. The results show a linear relationship between the response of the online EC detection system and the titrimetric partial alkalinity and total alkalinity of all tested samples. This suggests that an EC can be used as a simple online titration device for monitoring the buffer capacity of different industrial processes including wastewater treatment and anaerobic digestion processes.

pubmed23n0885_9567

Effect of melatonin on blood pressure and nitric oxide generation in rats with metabolic syndrome.

Melatonin, a multitasking indolamine, seems to be involved in a variety of physiological and metabolic processes via both receptor-mediated and receptor-independent mechanisms. The aim of our study was to find out whether melatonin can affect blood pressure (BP), nitric oxide synthase (NOS) activity, eNOS and nNOS protein expressions in rats with metabolic syndrome (SHR/cp). Rats were divided into four groups: 6-week-old male WKY andSHR/cp and age-matched WKY and SHR/cp treated with melatonin (10 mg/kg/day) for 3 weeks. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions were determined in the heart, aorta, brain cortex and cerebellum. MT(1) receptors were analyzed in the brain cortex and cerebellum. In SHR/cp rats, BP was decreased after melatonin treatment. In the same group, melatonin did not affect NOS activity and eNOS protein expression in the heart and aorta, while it increased both parameters in the brain cortex and cerebellum. Interestingly, melatonin elevated MT1 protein expression in the cerebellum. Neuronal NOS protein expression was not changed within the groups. In conclusion, increased NOS activity/eNOS upregulation in particular brain regions may contribute partially to BP decrease in SHR/cp rats after melatonin treatment. Participation of MT(1) receptors in this melatonin action may be supposed.

Effect of melatonin on blood pressure and nitric oxide generation in rats with metabolic syndrome. Melatonin, a multitasking indolamine, seems to be involved in a variety of physiological and metabolic processes via both receptor-mediated and receptor-independent mechanisms. The aim of our study was to find out whether melatonin can affect blood pressure (BP), nitric oxide synthase (NOS) activity, eNOS and nNOS protein expressions in rats with metabolic syndrome (SHR/cp). Rats were divided into four groups: 6-week-old male WKY andSHR/cp and age-matched WKY and SHR/cp treated with melatonin (10 mg/kg/day) for 3 weeks. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions were determined in the heart, aorta, brain cortex and cerebellum. MT(1) receptors were analyzed in the brain cortex and cerebellum. In SHR/cp rats, BP was decreased after melatonin treatment. In the same group, melatonin did not affect NOS activity and eNOS protein expression in the heart and aorta, while it increased both parameters in the brain cortex and cerebellum. Interestingly, melatonin elevated MT1 protein expression in the cerebellum. Neuronal NOS protein expression was not changed within the groups. In conclusion, increased NOS activity/eNOS upregulation in particular brain regions may contribute partially to BP decrease in SHR/cp rats after melatonin treatment. Participation of MT(1) receptors in this melatonin action may be supposed.

pubmed23n0717_21349

Repetitiveness in language disorders: a new analytical procedure.

A common feature of a wide range of language disorders is the tendency to repeat a particular linguistic form-or set of forms-with abnormal frequency. A brief overview is given of the different ways in which disordered language can be repetitive, and the nature of stereotyped and repetitive language is discussed in terms of the reciprocal relationship between frequency of occurrence and productivity. It is argued that measures such as lexical type-token ratio provide only a partial picture of repetitive language, and that linguistic units larger than the word also need to be taken into consideration. An analytical framework incorporating such units is proposed, which is able to characterize and quantify the extent to which a sample of language is repetitive independently of its aetiology. An illustrative analysis is given of a language sample from a brain-damaged adult, and the repetitiveness profiles of four different patients are compared.

Repetitiveness in language disorders: a new analytical procedure. A common feature of a wide range of language disorders is the tendency to repeat a particular linguistic form-or set of forms-with abnormal frequency. A brief overview is given of the different ways in which disordered language can be repetitive, and the nature of stereotyped and repetitive language is discussed in terms of the reciprocal relationship between frequency of occurrence and productivity. It is argued that measures such as lexical type-token ratio provide only a partial picture of repetitive language, and that linguistic units larger than the word also need to be taken into consideration. An analytical framework incorporating such units is proposed, which is able to characterize and quantify the extent to which a sample of language is repetitive independently of its aetiology. An illustrative analysis is given of a language sample from a brain-damaged adult, and the repetitiveness profiles of four different patients are compared.

pubmed23n0024_11457

[Electron-autoradiographic study of hepatic cell nuclei in chronic pathological process].

The development of a chronic pathological process in the liver induces changes in the structure and function of hepatocyte nuclei. Some of these changes, particularly an increase in the number of nucleoli, rearrangement of nucleous-associated chromatin, the appearance of ring-shaped nucleoli and intranuclear vacuoles are similar to senile changes in the nuclei. A quantitative analysis of these changes established a considerable increase in the number of ring-shaped nucleoli and intranuclear vacuoles in sick animals as compared with normal animals of any age. The number of nucleoli and nucleous-associated chromocenters also increases with the progress of the pathological process, however, it reaches the maximum level in the early stages of the process which is equal or insignificantly higher than the level in old animals, and subsequently does not change. These observations reveal a problem important for pathology, that of the existence of a limit in the development of reparative and dystrophic changes which may be attained sooner or later depending on the severity of a pathological process.

[Electron-autoradiographic study of hepatic cell nuclei in chronic pathological process]. The development of a chronic pathological process in the liver induces changes in the structure and function of hepatocyte nuclei. Some of these changes, particularly an increase in the number of nucleoli, rearrangement of nucleous-associated chromatin, the appearance of ring-shaped nucleoli and intranuclear vacuoles are similar to senile changes in the nuclei. A quantitative analysis of these changes established a considerable increase in the number of ring-shaped nucleoli and intranuclear vacuoles in sick animals as compared with normal animals of any age. The number of nucleoli and nucleous-associated chromocenters also increases with the progress of the pathological process, however, it reaches the maximum level in the early stages of the process which is equal or insignificantly higher than the level in old animals, and subsequently does not change. These observations reveal a problem important for pathology, that of the existence of a limit in the development of reparative and dystrophic changes which may be attained sooner or later depending on the severity of a pathological process.

pubmed23n0780_883

Identification of rare genetic variants in novel loci associated with Paget's disease of bone.

In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon-intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency &lt;0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).

Identification of rare genetic variants in novel loci associated with Paget's disease of bone. In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon-intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency &lt;0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).

pubmed23n0989_19716

In Vitro Models of Brain Disorders.

The brain is the most complex organ of the body, and many pathological processes underlying various brain disorders are poorly understood. Limited accessibility hinders observation of such processes in the in vivo brain, and experimental freedom is often insufficient to enable informative manipulations. In vitro preparations (brain slices or cultures of dissociated neurons) offer much better accessibility and reduced complexity and have yielded valuable new insights into various brain disorders. Both types of preparations have their advantages and limitations with regard to lifespan, preservation of in vivo brain structure, composition of cell types, and the link to behavioral outcome is often unclear in in vitro models. While these limitations hamper general usage of in vitro preparations to study, e.g., brain development, in vitro preparations are very useful to study neuronal and synaptic functioning under pathologic conditions. This chapter addresses several brain disorders, focusing on neuronal and synaptic functioning, as well as network aspects. Recent progress in the fields of brain circulation disorders, excitability disorders, and memory disorders will be discussed, as well as limitations of current in vitro models.

In Vitro Models of Brain Disorders. The brain is the most complex organ of the body, and many pathological processes underlying various brain disorders are poorly understood. Limited accessibility hinders observation of such processes in the in vivo brain, and experimental freedom is often insufficient to enable informative manipulations. In vitro preparations (brain slices or cultures of dissociated neurons) offer much better accessibility and reduced complexity and have yielded valuable new insights into various brain disorders. Both types of preparations have their advantages and limitations with regard to lifespan, preservation of in vivo brain structure, composition of cell types, and the link to behavioral outcome is often unclear in in vitro models. While these limitations hamper general usage of in vitro preparations to study, e.g., brain development, in vitro preparations are very useful to study neuronal and synaptic functioning under pathologic conditions. This chapter addresses several brain disorders, focusing on neuronal and synaptic functioning, as well as network aspects. Recent progress in the fields of brain circulation disorders, excitability disorders, and memory disorders will be discussed, as well as limitations of current in vitro models.

pubmed23n0246_7419

[Method of contrast enhancement of DNA-containing structures on ultrathin sections].

Thin epoxy sections of formaldehyde-fixed tissue underwent depurinizing hydrolysis with 5N HCl at room temperature for 1 hour, the treatment with an aldehyde blocking agent, 10% sodium bisulfite, at 60 degrees C during 90 min, and staining with 2% aqueous uranyl acetate. Introduction of bisulfite considerably enhanced the contrast of chromatin. Staining of DNA in these conditions is summed up of preferential binding of uranyl cations with phosphates of DNA and with bisulfite anions specifically bound to deoxyribose.

[Method of contrast enhancement of DNA-containing structures on ultrathin sections]. Thin epoxy sections of formaldehyde-fixed tissue underwent depurinizing hydrolysis with 5N HCl at room temperature for 1 hour, the treatment with an aldehyde blocking agent, 10% sodium bisulfite, at 60 degrees C during 90 min, and staining with 2% aqueous uranyl acetate. Introduction of bisulfite considerably enhanced the contrast of chromatin. Staining of DNA in these conditions is summed up of preferential binding of uranyl cations with phosphates of DNA and with bisulfite anions specifically bound to deoxyribose.

pubmed23n0573_5161

A randomized clinical trial to evaluate the effect of diet on quality of life and mood of people living with HIV and lipodystrophy.

The purpose of this study in 2002 was to evaluate a diet intervention in relation to the quality of life and mood of people living with HIV and lipodystrophy. HIV-positive people on antiretroviral treatments are normalizing their lives and facing a long-term future. Morphological changes in some cases may occur as a result of antiretroviral therapy, causing HIV-positive people to hesitate commencing treatment. The study sample consisted of 30 men over 18 years of age living with HIV and lipodystrophy. An experimental design incorporating pretests and posttests of experimental and control groups was used. All participants were surveyed by questionnaire, and their quality of life and mood were measured at baseline and 10 weeks. Results indicated a trend toward significant improvement in quality of life, and although mood states were not significantly improved between the two groups, the control group showed deterioration in mood status, compared with the intervention group, that was concluded to be clinically significant. Hence, in the study setting, the diet intervention showed a positive effect on men living with HIV and lipodystrophy.

A randomized clinical trial to evaluate the effect of diet on quality of life and mood of people living with HIV and lipodystrophy. The purpose of this study in 2002 was to evaluate a diet intervention in relation to the quality of life and mood of people living with HIV and lipodystrophy. HIV-positive people on antiretroviral treatments are normalizing their lives and facing a long-term future. Morphological changes in some cases may occur as a result of antiretroviral therapy, causing HIV-positive people to hesitate commencing treatment. The study sample consisted of 30 men over 18 years of age living with HIV and lipodystrophy. An experimental design incorporating pretests and posttests of experimental and control groups was used. All participants were surveyed by questionnaire, and their quality of life and mood were measured at baseline and 10 weeks. Results indicated a trend toward significant improvement in quality of life, and although mood states were not significantly improved between the two groups, the control group showed deterioration in mood status, compared with the intervention group, that was concluded to be clinically significant. Hence, in the study setting, the diet intervention showed a positive effect on men living with HIV and lipodystrophy.

pubmed23n0356_19364

Fifty landmark discoveries in gastroenterology during the past 50 years. A brief history of modern gastroenterology at the millennium: Part I. Gastrointestinal procedures and upper gastrointestinal disorders.

During the last half century, many outstanding discoverers have revolutionized the clinical practice and science of gastroenterology. Whereas the scientific results are widely disseminated, the discoverers have received inadequate recognition, and the history of their discoveries is poorly known. At the millennium, a committee selected the 50 landmark discoveries in gastroenterology during the past 50 years. A brief history of each landmark discovery is presented. Part I presents the landmark discoveries in gastrointestinal (GI) procedures and in upper GI disorders. Part II of this presentation, which covers landmark discoveries in other areas of gastroenterology, will publish in Part II of the volume on High Risk Gastrointestinal Bleeding.

Fifty landmark discoveries in gastroenterology during the past 50 years. A brief history of modern gastroenterology at the millennium: Part I. Gastrointestinal procedures and upper gastrointestinal disorders. During the last half century, many outstanding discoverers have revolutionized the clinical practice and science of gastroenterology. Whereas the scientific results are widely disseminated, the discoverers have received inadequate recognition, and the history of their discoveries is poorly known. At the millennium, a committee selected the 50 landmark discoveries in gastroenterology during the past 50 years. A brief history of each landmark discovery is presented. Part I presents the landmark discoveries in gastrointestinal (GI) procedures and in upper GI disorders. Part II of this presentation, which covers landmark discoveries in other areas of gastroenterology, will publish in Part II of the volume on High Risk Gastrointestinal Bleeding.

pubmed23n0349_10868

Improved derivation of results of D. E. Allen: two-count method for stripping short-lived activity out of an air sample.

An improved derivation of the critical levels and detection limits for a two-count method that attempts to measure long-lived activity in the presence of short-lived, naturally occurring progeny of radon is presented. A limitation of the two-count method is also mentioned.

Improved derivation of results of D. E. Allen: two-count method for stripping short-lived activity out of an air sample. An improved derivation of the critical levels and detection limits for a two-count method that attempts to measure long-lived activity in the presence of short-lived, naturally occurring progeny of radon is presented. A limitation of the two-count method is also mentioned.

pubmed23n0113_12062

[A biopsy forceps with a needle for a flexible endoscope].

Biopsy forceps with a suture needle were developed. They will enable to increase considerably the efficacy and accuracy of diagnostic procedures in early cancer and precancerous conditions, and the differentiation of malignant and benign affections of internal organs as well.

[A biopsy forceps with a needle for a flexible endoscope]. Biopsy forceps with a suture needle were developed. They will enable to increase considerably the efficacy and accuracy of diagnostic procedures in early cancer and precancerous conditions, and the differentiation of malignant and benign affections of internal organs as well.

pubmed23n0347_6193

Histological demonstration of haemosiderin deposits in lungs and liver from victims of chronic physical child abuse.

In the context of chronic physical child abuse, two entities have been described based on macroscopical and radiological criteria: the battered baby syndrome and the shaken baby syndrome. However, in some autopsy cases, clinico-radiological information may not be available. In these cases, histological examinations are necessary to look for sequelae of repeated haemorrhages, particularly in organs likely to have suffered traumatisms such as the lungs, or in organs belonging to the mononucleated macrophage resorption system, such as the liver and the spleen. We examined a series of 15 young children who died from proven chronic child abuse and compared them with 15 sex and age-matched control subjects who died from natural causes with no history of child abuse. Using Perl's stain for iron, we identified haemosiderin deposits in pulmonary, hepatic and splenic samples and the deposits were evaluated qualitatively and quantitatively. Haemosiderin deposits were significantly (P &lt; 0.001) more abundant in the lungs and liver of the chronic abuse victims than in those of the control subjects. However, they were not significantly more abundant in the spleens of child abuse victims than in controls. We conclude that haemosiderin deposits in lungs and liver could be proposed as a marker for chronic physical child abuse. This study stresses the importance of systematic histological examination to look for pulmonary and hepatic haemosiderin deposits in cases in which chronic child abuse is suspected.

Histological demonstration of haemosiderin deposits in lungs and liver from victims of chronic physical child abuse. In the context of chronic physical child abuse, two entities have been described based on macroscopical and radiological criteria: the battered baby syndrome and the shaken baby syndrome. However, in some autopsy cases, clinico-radiological information may not be available. In these cases, histological examinations are necessary to look for sequelae of repeated haemorrhages, particularly in organs likely to have suffered traumatisms such as the lungs, or in organs belonging to the mononucleated macrophage resorption system, such as the liver and the spleen. We examined a series of 15 young children who died from proven chronic child abuse and compared them with 15 sex and age-matched control subjects who died from natural causes with no history of child abuse. Using Perl's stain for iron, we identified haemosiderin deposits in pulmonary, hepatic and splenic samples and the deposits were evaluated qualitatively and quantitatively. Haemosiderin deposits were significantly (P &lt; 0.001) more abundant in the lungs and liver of the chronic abuse victims than in those of the control subjects. However, they were not significantly more abundant in the spleens of child abuse victims than in controls. We conclude that haemosiderin deposits in lungs and liver could be proposed as a marker for chronic physical child abuse. This study stresses the importance of systematic histological examination to look for pulmonary and hepatic haemosiderin deposits in cases in which chronic child abuse is suspected.

pubmed23n0859_107

The Timing of Midzone Stabilization during Cytokinesis Depends on Myosin II Activity and an Interaction between INCENP and Actin.

The final steps of cell division are tightly coordinated in space and time, but whether mechanisms exist to couple the actin and microtubule (MT) cytoskeletons during anaphase and cytokinesis (C phase) is largely unknown. During anaphase, MTs are incorporated into an anti-parallel array termed the spindle midzone (midzone MTs), whereas F-actin and non-muscle myosin II, together with other factors, organize into the cleavage furrow [1]. Previous studies in somatic cells have shown that midzone MTs become highly stable after furrows have begun ingression [2], indicating that furrow-to-MT communication may occur. Midzone formation is also inhibited in fly spermatocytes that fail to form a cleavage furrow [3] and during monopolar cytokinesis when myosin contractility is blocked by blebbistatin [4]. We show here that midzone MT stabilization is dependent on actomyosin contraction, suggesting that there is active coordination between furrow ingression and microtubule dynamics. Midzone microtubule stabilization also depends on the kinase activity of Aurora B, the catalytic subunit of the chromosomal passenger complex (CPC), uncovering a feedback mechanism that couples furrowing with microtubule dynamics. We further show that the CPC scaffolding protein INCENP (inner centromere protein) binds actin, an interaction that is important for cytokinesis and for midzone MT stabilization following furrow ingression. Stabilization of midzone MTs with low amounts of Taxol rescues cytokinesis in INCENP actin-binding mutant-expressing cells. Collectively, our work demonstrates that the actin and microtubule cytoskeletons are coordinated during cytokinesis and suggests that the CPC is integral for coupling furrow ingression with midzone microtubule stabilization.

The Timing of Midzone Stabilization during Cytokinesis Depends on Myosin II Activity and an Interaction between INCENP and Actin. The final steps of cell division are tightly coordinated in space and time, but whether mechanisms exist to couple the actin and microtubule (MT) cytoskeletons during anaphase and cytokinesis (C phase) is largely unknown. During anaphase, MTs are incorporated into an anti-parallel array termed the spindle midzone (midzone MTs), whereas F-actin and non-muscle myosin II, together with other factors, organize into the cleavage furrow [1]. Previous studies in somatic cells have shown that midzone MTs become highly stable after furrows have begun ingression [2], indicating that furrow-to-MT communication may occur. Midzone formation is also inhibited in fly spermatocytes that fail to form a cleavage furrow [3] and during monopolar cytokinesis when myosin contractility is blocked by blebbistatin [4]. We show here that midzone MT stabilization is dependent on actomyosin contraction, suggesting that there is active coordination between furrow ingression and microtubule dynamics. Midzone microtubule stabilization also depends on the kinase activity of Aurora B, the catalytic subunit of the chromosomal passenger complex (CPC), uncovering a feedback mechanism that couples furrowing with microtubule dynamics. We further show that the CPC scaffolding protein INCENP (inner centromere protein) binds actin, an interaction that is important for cytokinesis and for midzone MT stabilization following furrow ingression. Stabilization of midzone MTs with low amounts of Taxol rescues cytokinesis in INCENP actin-binding mutant-expressing cells. Collectively, our work demonstrates that the actin and microtubule cytoskeletons are coordinated during cytokinesis and suggests that the CPC is integral for coupling furrow ingression with midzone microtubule stabilization.

pubmed23n0981_11764

Evaluation of Intervention Impact on Health Inequality for Resource Allocation.

We describe a simplified distributional cost-effectiveness analysis based on aggregate data to estimate the health inequality impact of public health interventions. We extracted data on costs, health outcomes expressed as quality-adjusted life years (QALYs), and target populations for interventions within National Institute for Health and Care Excellence (NICE) public health guidance published up to October 2016. Evidence on variation by age, gender, and index of multiple deprivation informed socioeconomic distributions of incremental QALYs, health opportunity costs, and the baseline distribution of health. Total population QALYs, summary measures of inequality, and a health equity impact plane show results by intervention and by guideline. A value for inequality aversion from a general population survey in England let us combine impacts on health inequality and total health into a single measure of intervention value. Our estimates suggest that of 134 interventions considered by NICE, 70 (52%) reduce inequality and increase health, 21 (16%) involve a tradeoff between improving health and improving health inequality, and 43 (32%) reduce health and increase health inequality. Fully implemented, the potential impact of all recommendations was 23,336,181 additional QALYs for the population of England and Wales and a reduction of the gap in quality-adjusted life expectancy between the healthiest and least healthy from 13.78 to 13.34 QALYs. The combined value of the additional health and reduction in inequality was 28,723,776 QALYs. Our analysis takes account of the fact that existing public health spending likely benefits the most disadvantaged. This simple method applied separately to economic evaluation produces evidence of intervention impacts on the distribution of health that is vital in determining value for money when health inequality reduction is a policy goal.

Evaluation of Intervention Impact on Health Inequality for Resource Allocation. We describe a simplified distributional cost-effectiveness analysis based on aggregate data to estimate the health inequality impact of public health interventions. We extracted data on costs, health outcomes expressed as quality-adjusted life years (QALYs), and target populations for interventions within National Institute for Health and Care Excellence (NICE) public health guidance published up to October 2016. Evidence on variation by age, gender, and index of multiple deprivation informed socioeconomic distributions of incremental QALYs, health opportunity costs, and the baseline distribution of health. Total population QALYs, summary measures of inequality, and a health equity impact plane show results by intervention and by guideline. A value for inequality aversion from a general population survey in England let us combine impacts on health inequality and total health into a single measure of intervention value. Our estimates suggest that of 134 interventions considered by NICE, 70 (52%) reduce inequality and increase health, 21 (16%) involve a tradeoff between improving health and improving health inequality, and 43 (32%) reduce health and increase health inequality. Fully implemented, the potential impact of all recommendations was 23,336,181 additional QALYs for the population of England and Wales and a reduction of the gap in quality-adjusted life expectancy between the healthiest and least healthy from 13.78 to 13.34 QALYs. The combined value of the additional health and reduction in inequality was 28,723,776 QALYs. Our analysis takes account of the fact that existing public health spending likely benefits the most disadvantaged. This simple method applied separately to economic evaluation produces evidence of intervention impacts on the distribution of health that is vital in determining value for money when health inequality reduction is a policy goal.

pubmed23n0074_4318

Isolated ventral pancreatitis in a patient with pancreas divisum.

A previously healthy 22-yr-old woman was found to have chronic pancreatitis restricted to the ventral pancreas in association with pancreas divisum. When conservative treatment failed, sphincteroplasty of both papillae was performed with good results. This well-documented case represents a clear exception to the commonly held concept that obstruction of the dorsal duct is the essential pathogenic factor in the development of pancreatitis associated with pancreas divisum. The importance of visualizing both the dorsal and ventral pancreatic ducts to direct therapy for patients with idiopathic pancreatitis is discussed. Theories of the pathogenesis of concomitant pancreatitis and pancreas divisum are reviewed.

Isolated ventral pancreatitis in a patient with pancreas divisum. A previously healthy 22-yr-old woman was found to have chronic pancreatitis restricted to the ventral pancreas in association with pancreas divisum. When conservative treatment failed, sphincteroplasty of both papillae was performed with good results. This well-documented case represents a clear exception to the commonly held concept that obstruction of the dorsal duct is the essential pathogenic factor in the development of pancreatitis associated with pancreas divisum. The importance of visualizing both the dorsal and ventral pancreatic ducts to direct therapy for patients with idiopathic pancreatitis is discussed. Theories of the pathogenesis of concomitant pancreatitis and pancreas divisum are reviewed.

pubmed23n1104_21980

Genome of <i>Ganoderma</i> Species Provides Insights Into the Evolution, Conifers Substrate Utilization, and Terpene Synthesis for <i>Ganoderma tsugae</i>.

<iGanoderma tsugae</i is an endemic medicinal mushroom in Northeast China, providing important source of pharmaceutical product. Comparing with other <iGanoderma</i species, wild <iG. tsugae</i can utilize coniferous wood. However, functional genes related to medicinal component synthesis and the genetic mechanism of conifer substrate utilization is still obscure. Here, we assembled a high-quality <iG. tsugae</i genome with 18 contigs and 98.5% BUSCO genes and performed the comparative genomics with other <iGanoderma</i species. <iG. tsugae</i diverged from their common ancestor of <iG. lingzhi</i and <iG. sinense</i about 21 million years ago. Genes in <iG. tsugae</i-specific and <iG. tsugae</i-expanded gene families, such as <isalh</i, <iphea</i, <icyp53a1</i, and <icyp102a</i, and positively selected genes, such as <iglpk</i and <iamie</i, were functionally enriched in plant-pathogen interaction, benzoate degradation, and fanconi anemia pathway. Those functional genes might contribute to conifer substrate utilization of <iG. tsugae</i. Meanwhile, gene families in the terpene synthesis were identified and genome-wide SNP variants were detected in population. Finally, the study provided valuable genomic resources and offered useful hints for the functional gene mapping and investigation of key gene contributing to conifer cultivation substrate utilization and medicinal component biosynthesis.

Genome of <i>Ganoderma</i> Species Provides Insights Into the Evolution, Conifers Substrate Utilization, and Terpene Synthesis for <i>Ganoderma tsugae</i>. <iGanoderma tsugae</i is an endemic medicinal mushroom in Northeast China, providing important source of pharmaceutical product. Comparing with other <iGanoderma</i species, wild <iG. tsugae</i can utilize coniferous wood. However, functional genes related to medicinal component synthesis and the genetic mechanism of conifer substrate utilization is still obscure. Here, we assembled a high-quality <iG. tsugae</i genome with 18 contigs and 98.5% BUSCO genes and performed the comparative genomics with other <iGanoderma</i species. <iG. tsugae</i diverged from their common ancestor of <iG. lingzhi</i and <iG. sinense</i about 21 million years ago. Genes in <iG. tsugae</i-specific and <iG. tsugae</i-expanded gene families, such as <isalh</i, <iphea</i, <icyp53a1</i, and <icyp102a</i, and positively selected genes, such as <iglpk</i and <iamie</i, were functionally enriched in plant-pathogen interaction, benzoate degradation, and fanconi anemia pathway. Those functional genes might contribute to conifer substrate utilization of <iG. tsugae</i. Meanwhile, gene families in the terpene synthesis were identified and genome-wide SNP variants were detected in population. Finally, the study provided valuable genomic resources and offered useful hints for the functional gene mapping and investigation of key gene contributing to conifer cultivation substrate utilization and medicinal component biosynthesis.

pubmed23n0779_3680

Water quality assessment of rivers using diatom metrics across Mediterranean Europe: a methods intercalibration exercise.

The European Water Framework Directive establishes a framework for the protection of water resources. However, common water management tools demand common understanding of assessment methods, so quality goals are equally met. Intercalibration of methods ensures the comparability of biological elements across similar geographical areas. Many aspects can influence the outcome of intercalibration: data sampling, treatment methods, taxonomic reliability of databases, choice of metrics for ecological quality status classification, and criteria for selecting reference sites. This study describes the potentials and constraints of the intercalibration of indices using diatoms for assessment of Mediterranean rivers. Harmonisation of diatom taxonomy and nomenclature was based on a previous ring test which took place at the European level. Four diatom indices (Indice de Polluosensibilité Spécifique-IPS, Indice Biologique Diatomées-IBD 2007, Intercalibration Common Metric Italy-ICMi and Slovenian Ecological Status assessment system) were intercalibrated using data from six European Mediterranean countries (Cyprus, France, Italy, Portugal, Slovenia and Spain). Boundaries between High/Good and Good/Moderate quality classes were harmonised by means of the Intercalibration Common Metric (ICM). Comparability between countries was assured through boundary bias and class agreement. The national boundaries were adjusted when they deviated more than a quarter of a class equivalent (0.25) from the global mean. All national methods correlated well with the ICM, which was sensitive to water quality (negatively correlated to nutrients). Achnanthidium minutissimum sensu lato was the most discriminative species of Good ecological status class. Planothidium frequentissimum, Gomphonema parvulum and Nitzschia palea were the most contributive to Moderate ecological status class. Some taxa were discriminative for both Good and Moderate ecological status classes due to low indication and ecological discriminative power but also due to differences in taxonomy between countries. This intercalibration exercise allowed establishment of common water quality goals across Mediterranean Europe, which is substantiated with the ICM.

Water quality assessment of rivers using diatom metrics across Mediterranean Europe: a methods intercalibration exercise. The European Water Framework Directive establishes a framework for the protection of water resources. However, common water management tools demand common understanding of assessment methods, so quality goals are equally met. Intercalibration of methods ensures the comparability of biological elements across similar geographical areas. Many aspects can influence the outcome of intercalibration: data sampling, treatment methods, taxonomic reliability of databases, choice of metrics for ecological quality status classification, and criteria for selecting reference sites. This study describes the potentials and constraints of the intercalibration of indices using diatoms for assessment of Mediterranean rivers. Harmonisation of diatom taxonomy and nomenclature was based on a previous ring test which took place at the European level. Four diatom indices (Indice de Polluosensibilité Spécifique-IPS, Indice Biologique Diatomées-IBD 2007, Intercalibration Common Metric Italy-ICMi and Slovenian Ecological Status assessment system) were intercalibrated using data from six European Mediterranean countries (Cyprus, France, Italy, Portugal, Slovenia and Spain). Boundaries between High/Good and Good/Moderate quality classes were harmonised by means of the Intercalibration Common Metric (ICM). Comparability between countries was assured through boundary bias and class agreement. The national boundaries were adjusted when they deviated more than a quarter of a class equivalent (0.25) from the global mean. All national methods correlated well with the ICM, which was sensitive to water quality (negatively correlated to nutrients). Achnanthidium minutissimum sensu lato was the most discriminative species of Good ecological status class. Planothidium frequentissimum, Gomphonema parvulum and Nitzschia palea were the most contributive to Moderate ecological status class. Some taxa were discriminative for both Good and Moderate ecological status classes due to low indication and ecological discriminative power but also due to differences in taxonomy between countries. This intercalibration exercise allowed establishment of common water quality goals across Mediterranean Europe, which is substantiated with the ICM.

pubmed23n0131_18767

The effect of vitamin E and selenium on doxorubicin (Adriamycin) induced delayed toxicity in mice.

The antagonistic action of repeated administration of vitamin E and selenium on the lethality caused by a single intraperitoneal injection of doxorubicin 15 to 20 mg/kg has been investigated in mice. Mice were treated with vitamin E, 20 to 4100 mg/kg intraperitoneally/intramuscularly daily or once a week and/or selenium 27 micrograms/kg orally daily for 6 to 7 weeks, i.e. one or two weeks before and five weeks after doxorubicin administration. 30 mg/kg of doxorubicin intraperitoneally caused 100% lethality within 4 days, whereas 15 mg/kg caused no deaths within a week, but resulted in a delayed toxicity with a cumulative lethality of 80% at the end of the observation period of 6 months. Vitamin E protected the mice from the lethal effect of doxorubicin, 15 mg/kg during the administration, but the mice began to die when the vitamin E administration was discontinued. Selenium only protected the mice for two weeks in spite of the continuous administration of selenium. The combined administration of vitamin E and selenium had no protective effect on the lethality caused by doxorubicin, 20 mg/kg. The pathogenesis of the delayed lethality of a single doxorubicin administration in mice is discussed. It is concluded that vitamin E and/or selenium have no significant protective action against doxorubicin induced delayed lethality in mice.

The effect of vitamin E and selenium on doxorubicin (Adriamycin) induced delayed toxicity in mice. The antagonistic action of repeated administration of vitamin E and selenium on the lethality caused by a single intraperitoneal injection of doxorubicin 15 to 20 mg/kg has been investigated in mice. Mice were treated with vitamin E, 20 to 4100 mg/kg intraperitoneally/intramuscularly daily or once a week and/or selenium 27 micrograms/kg orally daily for 6 to 7 weeks, i.e. one or two weeks before and five weeks after doxorubicin administration. 30 mg/kg of doxorubicin intraperitoneally caused 100% lethality within 4 days, whereas 15 mg/kg caused no deaths within a week, but resulted in a delayed toxicity with a cumulative lethality of 80% at the end of the observation period of 6 months. Vitamin E protected the mice from the lethal effect of doxorubicin, 15 mg/kg during the administration, but the mice began to die when the vitamin E administration was discontinued. Selenium only protected the mice for two weeks in spite of the continuous administration of selenium. The combined administration of vitamin E and selenium had no protective effect on the lethality caused by doxorubicin, 20 mg/kg. The pathogenesis of the delayed lethality of a single doxorubicin administration in mice is discussed. It is concluded that vitamin E and/or selenium have no significant protective action against doxorubicin induced delayed lethality in mice.

pubmed23n1140_25082

Stochastic evaluation of four-component relativistic second-order many-body perturbation energies: A potentially quadratic-scaling correlation method.

A second-order many-body perturbation correction to the relativistic Dirac-Hartree-Fock energy is evaluated stochastically by integrating 13-dimensional products of four-component spinors and Coulomb potentials. The integration in the real space of electron coordinates is carried out by the Monte Carlo (MC) method with the Metropolis sampling, whereas the MC integration in the imaginary-time domain is performed by the inverse-cumulative distribution function method. The computational cost to reach a given relative statistical error for spatially compact but heavy molecules is observed to be no worse than cubic and possibly quadratic with the number of electrons or basis functions. This is a vast improvement over the quintic scaling of the conventional, deterministic second-order many-body perturbation method. The algorithm is also easily and efficiently parallelized with 92% strong scalability going from 64 to 4096 processors.

Stochastic evaluation of four-component relativistic second-order many-body perturbation energies: A potentially quadratic-scaling correlation method. A second-order many-body perturbation correction to the relativistic Dirac-Hartree-Fock energy is evaluated stochastically by integrating 13-dimensional products of four-component spinors and Coulomb potentials. The integration in the real space of electron coordinates is carried out by the Monte Carlo (MC) method with the Metropolis sampling, whereas the MC integration in the imaginary-time domain is performed by the inverse-cumulative distribution function method. The computational cost to reach a given relative statistical error for spatially compact but heavy molecules is observed to be no worse than cubic and possibly quadratic with the number of electrons or basis functions. This is a vast improvement over the quintic scaling of the conventional, deterministic second-order many-body perturbation method. The algorithm is also easily and efficiently parallelized with 92% strong scalability going from 64 to 4096 processors.

pubmed23n0621_13534

Exploring the potential role of neuromodulatory drugs in radical prostatectomy patients.

Since the introduction of the nerve-sparing radical prostatectomy (RP), potency preservation rates of between 20% and 90% have been reported. It is irrefutable that the nerve-sparing status of an RP is predictive of recovery of erectile function. Bilateral nerve sparing is associated with superior spontaneous and oral therapy-assisted recovery of erectile function compared to unilateral nerve sparing, which in turn is more likely to lead to functional erections than non-nerve-sparing surgery. Neural regeneration is the mechanism by which erectile function improves over time following RP. Although the degree of neural trauma that occurs intraoperatively is a determinant of long-term recovery of neural function, biological factors involved in neural regeneration are likely important determinants of the completeness of neural recovery. Furthermore, these biological factors are likely a major reason for the interindividual variation in recovery of erectile function after this operation. Recently, the development of rat models of cavernous nerve injury has facilitated the study of neuroprotective and neuroregenerative agents. This paper reviews the current knowledge on pharmacological neuromodulation as it pertains to the radical pelvic surgery patient. The animal evidence is highly supportive of such agents' having a positive impact on erectile function recovery after RP. Human trial data are awaited.

Exploring the potential role of neuromodulatory drugs in radical prostatectomy patients. Since the introduction of the nerve-sparing radical prostatectomy (RP), potency preservation rates of between 20% and 90% have been reported. It is irrefutable that the nerve-sparing status of an RP is predictive of recovery of erectile function. Bilateral nerve sparing is associated with superior spontaneous and oral therapy-assisted recovery of erectile function compared to unilateral nerve sparing, which in turn is more likely to lead to functional erections than non-nerve-sparing surgery. Neural regeneration is the mechanism by which erectile function improves over time following RP. Although the degree of neural trauma that occurs intraoperatively is a determinant of long-term recovery of neural function, biological factors involved in neural regeneration are likely important determinants of the completeness of neural recovery. Furthermore, these biological factors are likely a major reason for the interindividual variation in recovery of erectile function after this operation. Recently, the development of rat models of cavernous nerve injury has facilitated the study of neuroprotective and neuroregenerative agents. This paper reviews the current knowledge on pharmacological neuromodulation as it pertains to the radical pelvic surgery patient. The animal evidence is highly supportive of such agents' having a positive impact on erectile function recovery after RP. Human trial data are awaited.

pubmed23n0560_11350

[Does CT-navigation improve the outcome of functional endonasal sinus surgery?].

Computer-assisted surgery (CAS) has found widespread use in functional endonasal sinus surgery (FESS) over the past few years. The present study investigates if CAS leads to a better outcome in FESS. All patients who underwent endonasal sphenoethmoidectomy were enrolled in a prospective, non-randomized study. The procedures were done without CAS (group A) in 2003 and in 2004 with CAS (group B), using a Stryker navigation unit. 62 patients (113 sphenoidectomies) were included in group A and 61 patients (109 sphenoidectomies) in group B. The underlying disease was recurrent chronic sinusitis or polyposis nasi in all patients except for inverted papilloma in one patient of group A and in two patients of group B. The follow-up period was 6 months. Preoperatively and at 6 months postoperatively, a CT-scan was obtained and symptom scores were assessed using a questionnaire. No significant difference was found between group A and B with respect to symptom scores, and CT-scans preoperatively and at 6 months postoperatively. The operation strategy did not change by the introduction of CAS. The frontal sinus was entered in group A and B in 59% and 64%, respectively. All parameters significantly improved postoperatively, compared to the preoperative values. As far as complications are concerned, two anterior orbital injuries and one retrobulbar haematoma occurred in group A and one postoperative lacrimal stenosis in group B. CAS does not lead to a better clinical outcome in FESS. Our data suggest that the rate of complications may be reduced using CAS. However, studies with a much larger number of patients would be necessary for a definite answer to this issue.

[Does CT-navigation improve the outcome of functional endonasal sinus surgery?]. Computer-assisted surgery (CAS) has found widespread use in functional endonasal sinus surgery (FESS) over the past few years. The present study investigates if CAS leads to a better outcome in FESS. All patients who underwent endonasal sphenoethmoidectomy were enrolled in a prospective, non-randomized study. The procedures were done without CAS (group A) in 2003 and in 2004 with CAS (group B), using a Stryker navigation unit. 62 patients (113 sphenoidectomies) were included in group A and 61 patients (109 sphenoidectomies) in group B. The underlying disease was recurrent chronic sinusitis or polyposis nasi in all patients except for inverted papilloma in one patient of group A and in two patients of group B. The follow-up period was 6 months. Preoperatively and at 6 months postoperatively, a CT-scan was obtained and symptom scores were assessed using a questionnaire. No significant difference was found between group A and B with respect to symptom scores, and CT-scans preoperatively and at 6 months postoperatively. The operation strategy did not change by the introduction of CAS. The frontal sinus was entered in group A and B in 59% and 64%, respectively. All parameters significantly improved postoperatively, compared to the preoperative values. As far as complications are concerned, two anterior orbital injuries and one retrobulbar haematoma occurred in group A and one postoperative lacrimal stenosis in group B. CAS does not lead to a better clinical outcome in FESS. Our data suggest that the rate of complications may be reduced using CAS. However, studies with a much larger number of patients would be necessary for a definite answer to this issue.

pubmed23n0733_13445

Patient access to complex chronic disease records on the Internet.

Access to medical records on the Internet has been reported to be acceptable and popular with patients, although most published evaluations have been of primary care or office-based practice. We tested the feasibility and acceptability of making unscreened results and data from a complex chronic disease pathway (renal medicine) available to patients over the Internet in a project involving more than half of renal units in the UK. Content and presentation of the Renal PatientView (RPV) system was developed with patient groups. It was designed to receive information from multiple local information systems and to require minimal extra work in units. After piloting in 4 centres in 2005 it was made available more widely. Opinions were sought from both patients who enrolled and from those who did not in a paper survey, and from staff in an electronic survey. Anonymous data on enrollment and usage were extracted from the webserver. By mid 2011 over 17,000 patients from 47 of the 75 renal units in the UK had registered. Users had a wide age range (&lt;10 to &gt;90 yrs) but were younger and had more years of education than non-users. They were enthusiastic about the concept, found it easy to use, and 80% felt it gave them a better understanding of their disease. The most common reason for not enrolling was being unaware of the system. A minority of patients had security concerns, and these were reduced after enrolling. Staff responses were also strongly positive. They reported that it aided patient concordance and disease management, and increased the quality of consultations with a neutral effect on consultation length. Neither patient nor staff responses suggested that RPV led to an overall increase in patient anxiety or to an increased burden on renal units beyond the time required to enroll each patient. Patient Internet access to secondary care records concerning a complex chronic disease is feasible and popular, providing an increased sense of empowerment and understanding, with no serious identified negative consequences. Security concerns were present but rarely prevented participation. These are powerful reasons to make this type of access more widely available.

