Dysfunctional oxidative phosphorylation shunts branched-chain amino acid catabolism onto lipogenesis in skeletal muscle.

It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole-body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl-glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid ß-oxidation, and forces the catabolism of branched-chain amino acids (BCAA) to provide acetyl-CoA for de novo lipid synthesis. In turn, muscle accumulation of acetyl-CoA leads to acetylation-dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA-approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.

Psychological Group Interventions for Reducing Distress Symptoms in Healthcare Workers: A Systematic Review.

Healthcare workers exposed to emergencies and chronic stressors are at high risk of developing mental health problems. This review synthesized existing studies of group psychological therapy to reduce distress symptoms in healthcare workers (i.e., as complex and heterogeneous emotional states, characterized by the presence of symptoms associated with post-traumatic stress disorder, burnout, anxiety, depression and moral injury). Searches were conducted using PRISMA guidelines and databases such as PubMed, PsycINFO, Medline and Web of Science, along with manual searches of reference lists of relevant articles. The search returned a total of 1071 randomized trials, of which 23 met the inclusion criteria. Of the total studies, nine were mindfulness interventions, seven were cognitive behavioural programmes, one was a programme based on acceptance and commitment therapy, one was an EMDR protocol and two focused on systemic and art therapy. Most studies aimed to reduce burnout, anxiety and depression; only three focused on post-traumatic stress disorder, and no studies were found that addressed moral injury. The results suggested that group interventions could be an effective tool to improve the mental health of healthcare workers and reduce their symptoms of distress, although many of the studies have methodological deficiencies. Limitations and future directions are discussed.

Prevalence of Systemic Hypertension and Control of Systolic Blood Pressure in a Cohort of 14 Dogs with Adrenal-Dependent Hypercortisolism during the First Year of Trilostane Treatment or after Adrenalectomy.

Hypercortisolism in dogs is frequently associated with systemic hypertension (SH). However, there are no studies evaluating the changes in systolic blood pressure (SBP) in dogs with adrenal-dependent hypercortisolism (ADH) during trilostane treatment or after adrenalectomy and their response to antihypertensive treatments. For this reason, the objectives of this study were to evaluate the changes in SBP in dogs with ADH during the first year of trilostane treatment or after adrenalectomy, the relation with clinical control of hypercortisolism and certain laboratory parameters, and the response to antihypertensive drugs. Fourteen dogs newly diagnosed with ADH were prospectively included and evaluated at diagnosis (T0) and 1, 3, 6, and 12 months after (T1, T3, T6, and T12, respectively). Dogs were classified as hypertensive (HT; SBP ≥ 160 mmHg) and non-hypertensive. In HT dogs, benazepril was considered as the first-line drug, and, if necessary, amlodipine was prescribed. The prevalence of SH at T0 was 79%, and it was reduced to 25% at T12. Blood pressure (BP) was not associated with disease control or selected laboratory parameters at any endpoint. Only 22% of dogs with SH needed more than one drug to normalize their SBP. In all dogs surgically treated that were HT at T0, BP normalized at T3.

Survival of dogs with pituitary-dependent hyperadrenocorticism treated twice daily with low doses of trilostane.

BACKGROUND: Twice daily low trilostane doses have proven to be effective to manage canine Cushing's syndrome. However, survival and prognostic factors in dogs treated with this protocol have not been evaluated. The aim of the study was to evaluate survival and prognostic factors, including systolic blood pressure (SBP) at diagnosis, in dogs with pituitary-dependent hypercortisolism (PDH) treated with low trilostane doses. METHODS: Medical records of 91 dogs newly diagnosed with PDH initially treated with 0.2-1.1 mg/kg of trilostane twice daily were retrospectively included. Survival times were calculated using the Kaplan-Meier estimator. Univariable and multivariable analysis were performed using the Cox proportional hazard regression analysis. RESULTS: Overall, median survival was 998 days (range 26-1832 days, 95% confidence interval = 755-1241 days). In the multivariable analysis, age (hazard ratio [HR] = 1.337, p < 0.001), presence of calcinosis cutis (HR = 5.271, p < 0.001), body condition score (BCS) ≤3/9 (HR = 8.100, p < 0.001) and higher platelet count (HR = 1.002, p = 0.022) were negatively correlated with survival. SBP was not associated with survival. CONCLUSIONS: Low-dose trilostane treatment twice daily provides slightly longer survival than previously reported for dogs with PDH treated once or twice daily at higher doses. Older age, presence of calcinosis cutis, low BCS and higher platelet count, but not systemic hypertension, are predictive of poorer prognosis in dogs with PDH.