Estrogen worsens incipient hypertriglyceridemic glomerular injury in the obese Zucker rat

Estrogen worsens incipient hypertriglyceridemic glomerular injury in the obese Zucker rat.BackgroundThe obese Zucker rat (OZR) is a model of glomerulosclerosis and renal failure in the setting of hyperlipidemia, hyperinsulinemia, and obesity. Our prior work in OZRs has shown that ovariectomy attenuates glomerulosclerosis, while added estrogen worsens it. To investigate the mechanism of estrogen's effects on glomerular disease in this model, we evaluated the effects of ovariectomy and estrogen supplementation on seven-week peripubertal OZRs. At this time point, rats exhibit no overt histologic glomerular disease, but are just beginning to show elevated urinary albumin excretion.MethodsFemale OZRs fed ad libitum were ovariectomized at four weeks, with or without estrogen supplementation to raise estrogen levels to just below those of preoestral adults (mean 16.5 pg/mL). Sham-operated controls were included.ResultsOvariectomy normalized albuminuria, lowered total and very low-density lipoprotein triglycerides, and reduced glomerular fibronectin expression. Estrogen supplementation worsened albuminuria and raised total/very low-density lipoprotein triglycerides and total cholesterol. Estrogen-supplemented rats exhibited enhanced glomerular deposition of apo A-IV and apo B, increased glomerular expression of desmin and type IV collagen, and increased interstitial macrophage deposition.ConclusionEstrogen may be permissive for the early development of renal disease in OZRs and may act by increasing triglyceride-rich lipoproteins, which then bind to glomerular cells and initiate or accelerate glomerulosclerosis

How do women prepare for pregnancy? Preconception experiences of women attending antenatal services and views of health professionals

Copyright: © 2014 Stephenson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Main objective - To determine the extent to which women plan and prepare for pregnancy. Methods - Cross-sectional questionnaire survey of pregnant women attending three maternity services in London about knowledge and uptake of preconception care; including a robust measure of pregnancy planning, and phone interviews with a range of health care professionals. Main results - We recruited 1173/1288 (90%) women, median age of 32 years. 73% had clearly planned their pregnancy, 24% were ambivalent and only 3% of pregnancies were unplanned. 51% of all women and 63% of those with a planned pregnancy took folic acid before pregnancy. 21% of all women reported smoking and 61% reported drinking alcohol in the 3 months before pregnancy; 48% of smokers and 41% of drinkers reduced or stopped before pregnancy. The 51% of all women who reported advice from a health professional before becoming pregnant were more likely to adopt healthier behaviours before pregnancy [adjusted odds ratios for greatest health professional input compared with none were 2.34 (95% confidence interval 1.54–3.54) for taking folic acid and 2.18 (95% CI 1.42–3.36) for adopting a healthier diet before pregnancy]. Interviews with 20 health professionals indicated low awareness of preconception health issues, missed opportunities and confusion about responsibility for delivery of preconception care. Significance of the findings - Despite a high level of pregnancy planning, awareness of preconception health among women and health professionals is low, and responsibility for providing preconception care is unclear. However, many women are motivated to adopt healthier behaviours in the preconception period, as indicated by halving of reported smoking rates in this study. The link between health professional input and healthy behaviour change before pregnancy is a new finding that should invigorate strategies to improve awareness and uptake of pre-pregnancy health care, and bring wider benefits for public health.Department of Healt

Accurate and sensitive quantification of protein-DNA binding affinity

Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations in TF binding sites are increasingly found to be associated with human disease, yet we currently lack robust methods to predict these sites. Here, we developed a versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers a biophysical model of protein-DNA recognition across the full affinity range from a library of in vitro selected DNA binding sites. NRLB predicts human Max homodimer binding in near-perfect agreement with existing low-throughput measurements. It can capture the specificity of the p53 tetramer and distinguish multiple binding modes within a single sample. Additionally, we confirm that newly identified low-affinity enhancer binding sites are functional in vivo, and that their contribution to gene expression matches their predicted affinity. Our results establish a powerful paradigm for identifying protein binding sites and interpreting gene regulatory sequences in eukaryotic genomes

The Function Biomedical Informatics Research Network Data Repository

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical datasets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 dataset consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1.5 to 4 Tesla scanners. The FBIRN Phase 2 and Phase 3 datasets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN’s multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data

Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study

Purpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive reserve. Results Survivors and controls were 60 to 98 years of age, were well educated, and had similar baseline cognitive scores. Treatment was related to longitudinal cognition scores, with survivors who received chemotherapy having increasingly worse APE scores (P = .05) and those initiating hormonal therapy having lower LM scores at 12 months (P = .03) than other groups. These group-by-time differences varied by ApoE genotype, where only ε4+ survivors receiving hormone therapy had short-term decreases in adjusted LM scores (three-way interaction P = .03). For APE, the three-way interaction was not significant (P = .14), but scores were significantly lower for ε4+ survivors exposed to chemotherapy (−0.40; 95% CI, −0.79 to −0.01) at 24 months than ε4+ controls (0.01; 95% CI, 0.16 to 0.18; P < .05). Increasing age was associated with lower baseline scores on all cognitive measures (P < .001); frailty was associated with baseline APE and self-reported decline (P < .001). Conclusion Breast cancer systemic treatment and aging-related phenotypes and genotypes are associated with longitudinal decreases in cognitive function scores in older survivors. These data could inform treatment decision making and survivorship care planning

Wait Up!: Attachment and Sovereign Power.

Sociologists and feminist scholars have, over many decades, characterised attachment as a social construction that functions to support political and gender conservatism. We accept that attachment theory has seen use to these ends and consider recent deployments of attachment theory as justification for a minimal State within conservative political discourse in the UK since 2009. However, we contest that attachment is reducible to its discursive construction. We consider Judith Butler's depiction of the infant attached to an abusive caregiver as a foundation and parallel to the position of the adult citizen subjected to punitive cultural norms and political institutions. We develop and qualify Butler's account, drawing on the insights offered by the work of Lauren Berlant. We also return to Foucault's Psychiatric Power lectures, in which familial relations are situated as an island of sovereign power within the sea of modern disciplinary institutions. These reflections help advance analysis of three important issues: the social and political implications of attachment research; the relationship between disciplinary and sovereign power in the affective dynamic of subjection; and the political and ethical status of professional activity within the psy disciplines.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10767-014-9192-

Performance of the infrared array camera (IRAC) for SIRTF during instrument integration and test

The Infrared Array Camera (IRAC) is one of three focal plane instruments in the Space Infrared Telescope Facility (SIRTF). IRAC is a four-channel camera that obtains simultaneous images at 3.6, 4.5, 5.8, and 8 microns. Two adjacent 5.12x5.12 arcmin fields of view in the SIRTF focal plane are viewed by the four channels in pairs (3.6 and 5.8 microns; 4.5 and 8 microns). All four detector arrays in the camera are 256x256 pixels in size, with the two shorter wavelength channels using InSb and the two longer wavelength channels using Si:As IBC detectors. We describe here the results of the instrument functional and calibration tests completed at Ball Aerospace during the integration with the cryogenic telescope assembly, and provide updated estimates of the in-flight sensitivity and performance of IRAC in SIRTF

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification