Sparkswagner7147

Rationale Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in NS patients indicates an urgent need for new therapeutic approaches. Objective Bleeding disorders have recently been described in NS patients harboring mutations of LZTR1, an adaptor for CULLIN3 ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders.Methods and Results Whole-body and vascular specific knockout of Lztr1 results in perinatal lethality due to cardiovascular dysfunction. Lztr1 deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in Lztr1-depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III component CHMP1B, whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 and decreases blood levels of soluble VEGFR2 in Lztr1 haploinsufficient mice. Epibrassinolide clinical trial Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in Lztr1 knockout mice. Conclusions Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in NS patients. ELISA screening of soluble VEGFR2 in the blood of LZTR1-mutated NS patients may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in NS patients.Moderate-intensity continuous exercise (MICE) improves fat oxidation. High-intensity intermittent exercise (HIIE) is thought to have a greater potential for fat oxidation but it might be too demanding in the long term for patients. We hypothesized that an initial bout of HIIE could maximize fat oxidation during MICE and the following passive recovery. Eighteen healthy participants performed two acute isocaloric exercise sessions at random. MICE consisted of 45-min cycling at 50% of maximal aerobic power (Pmax). COMB began with five 1-min bouts of HIIE at Pmax (interspaced with 1-min recovery periods) followed by 35-min MICE. Gas exchange allowed substrate oxidation rate assessment.Expressed as a % of energy expenditure, fat oxidation (%) increased during in the passive recovery following COMB (Recovery 36.0 ± 19.4 vs 23.0 ± 20.3%; ES 0.66; p less then  0.0001). An initial bout of HIIE preceding a prolonged moderate-intensity exercise may potentiate fat oxidation during the following recovery. This might be relevant for health management of overweight/obese persons.Objective The aim of this study was to perform a systematic and multifaceted comparison of thermal effects during soft tissue ablation with various lasers and an electroscalpel (ES). Materials and methods ErYAG, Er,CrYSGG, CO2, Diode, NdYAG lasers (1 W, pulsed or continuous wave), an ES, and a scalpel (Sc; control), were employed for porcine gingival tissue ablation. Temperature changes during ablation were measured by using an infrared thermal imaging camera and a thermocouple. After ablations, the wounds were observed using stereomicroscopy and scanning electron microscopy (SEM), and histological sections were analyzed. Compositional analysis was also performed on ablated sites by SEM wavelength dispersive X-ray spectroscopy. Results The surface temperature during irradiation was highest with CO2 (over 500°C), followed by Diode (267°C) and NdYAG (258°C), ErYAG (164°C), ES (135°C), and Er,CrYSGG (85°C). Carbonization was negligible (ErYAG), slight (Er,CrYSGG), moderate (NdYAG and ES), and severe (CO2 and Diode). Under SEM observation, ErYAG and Er,CrYSGG showed smooth surfaces but other devices resulted in rough appearances. Histologically, the coagulated and thermally affected layer was extremely minimal (38 μm in thickness) and free from epithelial collapse for ErYAG. Compared with other devices, less compositional surface change was detected with ErYAG and Er,CrYSGG; additionally, the use of water spray further minimized thermal influence. Conclusions Among various power devices, ErYAG laser showed the most efficient and refined gingival ablation with minimal thermal influence on the surrounding tissues. ErYAG and Er,CrYSGG lasers with water spray could be considered as minimally invasive power devices for soft tissue surgery.Rationale Fibro-fatty infiltration of sub-epicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation (AF). Objective Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process. Methods and Results 109 human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial thickening and dense fibrofatty infiltrates in atrial tissue sections from patients aged over 70 years who had mitral valve disease or AF when compared to patients aged less than 70 years with ischemic cardiomyopathy as indicated using logistic regression adjusted for age and gender. Cells co-expressing markers of epicardial progenitors and fibroblasts were detected in fibro-fatty infiltrates. Such epicardial remodeling was reproduced in an experimental model of atrial cardiomyopathy in rat and in Wilm's Tumor-1 (WT1)CreERT2/+;ROSA-tdT+/- mice. In the latter, genetic lineage tracing demonstrated the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of human adult epicardial-derived cells (aEPDCs) expressing Platelet-derived growth factor receptor-alpha (PDGFRalpha were isolated and differentiated into myofibroblasts in the presence of angiotensin-II. Furthermore, single cell RNA-seqencing analysis identified several clusters of aEPDCs and revealed their specification from adipogenic to fibrogenic cells in the rat model of atrial cardiomyopathy. ConclusionsEpicardium is reactivated during the formation of the atrial cardiomyopathy. Subsets of aEPDCs, pre-programmed towards a specific cell fate, contribute to fibro-fatty infiltration of sub-epicardium of diseased atria. Our study reveals the biological basis for chronic atrial myocardial remodeling that paves the way of AF.