New approaches for estimating risk from exposure to diethylstilbestrol.

A subgroup from a National Institute of Environmental Health Sciences, workshop concerned with characterizing the effects of endocrine disruptors on human health at environmental exposure levels considered the question, If diethylstilbestrol (DES) were introduced into the market for human use today and likely to result in low-dose exposure of the human fetus, what would be required to assess risk? On the basis of an analysis of the quality of data on human DES exposure, the critical times and doses for inducing genital tract malformations and cancer must be determined. This would be facilitated through analysis of the ontogeny of estrogen receptor expression in the developing human genital tract. Models of low-dose estrogenic effects will have to be developed for human and rodent genital tract development. Mouse models offer many advantages over other potential animal models because of the wealth of the earlier literature, the availability of sensitive end points, the availability of mutant lines, and the possibility of generating genetically engineered model systems. Through multidisciplinary approaches, it should be possible to elucidate the cellular and molecular mechanisms of endocrine disruption elicited by estrogens during development and facilitate an assessment of risk to humans

Use of postmenopausal hormone replacement therapy and risk of non-Hodgkin's lymphoma: a Danish Population-based Cohort Study

Use of postmenopausal hormone replacement therapy (HRT) has been hypothesised to be associated with a reduced risk of non-Hodgkin's lymphoma (NHL), but the epidemiologic evidence is conflicting. To examine the risk of NHL in HRT users aged 40 and older, we conducted a cohort study in the County of North Jutland, Denmark (population 0.5 million) using data from population-based health registries for the period 1989–2002. We computed age-standardised NHL incidence rates and used Cox regression analysis to compute the relative risk (RR) and corresponding 95% confidence intervals (CI) of NHL among HRT users compared with non-users, adjusting for age and calendar period. The number of prescriptions redeemed (1, 2–4, 5–9, 10–19, or 20 or more prescriptions) was used as a proxy for duration of HRT. We identified 40 NHL cases among HRT users during 179 838 person-years of follow-up and 310 NHL cases among non-users during 1 247 302 person-years of follow-up. The age-standardised incidence rates of NHL were 25.7 per 100 000 among HRT users and 24.2 per 100 000 among non-users, yielding an adjusted RR of 0.99 (95% CI: 0.71–1.39). Our data did not support an association between HRT use and risk of NHL

Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism

<p>Abstract</p> <p>Background</p> <p>The mechanisms responsible for the cardiovascular mortality in type I diabetes (DM) have not been defined completely. We have shown in conscious dogs with DM that: <it>1</it>) baseline coronary blood flow (CBF) was significantly decreased, <it>2</it>) endothelium-dependent (ACh) coronary vasodilation was impaired, and <it>3</it>) reflex cholinergic NO-dependent coronary vasodilation was selectively depressed. The most likely mechanism responsible for the depressed reflex cholinergic NO-dependent coronary vasodilation was the decreased bioactivity of NO from the vascular endothelium. The goal of this study was to investigate changes in cardiac gene expression in a canine model of alloxan-induced type 1 diabetes.</p> <p>Methods</p> <p>Mongrel dogs were chronically instrumented and the dogs were divided into two groups: one normal and the other diabetic. In the diabetic group, the dogs were injected with alloxan monohydrate (40-60 mg/kg iv) over 1 min. The global changes in cardiac gene expression in dogs with alloxan-induced diabetes were studied using Affymetrix Canine Array. Cardiac RNA was extracted from the control and DM (n = 4).</p> <p>Results</p> <p>The array data revealed that 797 genes were differentially expressed (P < 0.01; fold change of at least ±2). 150 genes were expressed at significantly greater levels in diabetic dogs and 647 were significantly reduced. There was no change in eNOS mRNA. There was up regulation of some components of the NADPH oxidase subunits (gp91 by 2.2 fold, P < 0.03), and down-regulation of SOD1 (3 fold, P < 0.001) and decrease (4 - 40 fold) in a large number of genes encoding mitochondrial enzymes. In addition, there was down-regulation of Ca²⁺cycling genes (ryanodine receptor; SERCA2 Calcium ATPase), structural proteins (actin alpha). Of particular interests are genes involved in glutathione metabolism (glutathione peroxidase 1, glutathione reductase and glutathione S-transferase), which were markedly down regulated.</p> <p>Conclusion</p> <p>our findings suggest that type I diabetes might have a direct effect on the heart by impairing NO bioavailability through oxidative stress and perhaps lipid peroxidases.</p

From research to practice: Lay adherence counsellors' fidelity to an evidence-based intervention for promoting adherence to antiretroviral treatment in the Western Cape, South Africa

In the Western Cape, lay counsellors are tasked with supporting antiretroviral (ARV) adherence in public healthcare clinics. Thirty-nine counsellors in 21 Cape Town clinics were trained in Options for Health (Options), an evidence-based intervention based on motivational interviewing (MI). We evaluated counsellors’ ability to deliver Options for addressing poor adherence following 5 days training. Audio-recordings of counselling sessions collected following training were transcribed and translated into English. Thirty-five transcripts of sessions conducted by 35 counsellors were analysed for fidelity to the Options protocol, and using the Motivational Interviewing Treatment and Integrity (MITI) code. Counsellors struggled with some of the strategies associated with MI, such as assessing readiness-to-change and facilitating change talk. Overall, counsellors failed to achieve proficiency in the approach of MI according to the MITI. Counsellors were able to negotiate realistic plans for addressing patients’ barriers to adherence. Further efforts aimed at strengthening the ARV adherence counselling programme are needed.Department of HE and Training approved lis

Residential greenspace and lung function decline over 20 years in a prospective cohort: the ECRHS study

Background The few studies that have examined associations between greenspace and lung function in adulthood have yielded conflicting results and none have examined whether the rate of lung function decline is affected. Objective We explored the association between residential greenspace and change in lung function over 20 years in 5559 adults from 22 centers in 11 countries participating in the population-based, international European Community Respiratory Health Survey. Methods Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured by spirometry when participants were approximately 35 (1990–1994), 44 (1999–2003), and 55 (2010–2014) years old. Greenness was assessed as the mean Normalized Difference Vegetation Index (NDVI) in 500 m, 300 m, and 100 m circular buffers around the residential addresses at the time of lung function measurement. Green spaces were defined as the presence of agricultural, natural, or urban green spaces in a circular 300 m buffer. Associations of these greenspace parameters with the rate of lung function change were assessed using adjusted linear mixed effects regression models with random intercepts for subjects nested within centers. Sensitivity analyses considered air pollution exposures. Results A 0.2-increase (average interquartile range) in NDVI in the 500 m buffer was consistently associated with a faster decline in FVC (−1.25 mL/year [95% confidence interval: −2.18 to −0.33]). These associations were especially pronounced in females and those living in areas with low PM10 levels. We found no consistent associations with FEV1 and the FEV1/FVC ratio. Residing near forests or urban green spaces was associated with a faster decline in FEV1, while agricultural land and forests were related to a greater decline in FVC. Conclusions More residential greenspace was not associated with better lung function in middle-aged European adults. Instead, we observed slight but consistent declines in lung function parameters. The potentially detrimental association requires verification in future studies

The Actin-Binding Protein Capulet Genetically Interacts with the Microtubule Motor Kinesin to Maintain Neuronal Dendrite Homeostasis

BACKGROUND: Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation. METHODOLOGY/PRINCIPAL FINDINGS: From a Drosophila forward genetic screen, we identified a mutation in capulet--encoding a conserved actin-binding protein--that causes abnormal aggregates of actin within dendrites. Through interaction studies, we demonstrate that simultaneous genetic inactivation of capulet and kinesin heavy chain, a microtubule motor protein, produces elongate cofilin-actin rods within dendrites but not axons. These rods resemble actin-rich structures induced in both mammalian neurodegenerative and Drosophila Alzheimer's models, but have not previously been identified by loss of function mutations in vivo. We further demonstrate that mitochondria, which are transported by Kinesin, have impaired distribution along dendrites in a capulet mutant. While Capulet and Cofilin may biochemically cooperate in certain circumstances, in neuronal dendrites they genetically antagonize each other. CONCLUSIONS/SIGNIFICANCE: The present study is the first molecularly defined loss of function demonstration of actin-cofilin rods in vivo. This study suggests that simultaneous, seemingly minor perturbations in neuronal dendrites can synergize producing severe abnormalities affecting actin, microtubules and mitochondria/energy availability in dendrites. Additionally, as >90% of Alzheimer's and Parkinson's cases are sporadic this study suggests mechanisms by which multiple mutations together may contribute to neurodegeneration instead of reliance on single mutations to produce disease

Limited dissemination of the wastewater treatment plant core resistome

Horizontal gene transfer is a major contributor to the evolution of bacterial genomes and can facilitate the dissemination of antibiotic resistance genes between environmental reservoirs and potential pathogens. Wastewater treatment plants (WWTPs) are believed to play a central role in the dissemination of antibiotic resistance genes. However, the contribution of the dominant members of the WWTP resistome to resistance in human pathogens remains poorly understood. Here we use a combination of metagenomic functional selections and comprehensive metagenomic sequencing to uncover the dominant genes of the WWTP resistome. We find that this core resistome is unique to the WWTP environment, with <10% of the resistance genes found outside the WWTP environment. Our data highlight that, despite an abundance of functional resistance genes within WWTPs, only few genes are found in other environments, suggesting that the overall dissemination of the WWTP resistome is comparable to that of the soil resistome

Sexual dimorphism in cancer.

The incidence of many types of cancer arising in organs with non-reproductive functions is significantly higher in male populations than in female populations, with associated differences in survival. Occupational and/or behavioural factors are well-known underlying determinants. However, cellular and molecular differences between the two sexes are also likely to be important. In this Opinion article, we focus on the complex interplay that sex hormones and sex chromosomes can have in intrinsic control of cancer-initiating cell populations, the tumour microenvironment and systemic determinants of cancer development, such as the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment