1,045 research outputs found

    Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human

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    Effect of antiandrogen flutamide on measures of hepatic regeneration in rats

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    Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy. © 1989 Plenum Publishing Corporation

    A variational Bayes algorithm for fast and accurate multiple locus genome-wide association analysis

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    <p>Abstract</p> <p>Background</p> <p>The success achieved by genome-wide association (GWA) studies in the identification of candidate loci for complex diseases has been accompanied by an inability to explain the bulk of heritability. Here, we describe the algorithm V-Bay, a variational Bayes algorithm for multiple locus GWA analysis, which is designed to identify weaker associations that may contribute to this missing heritability.</p> <p>Results</p> <p>V-Bay provides a novel solution to the computational scaling constraints of most multiple locus methods and can complete a simultaneous analysis of a million genetic markers in a few hours, when using a desktop. Using a range of simulated genetic and GWA experimental scenarios, we demonstrate that V-Bay is highly accurate, and reliably identifies associations that are too weak to be discovered by single-marker testing approaches. V-Bay can also outperform a multiple locus analysis method based on the lasso, which has similar scaling properties for large numbers of genetic markers. For demonstration purposes, we also use V-Bay to confirm associations with gene expression in cell lines derived from the Phase II individuals of HapMap.</p> <p>Conclusions</p> <p>V-Bay is a versatile, fast, and accurate multiple locus GWA analysis tool for the practitioner interested in identifying weaker associations without high false positive rates.</p

    Mouse obesity network reconstruction with a variational Bayes algorithm to employ aggressive false positive control

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    <p>Abstract</p> <p>Background</p> <p>We propose a novel variational Bayes network reconstruction algorithm to extract the most relevant disease factors from high-throughput genomic data-sets. Our algorithm is the only scalable method for regularized network recovery that employs Bayesian model averaging and that can internally estimate an appropriate level of sparsity to ensure few false positives enter the model without the need for cross-validation or a model selection criterion. We use our algorithm to characterize the effect of genetic markers and liver gene expression traits on mouse obesity related phenotypes, including weight, cholesterol, glucose, and free fatty acid levels, in an experiment previously used for discovery and validation of network connections: an F2 intercross between the C57BL/6 J and C3H/HeJ mouse strains, where apolipoprotein E is null on the background.</p> <p>Results</p> <p>We identified eleven genes, Gch1, Zfp69, Dlgap1, Gna14, Yy1, Gabarapl1, Folr2, Fdft1, Cnr2, Slc24a3, and Ccl19, and a quantitative trait locus directly connected to weight, glucose, cholesterol, or free fatty acid levels in our network. None of these genes were identified by other network analyses of this mouse intercross data-set, but all have been previously associated with obesity or related pathologies in independent studies. In addition, through both simulations and data analysis we demonstrate that our algorithm achieves superior performance in terms of power and type I error control than other network recovery algorithms that use the lasso and have bounds on type I error control.</p> <p>Conclusions</p> <p>Our final network contains 118 previously associated and novel genes affecting weight, cholesterol, glucose, and free fatty acid levels that are excellent obesity risk candidates.</p

    Socioeconomic deprivation, urban-rural location and alcohol-related mortality in England and Wales

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    Background: Many causes of death are directly attributable to the toxic effects of alcohol and deaths from these causes are increasing in the United Kingdom. The aim of this study was to investigate variation in alcohol-related mortality in relation to socioeconomic deprivation, urban-rural location and age within a national context. Methods: An ecological study design was used with data from 8797 standard table wards in England and Wales. The methodology included using the Carstairs Index as a measure of socioeconomic deprivation at the small-area level and the national harmonised classification system for urban and rural areas in England and Wales. Alcohol-related mortality was defined using the National Statistics definition, devised for tracking national trends in alcohol-related deaths. Deaths from liver cirrhosis accounted for 85% of all deaths included in this definition. Deaths from 1999-2003 were examined and 2001 census ward population estimates were used as the denominators. Results: The analysis was based on 28,839 deaths. Alcohol-related mortality rates were higher in men and increased with increasing age, generally reaching peak levels in middle-aged adults. The 45-64 year age group contained a quarter of the total population but accounted for half of all alcohol-related deaths. There was a clear association between alcohol-related mortality and socioeconomic deprivation, with progressively higher rates in more deprived areas. The strength of the association varied with age. Greatest relative inequalities were seen amongst people aged 25-44 years, with relative risks of 4.73 (95% CI 4.00 to 5.59) and 4.24 (95% CI 3.50 to 5.13) for men and women respectively in the most relative to the least deprived quintiles. People living in urban areas experienced higher alcohol-related mortality relative to those living in rural areas, with differences remaining after adjustment for socioeconomic deprivation. Adjusted relative risks for urban relative to rural areas were 1.35 (95% CI 1.20 to 1.52) and 1.13 (95% CI 1.01 to 1.25) for men and women respectively. Conclusions: Large inequalities in alcohol-related mortality exist between sub-groups of the population in England and Wales. These should be considered when designing public health policies to reduce alcohol-related harm

    Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives

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    Inferring relatedness from genomic data is an essential component of genetic association studies, population genetics, forensics, and genealogy. While numerous methods exist for inferring relatedness, thorough evaluation of these approaches in real data has been lacking. Here, we report an assessment of 12 state-of-the-art pairwise relatedness inference methods using a data set with 2485 individuals contained in several large pedigrees that span up to six generations. We find that all methods have high accuracy (92–99%) when detecting first- and second-degree relationships, but their accuracy dwindles to \u3c43% for seventh-degree relationships. However, most identical by descent (IBD) segment-based methods inferred seventh-degree relatives correct to within one relatedness degree for \u3e76% of relative pairs. Overall, the most accurate methods are Estimation of Recent Shared Ancestry (ERSA) and approaches that compute total IBD sharing using the output from GERMLINE and Refined IBD to infer relatedness. Combining information from the most accurate methods provides little accuracy improvement, indicating that novel approaches, such as new methods that leverage relatedness signals from multiple samples, are needed to achieve a sizeable jump in performance

    Amnesia for violent crime among young offenders

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    Amnesia for the perpetration of violent offences is an important issue in medico-legal proceedings. Previous studies of amnesia have mainly relied on selected groups of unconvicted offenders, which raises the question of how reliable the findings are. The purpose of this study was to examine the prevalence and phenomenological qualities of amnesia in violent offenders. In semi-structured interviews with 105 young offenders convicted of serious violence, 20 (19%) reported partial amnesia for their offence and only one (1%) reported complete amnesia. Amnesia was associated with high alcohol intake, emotional ties to the victim, and cognitive processing during the assault. Complete amnesia for violent crime appears to be less frequent than suggested by previous reports using unconvicted samples. The findings have implications for the clinical assessment of claimed amnesia for violent crime and are potentially of medico-legal significance

    In-reach specialist nursing teams for residential care homes : uptake of services, impact on care provision and cost-effectiveness

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    Background: A joint NHS-Local Authority initiative in England designed to provide a dedicated nursing and physiotherapy in-reach team (IRT) to four residential care homes has been evaluated.The IRT supported 131 residents and maintained 15 'virtual' beds for specialist nursing in these care homes. Methods: Data captured prospectively (July 2005 to June 2007) included: numbers of referrals; reason for referral; outcome (e.g. admission to IRT bed, short-term IRT support); length of stay in IRT; prevented hospital admissions; early hospital discharges; avoided nursing home transfers; and detection of unrecognised illnesses. An economic analysis was undertaken. Results: 733 referrals were made during the 2 years (range 0.5 to 13.0 per resident per annum)resulting in a total of 6,528 visits. Two thirds of referrals aimed at maintaining the resident's independence in the care home. According to expert panel assessment, 197 hospital admissions were averted over the period; 20 early discharges facilitated; and 28 resident transfers to a nursing home prevented. Detection of previously unrecognised illnesses accounted for a high number of visits. Investment in IRT equalled £44.38 per resident per week. Savings through reduced hospital admissions, early discharges, delayed transfers to nursing homes, and identification of previously unrecognised illnesses are conservatively estimated to produce a final reduction in care cost of £6.33 per resident per week. A sensitivity analysis indicates this figure might range from a weekly overall saving of £36.90 per resident to a 'worst case' estimate of £2.70 extra expenditure per resident per week. Evaluation early in implementation may underestimate some cost-saving activities and greater savings may emerge over a longer time period. Similarly, IRT costs may reduce over time due to the potential for refinement of team without major loss in effectiveness. Conclusion: Introduction of a specialist nursing in-reach team for residential homes is at least cost neutral and, in all probability, cost saving. Further benefits include development of new skills in the care home workforce and enhanced quality of care. Residents are enabled to stay in familiar surroundings rather than unnecessarily spending time in hospital or being transferred to a higher dependency nursing home setting

    Energy Landscape and Global Optimization for a Frustrated Model Protein

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    The three-color (BLN) 69-residue model protein was designed to exhibit frustrated folding. We investigate the energy landscape of this protein using disconnectivity graphs and compare it to a Go model, which is designed to reduce the frustration by removing all non-native attractive interactions. Finding the global minimum on a frustrated energy landscape is a good test of global optimization techniques, and we present calculations evaluating the performance of basin-hopping and genetic algorithms for this system.Comparisons are made with the widely studied 46-residue BLN protein.We show that the energy landscape of the 69-residue BLN protein contains several deep funnels, each of which corresponds to a different β-barrel structure
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