Huntingtin gene repeat size variations affect risk of lifetime depression

Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = −0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression

A Systems Approach to Improving Rural Care in Ethiopia

Background: Multiple interventions have been launched to improve the quality, access, and utilization of primary health care in rural, low-income settings; however, the success of these interventions varies substantially, even within single studies where the measured impact of interventions differs across sites, centers, and regions. Accordingly, we sought to examine the variation in impact of a health systems strengthening intervention and understand factors that might explain the variation in impact across primary health care units. Methodology/Principal Findings: We conducted a mixed methods positive deviance study of 20 Primary Health Care Units (PHCUs) in rural Ethiopia. Using longitudinal data from the Ethiopia Millennium Rural Initiative (EMRI), we identified PHCUs with consistently higher performance (n = 2), most improved performance (n = 3), or consistently lower performance (n = 2) in the provision of antenatal care, HIV testing in antenatal care, and skilled birth attendance rates. Using data from site visits and in-depth interviews (n = 51), we applied the constant comparative method of qualitative data analysis to identify key themes that distinguished PHCUs with different performance trajectories. Key themes that distinguished PHCUs were 1) managerial problem solving capacity, 2) relationship with the woreda (district) health office, and 3) community engagement. In higher performing PHCUs and those with the greatest improvement after the EMRI intervention, health center and health post staff were more able to solve day-to-day problems, staff had better relationships with the woreda health official, an

Sox4 mediates Tbx3 transcriptional regulation of the gap junction protein Cx43

Tbx3, a T-box transcription factor, regulates key steps in development of the heart and other organ systems. Here, we identify Sox4 as an interacting partner of Tbx3. Pull-down and nuclear retention assays verify this interaction and in situ hybridization reveals Tbx3 and Sox4 to co-localize extensively in the embryo including the atrioventricular and outflow tract cushion mesenchyme and a small area of interventricular myocardium. Tbx3, SOX4, and SOX2 ChIP data, identify a region in intron 1 of Gja1 bound by all tree proteins and subsequent ChIP experiments verify that this sequence is bound, in vivo, in the developing heart. In a luciferase reporter assay, this element displays a synergistic antagonistic response to co-transfection of Tbx3 and Sox4 and in vivo, in zebrafish, drives expression of a reporter in the heart, confirming its function as a cardiac enhancer. Mechanistically, we postulate that Sox4 is a mediator of Tbx3 transcriptional activity

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Microsatellite Analysis of Voided-Urine Samples for Surveillance of Low-Grade Non-Muscle-Invasive Urothelial Carcinoma: Feasibility and Clinical Utility in a Prospective Multicenter Study (Cost-Effectiveness of Follow-Up of Urinary Bladder Cancer Trial [CEFUB])

Background: Microsatellite analysis (MA) of voided-urine samples has been promoted as an alternative for cystoscopy surveillance (UCS) of patients with low-grade non-muscle-invasive papillary urothelial carcinoma (UC). Objective: To assess the feasibility and clinical utility of MA on voided-urine samples in a routine setting to detect or predict bladder cancer recurrences. Design, setting, and participants: We evaluated 228 patients monitored by MA of voided-urine samples and synchronous UCS who participated in a longitudinal prospective study in 10 hospitals. Follow-up started after diagnosis of a primary or recurrent pTa, pT1, grade 1 or grade 2 papillary UC. Measurements: Clinico-pathological parameters and fibroblast growth factor receptor 3 (FGFR3) gene mutation status of the inclusion tumour were determined. MA outcome was analysed in 1012 urine samples during a mean follow-up of 41 mo. Poor DNA quality prevented MA in 19% (197/1012) of the samples, leaving 815 visits for a cross-sectional analysis of sensitivity and specificity. We determined the predictive value (PPV) in a longitudinal analysis for 458 series with persistent MA results. Factors influencing diagnostic quality of MA were investigated. Kaplan-Meier analysis was performed to relate MA results to recurrence. Results and limitations: Cross-sectional sensitivity and specificity of MA for detection of a recurrence were 58% (49/84) and 73% (531/731), respectively. One pT1 grade 3 UC was missed. In a longitudinal analysis, the 2-yr risk to develop a recurrence reached 83% if MA outcome was persistently positive and 22% when MA was persistently negative. PPV of MA was higher with wild-type FGFR3 gene status and smoking habits. All four upper urinary tract tumours detected were preceded by a positive MA test. Conclusions: Consecutive positive MA results are a strong predictor for future recurrences, but sensitivity needs to be improved, for example, by patient selection and testing of additional genetic markers in urine samples. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved

Examining characteristics, knowledge and regulatory practices of specialized drug shops in Sub-Saharan Africa: a systematic review of the literature.

BACKGROUND: Specialized drug shops such as pharmacies and drug shops are increasingly becoming important sources of treatment. However, knowledge on their regulatory performance is scarce. We set out to systematically review literature on the characteristics, knowledge and practices of specialized drug shops in Sub-Saharan Africa. METHODS: We searched PubMed, EMBASE, WEB of Science, CAB Abstracts, PsycINFO and websites for organizations that support medicine policies and usage. We also conducted open searches using Google Scholar, and searched manually through references of retrieved articles. Our search included studies of all designs that described characteristics, knowledge and practices of specialized drug shops. Information was abstracted on authors, publication year, country and location, study design, sample size, outcomes investigated, and primary findings using a uniform checklist. Finally, we conducted a structured narrative synthesis of the main findings. RESULTS: We obtained 61 studies, mostly from Eastern Africa, majority of which were conducted between 2006 and 2011. Outcome measures were heterogeneous and included knowledge, characteristics, and dispensing and regulatory practices. Shop location and client demand were found to strongly influence dispensing practices. Whereas shops located in urban and affluent areas were more likely to provide correct treatments, those in rural areas provided credit facilities more readily. However, the latter also charged higher prices for medicines. A vast majority of shops simply sold whatever medicines clients requested, with little history taking and counseling. Most shops also stocked popular medicines at the expense of policy recommended treatments. Treatment policies were poorly communicated overall, which partly explained why staff had poor knowledge on key aspects of treatment such as medicine dosage and side effects. Overall, very little is known on the link between regulatory enforcement and practices of specialized drug shops. CONCLUSIONS: Evidence suggests that characteristics and practices of specialized drug shops differ across rural and urban locations, and that these providers are highly responsive to client demand. However, there is a dearth in knowledge on how regulatory enforcement influences their characteristics and practices, and what strategies can be employed to strengthen the governance of the retail pharmaceutical sector

Genetics, diagnosis and future treatment strategies for primary ciliary dyskinesia

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder resulting in chronic oto-sino-pulmonary disease. While PCD is estimated to occur in 1 in 20,000 individuals, fewer than 1,000 patients in the US have a well-established diagnosis. AREAS COVERED: We provide an overview of the clinical manifestations of PCD, describe the evolution of diagnostic methods, and critique the literature on management of PCD. EXPERT OPINION: Although interest in clinical studies in non-CF bronchiectasis has increased in recent years, some of whom enroll patients with PCD, the literature regarding therapy for PCD as a distinct entity is lacking, as the numbers are small, and there have been no sub-analyses published. However, with improved screening and diagnostic methods, the development of clinical and research consortiums, and actively enrolling registries of PCD patients, the environment is conducive to perform longitudinal studies of disease course and therapeutic studies to alter that course

NanoLC/ESI+ HRMS3 Quantitation of DNA Adducts Induced by 1,3-Butadiene

Human exposure to 1,3-butadiene (BD) present in automobile exhaust, cigarette smoke, and forest fires is of great concern because of its potent carcinogenicity. The adverse health effects of BD are mediated by its epoxide metabolites such as 3,4-epoxy-1-butene (EB), which covalently modify genomic DNA to form promutagenic nucleobase adducts. Because of their direct role in cancer, BD-DNA adducts can be used as mechanism-based biomarkers of BD exposure. In the present work, a mass spectrometry-based methodology was developed for accurate, sensitive, and precise quantification of EB-induced N-7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) DNA adducts in vivo. In our approach, EB-GII adducts are selectively released from DNA backbone by neutral thermal hydrolysis, followed by ultrafiltration, offline HPLC purification, and isotope dilution nanoLC/ESI(+)-HRMS(3) analysis on an Orbitrap Velos mass spectrometer. Following method validation, EB-GII lesions were quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of EB and in liver tissues of rats exposed to sub ppm concentrations of BD (0.5–1.5 ppm). EB-GII concentrations increased linearly from 1.15±0.23 to 10.11±0.45adducts per 10(8) nucleotides in HT1080 cells treated with 0.5–10 μM DEB. EB-GII concentrations in DNA of laboratory rats exposed to 0.5, 1.0 and 1.5 ppm BD were 0.17±0.05, 0.33±0.08, and 0.50±0.04 adducts per 10(8) nucleotides, respectively. We also used the new method to determine the in vivo half-life of EB-GII adducts in rat liver DNA (2.20±0.12 days) and to detect EB-GII in human blood DNA. To our knowledge, this is the first application of nanoLC/ESI(+)-HRMS(3) Orbitrap methodology to quantitative analysis of DNA adducts in vivo