The endocannabinoid system (ECS) controls energy balance by regulating both energy intake and energy expenditure. Endocannabinoid levels are elevated in obesity suggesting a potential causal relationship. This study aimed to elucidate the rate of dysregulation of the ECS, and the metabolic organs involved, in diet-induced obesity. Eight groups of age-matched male C57Bl/6J mice were randomized to receive a chow diet (control) or receive a high fat diet (HFD, 45% of calories derived from fat) ranging from 1 day up to 18 weeks before euthanasia. Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (N-arachidonoylethanolamine, AEA), and related N-acylethanolamines, were quantified by UPLC-MS/MS and gene expression of components of the ECS was determined in liver, muscle, white adipose tissue (WAT) and brown adipose tissue (BAT) during the course of diet-induced obesity development. HFD feeding gradually increased 2-AG (+132% within 4 weeks, P < 0.05), accompanied by upregulated expression of its synthesizing enzymes Daglα and β in WAT and BAT. HFD also rapidly increased AEA (+81% within 1 week, P < 0.01), accompanied by increased expression of its synthesizing enzyme Nape-pld, specifically in BAT. Interestingly, Nape-pld expression in BAT correlated with plasma AEA levels (R2 = 0.171, β = 0.276, P < 0.001). We conclude that a HFD rapidly activates adipose tissue depots to increase the synthesis pathways of endocannabinoids that may aggravate the development of HFD-induced obesity.

What is already known about this subject? Hydroxychloroquine has been used as anti-malarial and anti-rheumatic drug for decades, with only very few reports of cardiac death after use of this drug.The current SARS-Cov-2 pandemic has raised renewed attention on hydroxychloroquine. Concerns were raised on the pro-arrhythmic effects of hydroxychloroquine, that are presumably caused by blockage of the cardiac hERG channel. This study analyzed the effect of hydroxychloroquine, dosed in a regular regimen for SARS-CoV-2 patients, on the ventricular repolarization in a concentration-effect analysis. What does this study add? There were no significant associations between hydroxychloroquine concentration and ECG characteristics, including QTcF-interval and T-wave morphology, measured with a Morphology Combination Score (MCS). Based on this analysis, hydroxychloroquine does not significantly affect the QTcFinterval and does not significantly increase the risk of arrhythmias in the studied dosing regimen and population. This outcome can be explained by the maximal plasma concentration of this dosing regimen, that is not high enough to exert hERG channel inhibition.

Background Depressive symptoms are associated with adverse clinical outcomes in patients with end-stage kidney disease. Yet, few small studies have examined this association in patients with earlier phases of chronic kidney disease (CKD). We studied associations between baseline depressive symptoms and clinical outcomes in older patients with advanced CKD and examined whether these associations differed depending on sex. Methods CKD patients (≥65 years; eGFR ≤ 20 mL/min/1.73m2) were included from a European multicenter prospective cohort between 2012 and 2019. Depressive symptoms were measured by the 5-item Mental Health Inventory (cut-off ≤ 70;0–100 scale). Cox proportional hazard analysis was used to study associations between depressive symptoms and time to dialysis initiation, all-cause mortality, and these outcomes combined. A joint model was used to study the association between depressive symptoms and kidney function over time. Analyses were adjusted for potential baseline confounders. Results Overall kidney function decline in 1326 patients was -0.12 mL/min/1.73m2/month. 515 patients showed depressive symptoms. No significant association was found between depressive symptoms and kidney function over time (p = 0.08). Men with depressive symptoms had an increased mortality rate compared to those without symptoms (adjusted HR 1.41, 95%CI 1.03;1.93), women had not. Depressive symptoms were not significantly associated with a higher hazard of dialysis initiation, nor with the combined outcome (i.e. dialysis initiation and all-cause mortality). Conclusions There was no significant association between depressive symptoms at baseline and decline in kidney function over time in older patients with advanced CKD. Depressive symptoms at baseline were associated with a higher mortality rate in men.

Context:Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism.Objective: We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics.Design: meta-analysis of two cross-sectional studies.Setting: Two population-based European cohort studies. Patients or other participants:Non-diabetic individuals from the Oxford BioBank (OBB; N=6,368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N=5,916; mean age 55.6 years, males 43%) studies. Intervention(s): Data on mean outdoor bright sunlight and temperature collected from local weather stations in the week prior to blood sampling. Main Outcome Measure(s): Serum levels of 148 metabolites measured using NMR spectroscopy, including 14 lipoprotein subclasses. Statistical analyses: Multivariable linear regression analyses adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. Summary statistics from the OBB and NEO cohorts were combined using fixed-effect meta-analyses.Results: A higher mean outdoor temperature was associated with increased concentrations of lipoprotein (sub)particles and certain amino acids such as phenylalanine and leucine. In contrast, longer mean hours of bright sunlight were specifically associated with lower concentrations of very low density lipoprotein (sub)particles. The direction of effects was consistent between the OBB and NEO, although effect sizes were generally larger in the OBB.3 Conclusions: Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.