Patient access to complex chronic disease records on the Internet. Access to medical records on the Internet has been reported to be acceptable and popular with patients, although most published evaluations have been of primary care or office-based practice. We tested the feasibility and acceptability of making unscreened results and data from a complex chronic disease pathway (renal medicine) available to patients over the Internet in a project involving more than half of renal units in the UK. Content and presentation of the Renal PatientView (RPV) system was developed with patient groups. It was designed to receive information from multiple local information systems and to require minimal extra work in units. After piloting in 4 centres in 2005 it was made available more widely. Opinions were sought from both patients who enrolled and from those who did not in a paper survey, and from staff in an electronic survey. Anonymous data on enrollment and usage were extracted from the webserver. By mid 2011 over 17,000 patients from 47 of the 75 renal units in the UK had registered. Users had a wide age range (&lt;10 to &gt;90 yrs) but were younger and had more years of education than non-users. They were enthusiastic about the concept, found it easy to use, and 80% felt it gave them a better understanding of their disease. The most common reason for not enrolling was being unaware of the system. A minority of patients had security concerns, and these were reduced after enrolling. Staff responses were also strongly positive. They reported that it aided patient concordance and disease management, and increased the quality of consultations with a neutral effect on consultation length. Neither patient nor staff responses suggested that RPV led to an overall increase in patient anxiety or to an increased burden on renal units beyond the time required to enroll each patient. Patient Internet access to secondary care records concerning a complex chronic disease is feasible and popular, providing an increased sense of empowerment and understanding, with no serious identified negative consequences. Security concerns were present but rarely prevented participation. These are powerful reasons to make this type of access more widely available.

pubmed23n1085_309

Rubber dam isolation for restorative treatment in dental patients.

The effective control of moisture and microbes is necessary for the success of restoration procedures. The rubber dam, as an isolation method, has been widely used in dental restorative treatments. The effects of rubber dam usage on the longevity and quality of dental restorations still require evidence-based discussion. This review compares the effects of rubber dam with other isolation methods in dental restorative treatments. This is an update of the Cochrane Review first published in 2016. To assess the effects of rubber dam isolation compared with other types of isolation used for direct and indirect restorative treatments in dental patients. Cochrane Oral Health's Information specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (searched 13 January 2021), Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 12) in the Cochrane Library (searched 13 January 2021), MEDLINE Ovid (1946 to 13 January 2021), Embase Ovid (1980 to 13 January 2021), LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 13 January 2021), and SciELO BIREME Virtual Health Library (1998 to 13 January 2021). We also searched Chinese BioMedical Literature Database (CBM, in Chinese) (1978 to 13 January 2021), VIP database (in Chinese) (1989 to 13 January 2021), and China National Knowledge Infrastructure (CNKI, in Chinese) (1994 to 13 January 2021). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform, OpenGrey, and Sciencepaper Online (in Chinese) for ongoing trials. There were no restrictions on the language or date of publication when searching the electronic databases. We included randomised controlled trials (including split-mouth trials) over one month in length assessing the effects of rubber dam compared with alternative isolation methods for dental restorative treatments. Two review authors independently screened the results of the electronic searches, extracted data, and assessed the risk of bias of the included studies. Disagreement was resolved by discussion. We strictly followed Cochrane's statistical guidelines and assessed the certainty of the evidence using GRADE. We included six studies conducted worldwide between 2010 and 2015 involving a total of 1342 participants (of which 233 participants were lost to follow-up). All the included studies were at high risk of bias. Five studies compared rubber dam with traditional cotton rolls isolation. One study was excluded from the analysis due to inconsistencies in the presented data. Of the four remaining trials, three reported survival rates of the restorations with a minimum follow-up of six months. Pooled results from two studies involving 192 participants indicated that the use of rubber dam isolation may increase the survival rates of direct composite restorations of non-carious cervical lesions (NCCLs) at six months (odds ratio (OR) 2.29, 95% confidence interval (CI) 1.05 to 4.99; low-certainty evidence). However, the use of rubber dam in NCCLs composite restorations may have little to no effect on the survival rates of the restorations compared to cotton rolls at 12 months (OR 1.38, 95% CI 0.45 to 4.28; 1 study, 30 participants; very low-certainty evidence) and at 18 months (OR 1.00, 95% CI 0.45 to 2.25; 1 study, 30 participants; very low-certainty evidence) but the evidence is very uncertain. At 24 months, the use of rubber dam may decrease the risk of failure of the restorations in children undergoing proximal atraumatic restorative treatment in primary molars but the evidence is very uncertain (hazard ratio (HR) 0.80, 95% CI 0.66 to 0.97; 1 study, 559 participants; very low-certainty evidence). None of the included studies mentioned adverse effects or reported the direct cost of the treatment. This review found some low-certainty evidence that the use of rubber dam in dental direct restorative treatments may lead to a lower failure rate of the restorations compared with cotton roll usage after six months. At other time points, the evidence is very uncertain. Further high-quality research evaluating the effects of rubber dam usage on different types of restorative treatments is required.

Rubber dam isolation for restorative treatment in dental patients. The effective control of moisture and microbes is necessary for the success of restoration procedures. The rubber dam, as an isolation method, has been widely used in dental restorative treatments. The effects of rubber dam usage on the longevity and quality of dental restorations still require evidence-based discussion. This review compares the effects of rubber dam with other isolation methods in dental restorative treatments. This is an update of the Cochrane Review first published in 2016. To assess the effects of rubber dam isolation compared with other types of isolation used for direct and indirect restorative treatments in dental patients. Cochrane Oral Health's Information specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (searched 13 January 2021), Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 12) in the Cochrane Library (searched 13 January 2021), MEDLINE Ovid (1946 to 13 January 2021), Embase Ovid (1980 to 13 January 2021), LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 13 January 2021), and SciELO BIREME Virtual Health Library (1998 to 13 January 2021). We also searched Chinese BioMedical Literature Database (CBM, in Chinese) (1978 to 13 January 2021), VIP database (in Chinese) (1989 to 13 January 2021), and China National Knowledge Infrastructure (CNKI, in Chinese) (1994 to 13 January 2021). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform, OpenGrey, and Sciencepaper Online (in Chinese) for ongoing trials. There were no restrictions on the language or date of publication when searching the electronic databases. We included randomised controlled trials (including split-mouth trials) over one month in length assessing the effects of rubber dam compared with alternative isolation methods for dental restorative treatments. Two review authors independently screened the results of the electronic searches, extracted data, and assessed the risk of bias of the included studies. Disagreement was resolved by discussion. We strictly followed Cochrane's statistical guidelines and assessed the certainty of the evidence using GRADE. We included six studies conducted worldwide between 2010 and 2015 involving a total of 1342 participants (of which 233 participants were lost to follow-up). All the included studies were at high risk of bias. Five studies compared rubber dam with traditional cotton rolls isolation. One study was excluded from the analysis due to inconsistencies in the presented data. Of the four remaining trials, three reported survival rates of the restorations with a minimum follow-up of six months. Pooled results from two studies involving 192 participants indicated that the use of rubber dam isolation may increase the survival rates of direct composite restorations of non-carious cervical lesions (NCCLs) at six months (odds ratio (OR) 2.29, 95% confidence interval (CI) 1.05 to 4.99; low-certainty evidence). However, the use of rubber dam in NCCLs composite restorations may have little to no effect on the survival rates of the restorations compared to cotton rolls at 12 months (OR 1.38, 95% CI 0.45 to 4.28; 1 study, 30 participants; very low-certainty evidence) and at 18 months (OR 1.00, 95% CI 0.45 to 2.25; 1 study, 30 participants; very low-certainty evidence) but the evidence is very uncertain. At 24 months, the use of rubber dam may decrease the risk of failure of the restorations in children undergoing proximal atraumatic restorative treatment in primary molars but the evidence is very uncertain (hazard ratio (HR) 0.80, 95% CI 0.66 to 0.97; 1 study, 559 participants; very low-certainty evidence). None of the included studies mentioned adverse effects or reported the direct cost of the treatment. This review found some low-certainty evidence that the use of rubber dam in dental direct restorative treatments may lead to a lower failure rate of the restorations compared with cotton roll usage after six months. At other time points, the evidence is very uncertain. Further high-quality research evaluating the effects of rubber dam usage on different types of restorative treatments is required.

pubmed23n0049_5816

Dental morphology of 45,XO human females: molar cusp area, volume, shape and linear measurements.

A three-dimensional analysis of the maxillary first molars of five 45,XO females and comparison with normal females and males demonstrated a reduction of cusp areas and volumes in the 45,XO females. Mesiodistal and faciolingual dimensions were also reduced. The reductions in basal area and volume were greater in the later developing, distal cusps. In normal females the second X chromosome apparently does not exert an effect on the cusp height but increases the basal area. The results further indicate that the Y chromosome in normal males increases both cusp height and basal area. The steepest cusps were found in 45,XO females while the shallowest were in the control males. Both sex chromosomes thus seem to affect the shape of the cusp but the resulting phenotypes differ.

Dental morphology of 45,XO human females: molar cusp area, volume, shape and linear measurements. A three-dimensional analysis of the maxillary first molars of five 45,XO females and comparison with normal females and males demonstrated a reduction of cusp areas and volumes in the 45,XO females. Mesiodistal and faciolingual dimensions were also reduced. The reductions in basal area and volume were greater in the later developing, distal cusps. In normal females the second X chromosome apparently does not exert an effect on the cusp height but increases the basal area. The results further indicate that the Y chromosome in normal males increases both cusp height and basal area. The steepest cusps were found in 45,XO females while the shallowest were in the control males. Both sex chromosomes thus seem to affect the shape of the cusp but the resulting phenotypes differ.

pubmed23n0059_5288

[The epidemic manifestation of natural foci of tick-borne encephalitis on the territory of the Maritime Territory. 2. The spatial differences in the seasonality of tick-borne encephalitis].

Using computer maps of the epidemic process season variations, tick-borne morbidity and lethality in the areas of the Maritime Territory [correction of Primorsky Region] have been analysed. According to season variations of the epidemic process the territory of Sikhote Alin has been divided into two separate parts--northern and southern, with morbidity peak in June and July, respectively.

[The epidemic manifestation of natural foci of tick-borne encephalitis on the territory of the Maritime Territory. 2. The spatial differences in the seasonality of tick-borne encephalitis]. Using computer maps of the epidemic process season variations, tick-borne morbidity and lethality in the areas of the Maritime Territory [correction of Primorsky Region] have been analysed. According to season variations of the epidemic process the territory of Sikhote Alin has been divided into two separate parts--northern and southern, with morbidity peak in June and July, respectively.

pubmed23n1102_26055

DcCCD4 catalyzes the degradation of α-carotene and β-carotene to affect carotenoid accumulation and taproot color in carrot.

Carotenoids are important natural pigments that give bright colors to plants. The difference in the accumulation of carotenoids is one of the key factors in the formation of various colors in carrot taproots. Carotenoid cleavage dioxygenases (CCDs), including CCD and 9-cis epoxycarotenoid dioxygenase, are the main enzymes involved in the cleavage of carotenoids in plants. Seven CCD genes have been annotated from the carrot genome. In this study, through expression analysis, we found that the expression level of DcCCD4 was significantly higher in the taproot of white carrot (low carotenoid content) than orange carrot (high carotenoid content). The overexpression of DcCCD4 in orange carrots caused the taproot color to be pale yellow, and the contents of α- and β-carotene decreased sharply. Mutant carrot with loss of DcCCD4 function exhibited yellow color (the taproot of the control carrot was white). The accumulation of β-carotene was also detected in taproot. Functional analysis of the DcCCD4 enzyme in vitro showed that it was able to cleave α- and β-carotene at the 9, 10 (9', 10') double bonds. In addition, the number of colored chromoplasts in the taproot cells of transgenic carrots overexpressing DcCCD4 was significantly reduced compared with that in normal orange carrots. Results showed that DcCCD4 affects the accumulation of carotenoids through cleavage of α- and β-carotene in carrot taproot.

DcCCD4 catalyzes the degradation of α-carotene and β-carotene to affect carotenoid accumulation and taproot color in carrot. Carotenoids are important natural pigments that give bright colors to plants. The difference in the accumulation of carotenoids is one of the key factors in the formation of various colors in carrot taproots. Carotenoid cleavage dioxygenases (CCDs), including CCD and 9-cis epoxycarotenoid dioxygenase, are the main enzymes involved in the cleavage of carotenoids in plants. Seven CCD genes have been annotated from the carrot genome. In this study, through expression analysis, we found that the expression level of DcCCD4 was significantly higher in the taproot of white carrot (low carotenoid content) than orange carrot (high carotenoid content). The overexpression of DcCCD4 in orange carrots caused the taproot color to be pale yellow, and the contents of α- and β-carotene decreased sharply. Mutant carrot with loss of DcCCD4 function exhibited yellow color (the taproot of the control carrot was white). The accumulation of β-carotene was also detected in taproot. Functional analysis of the DcCCD4 enzyme in vitro showed that it was able to cleave α- and β-carotene at the 9, 10 (9', 10') double bonds. In addition, the number of colored chromoplasts in the taproot cells of transgenic carrots overexpressing DcCCD4 was significantly reduced compared with that in normal orange carrots. Results showed that DcCCD4 affects the accumulation of carotenoids through cleavage of α- and β-carotene in carrot taproot.

pubmed23n0323_10844

Three-dimensional xenograft model of dysplastic human laryngeal mucosa.

