Contribution of the type VI secretion system encoded in SPI-19 to chicken colonization by Salmonella enterica serotypes Gallinarum and Enteritidis.
Salmonella Gallinarum is a pathogen with a host range specific to poultry, while Salmonella Enteritidis is a broad host range pathogen that colonizes poultry sub-clinically but is a leading cause of gastrointestinal salmonellosis in humans and many other species. Despite recent advances in our understanding of the complex interplay between Salmonella and their hosts, the molecular basis of host range restriction and unique pathobiology of Gallinarum remain largely unknown. Type VI Secretion System (T6SS) represents a new paradigm of protein secretion that is critical for the pathogenesis of many gram-negative bacteria. We recently identified a putative T6SS in the Salmonella Pathogenicity Island 19 (SPI-19) of Gallinarum. In Enteritidis, SPI-19 is a degenerate element that has lost most of the T6SS functions encoded in the island. In this work, we studied the contribution of SPI-19 to the colonization of Salmonella Gallinarum strain 287/91 in chickens. Non-polar deletion mutants of SPI-19 and the clpV gene, an essential T6SS component, colonized the ileum, ceca, liver and spleen of White Leghorn chicks poorly compared to the wild-type strain after oral inoculation. Return of SPI-19 to the DeltaSPI-19 mutant, using VEX-Capture, complemented this colonization defect. In contrast, transfer of SPI-19 from Gallinarum to Enteritidis resulted in transient increase in the colonization of the ileum, liver and spleen at day 1 post-infection, but at days 3 and 5 post-infection a strong colonization defect of the gut and internal organs of the experimentally infected chickens was observed. Our data indicate that SPI-19 and the T6SS encoded in this region contribute to the colonization of the gastrointestinal tract and internal organs of chickens by Salmonella Gallinarum and suggest that degradation of SPI-19 T6SS in Salmonella Enteritidis conferred an advantage in colonization of the avian host.


Iodine excess as an environmental risk factor for autoimmune thyroid disease.
The global effort to prevent iodine deficiency disorders through iodine supplementation, such as universal salt iodization, has achieved impressive progress during the last few decades. However, iodine excess, due to extensive environmental iodine exposure in addition to poor monitoring, is currently a more frequent occurrence than iodine deficiency. Iodine excess is a precipitating environmental factor in the development of autoimmune thyroid disease. Excessive amounts of iodide have been linked to the development of autoimmune thyroiditis in humans and animals, while intrathyroidal depletion of iodine prevents disease in animal strains susceptible to severe thyroiditis. Although the mechanisms by which iodide induces thyroiditis are still unclear, several mechanisms have been proposed: (1) excess iodine induces the production of cytokines and chemokines that can recruit immunocompetent cells to the thyroid; (2) processing excess iodine in thyroid epithelial cells may result in elevated levels of oxidative stress, leading to harmful lipid oxidation and thyroid tissue injuries; and (3) iodine incorporation in the protein chain of thyroglobulin may augment the antigenicity of this molecule. This review will summarize the current knowledge regarding excess iodide as an environmental toxicant and relate it to the development of autoimmune thyroid disease.


Prevalence of non alcoholic fatty liver and Non alcoholic Steatohepatitis in Peshawar Cantonment, Khyber Pakhtunkhwa, Pakistan.
Non-alcoholic fatty liver disease prevalence has not been well established. The aims of this study was to define prospectively non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) prevalence in hospitalized and ambulatory patients 20-65 years old during June 2013 to June 2014 were selected from Combined Military Hospital Peshawar Cantonment area. A base line questionnaire and right upper quadrant ultrasound was completed by all patients. On identifications of fatty liver among the selected cases further lab test data and liver biopsy reports were obtained. Mean BMI of female was 29.9 + 5.65 while prevalence of hypertension and diabetes was 49.8% and 16.6% respectively. Among all patients 62% were Punjabies, 23% were Pathans while 12% were Sindhies. Overall NAFLD prevalence was 47% while NASH was confirmed in 20 patients (12.3% of total and 30%of ultrasound positive patients). Pathans had the highest prevalence of NAFLD (58.5%) as compared to Punjabies (44.5%) and Sindhies (35.3%). Pathans also had a higher prevalence of NASH compared with Punjabies (19.5% VS 10%: P= 0.03). In general, NAFLD patients were more prevalent among male (59%), Diabetic (P<0.00005), hypertensive (P<0.00005) and older (P =0.005). They consumed more fast food (P=.049) had a higher BMI (P<0.0005) and had little or no exercise as compared to their normal or non NAFLD counter parts (P=0.02). NAFLD was found in 75% and NASH in 22.5% among the 26 diabetic patients. ALT, AST, BMI, insulin, quantitative insulin sensitivity checks index and cytokeratin - 18 correlated with NASH. It was concluded that NAFLD and NASH prevalence is higher than estimated previously, Pathans and Patients with diabetes are at high risk.


Comprehensive strategy for the design of precision drugs and identification of genetic signature behind proneness of the disease-a pharmacogenomic approach.
The proneness of diseases and susceptibility towards drugs vary from person to person. At present, there is a strong demand for the personalization of drugs. The genetic signature behind proneness of the disease has been studied through a comprehensive 'octopodial approach'. All the genetic variants included in the approach have been introduced. The breast cancer associated with BRCA1 mutation has been taken as the illustrative example to introduce all these factors. The genetic variants associated with the drug action of tamoxifen have been fully illustrated in the manuscript. The design of a new personalized anti-breast cancer drug has been explained in the third phase. For the design of new personalized drugs, a metabolite of anti-cancer drug chlorambucil has been taken as the template. The design of drug has been made with respect to the protein 1T15 of BRCA1 gene corresponding to the genetic signature of rs28897696.


Investigation of inter- and intraspecies variation through genome sequencing of Aspergillus section Nigri.
Aspergillus section Nigri comprises filamentous fungi relevant to biomedicine, bioenergy, health, and biotechnology. To learn more about what genetically sets these species apart, as well as about potential applications in biotechnology and biomedicine, we sequenced 23 genomes de novo, forming a full genome compendium for the section (26 species), as well as 6 Aspergillus niger isolates. This allowed us to quantify both inter- and intraspecies genomic variation. We further predicted 17,903 carbohydrate-active enzymes and 2,717 secondary metabolite gene clusters, which we condensed into 455 distinct families corresponding to compound classes, 49% of which are only found in single species. We performed metabolomics and genetic engineering to correlate genotypes to phenotypes, as demonstrated for the metabolite aurasperone, and by heterologous transfer of citrate production to Aspergillus nidulans. Experimental and computational analyses showed that both secondary metabolism and regulation are key factors that are significant in the delineation of Aspergillus species.


Obstacles to Help-Seeking for Sexual Offenders: Implications for Prevention of Sexual Abuse.
Persons with potentially harmful sexual interests such as attraction to minors are unlikely to seek or receive treatment before a sexual offense has been committed. The current study explored barriers to help-seeking in a sample of 372 individuals in treatment for sexual offending. Results revealed that the shame and secrecy resulting from stigma associated with pedophilic interests often prevented our respondents from seeking professional counseling, and only about 20% tried to talk to anyone about their sexual interests prior to their arrest. Barriers to seeking and receiving psychological services included concerns about confidentiality, fears of social and legal consequences, personal shame or confusion about the problem, affordability, and challenges finding competent therapists who were adequately equipped to help them. Understanding and ultimately reducing obstacles to help-seeking can improve the quality of life for people with harmful sexual interests and potentially prevent sexual abuse of children or other vulnerable individuals.


Insights into Sexism: Male Status and Performance Moderates Female-Directed Hostile and Amicable Behaviour.
Gender inequality and sexist behaviour is prevalent in almost all workplaces and rampant in online environments. Although there is much research dedicated to understanding sexist behaviour, we have almost no insight into what triggers this behaviour and the individuals that initiate it. Although social constructionist theory argues that sexism is a response towards women entering a male dominated arena, this perspective doesn't explain why only a subset of males behave in this way. We argue that a clearer understanding of sexist behaviour can be gained through an evolutionary perspective that considers evolved differences in intra-sexual competition. We hypothesised that female-initiated disruption of a male hierarchy incites hostile behaviour from poor performing males who stand to lose the most status. To test this hypothesis, we used an online first-person shooter video game that removes signals of dominance but provides information on gender, individual performance, and skill. We show that lower-skilled players were more hostile towards a female-voiced teammate, especially when performing poorly. In contrast, lower-skilled players behaved submissively towards a male-voiced player in the identical scenario. This difference in gender-directed behaviour became more extreme with poorer focal-player performance. We suggest that low-status males increase female-directed hostility to minimize the loss of status as a consequence of hierarchical reconfiguration resulting from the entrance of a woman into the competitive arena. Higher-skilled players, in contrast, were more positive towards a female relative to a male teammate. As higher-skilled players have less to fear from hierarchical reorganization, we argue that these males behave more positively in an attempt to support and garner a female player's attention. Our results provide the clearest picture of inter-sexual competition to date, highlighting the importance of considering an evolutionary perspective when exploring the factors that affect male hostility towards women.


Mechanotransduction - a field pulling together?
Mechanical stresses are ever present in the cellular environment, whether through external forces that are applied to tissues or endogenous forces that are generated within the active cytoskeleton. Despite the wide array of studies demonstrating that such forces affect cellular signaling and function, it remains unclear whether mechanotransduction in different contexts shares common mechanisms. Here, I discuss possible mechanisms by which applied forces, cell-generated forces and changes in substrate mechanics could exert changes in cell function through common mechanotransduction machinery. I draw from examples that are primarily focused on the role of adhesions in transducing mechanical forces. Based on this discussion, emerging themes arise that connect these different areas of inquiry and suggest multiple avenues for future studies.


Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways.
Epidemiological evidence strongly suggests that fruit consumption promotes many health benefits. Despite the general consensus that fruit and juice are nutritionally similar, epidemiological results for juice consumption are conflicting. Our objective was to use DNA methylation marks to characterize fruit and juice epigenetic signatures within PBMCs and identify shared and independent signatures associated with these groups. Genome-wide DNA methylation marks (Illumina Human Methylation 450k chip) for 2,148 individuals that participated in the Framingham Offspring exam 8 were analyzed for correlations between fruit or juice consumption using standard linear regression. CpG sites with low P-values (P < 0.01) were characterized using Gene Set Enrichment Analysis (GSEA), Ingenuity Pathway Analysis (IPA), and epigenetic Functional element Overlap analysis of the Results of Genome Wide Association Study Experiments (eFORGE). Fruit and juice-specific low P-value epigenetic signatures were largely independent. Genes near the fruit-specific epigenetic signature were enriched among pathways associated with antigen presentation and chromosome or telomere maintenance, while the juice-specific epigenetic signature was enriched for proinflammatory pathways. IPA and eFORGE analyses implicate fruit and juice-specific epigenetic signatures in the modulation of macrophage (fruit) and B or T cell (juice) activities. These data suggest a role for epigenetic regulation in fruit and juice-specific health benefits and demonstrate independent associations with distinct immune functions and cell types, suggesting that these groups may not confer the same health benefits. Identification of such differences between foods is the first step toward personalized nutrition and ultimately the improvement of human health and longevity.


Rational beliefs, happiness and optimism: An empirical assessment of REBT's model of psychological health.
This study sought to test the validity of the psychological health model of Rational Emotive Behaviour Therapy (REBT). Specifically, this study sought to investigate if rational beliefs were associated with happiness and optimism. A multinational sample of 397 university students completed self-report measures of rational beliefs, happiness and optimism. Structural equation modelling (SEM) was used in order to test the validity of the REBT model of psychological health. The result of the SEM analysis provided empirical support for REBT's psychological health model of happiness and optimism. The model as a whole explained 33% of variance in levels of happiness and 40% of variance in levels of optimism. Self-acceptance beliefs were positively and directly associated with happiness and optimism. Preference beliefs were positively and indirectly associated with happiness and optimism via self-acceptance beliefs. REBT may offer a viable psychotherapeutic method to not only alleviate psychological distress, but also build positive emotion. Current findings may help to bridge the divide between the fields of positive psychology and clinical psychology.


Genes encoding tetracycline resistance in a full-scale municipal wastewater treatment plant investigated during one year.
Tetracycline-resistant bacteria and genes encoding tetracycline resistance are common in anthropogenic environments. We studied how wastewater treatment affects the prevalence and concentration of two genes, tetA and tetB, that encode resistance to tetracycline. Using real-time polymerase chain reaction (PCR) we analysed wastewater samples collected monthly for one year at eight key-sites in a full-scale municipal wastewater treatment plant (WWTP). We detected tetA and tetB at each sampling site and the concentration of both genes, expressed per wastewater volume or per total-DNA, decreased over the treatment process. The reduction of tetA and tetB was partly the result of the sedimentation process. The ratio of tetA and tetB, respectively, to total DNA was lower in or after the biological processes. Taken together our data show that tetracycline resistance genes occur throughout the WWTP, and that the concentrations are reduced under conventional operational strategies.


Status and prospects of genetic disease.
The current status of our knowledge of genetic diseases is reviewed. The incidence of monogenic, multifactorial and chromosomal disorders, according to the literature to date, is given, and the possibilities of mass screening programmes are discussed. The prospects for antenatal diagnosis of genetic diseases are reviewed, with emphasis on the indications for amniocentesis and the safety of the procedure. Finally, speculations are made regarding the possible effects of medical and social practices on the frequency of genetic disorders in future generations.


The association between lower urinary tract symptoms and erectile dysfunction in four centres: the UrEpik study.
To report a large-scale multinational investigation of lower urinary tract symptoms (LUTS) and sexual function, designed to investigate the independent association between them, as recent small-scale epidemiological studies suggest an association between benign prostatic hyperplasia and sexual dysfunction; both conditions are strongly associated with age and no study has been able to exclude age as a confounding factor in this relationship. Culturally and linguistically validated versions of standard questionnaires were used to estimate the prevalence of LUTS (using the International Prostate Symptom Score, IPSS) and erectile dysfunction (ED) score (using O'Leary's Sexual Function Inventory) in regions of the UK (Birmingham), the Netherlands (Boxmeer), France (Auxerre) and Korea (Seoul). In each centre, stratified random samples were selected from population registers to provide representative samples of the population of men aged 40-79 years (and their partners) in each community. Direct interviews were held in Seoul and postal questionnaires used in the three European centres. The samples were selected randomly, providing representative samples in each community. In all, 4800 men and 3674 women responded; the response rates among men were 77% in Boxmeer, 21% in Auxerre, 42% in Birmingham and 65% in Seoul. The overall prevalence of ED for men aged 40-79, estimated as an ED score of 0-4, was 21.1%. There was evidence of a linear increase with age (P < 0.001) and the pattern was very similar in the four centres. From the weighted logistic model, there was evidence of an association between sexual dysfunction, other self-reported diseases and lifestyle. From the ED score, after adjusting for age and country, men with diabetes were more likely to score of 0-4 (odds ratio 1.57, 95% confidence interval 1.09-2.25), as were those with high blood pressure (1.38, 1.09-1.75) and with an IPSS of 8-35 (1.39, 1.10-1.74). For lifestyle, smokers were more likely to score 0-4 (1.54, 1.23-1.92), while physical activity during leisure time was slightly associated with a reduction in the chance of scoring 0-4 (0.87, 0.77-0.99). The analysis gave the same results when repeated using self-reported ED instead of the dichotomised score. ED is clearly age-related and a problem for a large proportion of men in the community. It can have a profound impact on the quality of life of the man and on his partner. Were all men with this problem to seek medical help there would be a large burden on healthcare systems. There are cultural and age effects on the assessment of this problem.


["Technetium crisis" - causes, possible solutions and consequences for planar scintigraphy and SPECT diagnostics].
Nuclear medicine is an important field of nuclear medicine, especially thanks to its role in in vivo imaging of important processes in human organism. An overwhelming majority of nuclear medicine examinations comprises of planar scintigraphy and single photon emission computed tomography, for decades relying on the labeling by metastable technetium nuclide (99mTc), used with a great diversity of ligands for various applications. Nuclear medicine departments utilize commercially available molybdenum technetium generators, being able to elute the nuclide at any time and prepare the radiopharmaceutical. The mother nuclide, molybdenum-99 (99Mo), is produced in just a handful of places around the world. The production places are without exception research nuclear reactors working far past their life expectancy. A concurrent temporary shutdown of two of them in the year 2009 caused a critical worldwide shortage of 99mTc. An unavoidable permanent shutdown of part of these capacities in the second decade of the 21st century will cause the second, and this time rather permanent "technetium crisis". The article focuses on history, present, potential future and possible solutions in regard to SPECT diagnostics.


Quality and safety in transitional care of the elderly: the study protocol of a case study research design (phase 1).
Although international studies have documented that patients' transitions between care providers are associated with the risk of adverse events and uncoordinated care, research directed towards the quality and safety of transitional care between primary and secondary health and care services, especially for the elderly receiving care from multiple healthcare providers due to complex health problems, is lacking. This study investigates how different aspects of transitional care can explain the quality and safety of elderly healthcare services in Norway. The overall aim of the study was to explore different aspects of transitional care of the elderly, in different contexts and how they might explain the quality and safety of care. The study applies a case study design. Two cases are chosen: one city-based hospital and one rural hospital with associated nursing homes and home-based nursing services. Admission and discharge to/from hospital to/from nursing homes or home-based nursing services constitute the main focal areas of the study, including the patient, next-of-kin and the professional perspective. The qualitative methods employed include participant observation, individual interviews and document analysis. To ensure trustworthiness in the data analysis, we will apply analyst triangulation and member checks. A total impression of the data material will first be created in a systematic text condensation approach. Second, the qualitative data analysis will involve in-depth analyses of two specific themes: the risk perspective and the patient perspective in transitional care. The study is approved by the Norwegian Regional Committees for Medical and Health Research Ethics. The study is based on informed written consent, and informants can withdraw from the study at any point in time. Interview and observation data material will be managed confidentially. It will be disseminated at research conferences, in peer-reviewed journals and through public presentations to people outside the academic community.


Generation and Quantitative Analysis of Pulsed Low Frequency Ultrasound to Determine the Sonic Sensitivity of Untreated and Treated Neoplastic Cells.
Low frequency ultrasound in the 20 to 60 kHz range is a novel physical modality by which to induce selective cell lysis and death in neoplastic cells. In addition, this method can be used in combination with specialized agents known as sonosensitizers to increase the extent of preferential damage exerted by ultrasound against neoplastic cells, an approach referred to as sonodynamic therapy (SDT). The methodology for generating and applying low frequency ultrasound in a preclinical in vitro setting is presented to demonstrate that reproducible cell destruction can be attained in order to examine and compare the effects of sonication on neoplastic and normal cells. This offers a means by which to reliably sonicate neoplastic cells at a level of consistency required for preclinical therapeutic assessment. In addition, the effects of cholesterol-depleting and cytoskeletal-directed agents on potentiating ultrasonic sensitivity in neoplastic cells are discussed in order to elaborate on mechanisms of action conducive to sonochemotherapeutic approaches.


Hemispheric differences in corticospinal excitability and in transcallosal inhibition in relation to degree of handedness.
In this study, we examined hemispheric differences in corticospinal excitability and in transcallosal inhibition in a selected group of young adults (n = 34) grouped into three handedness categories (RH: strongly right-handed, n = 17; LH: strongly left-handed, n = 10; MH: mixed-handed, n = 7) based on laterality quotients (LQ) derived from the Edinburgh Handedness Inventory. Performance measures were also used to derive a laterality index reflecting right-left asymmetries in manual dexterity (Dextli) and in finger tapping speed (Speedli). Corticospinal excitability was assessed in each hemisphere by means of transcranial magnetic stimulation (TMS) using the first dorsal interosseus as the target muscle. TMS measures consisted of resting motor threshold (rMT), motor evoked potential (MEP) recruitment curve (RC) and the contralateral silent period (cSP) with the accompanying MEP facilitation. Hemispheric interactions were assessed by means of the ipsilateral silent period (iSP) to determine the onset latency and the duration of transcallosal inhibition (i.e., LTI and DTI). Analysis of hemispheric variations in measures of corticospinal excitability revealed no major asymmetries in relation to degrees of laterality or handedness, with the exception of a rightward increase in rMTs in the LH group. Similarly, no clear asymmetries were found when looking at hemispheric variations in measures of transcallosal inhibition. However, a large group effect was detected for LTI measures, which were found to be significantly shorter in the MH group than in either the LH or RH group. MH participants also tended to show longer DTI than the other participants. Further inspection of overall variations in LTI and DTI measures as a function of LQs revealed that both variables followed a non-linear relationship, which was best described by a 2(nd) order polynomial function. Overall, these findings provide converging evidence for a link between mixed-handedness and more efficient interhemispheric communication when compared to either right- or left-handedness.


Cigarette smoking and alcohol consumption by parents of children with acute myeloid leukemia: an analysis within morphological subgroups--a report from the Childrens Cancer Group.
Data from a case-control study of childhood acute myeloid leukemia (AML) including 187 matched case-control pairs were examined for evidence of associations between parental cigarette smoking and alcohol consumption and the subsequent development of childhood AML. The cases were stratified by French-American-British morphology in order to evaluate potential differences in risk based on this classification system. There was little evidence of any association between cigarette smoking by parents during the index pregnancy and childhood AML. There was some evidence of an increased risk of AML among children who were diagnosed at or before 2 years of age and whose mothers reported consuming alcohol during their pregnancies (odds ratio, 3.00; 95% confidence interval, 1.23 to 8.35). This finding appeared to be especially pronounced for AML with a monocytic component (M4/M5) (odds ratio, 9.00; 95% confidence interval, 1.25 to 394.5), but a cautious interpretation of these data are advised because of the small number of subjects included in this subgroup analysis. Since this is one of the first case-control studies to evaluate specific French-American-British subtypes of AML, these results may be viewed as generating hypotheses. It is suggested that future studies of childhood AML include: (a) a sufficient number of cases to permit an evaluation of the morphological classification of the cases; and (b) additional questions on the alcohol consumption of the mother during the time of her pregnancy with the index child.


Primary Care Clinic Re-Design for Prescription Opioid Management.
The challenge of responding to prescription opioid overuse within the United States has fallen disproportionately on the primary care clinic setting. Here we describe a framework comprised of 6 Building Blocks to guide efforts within this setting to address the use of opioids for chronic pain. Investigators conducted site visits to thirty primary care clinics across the United States selected for their use of team-based workforce innovations. Site visits included interviews with leadership, clinic tours, observations of clinic processes and team meetings, and interviews with staff and clinicians. Data were reviewed to identify common attributes of clinic system changes around chronic opioid therapy (COT) management. These concepts were reviewed to develop narrative descriptions of key components of changes made to improve COT use. Twenty of the thirty sites had addressed improvements in COT prescribing. Across these sites a common set of 6 Building Blocks were identified: 1) providing leadership support; 2) revising and aligning clinic policies, patient agreements (contracts) and workflows; 3) implementing a registry tracking system; 4) conducting planned, patient-centered visits; 5) identifying resources for complex patients; and 6) measuring progress toward achieving clinic objectives. Common components of clinic policies, patient agreements and data tracked in registries to assess progress are described. In response to prescription opioid overuse and the resulting epidemic of overdose and addiction, primary care clinics are making improvements driven by a common set of best practices that address complex challenges of managing COT patients in primary care settings.


Computational prediction of molecular pathogen-host interactions based on dual transcriptome data.
Inference of inter-species gene regulatory networks based on gene expression data is an important computational method to predict pathogen-host interactions (PHIs). Both the experimental setup and the nature of PHIs exhibit certain characteristics. First, besides an environmental change, the battle between pathogen and host leads to a constantly changing environment and thus complex gene expression patterns. Second, there might be a delay until one of the organisms reacts. Third, toward later time points only one organism may survive leading to missing gene expression data of the other organism. Here, we account for PHI characteristics by extending NetGenerator, a network inference tool that predicts gene regulatory networks from gene expression time series data. We tested multiple modeling scenarios regarding the stimuli functions of the interaction network based on a benchmark example. We show that modeling perturbation of a PHI network by multiple stimuli better represents the underlying biological phenomena. Furthermore, we utilized the benchmark example to test the influence of missing data points on the inference performance. Our results suggest that PHI network inference with missing data is possible, but we recommend to provide complete time series data. Finally, we extended the NetGenerator tool to incorporate gene- and time point specific variances, because complex PHIs may lead to high variance in expression data. Sample variances are directly considered in the objective function of NetGenerator and indirectly by testing the robustness of interactions based on variance dependent disturbance of gene expression values. We evaluated the method of variance incorporation on dual RNA sequencing (RNA-Seq) data of Mus musculus dendritic cells incubated with Candida albicans and proofed our method by predicting previously verified PHIs as robust interactions.


Assessing the knowledge, attitudes and practices regarding cholera preparedness and prevention in Ga-Mampuru village, Limpopo, South Africa.
The study assessed the knowledge, attitudes and practices of cholera prevention and preparedness in Ga-Mampuru village (Limpopo, South Africa). Interviewers collected data using a two-pronged method, namely a household questionnaire (open- and closed-ended questions) to assess knowledge and attitudes about cholera and observations to assess practices in the prevention and management of the disease. Additionally, interviewers took pictures with the respondents' permission. Ninety-six respondents were interviewed. Most respondents (86%) indicated they knew how cholera was contracted with 84% indicating contaminated water as a source. Ninety percent of the respondents indicated they knew how to prevent contracting cholera. All respondents generally knew that cholera could be treated with medicine received at a health-care facility or worker. Fewer respondents (58%) had specific knowledge such as the use of rehydration solutions. The respondents' high level of prevention practices could be biased. Interviewers observed that many practices were not adhered to, like not washing hands, not using toilet paper and throwing waste in respondents' yards. Therefore, the community of Ga-Mampuru had not reached a stage of adequate cholera prevention and preparedness in spite of the fact that they were aware of cholera risks and risk-reduction measures.


TOP-2 is differentially required for the proper maintenance of the cohesin subunit REC-8 on meiotic chromosomes in Caenorhabditis elegans spermatogenesis and oogenesis.
During meiotic prophase I, accurate segregation of homologous chromosomes requires the establishment of chromosomes with a meiosis-specific architecture. The sister chromatid cohesin complex and the enzyme Topoisomerase II (TOP-2) are important components of meiotic chromosome architecture, but the relationship of these proteins in the context of meiotic chromosome segregation is poorly defined. Here, we analyzed the role of TOP-2 in the timely release of the sister chromatid cohesin subunit REC-8 during spermatogenesis and oogenesis of Caenorhabditis elegans. We show that there is a different requirement for TOP-2 in meiosis of spermatogenesis and oogenesis. The loss-of-function mutation top-2(it7) results in premature REC-8 removal in spermatogenesis, but not oogenesis. This correlates with a failure to maintain the HORMA-domain proteins HTP-1 and HTP-2 (HTP-1/2) on chromosome axes at diakinesis and mislocalization of the downstream components that control REC-8 release including Aurora B kinase. In oogenesis, top-2(it7) causes a delay in the localization of Aurora B to oocyte chromosomes but can be rescued through premature activation of the maturation promoting factor via knockdown of the inhibitor kinase WEE-1.3. The delay in Aurora B localization is associated with an increase in the length of diakinesis bivalents and wee-1.3 RNAi mediated rescue of Aurora B localization in top-2(it7) is associated with a decrease in diakinesis bivalent length. Our results imply that the sex-specific effects of TOP-2 on REC-8 release are due to differences in the temporal regulation of meiosis and chromosome structure in late prophase I in spermatogenesis and oogenesis.


Psychological generators of stress-headaches.
Psychological stress triggers headaches, but how this happens is unclear. To explore this, 38 migraine sufferers, 28 with tension-type headache (T-TH) and 20 controls rated nausea, negative affect, task-expectancies and headache at 5-min intervals during an aversive 20-min mental arithmetic task with a fixed failure rate. Blood pressure and pulse rate were measured every 3 min and salivary cortisol was sampled before and after the task. Multiple regression analysis indicated that irritation, anxiety and the absence of sluggishness (i.e., alertness) independently predicted increases in headache intensity during the task (p < .001), but increases in headache were unrelated to changes in cardiovascular activity or cortisol. Changes that preceded headache onset were explored in repeated measures ANOVAs, comparing those who developed headache with those who did not. In general, nausea, negative affect and self-efficacy expectancies were higher in participants who went on to develop headache than in those who remained headache-free (p < .05 to p < .001). Together, these findings suggest that headache developed when participants overextended themselves during a stressful task, adopting an information processing style which impeded emotional adjustment to changing situational demands. Learning to modify perceptions of threat, and adopting a more flexible, less outcome-dependent processing style, might help to prevent headache from spiralling upward.


Curcumin inhibits lymphangiogenesis in vitro and in vivo.
Curcumin, a dietary compound from turmeric, has potent antimetastatic effects; however, the underlying mechanisms are not well understood. The aim of this study is to investigate the effects and mechanisms of curcumin on lymphangiogenesis (formation of new lymphatic vessels), which plays a critical role in tumor metastasis. Curcumin inhibited vascular endothelial growth factor-C (VEGF-C) induced lymphangiogenesis in a Matrigel plug assay in mice, and VEGF-C induced tube formation in human dermal lymphatic endothelial cells, demonstrating its antilymphangiogenic action in vivo and in vitro. Curcumin inhibited lymphangiogenesis, in part through suppression of proliferation, cell-cycle progression and migration of lymphatic endothelial cells, while it had little effect on matrix metalloproteinase activities. Curcumin inhibited expressions of VEGF receptors (VEGFR2 and VEGFR3), as well as downstream signaling such as phosphorylation of ERK and FAK. Finally, curcumin sulfate and curcumin glucuronide, which are two major metabolites of curcumin in vivo, had little inhibitory effect on proliferation of human dermal lymphatic endothelial cells. Our results demonstrate that curcumin inhibits lymphangiogenesis in vitro and in vivo, which could contribute to the antimetastatic effects of curcumin.


Financial Conflicts of Interest at FDA Drug Advisory Committee Meetings.
The U.S. Food and Drug Administration's drug advisory committees provide expert assessments of the safety and efficacy of new therapies considered for approval. A committee hears from a variety of speakers, from six groups, including voting members of the committee, FDA staff members, employees of the pharmaceutical company seeking approval of a therapy, patient and consumer representatives, expert speakers invited by the company, and public participants. The committees convene at the request of the FDA when the risks and harms of novel products are not immediately clear, and their final decisions carry significant weight, as most therapies that receive advisory committee approval are subsequently approved by the FDA. In recent years, across a series of diverse publications, the financial conflicts of interest of each category of participants in the meetings have been investigated. Here, we summarize these findings and their ethical implications, focusing on the FDA Oncologic Drugs Advisory Committee, and we suggest ways to move toward more transparent and impartial advisory committee meetings.


X-ray irradiation synthesis of PEG-coated Au-Pd nanoparticles.
We demonstrate that the combination of x-ray irradiation and capping by polyethylene glycol (PEG) produces excellent flexibility in controlling the structure of Au-Pd nanoparticles while preserving their catalytic performance. We specifically adopted two different fabrication methods: co-reduction and seed-assisted reduction. In both cases, precursor composition plays an important role in controlling the phases and size of the bimetallic nanoparticles. The optimal catalytic performance is obtained with the highest Pd concentration and when the nanoparticles consist of a Au core and a Pd shell.


What it takes to become an orthopaedic surgeon: A comparison of orthopaedic surgical training programmes in 10 countries focusing on structure and fellowship requirements.
The quality of surgical training has been highlighted as one of the most important patient safety issues in the future. Training surgeons and supporting them to do their best should be considered integral in providing optimum and safe care for the individual patient and the best possible return on investment in training medical professionals. In 2011, an international consensus statement defined fundamental principles for surgical training. This study examines orthopaedic surgical training to explore the similarities and differences in the requirements for trainees to obtain board certification in ten countries. Countries of the Commonwealth Health Care Comparison: Canada, the United Kingdom, the United States of America, Australia, New Zealand, Germany, France, the Netherlands, Norway and Switzerland were chosen to be compared. The relevant information was extracted from official information from authorities and administrative bodies. The study revealed significant differences in duration, organisation and assessment of training. So-called "competency-based" training is not featured in every country, and the manner of its implementation is variable. In particular, the numbers in surgical cases required to be accredited varies by country ranging from 1260 (UK) to 340 (Norway). Despite the recommendation in 2011 for some degree of uniformity across surgical training in industrialised countries, evidence suggests wide variation in the training programmes which is likely to be a concern in both quality of training as well as present and future patient safety.


On the validity and generality of transfer effects in cognitive training research.
Evaluation of training effectiveness is a long-standing problem of cognitive intervention research. The interpretation of transfer effects needs to meet two criteria, generality and specificity. We introduce each of the two, and suggest ways of implementing them. First, the scope of the construct of interest (e.g., working memory) defines the expected generality of transfer effects. Given that the constructs of interest are typically defined at the latent level, data analysis should also be conducted at the latent level. Second, transfer should be restricted to measures that are theoretically related to the trained construct. Hence, the construct of interest also determines the specificity of expected training effects; to test for specificity, study designs should aim at convergent and discriminant validity. We evaluate the recent cognitive training literature in relation to both criteria. We conclude that most studies do not use latent factors for transfer assessment, and do not test for convergent and discriminant validity.


Identification of isometric contractions based on High Density EMG maps.
Identification of motion intention and muscle activation strategy is necessary to control human-machine interfaces like prostheses or orthoses, as well as other rehabilitation devices, games and computer-based training programs. Pattern recognition from sEMG signals has been extensively investigated in the last decades, however, most of the studies did not take into account different strengths and EMG distributions associated to the intended task. The identification of such quantities could be beneficial for the training of the subject or the control of assistive devices. Recent studies have shown the need to improve pattern-recognition classification by reducing sensitivity to changes in the exerted strength, muscle-electrode shifts and bad contacts. Surface High Density EMG (HD-EMG) obtained from 2-dimensional arrays can provide much more information than electrode pairs for inferring not only motion intention but also the strategy adopted to distribute the load between muscles as well as changes in the spatial distribution of motor unit action potentials within a single muscle because of it. The objectives of this study were: (a) the automatic identification of four isometric motor tasks associated with the degrees of freedom of the forearm: flexion-extension and supination-pronation and (b) the differentiation among levels of voluntary contraction at low-medium efforts. For this purpose, monopolar HD-EMG maps were obtained from five muscles of the upper-limb in healthy subjects. An original classifier is proposed, based on: (1) Two steps linear discriminant analysis of the EMG information for each type of contraction, and (2) features extracted from HD-EMG maps and related to its intensity and distribution in the 2D space. The classifier was trained and tested with different effort levels. Spatial distribution-based features by themselves are not sufficient to classify the type of task or the effort level with an acceptable accuracy; however, when calculated with the "isolated masses" method proposed in this study and combined with intensity-base features, the performance of the classifier is improved. The classifier is capable of identifying the tasks even at 10% of Maximum Voluntary Contraction, in the range of effort level developed by patients with neuromuscular disorders, showing that intention end effort of motion can be estimated from HD-EMG maps and applied in rehabilitation.


Adaptive information design for outdoor augmented reality.
Augmented Reality focuses on the enrichment of the user's natural field of view by consistent integration of text, symbols and interactive three-dimensional objects in real time. Placing virtual objects directly into the user's view in a natural context empowers highly dynamic applications. On the other hand, this necessitates deliberate choice of information design and density, in particular for deployment in hazardous environments like military combat scenarios. As the amount of information needed is not foreseeable and strongly depends on the individual mission, an appropriate system must offer adequate adaptation capabilities. The paper presents a prototypical, vehicle-mountable Augmented Reality vision system, designed for enhancing situation awareness in stressful urban warfare scenarios. Tracking, as one of the most crucial challenges for outdoor Augmented Reality, is accomplished by means of a Differential-GPS approach while the type of display to attach can be modified, ranging from ocular displays to standard LCD mini-screens. The overall concept also includes envisioning of own troops (blue forces), for which a multi-sensor tracking approach has been chosen. As a main feature, the system allows switching between different information categories, focusing on friendly, hostile, unidentified or neutral data. Results of an empirical study on the superiority of an in-view navigation cue approach conclude the paper.


Shear zones in granular media: three-dimensional contact dynamics simulation.
The properties of shear zones forming in slow three-dimensional granular flow are investigated. We simulate a straight version of the split-bottom shear cell. It is shown that the same type of wide shear zones is obtained in the presence as well as in the absence of gravity. We investigate the relaxation of the material toward stationary flow and analyze the stress and the velocity fields. A functional form of the widening of the shear zone inside the bulk is given. We discuss the growth of the region where the material is in the critical state. The growth of this critical zone turns out to be responsible for the initial transient of the shear zone.


Acute perforative appendicitis during preoperative chemotherapy for Wilms tumor.
Infectious complications are not uncommon in children undergoing treatment for cancer. Abdominal pain, especially right lower quadrant pain secondary to appendiceal and cecal inflammation, is a major concern in immunocompromised hosts and a potential source of sepsis. The authors report the case of a child who developed acute perforative appendicitis requiring appendectomy while on preoperative chemotherapy for Wilms tumor, stage IV, favorable histology. Problems related to diagnosis and management of acute abdominal pain and infection in an immunocompromised child with an abdominal mass are discussed along with a review of the literature.


Clinical significance of monocyte heterogeneity.
Monocytes are primitive hematopoietic cells that primarily arise from the bone marrow, circulate in the peripheral blood and give rise to differentiated macrophages. Over the past two decades, considerable attention to monocyte diversity and macrophage polarization has provided contextual clues into the role of myelomonocytic derivatives in human disease. Until recently, human monocytes were subdivided based on expression of the surface marker CD16. "Classical" monocytes express surface markers denoted as CD14(++)CD16(-) and account for greater than 70% of total monocyte count, while "non-classical" monocytes express the CD16 antigen with low CD14 expression (CD14(+)CD16(++)). However, recognition of an intermediate population identified as CD14(++)CD16(+) supports the new paradigm that monocytes are a true heterogeneous population and careful identification of specific subpopulations is necessary for understanding monocyte function in human disease. Comparative studies of monocytes in mice have yielded more dichotomous results based on expression of the Ly6C antigen. In this review, we will discuss the use of monocyte subpopulations as biomarkers of human disease and summarize correlative studies in mice that may yield significant insight into the contribution of each subset to disease pathogenesis.


[The expression of peroxiredoxin II in hepatocellular carcinoma and its significance].
To evaluate the mRNA and protein expressions of peroxiredoxin II (PrxII) in hepatocellular carcinoma (HCC) and their significance. HCC was induced by aflatoxin B1 (AFB1) in 6 tree shrews (Tupaia belangeri chinensis). The expression levels of PrxII mRNA and protein were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot on HCC tissues and on their surrounding liver tissues (para-HCC). Biopsied liver tissues were taken before the HCC induction (pre-HCC) from the same animals and from a group of blank controlled animals that served as controls. Liver biopsy specimens from 18 cases of human HCC and from 17 healthy human volunteers were studied using the same methods. The mRNA and protein expressions of PrxII in tree shrew HCC tissues were significantly higher than those in para-HCC and pre-HCC tissues, and also higher than those in the liver tissues from the control animals (all P < 0.05). The expression levels of PrxII mRNA and protein in human HCC tissues were also significantly higher than those in their para-HCC tissues and in the human normal liver tissues (P < 0.05). PrxII might play an important role in hepatocarcinogenesis and might be used as a molecular target for HCC prevention and treatment.


A Moderate Dose of Alcohol Does Not Influence Experience of Social Ostracism in Hazardous Drinkers.
Anecdotal and correlational evidence suggests a relationship between social ostracism and alcohol dependence. Furthermore, a recent fMRI investigation found differences in the neural correlates associated with ostracism in people with alcohol dependence compared to healthy controls. We predicted that acutely administered alcohol would reduce the negative effects of social ostracism. Alcohol (0.4 g/kg) or matched placebo was administered to a sample of 32 hazardous drinkers over two sessions in a randomized, double-blind, cross-over design. In each session, participants were exposed to an ostracism event via the computerized ball passing game, "Cyberball." In order to quantify the effects of ostracism, the fundamental needs questionnaire was completed twice on each testing session; immediately after (i) social inclusion and (ii) social exclusion. Ostracism caused robust changes to scores on the fundamental needs questionnaire, in line with previous literature. Alcohol administration did not influence the effects of simulated social ostracism, which was supported by a Bayesian analysis. Exploratory analyses revealed a negative relationship between age and ostracism induced fundamental needs threat across both sessions. In conclusion, a moderate dose of alcohol did not influence experience of simulated social ostracism in hazardous drinkers. Further research is needed to establish the effects of alcohol administration on social ostracism using different doses and populations of alcohol users.


Two ribeye genes in teleosts: the role of Ribeye in ribbon formation and bipolar cell development.
Ribeye is the only known protein specific to synaptic ribbon, but its function is unclear. We show that the teleost fish, Fugu and zebrafish, have two ribeye genes, ribeye a and ribeye b. Whole-mount in situ hybridization revealed that ribeye a is expressed in tissues containing synaptic ribbons, including the pineal gland, inner ear, and retina. Ribeye b is absent in the pineal gland. In the retina, ribeye a is expressed in both photoreceptors and bipolar cells, whereas ribeye b is detected only in photoreceptors. To study the function of Ribeye a in retina, we depleted it by morpholino antisense oligos. Fish deficient in Ribeye a lack an optokinetic response and have shorter synaptic ribbons in photoreceptors and fewer synaptic ribbons in bipolar cells. Their bipolar cells still target Syntaxin-3 proteins to the inner plexiform layer and have abundant vsx1 mRNA. However, they lack large synaptic terminals and show increased apoptosis. Rod bipolar cells are fewer in number and/or deficient in PKCalpha. Recovery of Ribeye a levels rescues the optokinetic response, increases the number of PKCalpha-positive bipolar cells, and stops apoptosis. We conclude that Ribeye a is important for late steps in bipolar cell development.


Tests for comparing mark-specific hazards and cumulative incidence functions.
It is of interest in some applications to determine whether there is a relationship between a hazard rate function (or a cumulative incidence function) and a mark variable which is only observed at uncensored failure times. We develop nonparametric tests for this problem when the mark variable is continuous. Tests are developed for the null hypothesis that the mark-specific hazard rate is independent of the mark versus ordered and two-sided alternatives expressed in terms of mark-specific hazard functions and mark-specific cumulative incidence functions. The test statistics are based on functionals of a bivariate test process equal to a weighted average of differences between a Nelson-Aalen-type estimator of the mark-specific cumulative hazard function and a nonparametric estimator of this function under the null hypothesis. The weight function in the test process can be chosen so that the test statistics are asymptotically distribution-free. Asymptotically correct critical values are obtained through a simple simulation procedure. The testing procedures are shown to perform well in numerical studies, and are illustrated with an AIDS clinical trial example. Specifically, the tests are used to assess if the instantaneous or absolute risk of treatment failure depends on the amount of accumulation of drug resistance mutations in a subject's HIV virus. This assessment helps guide development of anti-HIV therapies that surmount the problem of drug resistance.


Visceral adiposity is associated with SIRT1 expression in peripheral blood mononuclear cells: a pilot study.
Sirtuin1 (SIRT1) is activated during calorie restriction and appears to be related to energy balance through glucose or lipid metabolism and insulin signaling. These findings suggest that SIRT1 may play a role in the pathophysiology of visceral obesity. Therefore, we investigated the relationship between SIRT1 gene expression in circulating peripheral blood mononuclear cells (PBMCs) and abdominal visceral adiposity as measured by computed tomography. We recruited 43 men and women without history of diabetes or cardiovascular disease Biomarkers of metabolic disease and body composition by computed tomography were assessed. SIRT1 gene expression was determined using isolated PBMCs. SIRT1 expression levels negatively correlated with body mass index, waist circumference, abdominal visceral fat area, and homeostasis model of assessment of insulin resistance (HOMA-IR) and positively correlated with adiponectin levels. Results of step-wise multiple regression analysis revealed that abdominal visceral fat area and HOMA-IR were independently associated with SIRT1 expression. The significant association between abdominal visceral fat accumulation and SIRT1 gene expression in PBMCs suggests that SIRT1 may be a new therapeutic target for the prevention of disease related to obesity, especially visceral obesity.


Building sickness, are symptoms related to the office lighting?
Office lighting has been suggested as one of the possible factors in producing 'building sickness'. Health questionnaires were completed by 106 out of 109 (97%) workers in six randomly sampled multi-occupied offices in each of two buildings, one air-conditioned and one naturally ventilated. There was a significantly higher prevalence of work-related headache and work-related lethargy in the air-conditioned building than in the naturally ventilated one. There was also less daylight in the air-conditioned building and lower mean luminance and illuminance of the work positions despite there being more lights on (p less than 0.01). The workers had a greater dislike of fluorescent lighting (p less than 0.01) and overall found the lighting to be less comfortable (p less than 0.01) and glare readings were higher. The workers perceived their control of lighting as poorer (p less than 0.001) and consequently there was less agreement about it (p less than 0.001). Those with work-related headache found the lighting less comfortable (p = 0.059) and perceived more glare (p less than 0.05). This study suggests the need to maximize the use of natural light from untinted windows, to reduce the impingement of fluorescent tubes on the line of sight and to return the control of levels of lighting to each individual worker.


Evaluating summary statistics used to test for incomplete lineage sorting: mito-nuclear discordance in the reef sponge Callyspongia vaginalis.
Conflicting patterns of population differentiation between the mitochondrial and nuclear genomes (mito-nuclear discordance) have become increasingly evident as multilocus data sets have become easier to generate. Incomplete lineage sorting (ILS) of nucDNA is often implicated as the cause of such discordance, stemming from the large effective population size of nucDNA relative to mtDNA. However, selection, sex-biased dispersal and historical demography can also lead to mito-nuclear discordance. Here, we compare patterns of genetic diversity and subdivision for six nuclear protein-coding gene regions to those for mtDNA in a common Caribbean coral reef sponge, Callyspongia vaginalis, along the Florida reef tract. We also evaluated a suite of summary statistics to determine which are effective metrics for comparing empirical and simulated data when testing drivers of mito-nuclear discordance in a statistical framework. While earlier work revealed three divergent and geographically subdivided mtDNACOI haplotypes separated by 2.4% sequence divergence, nuclear alleles were admixed with respect to mitochondrial clade and geography. Bayesian analysis showed that substitution rates for the nuclear loci were up to 7 times faster than for mitochondrial COI. Coalescent simulations and neutrality tests suggested that mito-nuclear discordance in C. vaginalis is not the result of ILS in the nucDNA or selection on the mtDNA but is more likely caused by changes in population size. Sperm-mediated gene flow may also influence patterns of population subdivision in the nucDNA.


Do language fluency and other socioeconomic factors influence the use of PubMed and MedlinePlus?
Increased usage of MedlinePlus by Spanish-speakers was observed after introduction of MedlinePlus in Spanish. This probably reflects increased usage of MEDLINE and PubMed by those with greater fluency in the language in which it is presented; but this has never been demonstrated in English speakers. Evidence that lack of English fluency deters international healthcare personnel from using PubMed could support the use of multi-language search tools like Babel-MeSH. This study aims to measure the effects of language fluency and other socioeconomic factors on PubMed MEDLINE and MedlinePlus access by international users. We retrospectively reviewed server pageviews of PubMed and MedlinePlus from various periods of time, and analyzed them against country statistics on language fluency, GDP, literacy rate, Internet usage, medical schools, and physicians per capita, to determine whether they were associated. We found fluency in English to be positively associated with pageviews of PubMed and MedlinePlus in countries with high literacy rates. Spanish was generally found to be positively associated with pageviews of MedlinePlus en Español. The other parameters also showed varying degrees of association with pageviews. After adjusting for the other factors investigated in this study, language fluency was a consistently significant predictor of the use of PubMed, MedlinePlus English and MedlinePlus en Español. This study may support the need for multi-language search tools and may increase access of health information resources from non-English speaking countries.


Use of technological tools to evaluate handwriting production of the alphabet and pseudocharacters by Brazilian students.
This study aimed to characterize and compare the handwriting performance of Brazilian students from the 3rd to the 5th grade level of elementary school I with a computerized instrument that allowed the real performance to be observed during the execution of the handwriting. Ninety-five students, aged 8 years to 11 years and 11 months, were assigned the production tasks of handwriting letters and pseudocharacters to assess the variables of latency, letter duration production and movement fluency. The stimulus presentation and the analysis of the movements were analyzed by Ductus software. In relation to the writing duration, latency and fluency of the alphabet letters, there was a diminution of values from the 3rd to 5th grade. For the comparison between alphabet and pseudocharacter latency, the results indicated a difference between the alphabet letter and its corresponding pseudocharacter, with greater latency for the pseudocharacter. This finding suggests that a motor sequence has not been established, so it cannot be assumed that the production of the alphabet letters was automatic. The results of this study make it possible to verify the interaction failures between the central and peripheral processes, with progression between the 3rd and 5th grade. It also highlights the influence of the lack of systematized teaching of the tracing of letters for Brazilian students since proficiency in calligraphy is critically linked to academic performance. These findings provide a great contribution to Brazilian educational psychology and reflect both educational and clinical practices.


Characterising risk of in-hospital mortality following cardiac arrest using machine learning: A retrospective international registry study.
Resuscitated cardiac arrest is associated with high mortality; however, the ability to estimate risk of adverse outcomes using existing illness severity scores is limited. Using in-hospital data available within the first 24 hours of admission, we aimed to develop more accurate models of risk prediction using both logistic regression (LR) and machine learning (ML) techniques, with a combination of demographic, physiologic, and biochemical information. Patient-level data were extracted from the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database for patients who had experienced a cardiac arrest within 24 hours prior to admission to an intensive care unit (ICU) during the period January 2006 to December 2016. The primary outcome was in-hospital mortality. The models were trained and tested on a dataset (split 90:10) including age, lowest and highest physiologic variables during the first 24 hours, and key past medical history. LR and 5 ML approaches (gradient boosting machine [GBM], support vector classifier [SVC], random forest [RF], artificial neural network [ANN], and an ensemble) were compared to the APACHE III and Australian and New Zealand Risk of Death (ANZROD) predictions. In all, 39,566 patients from 186 ICUs were analysed. Mean (±SD) age was 61 ± 17 years; 65% were male. Overall in-hospital mortality was 45.5%. Models were evaluated in the test set. The APACHE III and ANZROD scores demonstrated good discrimination (area under the receiver operating characteristic curve [AUROC] = 0.80 [95% CI 0.79-0.82] and 0.81 [95% CI 0.8-0.82], respectively) and modest calibration (Brier score 0.19 for both), which was slightly improved by LR (AUROC = 0.82 [95% CI 0.81-0.83], DeLong test, p < 0.001). Discrimination was significantly improved using ML models (ensemble and GBM AUROCs = 0.87 [95% CI 0.86-0.88], DeLong test, p < 0.001), with an improvement in performance (Brier score reduction of 22%). Explainability models were created to assist in identifying the physiologic features that most contributed to an individual patient's survival. Key limitations include the absence of pre-hospital data and absence of external validation. ML approaches significantly enhance predictive discrimination for mortality following cardiac arrest compared to existing illness severity scores and LR, without the use of pre-hospital data. The discriminative ability of these ML models requires validation in external cohorts to establish generalisability.


The effect of estradiol benzoate administration on estrous response and synchronized pregnancy rate in dairy heifers after treatment with exogenous progesterone.
The objectives of this trial were to determine the effects of 0.5 mg estradiol benzoate administered intramuscularly 24 h after the removal of progesterone-containing intravaginal devices on the occurrence and timing of estrus, synchronized pregnancy rate and synchronized conception rate in dairy heifers. A clinical trial was conducted involving 750 dairy heifers in 13 herds. Within each herd heifers were randomly allocated to 1 of 2 estrus synchronization treatments. All heifers received a CIDR-B progesterone-containing intravaginal device containing a 10 mg estradiol benzoate capsule for 12 d. Twenty-four hours after CIDR-B removal one group received 0.5 mg, im estradiol benzoate while the other group received an intramuscular injection of a placebo. Estrus detection was performed at 48 and 72 h after intravaginal device removal, and heifers detected in estrus at those times were inseminated. Administration of estradiol benzoate 24 h after removal of CIDR-B devices significantly increased the number of heifers exhibiting estrus within the observation period (96.1 vs 90.5%; P < 0.01). It also altered the onset of estrus so that significantly more heifers were in estrus (86.6 vs 72.3%; P < 0.01) and conceived (47.1 vs 37.5%; P < 0.05) by 48 h after CIDR-B device removal. The synchronized conception rate was unaffected by treatment. The distribution of estrus was such that fixed-time insemination after estrus synchronization with this treatment program may be recommended.


Asthma and vitamin C.
To define what role vitamin C may or may not play in the treatment of asthma. A comprehensive literature search of relevant English-language papers identified through a Medline search and from bibliographies of the identified papers. We identified papers and studies pertaining to vitamin C in asthma and allergy and analyzed these studies according to their design, inclusion and exclusion criteria, population studied, variables or factors tested, method of intervention or treatment with vitamin C, and results and conclusions. We reviewed our data and divided it based on significant or insignificant roles of vitamin C in asthma and allergy. From our review, we found a number of studies that support the use of vitamin C in asthma and allergy. Significant results include positive effects on pulmonary function tests, bronchoprovocation challenges with methacholine or histamine or allergens, improvement in white blood cell function and motility, and a decrease in respiratory infections. Our review also revealed several studies that did not support a beneficial role in vitamin C in asthma and allergy. These studies did not report improvements in pulmonary function tests or bronchoprovocation challenges. No benefit was noted in these studies when testing cutaneous reactivity or specific immunologic factors and levels. Clearly from our review, the role of vitamin C in asthma and allergy is not well defined. The majority of the studies were short term and assessed immediate effects of vitamin C supplementation. Long term supplementation with vitamin C or delayed effects need to be studied. Although, the current literature does not support a definite indication for the use of vitamin C in asthma and allergy, the promising and positive studies revive curiosity and interest. With a large portion of health care dollars being spent on alternative medicine and vitamin C in particular, further studies are needed to define its role.


Yoga for persistent fatigue in breast cancer survivors: results of a pilot study.
Approximately one-third of breast cancer survivors experiences persistent fatigue for months or years after successful treatment completion. There is a lack of evidence-based treatments for cancer-related fatigue, particularly among cancer survivors. This single-arm pilot study evaluated the feasibility and preliminary efficacy of a yoga intervention for fatigued breast cancer survivors based on the Iyengar tradition. Iyengar yoga prescribes specific poses for individuals with specific medical problems and conditions; this trial emphasized postures believed to be effective for reducing fatigue among breast cancer survivors, including inversions and backbends performed with the support of props. Twelve women were enrolled in the trial, and 11 completed the full 12-week course of treatment. There was a significant improvement in fatigue scores from pre- to post-intervention that was maintained at the 3-month post-intervention followup. Significant improvements were also observed in measures of physical function, depressed mood, and quality of life. These results support the acceptability of this intervention and suggest that it may have beneficial effects on persistent post-treatment fatigue. However, results require replication in a larger randomized controlled trial.


Antiretroviral therapy and its influence on the stage of brain damage in patients with HIV - 1H MRS evaluation.
MR proton spectroscopy (1H MRS) enables early detection of metabolic changes, which occur in the course of AIDS Dementia Complex Syndrome (ADC). The goal of the study was the evaluation of highly active antiretroviral therapy (HAART) and its influence on the character and intensity of metabolic changes in brain 1H MRS spectra in clinically asymptomatic HIV-infected patients as well as search for correlation between the treatment and 1H MR spectroscopy results and immune deficit degree. In the group of 20 HIV+ patients, the examination of the central nervous system (CNS), MR and 1H MRS were conducted twice:before HAART treatment and during the therapy; on average after 6 months (4 -9 months of treatment). The levels of NAA/Cr in the control MRS examination were close to the values observed before treatment. However, statistically significant increase in NAA/Cho ratio (p<0.05) was noticed. The control examination showed statistically decrease of Cho/Cr and mI/Cr ratios, though statistically insignificant (p>0.05). NAA and Cr contents in reference to the signal of non-suppressed water increased insignificantly in the follow-up examination. However, statistically significant decrease in Cho/H(2)O and mI/H(2)O levels (p<0.05) was observed. The therapy with HAART affects normalization of metabolite levels in the central nervous system in clinically asymptomatic HIV+ patients and diminishes the risk of ADC occurrence. Myoinositol and choline levels estimated in 1H MRS might be the indices for antiretroviral treatment efficacy.


Bioaccumulation of Fluorotelomer Sulfonates and Perfluoroalkyl Acids in Marine Organisms Living in Aqueous Film-Forming Foam Impacted Waters.
The use of aqueous film-forming foams (AFFFs) has resulted in hot spots polluted with poly- and perfluorinated alkyl substances (PFASs). The phase out of long-chained perfluoroalkyl acids (PFAAs) from AFFFs resulted in the necessity for alternatives, and short-chained PFAAs and fluorotelomer-based surfactants have been used. Here, the distribution of PFAS contamination in the marine environment surrounding a military site in Norway was investigated. Up to 30 PFASs were analyzed in storm, leachate, and fjord water; marine sediments; marine invertebrates (snails, green shore crab, great spider crab, and edible crab); and teleost fish (Atlantic cod, European place, and Lemon sole). Perfluorooctanesulfonic acid (PFOS) was the most abundantly detected PFAS. Differences in PFAS accumulation levels were observed among species, likely reflecting different exposure routes among trophic levels and different capabilities for depuration and/or enzymatic degradation. In agreement with previous literature, almost no 6:2 fluorotelomer sulfonate (6:2 FTS) was detected in teleost fish. However, this study is one of the first to report considerable concentrations of 6:2 FTS in marine invertebrates, suggesting bioaccumulation. Biota monitoring and risk assessments of sites contaminated with fluorotelomer sulfonates (FTSs) and related compounds should not be limited to fish, but should also include invertebrates.


Variation in urinary flow rates according to demographic characteristics and body mass index in NHANES: potential confounding of associations between health outcomes and urinary biomarker concentrations.
Urinary analyte concentrations are affected both by exposure level and by urinary flow rate (UFR). Systematic variations in UFR with demographic characteristics or body mass index (BMI) could confound assessment of associations between health outcomes and biomarker concentrations. We assessed patterns of UFR (milliliters per hour) and body weight-adjusted UFR (UFRBW; milliliters per kilogram per hour) across age, sex, race/ethnicity, and BMI category in the NHANES (National Health and Nutrition Examination Survey) 2009-2012 data sets. Geometric mean (GM) UFR and UFRBW were compared across age-stratified (6-11, 12-19, 20-39, 40-59, and ≥ 60 years) subgroups (sex, race/ethnicity, and BMI category). Patterns of analyte urinary concentration or mass excretion rates (nanograms per hour and nanograms per kilogram per hour BW) were assessed in sample age groups for case study chemicals bisphenol A and 2,5-dichlorophenol. UFR increased from ages 6 to 60 years and then declined with increasing age. UFRBW varied inversely with age. UFR, but not UFRBW, differed significantly by sex (males > females after age 12 years). Differences in both metrics were observed among categories of race/ethnicity. UFRBW, but not UFR, varied inversely with BMI category and waist circumference in all age groups. Urinary osmolality increased with increasing BMI. Case studies demonstrated different exposure-outcome relationships depending on exposure metric. Conventional hydration status adjustments did not fully address the effect of flow rate variations. UFR and UFRBW exhibit systematic variations with age, sex, race/ethnicity, and BMI category. These variations can confound assessments of potential exposure-health outcome associations based on urinary concentration. Analyte excretion rates are valuable exposure metrics in such assessments.


Synthesis of and recognition by ribonuclease A imprinted polymers.
Ribonuclease (RNase), an enzyme which degrades RNA, is ubiquitous in living organisms, can renature after autoclaving, and is difficult to inactivate. The removal of RNase is especially necessary for the reverse transcription-polymerase chain reaction (RT-PCR) and for in vitro transcription and translation. Typically, RNase inhibitors must be added to these reactions nowadays. Molecularly imprinted polymers (MIPs) could offer many advantages for removal of undesired enzymes, including high binding selectivity, stability, low cost, and facile synthesis. Surface imprinting, employing immobilized RNase, was used in this study to make the most effective use of the template molecules-clearly, inaccessible binding sites, no matter how well imprinted, are not useful for target binding. Different monomers and cross-linkers were used to synthesize RNase-templated MIPs, and the rebinding capacity of each composition was characterized. We found that using polyethylene glycol 400 dimethacrylate (PEG400DMA) gave the highest imprinting effectiveness (i.e. the highest RNase binding ratio between imprinted and non-imprinted polymers). However, including styrene monomer (50 wt%) gave polymers with the highest overall affinity for ribonuclease A (RNase A). Finally, isothermal titration calorimetry was used as an auxiliary tool to help elucidate the mechanisms of the binding of monomers to templates, and ligands to MIPs.


Anti-tumor effect in an in vivo model by human-derived pancreatic RNase with basic fibroblast growth factor insertional fusion protein through antiangiogenic properties.
It is thought that the export of angiogenic fibroblast growth factors (FGF) from tumors may be involved in the onset of tumor angiogenesis. To create a new active targeting drug that inhibits the tumor angiogenic process without toxicities to normal cells, human basic FGF (h-bFGF) was inserted genetically into the Gly89 position of cross-linked RNase1 (the ribonuclease inhibitor protein [RI] binding site of cross-linked human pancreatic RNase) to prevent stereospecific binding to RI. The resultant insertional-fusion protein (CL-RFN89) was active both as h-bFGF and as RNase1. Furthermore, it acquired an additional ability of evading RI through steric blockade of RI binding caused by the fused h-bFGF domain. In the present study, the effect of the resultant protein, CL-RFN89, on the antitumor response though its antiangiogenic properties was investigated in an in vivo model. Continuous systemic treatment with CL-RFN89 significantly inhibited the growth of human A431 squamous cell carcinomas in vivo. Seven days of treatment with CL-RFN89 resulted in a 58.2% inhibition of tumor growth compared with control mice (P < 0.0001). Furthermore, immunohistochemistry using a rat antimouse CD31 antibody showed that treatment with CL-RFN89 reduced tumor vascularization. These findings identify CL-RFN89 as a potent systemic inhibitor of tumor growth as a result of its antiangiogenic properties. This protein appears to be a new systemic antitumor agent.


Postnatal growth rates covary weakly with embryonic development rates and do not explain adult mortality probability among songbirds on four continents.
Growth and development rates may result from genetic programming of intrinsic processes that yield correlated rates between life stages. These intrinsic rates are thought to affect adult mortality probability and longevity. However, if proximate extrinsic factors (e.g., temperature, food) influence development rates differently between stages and yield low covariance between stages, then development rates may not explain adult mortality probability. We examined these issues based on study of 90 songbird species on four continents to capture the diverse life-history strategies observed across geographic space. The length of the embryonic period explained little variation (ca. 13%) in nestling periods and growth rates among species. This low covariance suggests that the relative importance of intrinsic and extrinsic influences on growth and development rates differs between stages. Consequently, nestling period durations and nestling growth rates were not related to annual adult mortality probability among diverse songbird species within or among sites. The absence of a clear effect of faster growth on adult mortality when examined in an evolutionary framework across species may indicate that species that evolve faster growth also evolve physiological mechanisms for ameliorating costs on adult mortality. Instead, adult mortality rates of species in the wild may be determined more strongly by extrinsic environmental causes.


Gene expression, single nucleotide variant and fusion transcript discovery in archival material from breast tumors.
Advantages of RNA-Seq over array based platforms are quantitative gene expression and discovery of expressed single nucleotide variants (eSNVs) and fusion transcripts from a single platform, but the sensitivity for each of these characteristics is unknown. We measured gene expression in a set of manually degraded RNAs, nine pairs of matched fresh-frozen, and FFPE RNA isolated from breast tumor with the hybridization based, NanoString nCounter (226 gene panel) and with whole transcriptome RNA-Seq using RiboZeroGold ScriptSeq V2 library preparation kits. We performed correlation analyses of gene expression between samples and across platforms. We then specifically assessed whole transcriptome expression of lincRNA and discovery of eSNVs and fusion transcripts in the FFPE RNA-Seq data. For gene expression in the manually degraded samples, we observed Pearson correlations of >0.94 and >0.80 with NanoString and ScriptSeq protocols, respectively. Gene expression data for matched fresh-frozen and FFPE samples yielded mean Pearson correlations of 0.874 and 0.783 for NanoString (226 genes) and ScriptSeq whole transcriptome protocols respectively, p<2x10(-16). Specifically for lincRNAs, we observed superb Pearson correlation (0.988) between matched fresh-frozen and FFPE pairs. FFPE samples across NanoString and RNA-Seq platforms gave a mean Pearson correlation of 0.838. In FFPE libraries, we detected 53.4% of high confidence SNVs and 24% of high confidence fusion transcripts. Sensitivity of fusion transcript detection was not overcome by an increase in depth of sequencing up to 3-fold (increase from ~56 to ~159 million reads). Both NanoString and ScriptSeq RNA-Seq technologies yield reliable gene expression data for degraded and FFPE material. The high degree of correlation between NanoString and RNA-Seq platforms suggests discovery based whole transcriptome studies from FFPE material will produce reliable expression data. The RiboZeroGold ScriptSeq protocol performed particularly well for lincRNA expression from FFPE libraries, but detection of eSNV and fusion transcripts was less sensitive.


Violence against children and natural disasters: A systematic review and meta-analysis of quantitative evidence.
Reviews of violence against children in disaster settings focus on armed conflict. Little is understood about natural disasters which has implications in planning humanitarian response. We examined the magnitude and direction of the association between exposure to natural disasters and physical, emotional, and sexual violence against children, and assessed the quality of the evidence. We searched 15 health and social science databases from first record until May 16, 2018. Publications describing all types of quantitative study design were eligible for inclusion. We presented study characteristics and quality in a narrative form and generated pooled estimates using a three-level random effects model. We evaluated Cochrane's Q with p-values below 0.10 and radial plots to assess heterogeneity. Planned subgroup analyses explored differential results by violence form, study design, and analysis method. 11 publications met inclusion criteria. The majority were cross-sectional studies examining physical or sexual violence in the United States. We found no evidence of a consistent association or directional influence between natural disasters and violence against children. Combined categorical violence outcomes had substantial heterogeneity [Q (df = 66) = 252.83, p < 0.001]. Subgroups without evidence of heterogeneity had confidence intervals that included a possible null effect. Our findings were mainly limited by inconsistencies in operational definitions of violence, a lack of representative sampling, and unclear establishment of temporal order between natural disaster exposure and violence outcomes. Based on the available evidence, we cannot confidently conclude that natural disasters increase the level or severity of violence against children above non-disaster settings, however heterogeneity and study quality hamper our ability to draw firm conclusions. More nuanced and rigorous research is needed to inform practice and policy as natural disasters increasingly affect human populations.


Homoplastic microinversions and the avian tree of life.
Microinversions are cytologically undetectable inversions of DNA sequences that accumulate slowly in genomes. Like many other rare genomic changes (RGCs), microinversions are thought to be virtually homoplasy-free evolutionary characters, suggesting that they may be very useful for difficult phylogenetic problems such as the avian tree of life. However, few detailed surveys of these genomic rearrangements have been conducted, making it difficult to assess this hypothesis or understand the impact of microinversions upon genome evolution. We surveyed non-coding sequence data from a recent avian phylogenetic study and found substantially more microinversions than expected based upon prior information about vertebrate inversion rates, although this is likely due to underestimation of these rates in previous studies. Most microinversions were lineage-specific or united well-accepted groups. However, some homoplastic microinversions were evident among the informative characters. Hemiplasy, which reflects differences between gene trees and the species tree, did not explain the observed homoplasy. Two specific loci were microinversion hotspots, with high numbers of inversions that included both the homoplastic as well as some overlapping microinversions. Neither stem-loop structures nor detectable sequence motifs were associated with microinversions in the hotspots. Microinversions can provide valuable phylogenetic information, although power analysis indicates that large amounts of sequence data will be necessary to identify enough inversions (and similar RGCs) to resolve short branches in the tree of life. Moreover, microinversions are not perfect characters and should be interpreted with caution, just as with any other character type. Independent of their use for phylogenetic analyses, microinversions are important because they have the potential to complicate alignment of non-coding sequences. Despite their low rate of accumulation, they have clearly contributed to genome evolution, suggesting that active identification of microinversions will prove useful in future phylogenomic studies.


