MuRF-1 and Atrogin-1 Protein Expression and Quadriceps Fiber Size and Muscle Mass in Stable Patients with COPD

INTRODUCTION: Animal studies demonstrate the importance of the E3 ubiquitin ligases, Muscle RING-Finger Protein 1 (MuRF-1) and atrogin-1, in muscle protein degradation during acute muscle atrophy. Small clinical studies suggest MuRF-1 and atrogin-1 expression in the quadriceps muscle is also increased in stable patients with Chronic Obstructive Pulmonary Disease compared to controls. However, it remains unclear whether these ligases have a role in maintaining a muscle-wasted state in COPD patients. METHODS: 32 stable COPD patients (16 with a low fat-free mass index (FFMI), 16 with a normal FFMI) and 15 controls underwent lung function and quadriceps strength tests and a percutaneous quadriceps biopsy. Quadriceps MuRF-1 and atrogin-1 protein were quantified with western blotting. Quadriceps fiber cross-sectional area (CSA) and fiber proportions were determined by immunohistochemistry on muscle sections. MuRF-1 and atrogin-1 levels were compared between COPD patients with and without a low FFMI, and between patients and controls, and correlations between MuRF-1 and atrogin-1 levels and quadriceps fiber CSA in the patients were investigated. RESULTS: Atrogin-1 protein levels were lower in patients than controls, but similar in patients with a low and normal FFMI. MuRF-1 levels did not differ between any groups. MuRF-1 and atrogin-1 levels were not associated with quadriceps fiber CSA or quadriceps strength in patients. CONCLUSIONS: Chronic upregulation of ubiquitin ligases was not evident in the quadriceps muscle of stable COPD patients with a low muscle mass. This does not exclude the possibility of transient increases in ubiquitin ligases during acute catabolic episodes

Who Is Doing the Housework in Multicultural Britain?

There is an extensive literature on the domestic division of labour within married and cohabiting couples and its relationship to gender equality within the household and the labour market. Most UK research focuses on the white majority population or is ethnicity ‘blind’, effectively ignoring potentially significant intersections between gender, ethnicity, socio-economic position and domestic labour. Quantitative empirical research on the domestic division of labour across ethnic groups has not been possible due to a lack of data that enables disaggregation by ethnic group. We address this gap using data from a nationally representative panel survey, Understanding Society, the UK Household Longitudinal Study containing sufficient sample sizes of ethnic minority groups for meaningful comparisons. We find significant variations in patterns of domestic labour by ethnic group, gender, education and employment status after controlling for individual and household characteristics

Next generation sequencing reveals novel genetic variants (SRY, DMRT1, NR5A1, DHH, DHX37) in adults with 46,XY DSD

Context: The genetic basis of human sex development is slowly being elucidated and more than 40 different genetic causes of differences (or disorders) of sex development (DSD) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available. / Objective: We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSD in individuals with no specific molecular diagnosis. / Partcipants and Design: We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17β-hydroxysteroid dehydrogenase deficiency type 3, 5α-reductase deficiency type 2 and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n=27) and partially-virilised 46,XY DSD (pvDSD) (n=25), a group that included partial gonadal dysgenesis (PGD) and those with a broad ”partial androgen insensitivity syndrome” label. Targetted sequencing of 168 genes was undertaken. / Results: Overall a likely genetic cause was found in 16/52 (30.8%) individuals (22.2% CGD; 40.0% pvDSD). Pathogenic variants were found in SRY (n=3), DMRT1 (n=1), NR5A1/SF-1 (n=1) and DHH (n=1) in the CGD group, and in NR5A1 (n=5), DHH (n=1) and DHX37 (n=4) in the pvDSD group. / Conclusions: Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible

Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. While dominantly-inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remain challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G > C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G > C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the nineteenth (19th) locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes

Radiological research activity 1998–2007: relationship to gross domestic product, health expenditure and public expenditure on education

Objective The purpose of this study was to evaluate the relationship of the radiological research activity from 1998 to 2007 to the gross domestic product (GDP), health expenditure and public expenditure on education. Methods The population-adjusted research activity determined by the number of articles published, the cumulative impact factor (IF) and the cumulative IF per capita were correlated with per capita values of the GDP, health expenditure and public education expenditure. Linear regression analysis and multiple regression analysis were used for statistical analysis. Results The cumulative IF per capita correlated with the GDP per capita (R = 0.94, P  0.05). Conclusion Radiological research activity demonstrates a close relationship to the GDP, health expenditure and public expenditure on education. The last factor independently predicts research activity

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Objectives The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research. Methods Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use

Systematic review of worldwide variations of the prevalence of wheezing symptoms in children

Background: Considerable variation in the prevalence of childhood asthma and its symptoms (wheezing) has been observed in previous studies and there is evidence that the prevalence has been increasing over time. Methods: We have systematically reviewed the reported prevalence and time trends of wheezing symptoms among children, worldwide and within the same country over time. All studies comprising more than 1000 persons and meeting certain other quality criteria published over a 16-year period, between January 1990 and December 2005, are reported and a comparison of ISAAC (International Study of Asthma and Allergies in Childhood) and non-ISAAC studies is made, in part as a way of expanding the power to examine time trends (the older studies tend to be non-ISAAC), but also to examine possible methodological differences between ISAAC and non-ISAAC questions. Results: A wide range of current prevalence of wheeze was observed between and within countries over time. The UK had the highest recorded prevalence of 32.2% in children aged 13–14 in 1994–5 and Ethiopia had the lowest prevalence, 1.7% in children aged 10–19 in 1996. All studies in Australia and the UK were compared using multiple logistic regression. ISAAC phase I and III studies reported significantly higher prevalence of current wheeze (OR = 1.638) compared with non-ISAAC studies, after adjusting for various other factors (country, survey year, age of child, parental vs child response to the survey). Australia showed a significantly higher prevalence of current wheezing (OR = 1.343) compared with the UK, there was a significant increase in the prevalence odds ratio per survey year (2.5% per year), a significant decrease per age of child (0.7% per year), and a significantly higher response in current wheezing if the response was self-completed by the child (OR = 1.290). These factors, when explored separately for ISAAC and non-ISAAC studies, showed very different results. In ISAAC studies, or non-ISAAC studies using ISAAC questions, there was a significant decrease in current wheezing prevalence over time (2.5% per year). In non-ISAAC studies, which tend to cover an earlier period, there was a significant increase (2.6% per year) in current wheezing prevalence over time. This is very likely to be a result of prevalence of wheezing increasing from the 1970s up to the early 1990s, but decreasing since then. Conclusion: The UK has the highest recorded prevalence of wheezing and Ethiopia the lowest. Prevalence of wheezing in Australia and the UK has increased from the 1970s up to the early 1990s, but decreased since then and ISAAC studies report significantly higher prevalences than non-ISAAC studies

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii on computer interface surfaces of hospital wards and association with clinical isolates

<p>Abstract</p> <p>Background</p> <p>Computer keyboards and mice are potential reservoirs of nosocomial pathogens, but routine disinfection for non-water-proof computer devices is a problem. With better hand hygiene compliance of health-care workers (HCWs), the impact of these potential sources of contamination on clinical infection needs to be clarified.</p> <p>Methods</p> <p>This study was conducted in a 1600-bed medical center of southern Taiwan with 47 wards and 282 computers. With education and monitoring program of hand hygiene for HCWs, the average compliance rate was 74% before our surveillance. We investigated the association of methicillin-resistant <it>Staphylococcus aureus </it>(MRSA), <it>Pseudomonas aeruginosa </it>and <it>Acinetobacter baumannii</it>, three leading hospital-acquired pathogens, from ward computer keyboards, mice and from clinical isolates in non-outbreak period by pulsed field gel electrophoresis and antibiogram.</p> <p>Results</p> <p>Our results revealed a 17.4% (49/282) contamination rate of these computer devices by <it>S. aureus</it>, <it>Acinetobacter </it>spp. or <it>Pseudomonas </it>spp. The contamination rates of MRSA and <it>A. baumannii </it>in the ward computers were 1.1% and 4.3%, respectively. No <it>P. aeruginosa </it>was isolated. All isolates from computers and clinical specimens at the same ward showed different pulsotypes. However, <it>A. baumannii </it>isolates on two ward computers had the same pulsotype.</p> <p>Conclusion</p> <p>With good hand hygiene compliance, we found relatively low contamination rates of MRSA, <it>P. aeruginosa </it>and <it>A. baumannii </it>on ward computer interface, and without further contribution to nosocomial infection. Our results suggested no necessity of routine culture surveillance in non-outbreak situation.</p