Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo

Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand

Cardiovascular mortality and exposure to extremely low frequency magnetic fields: a cohort study of Swiss railway workers

<p>Abstract</p> <p>Background</p> <p>Exposure to intermittent magnetic fields of 16 Hz has been shown to reduce heart rate variability, and decreased heart rate variability predicts cardiovascular mortality. We examined mortality from cardiovascular causes in railway workers exposed to varying degrees to intermittent 16.7 Hz magnetic fields.</p> <p>Methods</p> <p>We studied a cohort of 20,141 Swiss railway employees between 1972 and 2002, including highly exposed train drivers (median lifetime exposure 120.5 μT-years), and less or little exposed shunting yard engineers (42.1 μT-years), train attendants (13.3 μT-years) and station masters (5.7 μT-years). During 464,129 person-years of follow up, 5,413 deaths were recorded and 3,594 deaths were attributed to cardio-vascular diseases. We analyzed data using Cox proportional hazards models.</p> <p>Results</p> <p>For all cardiovascular mortality the hazard ratio compared to station masters was 0.99 (95%CI: 0.91, 1.08) in train drivers, 1.13 (95%CI: 0.98, 1.30) in shunting yard engineers, and 1.09 (95%CI: 1.00, 1.19) in train attendants.Corresponding hazard ratios for arrhythmia related deaths were 1.04 (95%CI: 0.68, 1.59), 0.58 (95%CI: 0.24, 1.37) and 1.30 (95%CI: 0.87, 1.93) and for acute myocardial infarction 1.00 (95%CI: 0.73, 1.36), 1.56 (95%CI: 1.04, 2.32), and 1.14 (95%CI: 0.85, 1.53). The hazard ratio for arrhythmia related deaths per 100 μT-years of cumulative exposure was 0.94 (95%CI: 0.71, 1.24) and 0.91 (95%CI: 0.75, 1.11) for acute myocardial infarction.</p> <p>Conclusion</p> <p>This study provides evidence against an association between long-term occupational exposure to intermittent 16.7 Hz magnetic fields and cardiovascular mortality.</p

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1’s phenotype

Is the Femoro-Epiphyseal Acetabular Roof (FEAR) index on MRI a relevant predictive factor of instability in a borderline dysplastic hip?

Aims A borderline dysplastic hip can behave as either stable or unstable and this makes surgical decision making challenging. While an unstable hip may be best treated by acetabular reorientation, stable hips can be treated arthroscopically. Several imaging parameters can help to identify the appropriate treatment, including the Femoro-Epiphyseal Acetabular Roof (FEAR) index, measured on plain radiographs. The aim of this study was to assess the reliability and the sensitivity of FEAR index on MRI compared with its radiological measurement. Patients and Methods The technique of measuring the FEAR index on MRI was defined and its reliability validated. A retrospective study assessed three groups of 20 patients: an unstable group of 'borderline dysplastic hips' with lateral centre edge angle (LCEA) less than 25° treated successfully by periacetabular osteotomy; a stable group of 'borderline dysplastic hips' with LCEA less than 25° treated successfully by impingement surgery; and an asymptomatic control group with LCEA between 25° and 35°. The following measurements were performed on both standardized radiographs and on MRI: LCEA, acetabular index, femoral anteversion, and FEAR index. Results The FEAR index showed excellent intraobserver and interobserver reliability on both MRI and radiographs. The FEAR index was more reliable on radiographs than on MRI. The FEAR index on MRI was lower in the stable borderline group (mean -4.2° (sd 9.1°)) compared with the unstable borderline group (mean 7.9° (sd 6.8°)). With a FEAR index cut-off value of 2°, 90% of patients were correctly identified as stable or unstable using the radiological FEAR index, compared with 82.5% using the FEAR index on MRI. The FEAR index was a better predictor of instability on plain radiographs than on MRI. Conclusion The FEAR index measured on MRI is less reliable and less sensitive than the FEAR index measured on radiographs. The cut-off value of 2° for radiological FEAR index predicted hip stability with 90% probability. Cite this article: Bone Joint J 2019;101-B:1578-158