High-throughput sequencing of IL23R reveals a low-frequency, nonsynonymous single-nucleotide polymorphism that is associated with ankylosing spondylitis in a Han Chinese population

Objective Ankylosing spondylitis (AS) is a highly heritable common inflammatory arthritis that targets the spine and sacroiliac joints of the pelvis, causing pain and stiffness and leading eventually to joint fusion. Although previous studies have shown a strong association of IL23R with AS in white Europeans, similar studies in East Asian populations have shown no association with common variants of IL23R, suggesting either that IL23R variants have no role or that rare genetic variants contribute. The present study was undertaken to screen IL23R to identify rare variants associated with AS in Han Chinese. Methods A 170-kb region containing IL23R and its flanking regions was sequenced in 50 patients with AS and 50 ethnically matched healthy control subjects from a Han Chinese population. In addition, the 30-kb region of peak association in white Europeans was sequenced in 650 patients with AS and 1,300 healthy controls. Validation genotyping was undertaken in 846 patients with AS and 1,308 healthy controls. Results We identified 1,047 variants, of which 729 were not found in the dbSNP genomic build 130. Several potentially functional rare variants in IL23R were identified, including one nonsynonomous single-nucleotide polymorphism (nsSNP), Gly149Arg (position 67421184 GA on chromosome 1). Validation genotyping showed that the Gly149Arg variant was associated with AS (odds ratio 0.61, P = 0.0054). Conclusion This is the first study to implicate rare IL23R variants in the pathogenesis of AS. The results identified a low-frequency nsSNP with predicted loss-of-function effects that was protectively associated with AS in Han Chinese, suggesting that decreased function of the interleukin-23 (IL-23) receptor protects against AS. These findings further support the notion that IL-23 signaling has an important role in the pathogenesis of AS.

Cohort profile: Andhra Pradesh Children and Parents Study (APCAPS)

The Andhra Pradesh Children and Parents Study (APCAPS) was originally established to study the long-term effects of early-life undernutrition on risk of cardiovascular disease. Its aims were subsequently expanded to include trans-generational influences of other environmental and genetic factors on chronic diseases in rural India. It builds on the Hyderabad Nutrition Trial (HNT) conducted in 1987–90 to compare the effects on birthweight of a protein-calorie supplement for pregnant women and children. The index children of HNT and their mothers were retraced and examined in 2003–05, and the children re-examined as young adults aged 18–21 years in 2009–10. The cohort was expanded to include both parents and siblings of the index children in a recently completed follow-up conducted in 2010–12 (N = ∼6225 out of 10 213 participants). Recruitment of the remaining residents of these 29 villages (N = ∼55 000) in Ranga Reddy district of Andhra Pradesh is now under way. Extensive data on socio-demographic, lifestyle, medical, anthropometric, physiological, vascular and body composition measures, DNA, stored plasma, and assays of lipids and inflammatory markers on APCAPS participants are available. Details of how to access these data are available from the corresponding author.

Life-course determinants of bone mass in young adults from a transitional rural community in India: The Andhra Pradesh Children and Parents Study (APCAPS)

Background: Undernutrition and physical inactivity are both associated with lower bone mass. Objective: This study aimed to investigate the combined effects of early-life undernutrition and urbanized lifestyles in later life on bone mass accrual in young adults from a rural community in India that is undergoing rapid socioeconomic development. Design: This was a prospective cohort study of participants of the Hyderabad Nutrition Trial (1987–1990), which offered balanced protein-calorie supplementation to pregnant women and preschool children younger than 6 y in the intervention villages. The 2009–2010 follow-up study collected data on current anthropometric measures, bone mineral density (BMD) measured by dual-energy X-ray absorptiometry, blood samples, diet, physical activity, and living standards of the trial participants (n = 1446, aged 18–23 y). Results: Participants were generally lean and had low BMD [mean hip BMD: 0.83 (women), 0.95 (men) g/cm2; lumbar spine: 0.86 (women), 0.93 (men) g/cm2]. In models adjusted for current risk factors, no strong evidence of a positive association was found between BMD and early-life supplementation. On the other hand, current lean mass and weight-bearing physical activity were positively associated with BMD. No strong evidence of an association was found between BMD and current serum 25-hydroxyvitamin D or dietary intake of calcium, protein, or calories. Conclusions: Current lean mass and weight-bearing physical activity were more important determinants of bone mass than was early-life undernutrition in this population. In transitional rural communities from low-income countries, promotion of physical activity may help to mitigate any potential adverse effects of early nutritional disadvantage.

