L-Carnitine Reduces in Human Conjunctival Epithelial Cells Hypertonic- Induced Shrinkage through Interacting with TRPV1 Channels

Background/Aims: Ocular surface health depends on conjunctival epithelial (HCjE) layer integrity since it protects against pathogenic infiltration and contributes to tissue hydration maintenance. As the same increases in tear film hyperosmolarity described in dry eye disease can increase corneal epithelial transient receptor potential vanilloid type-1 (TRPV1) channel activity, we evaluated its involvement in mediating an osmoprotective effect by L-carnitine against such stress. Methods: Using siRNA gene silencing, Ca2+imaging, planar patch- clamping and relative cell volume measurements, we determined if the protective effects of this osmolyte stem from its interaction with TRPV1. Results: TRPV1 activation by capsaicin (CAP) and an increase in osmolarity to≈450 mOsM both induced increases in Ca2+levels. In contrast, blocking TRPV1 activation with capsazepine (CPZ) fully reversed this response. Similarly, L-carnitine (1 mM) also reduced underlying whole-cell currents. In calcein-AM loaded cells, hypertonic-induced relative cell volume shrinkage was fully blocked during exposure to L-carnitine. On the other hand, in TRPV1 gene-silenced cells, this protective effect by L-carnitine was obviated. Conclusion: The described L-carnitine osmoprotective effect is elicited through suppression of hypertonic-induced TRPV1 activation leading to increases in L-carnitine uptake through a described Na+-dependent L-carnitine transporter

Internal consistency and convergent validity of the International Spinal Cord Injury Quality of Life Basic Data Set at discharge from first rehabilitation

Study design This study is a cross-sectional analysis using data from the Swiss Spinal Cord Injury Cohort Study. Objectives To examine internal consistency and convergent validity of the International Spinal Cord Injury Quality of Life Basic Data Set (QoL-BDS) at discharge from first inpatient rehabilitation. Setting The study was performed at four rehabilitation centers in Switzerland. Methods Participants were Swiss residents aged over 16 years newly diagnosed with traumatic or non-traumatic spinal cord injury (SCI). Measures included the QoL-BDS, World Health Organization Quality of Life (WHOQOL) items, Hospital Anxiety and Depression Scale (HADS), and Spinal Cord Independence Measure III (SCIM). Results A total of 495 participants were included. In all, 57% had a traumatic SCI, 71.1% a motor complete SCI, and 33.3% had tetraplegia. Mean age was 53 (SD = 16.4) years and 68% were male. No floor or ceiling effects were found. Inter-correlations were strong (0.73-0.80) and Cronbach's alpha was good (0.88). QoL-BDS mean scores were 6.4 (SD = 2.2) for life satisfaction, 5.8 (SD = 2.4) for physical health, 6.9 (SD = 2.4) for psychological health, and 6.4 (SD = 2.1) for total QoL. Correlations with reference measures were strongest for QoL-BDS total and WHOQOL general quality of life (r = 0.67), QoL-BDS physical health and WHOQOL health and daily activities (r = 0.64 and 0.53), and QoL-BDS psychological health and HADS depression and anxiety (r = -0.64 and -0.69). SCIM correlated weakly with all QoL-BDS items. Conclusions The QoL-BDS revealed no floor or ceiling effects and demonstrated good internal consistency and convergent validity in individuals with SCI assessed at discharge from first rehabilitation. This study supports the clinical routine use of the QoL-BDS

GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk

Male pattern baldness (MPB) or androgenetic alopecia is one of the most common conditions affecting men, reaching a prevalence of similar to 50% by the age of 50; however, the known genes explain little of the heritability. Here, we present the results of a genome-wide association study including more than 70,000 men, identifying 71 independently replicated loci, of which 30 are novel. These loci explain 38% of the risk, suggesting that MPB is less genetically complex than other complex traits. We show that many of these loci contain genes that are relevant to the pathology and highlight pathways and functions underlying baldness. Finally, despite only showing genome-wide genetic correlation with height, pathway-specific genetic correlations are significant for traits including lifespan and cancer. Our study not only greatly increases the number of MPB loci, illuminating the genetic architecture, but also provides a new approach to disentangling the shared biological pathways underlying complex diseases

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (