Towards a realistic in vitro experience of epidural Tuohy needle insertion.

The amount of pressure exerted on the syringe and the depth of needle insertion are the two key factors for successfully carrying out epidural procedure. The force feedback from the syringe plunger is helpful in judging the loss of pressure, and the depth of the needle insertion is crucial in identifying when the needle is precisely placed in the epidural space. This article presents the development of two novel wireless devices to measure these parameters to precisely guide the needle placement in the epidural space. These techniques can be directly used on patients or implemented in a simulator for improving the safety of procedure. A pilot trial has been conducted to collect depth and pressure data with the devices on a porcine cadaver. These measurements are then combined to accurately configure a haptic device for creating a realistic in vitro experience of epidural needle insertion

Behavioural Susceptibility Theory: Professor Jane Wardle and the Role of Appetite in Genetic Risk of Obesity

Purpose of Review: There is considerable variability in human body weight, despite the ubiquity of the 'obesogenic' environment. Human body weight has a strong genetic basis and it has been hypothesised that genetic susceptibility to the environment explains variation in human body weight, with differences in appetite being implicated as the mediating mechanism; so-called 'behavioural susceptibility theory' (BST), first described by Professor Jane Wardle. This review summarises the evidence for the role of appetite as a mediator of genetic risk of obesity. Recent Findings: Variation in appetitive traits is observable from infancy, drives early weight gain and is highly heritable in infancy and childhood. Obesity-related common genetic variants identified through genome-wide association studies show associations with appetitive traits, and appetite mediates part of the observed association between genetic risk and adiposity. Summary: Obesity results from an interaction between genetic susceptibility to overeating and exposure to an 'obesogenic' food environment

Epigenetic Signatures of Cigarette Smoking

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10$^{-7}$ (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10$^{-7}$ (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.Biotechnology and Biological Sciences Research Council, British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society, Wellcome Trus

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10−8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.This research has been conducted using the UK Biobank Resource. The Fenland Study is supported by the UK Medical Research Council (MRC) (MC_UU_12015/1; MC_UU_12015/2; MC_UU_12015/3). EPIC-Norfolk is supported by the MRC (G401527, G1000143) and Cancer Research UK (A8257). The HCS is gratefully supported by the University of Newcastle (Australia) and the Fairfax Family Foundation. Sydney MAS is supported by the Australian National Health and Medical Research Council (NHMRC), grants ID568969, ID350833 and ID109308. Sydney MAS DNA was extracted by Genetic Repositories Australia, funded by NHMRC Enabling Grant 401184. The GEFOS Study, used as controls for the US and Jamaican athletes, was supported in part by NIH grants U01 HG004436 and P30 DK072488, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). TwinsUK was funded by the Wellcome Trust (WT), MRC, and European Union. The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP Genotyping was performed by The WT Sanger Institute and National Eye Institute via NIH/CIDR. M.McC is a WT Senior Investigator and receives support from WT 090532 and 098381. TW is the recipient of a studentship from MedImmune. Research by A. Lucia is supported by Fondo de Investigaciones Sanitarias and Fondos Feder (grant # PI15/0558). EM-M. was a recipient of a Grant-in-Aid for JSPS Fellow from the Japan Society for the Promotion of Science. This work was supported in part by grants from the Grant-in-Aid for Scientific Research (B) (15H03081 to NF) of the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a grant-in-aid for scientific research (to M. Miyachi) from the Japanese Ministry of Health, Labor, and Welfare. This work was further supported by NIH grants R01 AR41398 and U24 AG051129

Molecular insights into the aetiology of female reproductive ageing

As age at pubertal onset declines and age at first pregnancy increases, the mechanisms that regulate female reproductive lifespan become increasingly relevant to population health. The timing of menarche and menopause can have profound effects not only on fertility but also on the risk of diseases such as type 2 diabetes mellitus, cardiovascular disease and breast cancer. Genetic studies have identified dozens of highly penetrant rare mutations associated with reproductive disorders, and also approximately 175 common genetic variants associated with the timing of puberty or menopause. These findings, alongside other functional studies, have highlighted a diverse range of mechanisms involved in reproductive ageing, implicating core biological processes such as cell cycle regulation and energy homeostasis. The aim of this article is to review the contribution of such genetic findings to our understanding of the molecular regulation of reproductive timing, as well as the biological basis of the epidemiological links between reproductive ageing and disease risk