Multifocal electroretinogram responses in Nepalese diabetic patients without retinopathy

Purpose To determine neuroretinal function with multifocal electroretinogram (mfERG) in diabetic subjects without retinopathy. Methods Multifocal electroretinogram (mfERG) was performed in 18 eyes of 18 diabetic subjects without retinopathy and 17 eyes of 17 age and gender-matched healthy control participants. Among 18 diabetic subjects, two had type 1 and 16 had type 2 diabetes. MfERG responses were averaged by the retinal areas of six concentric rings and four quadrants, and 103 retinal locations; N1–P1 amplitude and P1-implicit time were analysed. Results Average mfERG N1–P1 amplitude (in nv/deg2) of 103 retinal locations was 56.3 ± 17.2 (mean ± SD) in type 1 diabetic subjects, 47.2 ± 9.3 in type 2 diabetic subjects and 71.5 ± 12.7 in controls. Average P1-implicit time (in ms) was 43.0 ± 1.3 in type 1 diabetic subjects, 43.9 ± 2.3 in type 2 diabetic subjects and 41.9 ± 2.1 in controls. There was significant reduction in average N1–P1 amplitude and delay in P1-implicit time in type 2 diabetic subjects in comparison to controls. mfERG amplitude did not show any significant correlation with diabetes duration and blood sugar level. However, implicit time showed a positive correlation with diabetes duration in type 2 diabetic subjects with diabetes duration ≥5 years. Conclusions This is the first study in a Nepalese population with diabetes using multifocal electroretinography. We present novel findings that mfERG N1–P1 amplitude is markedly reduced along with delay in P1-implicit time in type 2 diabetic subjects without retinopathy. These findings indicate that there might be significant dysfunction of inner retina before the development of diabetic retinopathy in the study population, which have higher prevalence of diabetes than the global estimate and uncontrolled blood sugar level.

Autonomy-supportive pedagogical approach to sports coaching: Research, challenges and opportunities

There has been an increasing body of research on autonomy- or need-support specific to a coaching context that warrants some review of what we know and don't know, and what might be generative for future research. The previous studies reviewed within this article have shown consistent support for Self-determination theory with autonomy-supportive environments linked with adaptive outcomes, such as superior performance, enhanced self-worth, increased effort, and self-determined motivation; while controlling environments have been linked with increased attrition and extrinsic motivation or amotivation. In this way, much of the research in autonomy-supportive coaching has focused on the impact of coaching behaviours on athlete outcomes. While this is an important focus of inquiry, there has been a dearth of research examining those causal factors that impact coaches' pedagogical behaviours in the first case. This review underscores the need for future research to examine the antecedents to coaching behaviours, which is central to understanding the complexity and challenges in promoting an autonomy-supportive approach to sport coaching.

Partial epilepsy syndrome in a Gypsy family linked to 5q31.3-q32

PURPOSE The restricted genetic diversity and homogeneous molecular basis of Mendelian disorders in isolated founder populations have rarely been explored in epilepsy research. Our long-term goal is to explore the genetic basis of epilepsies in one such population, the Gypsies. The aim of this report is the clinical and genetic characterization of a Gypsy family with a partial epilepsy syndrome. METHODS Clinical information was collected using semistructured interviews with affected subjects and informants. At least one interictal electroencephalography (EEG) recording was performed for each patient and previous data obtained from records. Neuroimaging included structural magnetic resonance imaging (MRI). Linkage and haplotype analysis was performed using the Illumina IVb Linkage Panel, supplemented with highly informative microsatellites in linked regions and Affymetrix SNP 5.0 array data. RESULTS We observed an early-onset partial epilepsy syndrome with seizure semiology strongly suggestive of temporal lobe epilepsy (TLE), with mild intellectual deficit co-occurring in a large proportion of the patients. Psychiatric morbidity was common in the extended pedigree but did not cosegregate with epilepsy. Linkage analysis definitively excluded previously reported loci, and identified a novel locus on 5q31.3-q32 with an logarithm of the odds (LOD) score of 3 corresponding to the expected maximum in this family. DISCUSSION The syndrome can be classified as familial temporal lobe epilepsy (FTLE) or possibly a new syndrome with mild intellectual deficit. The linked 5q region does not contain any ion channel-encoding genes and is thus likely to contribute new knowledge about epilepsy pathogenesis. Identification of the mutation in this family and in additional patients will define the full phenotypic spectrum.

Crash risk perception of sleepy driving and its comparisons with drink driving and speeding: Which behavior is perceived as the riskiest?

- Objective Driver sleepiness is a major crash risk factor, but may be under-recognized as a risky driving behavior. Sleepy driving is usually rated as less of a road safety issue than more well-known risky driving behaviors, such as drink driving and speeding. The objective of this study was to compare perception of crash risk of sleepy driving, drink driving, and speeding. - Methods In total, 300 Australian drivers completed a questionnaire that assessed crash risk perceptions for sleepy driving, drink driving, and speeding. Additionally, the participants perception of crash risk was assessed for five different contextual scenarios that included different levels of sleepiness (low, high), driving duration (short, long), and time of day/circadian influences (afternoon, night-time) of driving. - Results The analysis confirmed that sleepy driving was considered a risky driving behavior, but not as risky as high levels of speeding (p < .05). Yet, the risk of crashing at 4 am was considered as equally risky as low levels of speeding (10 km over the limit). The comparisons of the contextual scenarios revealed driving scenarios that would arguably be perceived as quite risky due to time of day/circadian influences were not reported as high risk. - Conclusions The results suggest a lack of awareness or appreciation of circadian rhythm functioning, particularly the descending phase of circadian rhythm that promotes increased sleepiness in the afternoon and during the early hours of the morning. Yet, the results suggested an appreciation of the danger associated with long distance driving and driver sleepiness. Further efforts are required to improve the community’s awareness of the impairing effects from sleepiness and in particular, knowledge regarding the human circadian rhythm and the increased sleep propensity during the circadian nadir.