Development of new therapeutic interventions in head and neck squamous cell carcinoma (HNSCC) will be facilitated by a model system that incorporates the ease of manipulation found in current tissue culture systems while retaining the three dimensional architecture that defines these malignancies. Original scientific investigation. We describe a modification of a normal respiratory mucosa model system which recreates premalignant mucosal histology. Grossly normal appearing human mucosa is harvested from laryngectomy specimens, the mucosal epithelium selectively removed by protease treatment and placed in conventional tissue culture. After 7 days, the cells are seeded into denuded rat tracheas, which are in turn implanted in flank pockets of athymic nu/nu mice. The tracheas are incubated for three weeks, removed and the mucosa examined histologically. As originally described, normal pseudostratified squamous epithelium can be re-established in this system. Using human dysplastic mucosa as a starting material, mucosal histologies of respiratory dysplasia, squamous metaplasia, squamous dysplasia and squamous carcinoma in situ can be established. This system will provide a paradigm for future therapeutic interventions to modify the progression of squamous metaplasia to dysplasia, carcinoma in situ and invasive squamous cell carcinoma.

Three-dimensional xenograft model of dysplastic human laryngeal mucosa. Development of new therapeutic interventions in head and neck squamous cell carcinoma (HNSCC) will be facilitated by a model system that incorporates the ease of manipulation found in current tissue culture systems while retaining the three dimensional architecture that defines these malignancies. Original scientific investigation. We describe a modification of a normal respiratory mucosa model system which recreates premalignant mucosal histology. Grossly normal appearing human mucosa is harvested from laryngectomy specimens, the mucosal epithelium selectively removed by protease treatment and placed in conventional tissue culture. After 7 days, the cells are seeded into denuded rat tracheas, which are in turn implanted in flank pockets of athymic nu/nu mice. The tracheas are incubated for three weeks, removed and the mucosa examined histologically. As originally described, normal pseudostratified squamous epithelium can be re-established in this system. Using human dysplastic mucosa as a starting material, mucosal histologies of respiratory dysplasia, squamous metaplasia, squamous dysplasia and squamous carcinoma in situ can be established. This system will provide a paradigm for future therapeutic interventions to modify the progression of squamous metaplasia to dysplasia, carcinoma in situ and invasive squamous cell carcinoma.

pubmed23n0480_21038

Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector.

We describe the in vitro isolation and expansion of cells capable of forming neurosphere-like aggregates from human adult bone marrow. Cells within these passaged spheroids can differentiate into astrocytes, specific neuronal subtypes, and oligodendrocytes and have gene expression profiles similar to human fetal brain-derived neural stem cells. Genetically modified neural-competent bone marrow-derived cells efficiently migrate toward distant sites of brain injury and tumor in vivo, where they differentiate and express therapeutic transgenes when transplanted into the brains of mice. These studies suggest that adult bone marrow may serve as a large reservoir for autologous neural stem-like cells for future therapeutic strategies.

Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector. We describe the in vitro isolation and expansion of cells capable of forming neurosphere-like aggregates from human adult bone marrow. Cells within these passaged spheroids can differentiate into astrocytes, specific neuronal subtypes, and oligodendrocytes and have gene expression profiles similar to human fetal brain-derived neural stem cells. Genetically modified neural-competent bone marrow-derived cells efficiently migrate toward distant sites of brain injury and tumor in vivo, where they differentiate and express therapeutic transgenes when transplanted into the brains of mice. These studies suggest that adult bone marrow may serve as a large reservoir for autologous neural stem-like cells for future therapeutic strategies.

pubmed23n0560_7714

Isolation and Characterization of Sex-Linked Female-Sterile Mutants in DROSOPHILA MELANOGASTER with Special Attention to Eggshell Mutants.

To study genes that function mainly or exclusively during oogenesis, we have isolated and analyzed female-sterile mutations, with special emphasis on those that affect eggshell formation. Following treatment that induced 61 to 66% lethals, 8.1% of the 1071 X chromosomes tested carried recessive female sterility mutations (87 isolates), and 8.0% carried partial female-sterile mutations (86 isolates), respectively. In addition, three dominant female steriles were recovered. Some of the mutants had very low fecundity, and others laid morphologically normal eggs that failed to develop. A third category included 29 mutants that laid eggs with morphological abnormalities: 26 were female steriles, two were partial female steriles and one was fertile. Mutants of this third category were characterized in some detail and compared with 40 previously isolated mutants that laid similarly abnormal eggs. Approximately 28-31 complementation groups with morphological abnormalities were detected, some of which were large allelic series (11, 9, 7, 6 and 5 alleles). Twenty-four groups were mapped genetically or cytogenetically, and 21 were partially characterized by ultrastructural and biochemical procedures. Of the latter, one group showed clear deficiency of yolk proteins, and nine showed prominent ultrastructural defects in the chorion (at least eight accompanied by deficiencies in characterized chorion proteins). At least six groups with clear-cut effects were found at loci not previously identified with known chorion structural genes.

Isolation and Characterization of Sex-Linked Female-Sterile Mutants in DROSOPHILA MELANOGASTER with Special Attention to Eggshell Mutants. To study genes that function mainly or exclusively during oogenesis, we have isolated and analyzed female-sterile mutations, with special emphasis on those that affect eggshell formation. Following treatment that induced 61 to 66% lethals, 8.1% of the 1071 X chromosomes tested carried recessive female sterility mutations (87 isolates), and 8.0% carried partial female-sterile mutations (86 isolates), respectively. In addition, three dominant female steriles were recovered. Some of the mutants had very low fecundity, and others laid morphologically normal eggs that failed to develop. A third category included 29 mutants that laid eggs with morphological abnormalities: 26 were female steriles, two were partial female steriles and one was fertile. Mutants of this third category were characterized in some detail and compared with 40 previously isolated mutants that laid similarly abnormal eggs. Approximately 28-31 complementation groups with morphological abnormalities were detected, some of which were large allelic series (11, 9, 7, 6 and 5 alleles). Twenty-four groups were mapped genetically or cytogenetically, and 21 were partially characterized by ultrastructural and biochemical procedures. Of the latter, one group showed clear deficiency of yolk proteins, and nine showed prominent ultrastructural defects in the chorion (at least eight accompanied by deficiencies in characterized chorion proteins). At least six groups with clear-cut effects were found at loci not previously identified with known chorion structural genes.

pubmed23n0268_15911

Laryngeal pacing as a treatment for vocal fold paralysis.

We summarize etiologies of vocal fold paralysis and current treatments. The recent literature involving electrical stimulation of the larynx is reviewed. Four canines were involved in a study to test a new laryngeal pacemaker system. This system was used to stimulate both the lateral cricoarytenoid and thyroarytenoid muscles. The data are taken from two of these canines. One of the goals was to stimulate the paralyzed side of the larynx based on the activity of the normal (nonparalyzed) side of the larynx. The best stimulation parameters for full addition of the paralyzed vocal cord were 3-7 V, pulse duration of 0.5 ms at a frequency of 84-100 Hz. Principles for electrode design and electrophysiologic parameters pertaining to laryngeal pacing are discussed. We believe that unilateral vocal fold paralysis may someday be treated by stimulating the paralyzed lateral cricoarytenoid and thyroarytenoid muscles to move in synchrony with the normal, unparalyzed, lateral cricoarytenoid and thyroarytenoid muscles.

Laryngeal pacing as a treatment for vocal fold paralysis. We summarize etiologies of vocal fold paralysis and current treatments. The recent literature involving electrical stimulation of the larynx is reviewed. Four canines were involved in a study to test a new laryngeal pacemaker system. This system was used to stimulate both the lateral cricoarytenoid and thyroarytenoid muscles. The data are taken from two of these canines. One of the goals was to stimulate the paralyzed side of the larynx based on the activity of the normal (nonparalyzed) side of the larynx. The best stimulation parameters for full addition of the paralyzed vocal cord were 3-7 V, pulse duration of 0.5 ms at a frequency of 84-100 Hz. Principles for electrode design and electrophysiologic parameters pertaining to laryngeal pacing are discussed. We believe that unilateral vocal fold paralysis may someday be treated by stimulating the paralyzed lateral cricoarytenoid and thyroarytenoid muscles to move in synchrony with the normal, unparalyzed, lateral cricoarytenoid and thyroarytenoid muscles.

pubmed23n1115_9521

Influence of an increased content of pea and yellow lupin protein in the diet of pigs on meat quality.

The aim of the study was to test the effect of replacing soya beans with pea and yellow lupin seeds in the diet of pigs on meat quality. The meat for the tests was obtained from 60 fattening crossbred pigs F<sub1</sub (Polish Large White × Polish Landrace)  × F1 (Pietrain × Duroc). The animals belonged to three feeding groups depending on the feed used with the total share of soybeans and its reduction. Water holding capacity, colour, and tenderness were measured and visual and tactile evaluation (colour, marbling and firmness) was performed for meat samples collected from the longissimus lumborum muscle. The chemical composition of the meat and the content of minerals were determined. The content of amino acids, fatty acids and cholesterol was determined. There was no significant differences among the assessed physicochemical characteristics of the meat. The obtained meat was of good quality, regardless of the proportion of proteins from legumes in the diet of pigs. The results of the subjective evaluation of meat, its colour, and the content of muscle pigments were uniform in all food groups. Similarly, a uniform, high protein content was found in all tested groups (C-24.98%; E1-24.82%; E2-25.09%) and the content of macro- and micronutrients in the tested meat was equivalent. The profile of fatty acids was not significantly affected by dietary treatment. Palmitoleic acid content was significantly higher (P &lt; 0.05) in the E2 group compared to the E1 group (3.279% compared to 2.844%). The content of amino acids in meat samples was influenced by dietary treatment. Almost all the monitored essential amino acids (threonine, valine, leucine, phenylalanine and lysine) and some of nonessential amino acids' proportion was increased in the experimental groups (E1, E2). Replacing soya bean protein in the pigs' diet with legume protein (peas and yellow lupin) did not adversely affect meat quality. This applies to both the physicochemical characteristics, the basic composition and the fatty acid profile. The meat of fattening pigs fed with the highest proportion of pea and lupin in the ration was characterized by more favourable proportion of essential amino acids.

Influence of an increased content of pea and yellow lupin protein in the diet of pigs on meat quality. The aim of the study was to test the effect of replacing soya beans with pea and yellow lupin seeds in the diet of pigs on meat quality. The meat for the tests was obtained from 60 fattening crossbred pigs F<sub1</sub (Polish Large White × Polish Landrace)  × F1 (Pietrain × Duroc). The animals belonged to three feeding groups depending on the feed used with the total share of soybeans and its reduction. Water holding capacity, colour, and tenderness were measured and visual and tactile evaluation (colour, marbling and firmness) was performed for meat samples collected from the longissimus lumborum muscle. The chemical composition of the meat and the content of minerals were determined. The content of amino acids, fatty acids and cholesterol was determined. There was no significant differences among the assessed physicochemical characteristics of the meat. The obtained meat was of good quality, regardless of the proportion of proteins from legumes in the diet of pigs. The results of the subjective evaluation of meat, its colour, and the content of muscle pigments were uniform in all food groups. Similarly, a uniform, high protein content was found in all tested groups (C-24.98%; E1-24.82%; E2-25.09%) and the content of macro- and micronutrients in the tested meat was equivalent. The profile of fatty acids was not significantly affected by dietary treatment. Palmitoleic acid content was significantly higher (P &lt; 0.05) in the E2 group compared to the E1 group (3.279% compared to 2.844%). The content of amino acids in meat samples was influenced by dietary treatment. Almost all the monitored essential amino acids (threonine, valine, leucine, phenylalanine and lysine) and some of nonessential amino acids' proportion was increased in the experimental groups (E1, E2). Replacing soya bean protein in the pigs' diet with legume protein (peas and yellow lupin) did not adversely affect meat quality. This applies to both the physicochemical characteristics, the basic composition and the fatty acid profile. The meat of fattening pigs fed with the highest proportion of pea and lupin in the ration was characterized by more favourable proportion of essential amino acids.

pubmed23n1108_20078

Learning Fast and Slow: Propedeutica for Real-Time Malware Detection.

Existing malware detectors on safety-critical devices have difficulties in runtime detection due to the performance overhead. In this article, we introduce Propedeutica, a framework for efficient and effective real-time malware detection, leveraging the best of conventional machine learning (ML) and deep learning (DL) techniques. In Propedeutica, all software start executions are considered as benign and monitored by a conventional ML classifier for fast detection. If the software receives a borderline classification from the ML detector (e.g., the software is 50% likely to be benign and 50% likely to be malicious), the software will be transferred to a more accurate, yet performance demanding DL detector. To address spatial-temporal dynamics and software execution heterogeneity, we introduce a novel DL architecture (DeepMalware) for Propedeutica with multistream inputs. We evaluated Propedeutica with 9115 malware samples and 1338 benign software from various categories for the Windows OS. With a borderline interval of [30%, 70%], Propedeutica achieves an accuracy of 94.34% and a false-positive rate of 8.75%, with 41.45% of the samples moved for DeepMalwareanalysis. Even using only CPU, Propedeutica can detect malware within less than 0.1 s.

Learning Fast and Slow: Propedeutica for Real-Time Malware Detection. Existing malware detectors on safety-critical devices have difficulties in runtime detection due to the performance overhead. In this article, we introduce Propedeutica, a framework for efficient and effective real-time malware detection, leveraging the best of conventional machine learning (ML) and deep learning (DL) techniques. In Propedeutica, all software start executions are considered as benign and monitored by a conventional ML classifier for fast detection. If the software receives a borderline classification from the ML detector (e.g., the software is 50% likely to be benign and 50% likely to be malicious), the software will be transferred to a more accurate, yet performance demanding DL detector. To address spatial-temporal dynamics and software execution heterogeneity, we introduce a novel DL architecture (DeepMalware) for Propedeutica with multistream inputs. We evaluated Propedeutica with 9115 malware samples and 1338 benign software from various categories for the Windows OS. With a borderline interval of [30%, 70%], Propedeutica achieves an accuracy of 94.34% and a false-positive rate of 8.75%, with 41.45% of the samples moved for DeepMalwareanalysis. Even using only CPU, Propedeutica can detect malware within less than 0.1 s.

pubmed23n0912_4796

East River and East River #2 by Mitchell Johnson.

Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author.

East River and East River #2 by Mitchell Johnson. Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author.

pubmed23n0532_7483

In Vitro Evolution and Preliminary Characterization of a Cadmium-Resistant Population of Chlamydomonas reinhardtii.

A cadmium-tolerant population of Chlamydomonas reinhardtii was derived from a Cd-sensitive cell wall-deficient strain by long-term selection in liquid culture. A comparison of Cd-sensitive and Cd-tolerant cells revealed that Cd tolerance was due to genetically determined alterations of metabolism rather than to increased efficiency of a detoxification system.

In Vitro Evolution and Preliminary Characterization of a Cadmium-Resistant Population of Chlamydomonas reinhardtii. A cadmium-tolerant population of Chlamydomonas reinhardtii was derived from a Cd-sensitive cell wall-deficient strain by long-term selection in liquid culture. A comparison of Cd-sensitive and Cd-tolerant cells revealed that Cd tolerance was due to genetically determined alterations of metabolism rather than to increased efficiency of a detoxification system.

pubmed23n0714_21663

Synaptic plasticity modulates autonomous transitions between waking and sleep states: insights from a Morris-Lecar model.

The transitions between waking and sleep states are characterized by considerable changes in neuronal firing. During waking, neurons fire tonically at irregular intervals and a desynchronized activity is observed at the electroencephalogram. This activity becomes synchronized with slow wave sleep onset when neurons start to oscillate between periods of firing (up-states) and periods of silence (down-states). Recently, it has been proposed that the connections between neurons undergo potentiation during waking, whereas they weaken during slow wave sleep. Here, we propose a dynamical model to describe basic features of the autonomous transitions between such states. We consider a network of coupled neurons in which the strength of the interactions is modulated by synaptic long term potentiation and depression, according to the spike time-dependent plasticity rule (STDP). The model shows that the enhancement of synaptic strength between neurons occurring in waking increases the propensity of the network to synchronize and, conversely, desynchronization appears when the strength of the connections become weaker. Both transitions appear spontaneously, but the transition from sleep to waking required a slight modification of the STDP rule with the introduction of a mechanism which becomes active during sleep and changes the proportion between potentiation and depression in accordance with biological data. At the neuron level, transitions from desynchronization to synchronization and vice versa can be described as a bifurcation between two different states, whose dynamical regime is modulated by synaptic strengths, thus suggesting that transition from a state to an another can be determined by quantitative differences between potentiation and depression.

Synaptic plasticity modulates autonomous transitions between waking and sleep states: insights from a Morris-Lecar model. The transitions between waking and sleep states are characterized by considerable changes in neuronal firing. During waking, neurons fire tonically at irregular intervals and a desynchronized activity is observed at the electroencephalogram. This activity becomes synchronized with slow wave sleep onset when neurons start to oscillate between periods of firing (up-states) and periods of silence (down-states). Recently, it has been proposed that the connections between neurons undergo potentiation during waking, whereas they weaken during slow wave sleep. Here, we propose a dynamical model to describe basic features of the autonomous transitions between such states. We consider a network of coupled neurons in which the strength of the interactions is modulated by synaptic long term potentiation and depression, according to the spike time-dependent plasticity rule (STDP). The model shows that the enhancement of synaptic strength between neurons occurring in waking increases the propensity of the network to synchronize and, conversely, desynchronization appears when the strength of the connections become weaker. Both transitions appear spontaneously, but the transition from sleep to waking required a slight modification of the STDP rule with the introduction of a mechanism which becomes active during sleep and changes the proportion between potentiation and depression in accordance with biological data. At the neuron level, transitions from desynchronization to synchronization and vice versa can be described as a bifurcation between two different states, whose dynamical regime is modulated by synaptic strengths, thus suggesting that transition from a state to an another can be determined by quantitative differences between potentiation and depression.

pubmed23n0334_602

Fermentation substrate and dilution rate interact to affect microbial growth and efficiency.

The effect of dilution rate (D) on carbohydrate, fibrous and nonfibrous, and protein fermentation by ruminal microorganisms was studied using a single-effluent continuous-culture system. The diets of fibrous carbohydrate, nonfibrous carbohydrate, or protein were formulated with soybean hulls (FC), ground corn (NFC), or isolated soy protein (PR) as the primary ingredient, respectively. Six dilution rates (.025, .050, .075, .10, .15, and .20/h of fermenter volume) were used. Digestibilities of DM, OM, and CP for the three diets and of NDF and ADF for the FC diet decreased (P&lt;.001) as D increased, although the response of the digestibility to D varied with diet. Increasing D resulted in an increase in pH (P&lt;.001) and a decrease (P&lt;.001) in ammonia concentration. Daily volatile fatty acid production increased (quadratic; P&lt;.01) for the FC and NFC diets, but decreased (quadratic; P&lt;.001) for the PR diet. Increasing D quadratically increased (P&lt;.001) the molar percentage of acetate and propionate, but quadratically decreased (P&lt;.001) butyrate and valerate for the FC and NFC diets. For the PR diet, the molar percentage of propionate and valerate increased (quadratic; P&lt;.01), whereas acetate and butyrate decreased (linear; P&lt;.001) in response to increasing D. Molar percentage of isobutyrate and isovalerate decreased (P&lt;.01) with increasing D for all three diets. As D increased, daily microbial N production showed quadratic responses with maximum values achieved at .126, .143, and .187/h D for the FC, NFC, and PR diet, respectively. There was a positive correlation between microbial growth efficiency (MOEFF) and D. A quadratic model fit the data of MOEFF as affected by D, and maximum MOEFF of 37.3, 59.6, and 71.4 g of bacterial N/kg OM truly fermented were calculated to be achieved at .177, .314, and .207/h D for the FC, NFC, and PR diet, respectively. Dilution rate significantly influenced the ruminal microbial fermentation of fibrous and nonfibrous carbohydrates and proteins, and was positively related to microbial yield and growth efficiency. In addition, microbial nitrogen composition, and therefore efficiency, was affected by substrate fermented.

Fermentation substrate and dilution rate interact to affect microbial growth and efficiency. The effect of dilution rate (D) on carbohydrate, fibrous and nonfibrous, and protein fermentation by ruminal microorganisms was studied using a single-effluent continuous-culture system. The diets of fibrous carbohydrate, nonfibrous carbohydrate, or protein were formulated with soybean hulls (FC), ground corn (NFC), or isolated soy protein (PR) as the primary ingredient, respectively. Six dilution rates (.025, .050, .075, .10, .15, and .20/h of fermenter volume) were used. Digestibilities of DM, OM, and CP for the three diets and of NDF and ADF for the FC diet decreased (P&lt;.001) as D increased, although the response of the digestibility to D varied with diet. Increasing D resulted in an increase in pH (P&lt;.001) and a decrease (P&lt;.001) in ammonia concentration. Daily volatile fatty acid production increased (quadratic; P&lt;.01) for the FC and NFC diets, but decreased (quadratic; P&lt;.001) for the PR diet. Increasing D quadratically increased (P&lt;.001) the molar percentage of acetate and propionate, but quadratically decreased (P&lt;.001) butyrate and valerate for the FC and NFC diets. For the PR diet, the molar percentage of propionate and valerate increased (quadratic; P&lt;.01), whereas acetate and butyrate decreased (linear; P&lt;.001) in response to increasing D. Molar percentage of isobutyrate and isovalerate decreased (P&lt;.01) with increasing D for all three diets. As D increased, daily microbial N production showed quadratic responses with maximum values achieved at .126, .143, and .187/h D for the FC, NFC, and PR diet, respectively. There was a positive correlation between microbial growth efficiency (MOEFF) and D. A quadratic model fit the data of MOEFF as affected by D, and maximum MOEFF of 37.3, 59.6, and 71.4 g of bacterial N/kg OM truly fermented were calculated to be achieved at .177, .314, and .207/h D for the FC, NFC, and PR diet, respectively. Dilution rate significantly influenced the ruminal microbial fermentation of fibrous and nonfibrous carbohydrates and proteins, and was positively related to microbial yield and growth efficiency. In addition, microbial nitrogen composition, and therefore efficiency, was affected by substrate fermented.

pubmed23n0952_1328

Where Do Recent Small Molecule Clinical Development Candidates Come From?

An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (&gt;50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

Where Do Recent Small Molecule Clinical Development Candidates Come From? An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (&gt;50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

pubmed23n1106_3214

Difluoromethyl Radical Triggered Tandem Reaction of <i>N</i>-Allyl Amides to Difluoromethylated β-Amino Alcohols by Photoredox Catalysis.

An elegant tandem reaction process for transferring <iN</i-allyl amide into CF<sub2</subH-β-amino alcohol is described. This approach proceeded smoothly under visible light irradiation in the presence of a 3 mol % Ir complex, exhibiting a broad substrate scope and functional group tolerance, and a variety of CF<sub2</subH-β-amino alcohols were readily accessed in good to excellent yields under mild conditions. The reliable mechanistic studies revealed that sequential difluoromethyl radical addition/carbocation trap/rearrangement is involved.

Difluoromethyl Radical Triggered Tandem Reaction of <i>N</i>-Allyl Amides to Difluoromethylated β-Amino Alcohols by Photoredox Catalysis. An elegant tandem reaction process for transferring <iN</i-allyl amide into CF<sub2</subH-β-amino alcohol is described. This approach proceeded smoothly under visible light irradiation in the presence of a 3 mol % Ir complex, exhibiting a broad substrate scope and functional group tolerance, and a variety of CF<sub2</subH-β-amino alcohols were readily accessed in good to excellent yields under mild conditions. The reliable mechanistic studies revealed that sequential difluoromethyl radical addition/carbocation trap/rearrangement is involved.

pubmed23n0567_20353

Distribution of eschars on the body of scrub typhus patients: a prospective study.

Eschar is an important finding for the diagnosis of scrub typhus. The IFA test for possible scrub typhus was performed. The presence or absence of eschar was thoroughly examined. Among the 176 scrub typhus cases confirmed by IFA, 162 (92.0%) cases had eschar; 128 patients (79.5%) had eschars on the front of the body. Eschars were primarily detected in males within 30 cm below the umbilicus (19 patients, 35.8%). Distributions on the lower extremities and the front chest above the umbilicus were 22.6% (12 patients) and 20.8% (11 patients), respectively. A different pattern was seen in females. The most prevalent area was the front chest above the umbilicus, which accounted for 40.7% (44 patients) of all the detected eschars. Our study is the first report of a schematic diagram that shows the differences between the males and females with respect to eschar location in scrub typhus patients.

Distribution of eschars on the body of scrub typhus patients: a prospective study. Eschar is an important finding for the diagnosis of scrub typhus. The IFA test for possible scrub typhus was performed. The presence or absence of eschar was thoroughly examined. Among the 176 scrub typhus cases confirmed by IFA, 162 (92.0%) cases had eschar; 128 patients (79.5%) had eschars on the front of the body. Eschars were primarily detected in males within 30 cm below the umbilicus (19 patients, 35.8%). Distributions on the lower extremities and the front chest above the umbilicus were 22.6% (12 patients) and 20.8% (11 patients), respectively. A different pattern was seen in females. The most prevalent area was the front chest above the umbilicus, which accounted for 40.7% (44 patients) of all the detected eschars. Our study is the first report of a schematic diagram that shows the differences between the males and females with respect to eschar location in scrub typhus patients.

pubmed23n0970_17562

Genetic analysis of KillerRed in C. elegans identifies a shared role of calcium genes in ROS-mediated neurodegeneration.

In C. elegans, neurodegeneration induced by excitotoxicity or aggregation of misfolded proteins is dependent on genes involved in calcium release from the endoplasmic reticulum. Reactive oxygen species (ROS) can also induce neurodegeneration, but the relationship between ROS-mediated neurodegeneration and calcium has not been established. We activated KillerRed in the GABA neurons of C. elegans to produce ROS that leads to functional loss and structural degeneration of these neurons and demonstrated that the severity of neurodegeneration was dependent on extent of KillerRed activation. To genetically examine the role of calcium in ROS-mediated neurodegeneration, we measured functional neurodegeneration in itr-1 (inositol trisphosphate receptor), crt-1 (caltreticulin), and unc-68 (ryanodine receptor) mutants. Similar to other neurotoxic conditions, neurodegeneration triggered by KillerRed was reduced in itr-1 and crt-1 mutants. Somewhat unexpectedly, genetic or pharmacological disruption of unc-68 had a minimal effect on neurodegeneration. Our results indicate ROS-mediated neurodegeneration occurs through a conserved calcium regulated mechanism and suggest that components of the degeneration process have different sensitivities to ROS.

Genetic analysis of KillerRed in C. elegans identifies a shared role of calcium genes in ROS-mediated neurodegeneration. In C. elegans, neurodegeneration induced by excitotoxicity or aggregation of misfolded proteins is dependent on genes involved in calcium release from the endoplasmic reticulum. Reactive oxygen species (ROS) can also induce neurodegeneration, but the relationship between ROS-mediated neurodegeneration and calcium has not been established. We activated KillerRed in the GABA neurons of C. elegans to produce ROS that leads to functional loss and structural degeneration of these neurons and demonstrated that the severity of neurodegeneration was dependent on extent of KillerRed activation. To genetically examine the role of calcium in ROS-mediated neurodegeneration, we measured functional neurodegeneration in itr-1 (inositol trisphosphate receptor), crt-1 (caltreticulin), and unc-68 (ryanodine receptor) mutants. Similar to other neurotoxic conditions, neurodegeneration triggered by KillerRed was reduced in itr-1 and crt-1 mutants. Somewhat unexpectedly, genetic or pharmacological disruption of unc-68 had a minimal effect on neurodegeneration. Our results indicate ROS-mediated neurodegeneration occurs through a conserved calcium regulated mechanism and suggest that components of the degeneration process have different sensitivities to ROS.

pubmed23n0701_18459

The inability of emergency physicians to adequately clinically estimate the underlying hemodynamic profiles of acutely ill patients.

Emergency physicians (EPs) estimate the underlying hemodynamics of acutely ill patients and use them to help both diagnose and formulate a treatment plan. This trial compared the EP clinically derived estimates of cardiac output (CO) and systemic vascular resistance (SVR) to those measured noninvasively. Forty acutely ill emergency department patients with a broad range of diagnosis and blood pressure (BP) and pulse were monitored for 2 hours using novel noninvasive finger cuff technology (Nexfin; BMEYE, Amsterdam, The Netherlands). The Nexfin device provides continuous BP monitoring and, from the resulting pulse pressure waveform, calculates beat-to-beat CO and SVR. At baseline assessment and after 2 hours of testing and therapy, treating EPs were asked to estimate the CO and SVR (low, normal, or high), and these were compared with Nexfin measurements. Twenty-five men and 15 women were enrolled with a mean age of 62.2 years (SD, 12.6 years). Eighteen had acute shortness of breath; 11, with probable stroke syndrome; 3, with suspected sepsis; and 8, with a systolic BP greater than 180 or less than 100 mm Hg. Concordance tables showed that there was very little agreement (κ values) between either the compared initial CO (-0.0873) and SVR (-0.0645) or the 2-hour values (-0.0645 and -0.1949, respectively). Emergency physicians cannot accurately estimate the underlying hemodynamic profiles of acutely ill patients when compared with more objective measurements. This inaccuracy may have important clinical ramifications. Further study is needed to determine how to use these measured continuous CO and SVR monitoring values.

The inability of emergency physicians to adequately clinically estimate the underlying hemodynamic profiles of acutely ill patients. Emergency physicians (EPs) estimate the underlying hemodynamics of acutely ill patients and use them to help both diagnose and formulate a treatment plan. This trial compared the EP clinically derived estimates of cardiac output (CO) and systemic vascular resistance (SVR) to those measured noninvasively. Forty acutely ill emergency department patients with a broad range of diagnosis and blood pressure (BP) and pulse were monitored for 2 hours using novel noninvasive finger cuff technology (Nexfin; BMEYE, Amsterdam, The Netherlands). The Nexfin device provides continuous BP monitoring and, from the resulting pulse pressure waveform, calculates beat-to-beat CO and SVR. At baseline assessment and after 2 hours of testing and therapy, treating EPs were asked to estimate the CO and SVR (low, normal, or high), and these were compared with Nexfin measurements. Twenty-five men and 15 women were enrolled with a mean age of 62.2 years (SD, 12.6 years). Eighteen had acute shortness of breath; 11, with probable stroke syndrome; 3, with suspected sepsis; and 8, with a systolic BP greater than 180 or less than 100 mm Hg. Concordance tables showed that there was very little agreement (κ values) between either the compared initial CO (-0.0873) and SVR (-0.0645) or the 2-hour values (-0.0645 and -0.1949, respectively). Emergency physicians cannot accurately estimate the underlying hemodynamic profiles of acutely ill patients when compared with more objective measurements. This inaccuracy may have important clinical ramifications. Further study is needed to determine how to use these measured continuous CO and SVR monitoring values.

pubmed23n0118_11249

[Various approaches to optimizing the hemodynamics of myocardial infarct patients].

Combined investigation of systemic and intracardiac hemodynamic parameters (radiocardiography and Fick's procedure, transvenous catheterization, and right-ventricular and pulmonary arterial blood pressure measurement) was carried out in 428 myocardial infarction patients admitted to hospital within the early hours after the attack; changes in necrotic area were monitored for 7 days (precordial ECG cartography and serial serum CPK assays). Computer-assisted combined data analysis made use of image identification techniques, the images being based on a general approximation algorithm and informative coefficient. The algorithm permitted a classification of patients' condition by left-ventricular insufficiency (a 77.4% reliability) and by the spread of necrotic area (a 72.5% reliability). The prognosis chart, constructed on the basis of comparison between actual hemodynamic values and their standard vectors, brought out optimum regimens for every parameter associated with the least risk of left-ventricular insufficiency and necrotic spread.

[Various approaches to optimizing the hemodynamics of myocardial infarct patients]. Combined investigation of systemic and intracardiac hemodynamic parameters (radiocardiography and Fick's procedure, transvenous catheterization, and right-ventricular and pulmonary arterial blood pressure measurement) was carried out in 428 myocardial infarction patients admitted to hospital within the early hours after the attack; changes in necrotic area were monitored for 7 days (precordial ECG cartography and serial serum CPK assays). Computer-assisted combined data analysis made use of image identification techniques, the images being based on a general approximation algorithm and informative coefficient. The algorithm permitted a classification of patients' condition by left-ventricular insufficiency (a 77.4% reliability) and by the spread of necrotic area (a 72.5% reliability). The prognosis chart, constructed on the basis of comparison between actual hemodynamic values and their standard vectors, brought out optimum regimens for every parameter associated with the least risk of left-ventricular insufficiency and necrotic spread.

pubmed23n0826_21771

Blood Metabolome Changes Before and After Bariatric Surgery: A (1)H NMR-Based Clinical Investigation.

Excessive body fat and obesity have adverse health effects and result in significant morbidity such as type 2 diabetes mellitus. The health burden of obesity can be reduced with the Roux-en-Y gastric bypass (RYGB) weight-loss bariatric surgery. Little is known on the molecular changes that occur at the metabolome level before and after bariatric surgery, with a view to clinical biomarker development. Hence, we employed a metabolomics approach in 10 obese diabetic patients who underwent bariatric surgery. Metabolomics data were obtained by T2- and diffusion-edited hydrogen nuclear magnetic resonance ((1)H NMR) spectra to monitor the metabolic and lipoprotein profiles, and gas chromatography-mass spectrometry (CG-MS) to access the fatty acid profile before and 12 months after RYGB. Using hierarchical partial least squares discriminant analysis, we found that RYGB induces several key metabolic alterations associated with glucose homeostasis, as well as fatty acid and amino acid metabolism. The levels of lactate (Krebs' intermediate cycle) decreased after RYGB. The leucine, isoleucine, valine, lactate, and glucose levels were higher in the samples before RYGB (p&lt;0.05). Additionally, the levels of very low-density lipoprotein, unsaturated lipids, and N-acetyl-glycoprotein were higher before RYGB. By contrast, levels of the high-density lipoprotein and phosphatidylcholine were higher after bariatric surgery. These results collectively offer important holistic integrative biology data to develop future clinically relevant metabolomics biomarkers related to bariatric surgery in connection with obesity.

Blood Metabolome Changes Before and After Bariatric Surgery: A (1)H NMR-Based Clinical Investigation. Excessive body fat and obesity have adverse health effects and result in significant morbidity such as type 2 diabetes mellitus. The health burden of obesity can be reduced with the Roux-en-Y gastric bypass (RYGB) weight-loss bariatric surgery. Little is known on the molecular changes that occur at the metabolome level before and after bariatric surgery, with a view to clinical biomarker development. Hence, we employed a metabolomics approach in 10 obese diabetic patients who underwent bariatric surgery. Metabolomics data were obtained by T2- and diffusion-edited hydrogen nuclear magnetic resonance ((1)H NMR) spectra to monitor the metabolic and lipoprotein profiles, and gas chromatography-mass spectrometry (CG-MS) to access the fatty acid profile before and 12 months after RYGB. Using hierarchical partial least squares discriminant analysis, we found that RYGB induces several key metabolic alterations associated with glucose homeostasis, as well as fatty acid and amino acid metabolism. The levels of lactate (Krebs' intermediate cycle) decreased after RYGB. The leucine, isoleucine, valine, lactate, and glucose levels were higher in the samples before RYGB (p&lt;0.05). Additionally, the levels of very low-density lipoprotein, unsaturated lipids, and N-acetyl-glycoprotein were higher before RYGB. By contrast, levels of the high-density lipoprotein and phosphatidylcholine were higher after bariatric surgery. These results collectively offer important holistic integrative biology data to develop future clinically relevant metabolomics biomarkers related to bariatric surgery in connection with obesity.

pubmed23n0955_3617

Growth of mountain belts in central Asia triggers a new collision zone in central India.

Several unusual strong earthquakes occurred in central India along the Narmada-Son Lineament (NSL) zone, far from active plate boundaries. To understand the role of collisional processes in the origin of this seismicity, we develop a numerical thermomechanical model of shortening between the Indian Plate and Asia. We show that at the final stage of collision, the shortening rate of the high mountain areas slows. The continuing convergence of India and Asia triggers the initiation of a new collision zone in continental part of India. Various geological and geophysical observations indicate that the NSL is a weakest zone with northward thrusting of the thinner central Indian lithosphere underneath the thicker northern part of the Indian Plate. We hypothesize that the NSL was reactivated during the final stage of the India Asia convergence and it will possibly form a new mountain belt within the Indian continent.

Growth of mountain belts in central Asia triggers a new collision zone in central India. Several unusual strong earthquakes occurred in central India along the Narmada-Son Lineament (NSL) zone, far from active plate boundaries. To understand the role of collisional processes in the origin of this seismicity, we develop a numerical thermomechanical model of shortening between the Indian Plate and Asia. We show that at the final stage of collision, the shortening rate of the high mountain areas slows. The continuing convergence of India and Asia triggers the initiation of a new collision zone in continental part of India. Various geological and geophysical observations indicate that the NSL is a weakest zone with northward thrusting of the thinner central Indian lithosphere underneath the thicker northern part of the Indian Plate. We hypothesize that the NSL was reactivated during the final stage of the India Asia convergence and it will possibly form a new mountain belt within the Indian continent.

pubmed23n0829_20983

Developmental Competence of Vitrified-Warmed Bovine Oocytes at the Germinal-Vesicle Stage is Improved by Cyclic Adenosine Monophosphate Modulators during In Vitro Maturation.

Cryopreservation of mature oocytes and embryos has provided numerous benefits in reproductive medicine. Although successful cryopreservation of germinal-vesicle stage (GV) oocytes holds promise for further advances in reproductive biology and clinical embryology fields, reports regarding cryopreservation of immature oocytes are limited. Oocyte survival and maturation rates have improved since vitrification is being performed at the GV stage, but the subsequent developmental competence of GV oocytes is still low. The purpose of this study was to evaluate the effects of supplementation of the maturation medium with cyclic adenosine monophosphate (cAMP) modulators on the developmental competence of vitrified-warmed GV bovine oocytes. GV oocytes were vitrified-warmed and cultured to allow for oocyte maturation, and then parthenogenetically activated or fertilized in vitro. Our results indicate that addition of a cAMP modulator forskolin (FSK) or 3-isobutyl-1-methylxanthine (IBMX) to the maturation medium significantly improved the developmental competence of vitrified-warmed GV oocytes. We also demonstrated that vitrification of GV oocytes led to a decline in cAMP levels and maturation-promoting factor (MPF) activity in the oocytes during the initial and final phases of maturation, respectively. Nevertheless, the addition of FSK or IBMX to the maturation medium significantly elevated cAMP levels and MPF activity during IVM. Taken together, our results suggest that the cryopreservation-associated meiotic and developmental abnormalities observed in GV oocytes may be ameliorated by an artificial increase in cAMP levels during maturation culture after warming.

Developmental Competence of Vitrified-Warmed Bovine Oocytes at the Germinal-Vesicle Stage is Improved by Cyclic Adenosine Monophosphate Modulators during In Vitro Maturation. Cryopreservation of mature oocytes and embryos has provided numerous benefits in reproductive medicine. Although successful cryopreservation of germinal-vesicle stage (GV) oocytes holds promise for further advances in reproductive biology and clinical embryology fields, reports regarding cryopreservation of immature oocytes are limited. Oocyte survival and maturation rates have improved since vitrification is being performed at the GV stage, but the subsequent developmental competence of GV oocytes is still low. The purpose of this study was to evaluate the effects of supplementation of the maturation medium with cyclic adenosine monophosphate (cAMP) modulators on the developmental competence of vitrified-warmed GV bovine oocytes. GV oocytes were vitrified-warmed and cultured to allow for oocyte maturation, and then parthenogenetically activated or fertilized in vitro. Our results indicate that addition of a cAMP modulator forskolin (FSK) or 3-isobutyl-1-methylxanthine (IBMX) to the maturation medium significantly improved the developmental competence of vitrified-warmed GV oocytes. We also demonstrated that vitrification of GV oocytes led to a decline in cAMP levels and maturation-promoting factor (MPF) activity in the oocytes during the initial and final phases of maturation, respectively. Nevertheless, the addition of FSK or IBMX to the maturation medium significantly elevated cAMP levels and MPF activity during IVM. Taken together, our results suggest that the cryopreservation-associated meiotic and developmental abnormalities observed in GV oocytes may be ameliorated by an artificial increase in cAMP levels during maturation culture after warming.

pubmed23n0980_23855

Incidence, demographics, types and risk factors of dry eye disease in India: Electronic medical records driven big data analytics report I.

To describe the incidence, demographics, types and risk-factors of dry eye disease (DED) in patients presenting to a multi-tier ophthalmology hospital network in India. This was an observational hospital-based study of 1,458,830 new patients presenting between 2010 and 2018. Patients with recent onset of both symptoms and signs, as defined by the tear film and ocular surface society dry eye work shop (TFOS DEWS) II guidelines, were considered as DED subjects. The data was prospectively collected using an electronic medical record system. Multiple logistic regression with odds ratio (OR) estimation was performed to identify the high risk-factors of DED. Overall, 21,290 (1.46%) patients were diagnosed with recent-onset DED. The incidence of DED was 2688 and 16,482 per million population in children and adults, respectively (p &lt; 0.0001). While incidence was significantly greater in males in 3rd, 4th, 9th and 10th decade (p &lt; 0.03), it was greater in females in 5th and 6th decade (p &lt; 0.0001) of life. Classified etiologically 35.5%, 20.6% and 39.9% of patients had evaporative, aqueous deficient and mixed type of DED, respectively. Age (OR 3.7-13.5), urban residence (OR 1.6), professional work (OR 1.5); homemaking (OR 1.42), retirement/unemployment (OR 1.24) and socio-economic affluence (OR 1.6-3.2) were identified as high risk-factors for developing DED. The study results indicate that age, sex, residence, occupation, and socio-economic status have significant impact on development of DED. Since India is an emerging economy with a growing middle-class, increasing urban-migration and large aging population, the country is on the brink of a DED epidemic.

Incidence, demographics, types and risk factors of dry eye disease in India: Electronic medical records driven big data analytics report I. To describe the incidence, demographics, types and risk-factors of dry eye disease (DED) in patients presenting to a multi-tier ophthalmology hospital network in India. This was an observational hospital-based study of 1,458,830 new patients presenting between 2010 and 2018. Patients with recent onset of both symptoms and signs, as defined by the tear film and ocular surface society dry eye work shop (TFOS DEWS) II guidelines, were considered as DED subjects. The data was prospectively collected using an electronic medical record system. Multiple logistic regression with odds ratio (OR) estimation was performed to identify the high risk-factors of DED. Overall, 21,290 (1.46%) patients were diagnosed with recent-onset DED. The incidence of DED was 2688 and 16,482 per million population in children and adults, respectively (p &lt; 0.0001). While incidence was significantly greater in males in 3rd, 4th, 9th and 10th decade (p &lt; 0.03), it was greater in females in 5th and 6th decade (p &lt; 0.0001) of life. Classified etiologically 35.5%, 20.6% and 39.9% of patients had evaporative, aqueous deficient and mixed type of DED, respectively. Age (OR 3.7-13.5), urban residence (OR 1.6), professional work (OR 1.5); homemaking (OR 1.42), retirement/unemployment (OR 1.24) and socio-economic affluence (OR 1.6-3.2) were identified as high risk-factors for developing DED. The study results indicate that age, sex, residence, occupation, and socio-economic status have significant impact on development of DED. Since India is an emerging economy with a growing middle-class, increasing urban-migration and large aging population, the country is on the brink of a DED epidemic.

pubmed23n0947_6122

Ultrasound Guided Transversus Thoracic Plane block, Parasternal block and fascial planes hydrodissection for internal mammary post thoracotomy pain syndrome.

Pectoral Nerves Block (PECS) and Serratus Plane Block (SPB) have been used to treat persistent post-surgical pain after breast and thoracic surgery; however, they cannot block the internal mammary region, so a residual pain may occur in that region. Parasternal block (PSB) and Thoracic Transversus Plane Block (TTP) anaesthetize the anterior branches of T2-6 intercostal nerves thus they can provide analgesia to the internal mammary region. We describe a 60-year-old man suffering from right post-thoracotomy pain syndrome with residual pain located in the internal mammary region after a successful treatment with PECS and SPB. We performed a PSB and TTP and hydrodissection of fascial planes with triamcinolone and Ropivacaine. Pain disappeared and the result was maintained 3 months later. This report suggests that PSB and TTP with local anaesthetic and corticosteroid with hydrodissection of fascial planes might be useful to treat a post thoracotomy pain syndrome located in the internal mammary region. The use of Transversus Thoracic Plane and Parasternal Blocks and fascial planes hydrodissection as a novel therapeutic approach to treat a residual post thoracotomy pain syndrome even when already treated with Pectoral Nerves Block and Serratus Plane Block.

Ultrasound Guided Transversus Thoracic Plane block, Parasternal block and fascial planes hydrodissection for internal mammary post thoracotomy pain syndrome. Pectoral Nerves Block (PECS) and Serratus Plane Block (SPB) have been used to treat persistent post-surgical pain after breast and thoracic surgery; however, they cannot block the internal mammary region, so a residual pain may occur in that region. Parasternal block (PSB) and Thoracic Transversus Plane Block (TTP) anaesthetize the anterior branches of T2-6 intercostal nerves thus they can provide analgesia to the internal mammary region. We describe a 60-year-old man suffering from right post-thoracotomy pain syndrome with residual pain located in the internal mammary region after a successful treatment with PECS and SPB. We performed a PSB and TTP and hydrodissection of fascial planes with triamcinolone and Ropivacaine. Pain disappeared and the result was maintained 3 months later. This report suggests that PSB and TTP with local anaesthetic and corticosteroid with hydrodissection of fascial planes might be useful to treat a post thoracotomy pain syndrome located in the internal mammary region. The use of Transversus Thoracic Plane and Parasternal Blocks and fascial planes hydrodissection as a novel therapeutic approach to treat a residual post thoracotomy pain syndrome even when already treated with Pectoral Nerves Block and Serratus Plane Block.

pubmed23n1126_146

DAB2IP predicts treatment response and prognosis of ESCC patients and modulates its radiosensitivity through enhancing IR-induced activation of the ASK1-JNK pathway.

Disabled homolog 2 interacting protein (DAB2IP) plays a tumor-suppressive role in several types of human cancers. However, the molecular status and function of the DAB2IP gene in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy is rarely reported. We examined the expression dynamics of DAB2IP by immunohistochemistry (IHC) in 140 ESCC patients treated with definitive chemoradiotherapy. A series of in vivo and in vitro experiments were performed to elucidate the effect of DAB2IP on the chemoradiotherapy (CRT) response and its underlying mechanisms in ESCC. Decreased expression of DAB2IP in ESCCs correlated positively with ESCC resistance to CRT and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Furthermore, the therapeutic sensitivity of CRT was substantially increased by ectopic overexpression of DAB2IP in ESCC cells. In addition, knockdown of DAB2IP dramatically enhanced resistance to CRT in ESCC. Finally, we demonstrated that DAB2IP regulates ESCC cell radiosensitivity through enhancing ionizing radiation (IR)-induced activation of the ASK1-JNK signaling pathway. Our data highlight the molecular etiology and clinical significance of DAB2IP in ESCC, which may represent a new therapeutic strategy to improve therapy and survival for ESCC patients.

DAB2IP predicts treatment response and prognosis of ESCC patients and modulates its radiosensitivity through enhancing IR-induced activation of the ASK1-JNK pathway. Disabled homolog 2 interacting protein (DAB2IP) plays a tumor-suppressive role in several types of human cancers. However, the molecular status and function of the DAB2IP gene in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy is rarely reported. We examined the expression dynamics of DAB2IP by immunohistochemistry (IHC) in 140 ESCC patients treated with definitive chemoradiotherapy. A series of in vivo and in vitro experiments were performed to elucidate the effect of DAB2IP on the chemoradiotherapy (CRT) response and its underlying mechanisms in ESCC. Decreased expression of DAB2IP in ESCCs correlated positively with ESCC resistance to CRT and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Furthermore, the therapeutic sensitivity of CRT was substantially increased by ectopic overexpression of DAB2IP in ESCC cells. In addition, knockdown of DAB2IP dramatically enhanced resistance to CRT in ESCC. Finally, we demonstrated that DAB2IP regulates ESCC cell radiosensitivity through enhancing ionizing radiation (IR)-induced activation of the ASK1-JNK signaling pathway. Our data highlight the molecular etiology and clinical significance of DAB2IP in ESCC, which may represent a new therapeutic strategy to improve therapy and survival for ESCC patients.

pubmed23n0046_13381

Restrictive left ventricular diastolic filling identifies patients with heart failure after acute myocardial infarction.

Left ventricular diastolic filling was characterized by transmitral pulsed-wave Doppler velocities in 62 patients with acute myocardial infarction, and diastolic filling variables were correlated with the presence of clinical heart failure. At the time of admission, 47 patients were free of heart failure and 15 patients were in Killip class II to IV. In the latter group of patients with heart failure, peak velocity of late filling wave caused by atrial contraction (A) was lower (0.48 versus 0.59 m/sec, p &lt; 0.05), ratio of peak velocity of early rapid filling wave to peak velocity of late filling wave caused by atrial contraction (E/A) was higher (1.5 versus 1.1, p &lt; 0.01), and deceleration time (136 versus 196 msec, p = 0.0001) was shorter when compared with the patients not in heart failure after acute myocardial infarction. Multivariate analysis showed that the deceleration time was a powerful independent predictor of presence of heart failure after controlling for systolic functional variables. Therefore, diastolic filling variables can complement systolic functional variables in the identification of the patients with postinfarction left ventricular failure.

Restrictive left ventricular diastolic filling identifies patients with heart failure after acute myocardial infarction. Left ventricular diastolic filling was characterized by transmitral pulsed-wave Doppler velocities in 62 patients with acute myocardial infarction, and diastolic filling variables were correlated with the presence of clinical heart failure. At the time of admission, 47 patients were free of heart failure and 15 patients were in Killip class II to IV. In the latter group of patients with heart failure, peak velocity of late filling wave caused by atrial contraction (A) was lower (0.48 versus 0.59 m/sec, p &lt; 0.05), ratio of peak velocity of early rapid filling wave to peak velocity of late filling wave caused by atrial contraction (E/A) was higher (1.5 versus 1.1, p &lt; 0.01), and deceleration time (136 versus 196 msec, p = 0.0001) was shorter when compared with the patients not in heart failure after acute myocardial infarction. Multivariate analysis showed that the deceleration time was a powerful independent predictor of presence of heart failure after controlling for systolic functional variables. Therefore, diastolic filling variables can complement systolic functional variables in the identification of the patients with postinfarction left ventricular failure.

pubmed23n0558_13994

Hydrogen metabolism in Shewanella oneidensis MR-1.

Shewanella oneidensis MR-1 is a facultative sediment microorganism which uses diverse compounds, such as oxygen and fumarate, as well as insoluble Fe(III) and Mn(IV) as electron acceptors. The electron donor spectrum is more limited and includes metabolic end products of primary fermenting bacteria, such as lactate, formate, and hydrogen. While the utilization of hydrogen as an electron donor has been described previously, we report here the formation of hydrogen from pyruvate under anaerobic, stationary-phase conditions in the absence of an external electron acceptor. Genes for the two S. oneidensis MR-1 hydrogenases, hydA, encoding a periplasmic [Fe-Fe] hydrogenase, and hyaB, encoding a periplasmic [Ni-Fe] hydrogenase, were found to be expressed only under anaerobic conditions during early exponential growth and into stationary-phase growth. Analyses of DeltahydA, DeltahyaB, and DeltahydA DeltahyaB in-frame-deletion mutants indicated that HydA functions primarily as a hydrogen-forming hydrogenase while HyaB has a bifunctional role and represents the dominant hydrogenase activity under the experimental conditions tested. Based on results from physiological and genetic experiments, we propose that hydrogen is formed from pyruvate by multiple parallel pathways, one pathway involving formate as an intermediate, pyruvate-formate lyase, and formate-hydrogen lyase, comprised of HydA hydrogenase and formate dehydrogenase, and a formate-independent pathway involving pyruvate dehydrogenase. A reverse electron transport chain is potentially involved in a formate-hydrogen lyase-independent pathway. While pyruvate does not support a fermentative mode of growth in this microorganism, pyruvate, in the absence of an electron acceptor, increased cell viability in anaerobic, stationary-phase cultures, suggesting a role in the survival of S. oneidensis MR-1 under stationary-phase conditions.

Hydrogen metabolism in Shewanella oneidensis MR-1. Shewanella oneidensis MR-1 is a facultative sediment microorganism which uses diverse compounds, such as oxygen and fumarate, as well as insoluble Fe(III) and Mn(IV) as electron acceptors. The electron donor spectrum is more limited and includes metabolic end products of primary fermenting bacteria, such as lactate, formate, and hydrogen. While the utilization of hydrogen as an electron donor has been described previously, we report here the formation of hydrogen from pyruvate under anaerobic, stationary-phase conditions in the absence of an external electron acceptor. Genes for the two S. oneidensis MR-1 hydrogenases, hydA, encoding a periplasmic [Fe-Fe] hydrogenase, and hyaB, encoding a periplasmic [Ni-Fe] hydrogenase, were found to be expressed only under anaerobic conditions during early exponential growth and into stationary-phase growth. Analyses of DeltahydA, DeltahyaB, and DeltahydA DeltahyaB in-frame-deletion mutants indicated that HydA functions primarily as a hydrogen-forming hydrogenase while HyaB has a bifunctional role and represents the dominant hydrogenase activity under the experimental conditions tested. Based on results from physiological and genetic experiments, we propose that hydrogen is formed from pyruvate by multiple parallel pathways, one pathway involving formate as an intermediate, pyruvate-formate lyase, and formate-hydrogen lyase, comprised of HydA hydrogenase and formate dehydrogenase, and a formate-independent pathway involving pyruvate dehydrogenase. A reverse electron transport chain is potentially involved in a formate-hydrogen lyase-independent pathway. While pyruvate does not support a fermentative mode of growth in this microorganism, pyruvate, in the absence of an electron acceptor, increased cell viability in anaerobic, stationary-phase cultures, suggesting a role in the survival of S. oneidensis MR-1 under stationary-phase conditions.