Drug labeling: The study of compliance of regulatory requirements for prescription drugs in India.
The objective was to check the compliance of regulatory requirements of drug labeling in India according to guidelines given under the Drug and Cosmetic Rules (D & CRs) 1945, Section 96, 97; drug samples were collected from government drug supply and private practitioners (PPs). A total of 100 drugs were selected randomly from schedule H. They were divided into two groups, each containing 50 drugs: (1) drug samples from drug store of a government hospital, manufactured for Gujarat government and (2) drug samples from PPs which are given to them by pharmaceutical companies. Each drug label was checked according to the criteria given under the D & CRs 1945, Section 96, 97. Data entry was done in Microsoft Excel 2013 and analysis was done. Major deficiencies were seen in criteria of pharmacopeia (absent in 8% samples from government supply [GS] and 64% in samples from PPs), schedule (absent in 18% GS samples and 32% in PP samples), warning of schedule (absent in 6% GS samples and 4% in PP samples), Rx (absent in 22% GS samples and 28% in PP samples), red line (absent in 14% GS samples), and drug warning (absent in 84% GS samples and 72% in PP samples). As the study results show lacunae in the contents of the labeling of prescribed drugs in samples from both the groups, there should be strict enforcement of D & CR 1945 and monitoring of drug labels for better and safer use of medicines.


Continuing education training focused on the development of behavioral telehealth competencies in behavioral healthcare providers.
Telehealth allows behavioral health care and specialty services to be extended to rural residents. Telehealth is an important resource for the Alaskan healthcare system, which is tasked with providing services to culturally diverse populations living in remote areas. Training competent providers to deliver telehealth services is vital for the implementation of successful telehealth programs. Yet, the literature is lacking in the area of provider behavioral telehealth competency training. This study assessed the impact of a Behavioral Telehealth Ethical Competencies Training program on 16 behavioral health providers' development of behavioral telehealth competency. A total of 14 competencies were developed, which required participants to understand the roles and responsibilities of a behavioral telehealth coordinator working at the distal site as well as the roles and responsibilities of the therapist. Video vignettes evaluating the 14 competencies, self-reported competence surveys and follow-up surveys of progress on telehealth goals were utilized to assess effects of the training. Results indicated participants' behavioral telehealth competencies increased following training. Participants reported positive perceptions regarding their competency, and achieved progress on the majority of behavioral telehealth goals set during the training. This study provides a baseline for developing a best practice model for behavioral telehealth service delivery by identifying specific provider competencies for administering effective behavioral telehealth services. A unique continuing education training model, led by content experts including university professors and Alaska Native Elders, incorporating behavioral telehealth, rural ethics, cultural competency and vicarious trauma training is described. Lastly, this study details the use of an innovative video vignette assessment instrument for evaluating the effectiveness of continuing education training.


Demonstration of the granular layer and the fate of the hyaline layer during the development of a sea urchin (Lytechinus variegatus).
Employing electron-microscopic methods that help retain polyanionic materials, we describe the extracellular coverings of a sea urchin (Lytechinus variegatus) throughout ontogeny. The surface of the embryo is covered by a two-layered cuticle (commonly called the hyaline layer), which in turn is covered by a granular layer. The granular layer is retained after addition of alcian blue to the fixative solutions, and has not been previously described for any sea urchin. After hatching, the granular layer disappears, but the hyaline layer continues to cover most of the larval surface until settlement and metamorphosis. A few days before metamorphosis, the hyaline layer lining the vestibular invagination of the competent pluteus larva is replaced by a three-layered cuticle resembling that of the adult sea urchin. The hyaline layer covering the rest of the larva is evidently lost at metamorphosis during the involution of the general epidermis.


Shoot apical meristem form and function.
The shoot apical meristem (SAM) generates above-ground aerial organs throughout the lifespan of higher plants. In order to fulfill this function, the meristem must maintain a balance between the self-renewal of a reservoir of central stem cells and organ initiation from peripheral cells. The activity of the pluripotent stem cell population in the SAM is dynamically controlled by complex, overlapping signaling networks that include the feedback regulation of meristem maintenance genes and the signaling of plant hormones. Organ initiation likewise requires the function of multifactor gene regulatory networks, as well as instructive cues from the plant hormone auxin and reciprocal signals from the shoot meristem. Floral meristems (FMs) are products of the reproductive SAM that sustains a transient stem cell reservoir for flower formation. Regulation of FM activity involves both feedback loops shared with the SAM and floral-specific factors. Recent studies have rapidly advanced our understanding of SAM function by adopting newly developed molecular and computational techniques. These advances are becoming integrated with data from traditional molecular genetics methodologies to develop a framework for understanding the central principles of SAM function.


Phenotypic plasticity in blood-oxygen transport in highland and lowland deer mice.
In vertebrates living at high altitude, arterial hypoxemia may be ameliorated by reversible changes in the oxygen-carrying capacity of the blood (regulated by erythropoiesis) and/or changes in blood-oxygen affinity (regulated by allosteric effectors of hemoglobin function). These hematological traits often differ between taxa that are native to different elevational zones, but it is often unknown whether the observed physiological differences reflect fixed, genetically based differences or environmentally induced acclimatization responses (phenotypic plasticity). Here, we report measurements of hematological traits related to blood-O2 transport in populations of deer mice (Peromyscus maniculatus) that are native to high- and low-altitude environments. We conducted a common-garden breeding experiment to assess whether altitude-related physiological differences were attributable to developmental plasticity and/or physiological plasticity during adulthood. Under conditions prevailing in their native habitats, high-altitude deer mice from the Rocky Mountains exhibited a number of pronounced hematological differences relative to low-altitude conspecifics from the Great Plains: higher hemoglobin concentrations, higher hematocrits, higher erythrocytic concentrations of 2,3-diphosphoglycerate (an allosteric regulator of hemoglobin-oxygen affinity), lower mean corpuscular hemoglobin concentrations and smaller red blood cells. However, these differences disappeared after 6 weeks of acclimation to normoxia at low altitude. The measured traits were also indistinguishable between the F1 progeny of highland and lowland mice, indicating that there were no persistent differences in phenotype that could be attributed to developmental plasticity. These results indicate that the naturally occurring hematological differences between highland and lowland mice are environmentally induced and are largely attributable to physiological plasticity during adulthood.


Novel heme ligation in a c-type cytochrome involved in thiosulfate oxidation: EPR and MCD of SoxAX from Rhodovulum sulfidophilum.
The SoxAX complex of the bacterium Rhodovulum sulfidophilum is a heterodimeric c-type cytochrome that plays an essential role in photosynthetic thiosulfate and sulfide oxidation. The three heme sites of SoxAX have been analyzed using electronic absorption, electron paramagnetic resonance, and magnetic circular dichroism spectroscopies. Heme-3 in the ferric state is characterized by a Large g(max) EPR signal and has histidine and methionine axial heme iron ligands which are retained on reduction to the ferrous state. Hemes-1 and -2 both have thiolate plus nitrogenous ligand sets in the ferric state and give rise to rhombic EPR spectra. Heme-1, whose ligands derive from cysteinate and histidine residues, remains ferric in the presence of dithionite ion. Ferric heme-2 exists with a preparation-dependent mixture of two different ligand sets, one being cysteinate/histidine, the other an unidentified pair with a weaker crystal-field strength. Upon reduction of the SoxAX complex with dithionite, a change occurs in the ligands of heme-2 in which the thiolate is either protonated or replaced by an unidentified ligand. Sequence analysis places the histidine/methionine-coordinated heme in SoxX and the thiolate-liganded hemes in SoxA. SoxAX is the first naturally occurring c-type cytochrome in which a thiolate-coordinated heme has been identified.


Repetitive transcranial magnetic stimulation in chronic tension-type headache: A pilot study.
Tension-type headache (TTH) is the most common type of primary headache disorder. Its chronic form is often the most ignored and challenging to treat. Transcranial magnetic stimulation (TMS) is a novel technique in the treatment of chronic pain. The aim of this pilot study was to explore the effect of low-frequency repetitive TMS (rTMS) on pain status in chronic TTH (CTTH) by subjective and objective pain assessment. Patients (n=30) diagnosed with CTTH were randomized into rTMS (n=15) and placebo (n=15) groups in this study. Pre-intervention detailed history of patients was taken. Numerical Rating Scale (NRS) for Pain and questionnaires [Headache Impact Test-6 (HIT-6), McGill Pain Questionnaire, Pain Beliefs Questionnaire, Coping Strategies Questionnaire, State-Trait Anxiety Inventory Test, Hamilton Rating Scale for Depression and WHO-Quality of Life Questionnaire-Brief version] were filled, and objective assessments such as nociceptive flexion reflex (NFR) and conditioned pain modulation were done. The tests were repeated after 20 sessions (5 days/week). In the rTMS group, 1200 pulses in eight trains of 150 pulses each were given at 1Hz over the right dorsolateral prefrontal cortex (RDLPFC). In the placebo group, the rTMS coil was placed such that magnetic stimulation did not reach the cortex. The NRS score decreased significantly (P<0.001) and NFR thresholds increased significantly (P=0.011) in the rTMS group when compared to placebo group. Subjective improvements in the NRS, HIT-6, McGill Present Pain Intensity, trait of anxiety and psychological pain beliefs were observed. The increase in the thresholds of NFR served as an objective marker for improvement in pain status. Further studies need to be done to confirm our preliminary findings.