Relationship between malnutrition and selected risk factors in two hospitals in Vietnam

Aim: The purpose of this study was to determine the percentage of patients assessed as malnourished using the Subjective Global Assessment in two hospitals in Ho Chi Minh City and Can Tho across multiple wards; and to investigate the association with factors including gender, age, days since admission, medical diagnosis and number of medications used. Methods: This cross-sectional study involved 205 inpatients from a hospital in Ho Chi Minh City and 78 inpatients and 89 outpatients from a hospital in Can Tho. Malnutrition status was assessed using Subjective Global Assessment. Ward, gender, age, medical diagnosis, time since admission and medication number were extracted from medical records. Results: 35.6% of inpatients and 9.0% of outpatients were malnourished. Multivariate analysis revealed factors predicting malnutrition status within inpatients (OR (95%CI)) were: age (OR = 1.03 (1.01-1.06)); cancer diagnosis (OR = 34.25 (3.16-370.89)); respiratory ward (11.49 (1.05-125.92)); or general medicine ward (20.34 (2.10-196.88)). Conclusions: Results indicate that malnutrition is a common problem in hospitals in Vietnam. Further research is needed to confirm this finding across a wider range of hospitals and to investigate the feasibility and efficacy of implementation of nutrition interventions in hospital settings.

Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1

Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgenindependent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.

Estimating cell diffusivity and cell proliferation rate by interpreting IncuCyte ZOOM™ assay data using the Fisher-Kolmogorov model

Background: Standard methods for quantifying IncuCyte ZOOM™ assays involve measurements that quantify how rapidly the initially-vacant area becomes re-colonised with cells as a function of time. Unfortunately, these measurements give no insight into the details of the cellular-level mechanisms acting to close the initially-vacant area. We provide an alternative method enabling us to quantify the role of cell motility and cell proliferation separately. To achieve this we calibrate standard data available from IncuCyte ZOOM™ images to the solution of the Fisher-Kolmogorov model. Results: The Fisher-Kolmogorov model is a reaction-diffusion equation that has been used to describe collective cell spreading driven by cell migration, characterised by a cell diffusivity, D, and carrying capacity limited proliferation with proliferation rate, λ, and carrying capacity density, K. By analysing temporal changes in cell density in several subregions located well-behind the initial position of the leading edge we estimate λ and K. Given these estimates, we then apply automatic leading edge detection algorithms to the images produced by the IncuCyte ZOOM™ assay and match this data with a numerical solution of the Fisher-Kolmogorov equation to provide an estimate of D. We demonstrate this method by applying it to interpret a suite of IncuCyte ZOOM™ assays using PC-3 prostate cancer cells and obtain estimates of D, λ and K. Comparing estimates of D, λ and K for a control assay with estimates of D, λ and K for assays where epidermal growth factor (EGF) is applied in varying concentrations confirms that EGF enhances the rate of scratch closure and that this stimulation is driven by an increase in D and λ, whereas K is relatively unaffected by EGF. Conclusions: Our approach for estimating D, λ and K from an IncuCyte ZOOM™ assay provides more detail about cellular-level behaviour than standard methods for analysing these assays. In particular, our approach can be used to quantify the balance of cell migration and cell proliferation and, as we demonstrate, allow us to quantify how the addition of growth factors affects these processes individually.

Nutritional intake of opioid replacement therapy patients in community pharmacies: A pilot study

Aim: Opioid replacement therapy (ORT) is an established therapy for a patient group that has been associated with nutrition-related comorbidities. This paper aims to assess the nutritional intake and supplementation in ORT patients, determine the extent of nutritional/dietary advice supplied to ORT patients and to briefly examine patients' perception of pharmacists' provision of nutritional advice. Methods: The nutritional intake of ORT patients receiving treatment in community pharmacies within the Australian Capital Territory was assessed via a 24-hour recall survey. Food intake data were analysed via nutrient analysis software and compared with Australian Nutrition Reference Values and the nutrient intakes of the Australian population. Patients were surveyed to determine supplement use and perceptions of nutritional advice gained by pharmacists. Results: Potential insufficient intake of various macronutrients and micronutrients was observed in both sexes. Less than 25 of patients recorded supplement use. Fifteen percent of males and 21 of females stated that they had approached a pharmacist with a nutrition-related query. All patients who received nutritional advice followed the advice. Conclusions: ORT patients dosing at community pharmacies appear to have poor nutritional intake. ORT patients appear to be receptive to pharmacist's advice. Community pharmacists can potentially increase the beneficial health outcomes in this population through the proactive supply of accurate nutritional advice.

CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4x10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.