Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene

In animal models, prenatal and postnatal stress is associated with elevated hypothalamic–pituitary axis (HPA) reactivity mediated via altered glucocorticoid receptor (GR) gene expression. Postnatal tactile stimulation is associated with reduced HPA reactivity mediated via increased GR gene expression. In this first study in humans to examine the joint effects of prenatal and postnatal environmental exposures, we report that GR gene (NR3C1) 1-F promoter methylation in infants is elevated in the presence of increased maternal postnatal depression following low prenatal depression, and that this effect is reversed by self-reported stroking of the infants by their mothers over the first weeks of life

Structure-activity relationships of the Human Immunodeficiency Virus type 1 maturation inhibitor PF-46396

This work was funded by the University of St Andrews and Society for Applied Microbiology New Lecturer Research Grant awarded to CSA, Wellcome Trust grant (093228) awarded to TKS.HIV-1 maturation inhibitors are a novel class of antiretroviral compounds, which consist of two structurally distinct chemical classes; betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by a similar mode of action to generate aberrant non-infectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study we utilized a series of novel analogues, with decreasing similarity to PF-46396, to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into WT immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity, but not an absolute requirement for Gag binding, (ii) the trifluromethyl group is optimal but not essential for antiviral activity and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but not essential as its replacement is tolerated.Publisher PDFPeer reviewe

Patterns of satellite tagged hen harrier disappearances suggest widespread illegal killing on British grouse moors

Natural England commenced a Hen Harrier Recovery Project in 2002. This tracking study was funded exclusively by Natural England and is part of their on-going work on hen harrier conservation. We thank Hamish Smith and staff at the Hawk and Owl Trust for contributing data from four hen harriers they have tracked. We are grateful for the time of many volunteers in the field who monitored and searched for harriers: Pat Martin, Gavin Craggs, Pete Davies, Derek Hayward, Martin Davison, Mick Carroll, Paul Howarth, Ian Thomson, and Elsie Ashworth. We thank Judith Smith and Phil Skinner for sponsoring tags. Also we would like to thank the Wildlife Crime Officers in Lancashire, Yorkshire, Co Durham and Northumberland for their assistance. Thanks also to Jeremy Wilson and Pat Thompson for useful comments on this manuscript. We are grateful to staff at Microwave Telemetry Inc. and CLS France for data archiving. The complete data sets analysed in this study are not publicly available due to the sensitivity of the locational data but are available from the corresponding author on reasonable request and with permission of Natural England. The source data for Figs. 1 and 2 have been provided as a Source Data file.Peer reviewedPublisher PD

Does bariatric surgery prior to total hip or knee arthroplasty reduce post-operative complications and improve clinical outcomes for obese patients? Systematic review and meta-analysis.

AIMS: Our aim was to determine whether, based on the current literature, bariatric surgery prior to total hip (THA) or total knee arthroplasty (TKA) reduces the complication rates and improves the outcome following arthroplasty in obese patients. METHODS: A systematic literature search was undertaken of published and unpublished databases on the 5 November 2015. All papers reporting studies comparing obese patients who had undergone bariatric surgery prior to arthroplasty, or not, were included. Each study was assessed using the Downs and Black appraisal tool. A meta-analysis of risk ratios (RR) and 95% confidence intervals (CI) was performed to determine the incidence of complications including wound infection, deep vein thrombosis (DVT), pulmonary embolism (PE), revision surgery and mortality. RESULTS: From 156 potential studies, five were considered to be eligible for inclusion in the study. A total of 23 348 patients (657 who had undergone bariatric surgery, 22 691 who had not) were analysed. The evidence-base was moderate in quality. There was no statistically significant difference in outcomes such as superficial wound infection (relative risk (RR) 1.88; 95% confidence interval (CI) 0.95 to 0.37), deep wound infection (RR 1.04; 95% CI 0.65 to 1.66), DVT (RR 0.57; 95% CI 0.13 to 2.44), PE (RR 0.51; 95% CI 0.03 to 8.26), revision surgery (RR 1.24; 95% CI 0.75 to 2.05) or mortality (RR 1.25; 95% CI 0.16 to 9.89) between the two groups. CONCLUSION: For most peri-operative outcomes, bariatric surgery prior to THA or TKA does not significantly reduce the complication rates or improve the clinical outcome. This study questions the previous belief that bariatric surgery prior to arthroplasty may improve the clinical outcomes for patients who are obese or morbidly obese. This finding is based on moderate quality evidence. Cite this article: Bone Joint J 2016;98-B:1160-6

Assessment of Acute and Chronic Pharmacological Effects on Energy Expenditure and Macronutrient Oxidation in Humans: Responses to Ephedrine

Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID (n = 8) or placebo (n = 6) were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds

Centile reference chart for resting metabolic rate through the life course

OBJECTIVE: Reference centile charts are widely used for the assessment of growth and have progressed from describing height and weight to include body composition variables such as fat and lean mass. Here, we present centile charts for an index of resting energy expenditure (REE) or metabolic rate, adjusted for lean mass versus age, including both children and adults across the life course. DESIGN, PARTICIPANTS AND INTERVENTION: Measurements of REE by indirect calorimetry and body composition using dual-energy X-ray absorptiometry were made in 411 healthy children and adults (age range 6-64 years) and serially in a patient with resistance to thyroid hormone α (RTHα) between age 15 and 21 years during thyroxine therapy. SETTING: NIHR Cambridge Clinical Research Facility, UK. RESULTS: The centile chart indicates substantial variability, with the REE index ranging between 0.41 and 0.59 units at age 6 years, and 0.28 and 0.40 units at age 25 years (2nd and 98th centile, respectively). The 50th centile of the index ranged from 0.49 units (age 6 years) to 0.34 units (age 25 years). Over 6 years, the REE index of the patient with RTHα varied from 0.35 units (25th centile) to 0.28 units (<2nd centile), depending on changes in lean mass and adherence to treatment. CONCLUSION: We have developed a reference centile chart for an index of resting metabolic rate in childhood and adults, and shown its clinical utility in assessing response to therapy of an endocrine disorder during a patient's transition from childhood to adult

Skeletal muscle ATP turnover by 31P magnetic resonance spectroscopy during moderate and heavy bilateral knee-extension

During constant-power high-intensity exercise, the expected increase in oxygen uptake (V̇O2) is supplemented by a V̇O2 slow component (V̇O2 sc ), reflecting reduced work efficiency, predominantly within the locomotor muscles. The intracellular source of inefficiency is postulated to be an increase in the ATP cost of power production (an increase in P/W). To test this hypothesis, we measured intramuscular ATP turnover with (31)P magnetic resonance spectroscopy (MRS) and whole-body V̇O2 during moderate (MOD) and heavy (HVY) bilateral knee-extension exercise in healthy participants (n = 14). Unlocalized (31)P spectra were collected from the quadriceps throughout using a dual-tuned ((1)H and (31)P) surface coil with a simple pulse-and-acquire sequence. Total ATP turnover rate (ATPtot) was estimated at exercise cessation from direct measurements of the dynamics of phosphocreatine (PCr) and proton handling. Between 3 and 8 min during MOD, there was no discernable V̇O2 sc (mean ± SD, 0.06 ± 0.12 l min(-1)) or change in [PCr] (30 ± 8 vs. 32 ± 7 mm) or ATPtot (24 ± 14 vs. 17 ± 14 mm min(-1); each P = n.s.). During HVY, the V̇O2 sc was 0.37 ± 0.16 l min(-1) (22 ± 8%), [PCr] decreased (19 ± 7 vs. 18 ± 7 mm, or 12 ± 15%; P < 0.05) and ATPtot increased (38 ± 16 vs. 44 ± 14 mm min(-1), or 26 ± 30%; P < 0.05) between 3 and 8 min. However, the increase in ATPtot (ΔATPtot) was not correlated with the V̇O2 sc during HVY (r(2) = 0.06; P = n.s.). This lack of relationship between ΔATPtot and V̇O2 sc , together with a steepening of the [PCr]-V̇O2 relationship in HVY, suggests that reduced work efficiency during heavy exercise arises from both contractile (P/W) and mitochondrial sources (the O2 cost of ATP resynthesis; P/O)

Rates of referable eye disease in the Scottish National Diabetic Retinopathy Screening Programme

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.Peer reviewedPublisher PD

Band gap reduction in InNxSb1-x alloys: Optical absorption, k . P modeling, and density functional theory

Using infrared absorption, the room temperature band gap of InSb is found to reduce from 174 (7.1 μm) to 85 meV (14.6 μm) upon incorporation of up to 1.13% N, a reduction of ∼79 meV/%N. The experimentally observed band gap reduction in molecular-beam epitaxial InNSb thin films is reproduced by a five band k ⋅· P band anticrossing model incorporating a nitrogen level, EN, 0.75 eV above the valence band maximum of the host InSb and an interaction coupling matrix element between the host conduction band and the N level of β = 1.80 eV. This observation is consistent with the presented results from hybrid density functional theory