Accepted

Calcium ion movements between cellular stores and the cytosol govern muscle contraction, the most energy-consuming function in mammals, which confers skeletal myofibers a pivotal role in glycemia regulation. Chronic myoplasmic calcium elevation ("calcium stress"), found in malignant hyperthermia-susceptible (MHS) patients and multiple myopathies, has been suggested to underlie the progression from hyperglycemia to insulin resistance. What drives such progression remains elusive. We find that muscle cells derived from MHS patients have increased content of an activated fragment of GSK3β – a specialized kinase that inhibits glycogen synthase, impairing glucose utilization and delineating a path to hyperglycemia. We also find decreased content of junctophilin1, an essential structural protein that colocalizes in the couplon with the voltage-sensing Ca1.1, the calcium channel RyR1 and calpain1, accompanied by an increase in a 44 kDa junctophilin1 fragment (JPh44) that moves into nuclei. We trace these changes to activated proteolysis by calpain1, secondary to increased myoplasmic calcium. We demonstrate that a JPh44-like construct induces transcriptional changes predictive of increased glucose utilization in myoblasts, including less transcription and translation of GSK3β and decreased transcription of proteins that reduce utilization of glucose. These effects reveal a stress-adaptive response, mediated by the novel regulator of transcription JPh44.

The aim was to assess the presence of socioeconomic inequalities in the management of back pain among Brazilians. Cross-sectional study with data from the National Health Survey (2019). The management of back pain care was assessed using five outcomes: regular exercise; physiotherapy; use of medications or injections; integrative and complementary practice; regular follow-up with a health professional. The magnitude of inequalities of each outcome in relation to exposures (education and income) was estimated using two indices: slope index of inequality (SII) and concentration index (CIX). Of the 90,846 interviewees, 19,206 individuals (21.1%) reported some chronic back problem. The most prevalent outcomes were use of medications and injections (45.3%), physical exercise (26.3%) and regular follow-up with a health professional (24.7%). The existence of inequalities in the management of back pain in the Brazilian population was evident. The adjusted analysis showed that the richest and most educated performed two to three times more physical exercise, physiotherapy, integrative and complementary practices (ICPS) and regular follow-up with a health professional than the poorest and least educated. Absolute (SII) and relative (CIX) inequalities were significant for all outcomes.

Erythrodermic atopic dermatitis (AD) is a severe AD subtype defined by extensive skin involvement, leading to complications and sometimes hospitalization.

The primary objective of this paper is to (1) provide a summary of human studies that have used brain derived neurotrophic factor (BDNF) as a biomarker, (2) review animal studies that help to elucidate the mechanistic involvement of BDNF in the development and maintenance of neuropathic pain (NP), and (3) provide a critique of the existing measurement techniques to highlight the limitations of the methods utilized to quantify BDNF in different biofluids in the blood (i.e., serum and plasma) with the intention of presenting a case for the most reliable and valid technique. Lastly, this review also explores potential moderators that can influence the measurement of BDNF and provides recommendations to standardize its quantification to reduce the inconsistencies across studies.

Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser assisted in situ keratomileusis (LASIK). While most patients do not experience post-operative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons – the ensemble of ion channels and receptors that regulate excitability within these cells -including SCN9A, which encodes sodium channel Nav1.7, a threshold channel abundantly expressed in sensory neurons, that has been implicated in a number of pain-related disorders. Here, we describe the biophysical and electrophysiological profiling of the P610T-Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery. Our results indicate that this mutation impairs the slow inactivation of Nav1.7. As expected from this pro-excitatory change in channel function, we also demonstrate that this mutation produces hyperexcitability in trigeminal ganglion neurons. These findings suggest that this gain-of-function mutation in Nav1.7 may contribute to pain after injury to the axons of trigeminal ganglion neurons.