Lesliebitsch2714

Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; α-synuclein and OLGs. The difficulty originates from several enigmas 1) what triggers the initial generation and possible propagation of pathogenic α-synuclein species? 2) what contributes to OLG-specific accumulation of α-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affIs, insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and α-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms. © The Author(s). 2020.Natriuretic peptides (NP) are strongly associated with perioperative cardiovascular events. However, in patients with raised NP, it remains unknown whether treatment to reduce NP levels prior to surgery results in better perioperative outcomes. In this systematic review and meta-analysis, we investigate NP-directed medical therapy in non-surgical patients to provide guidance for NP-directed medical therapy in surgical patients. The protocol was registered with PROSPERO (CRD42017051468). The database search included MEDLINE (PubMed), CINAHL (EBSCO host), EMBASE (EBSCO host), ProQuest, Web of Science, and Cochrane database. The primary outcome was to determine whether NP-directed medical therapy is effective in reducing NP levels within 6 months, compared to standard of care. The secondary outcome was to determine whether reducing NP levels is associated with decreased mortality. Full texts of 18 trials were reviewed. NP-directed medical therapy showed no significant difference compared to standard care in decreasing NP levels (standardized mean difference - 0.04 (- 0.16, 0.07)), but was associated with a 6-month (relative risk (RR) 0.82 (95% confidence interval (CI) 0.68-0.99)) reduction in mortality. © The Author(s). 2020.This study explores the integration of separation performance of rGO membrane with heterogeneous oxidation reactions for remediation of organic contaminants from water. Herein, an approach was introduced based on layer-by-layer assembly for functionalizing rGO membranes with polyacrylic acid and then by in situ synthesis of Fe based reactive nanoparticles. TEM characterization of the cross-section lamella of the membranes showed a high density of nanoparticles (12% Fe) in the functionalized domain, signifying the importance of polyacrylic acid for in situ synthesis of nanoparticles. The membranes exhibited a pure water permeability of 1.9 LMH bar-1. The membranes had low to moderate salt retention, and more than 90% neutral red retention (organic probe molecule, size 1.2 nm). The membranes also exhibited high retention of humic acids (80%), preventing these organics from entering the reactive domain, and thus potentially reducing the formation of undesired by-products. A persulfate mediated oxidative pathway was employed to demonstrate the reactive removal of organic contaminants. The membranes achieved >95% conversion by convectively passing 2 mM persulfate feed at a transmembrane pressure of 0.4 bar. Successful degradation of TCE (up to 61%) was achieved in a single pass by convective flowing of the feed solution through the membrane, generating up to 80% of the theoretical maximum chloride as one of the byproducts. Elevated temperatures significantly enhanced persulfate mediated TCE oxidation extent from 24% at 23 oC to 54% at 40 o C under batch operating conditions.Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. IDN-6556 chemical structure A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials. © The Author(s) 2020.