Underwoodstefansen7892

BACKGROUND Telmisartan is an angiotensin II receptor blocker that has pleiotropic effects and protective properties in different cell types. Moreover, telmisartan has also shown partial agonism on the peroxisome proliferator-activated receptor γ (PPAR-γ). Auditory hair cells (HCs) express PPAR-γ, and the protective role of PPAR-γ agonists on HCs has been shown. OBJECTIVES The objective of this study was to investigate the effects of telmisartan on gentamicin-induced ototoxicity in vitro. METHODS Cochlear explants were exposed to gentamicin with or without telmisartan, and/or GW9662, an irreversible PPAR-γ antagonist. RESULTS Telmisartan protected auditory HCs against gentamicin-induced ototoxicity. GW9662 completely blocked this protective effect, suggesting that it was mediated by PPAR-γ signaling. Exposure to GW9662 or telmisartan alone was not toxic to auditory HCs. CONCLUSIONS We found that telmisartan, via PPAR-γ signaling, protects auditory HCs from gentamicin-induced ototoxicity. Therefore, telmisartan could potentially be used in the future to prevent or treat sensorineural hearing loss. © 2020 The Author(s) Published by S. Karger AG, Basel.BACKGROUND Two recent cerebrovascular studies, Clopidogrel (Clo) in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT), have purportedly demonstrated the superiority of early dual antiplatelet therapy (DAPT), using aspirin (ASA) plus Clo, in comparison to ASA alone following the occurrence of acute minor cerebral infarction or transient ischemic attack. However, limitations to these trials exist that may not have been adequately explored and presented in the literature, and which may impact the overall efficacy and benefit of DAPT in these situations. Herein we provide a detailed and extensive critique of these 2 trials and of a combined analysis, with particular attention to study data and analyses pertaining to hemorrhagic complications. SUMMARY DAPT may be superior to ASA alone in preventing recurrent cerebral ischemic events, but exclusively during the first 7-10 days of treatment, and probably only in the presence of acute infarction on cerebral imaging. The impact of minor hemorrhages, which are often clinically consequential and which frequently lead to permanent DAPT discontinuation, has not been adequately considered in the available analyses. Based on data from the trials, DAPT use causes more major and minor hemorrhages than ASA use alone or Clo alone, and Clo use results in fewer hemorrhages than the use of ASA alone. Analyses that include hemorrhage data from the period of Clo alone use as part of the DAPT data may provide inaccurate and erroneous conclusions regarding the relative safety and overall net benefit of DAPT use over ASA alone. © 2020 S. Karger AG, Basel.NR5A1 (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous NR5A1 mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with NR5A1 genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous NR5A1 genetic variants. In the boys, pathogenetic NR5A1 gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that NR5A1 gene mutations may present with variable genital phenotypes. selleckchem Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with NR5A1 mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward. © 2020 S. Karger AG, Basel.BACKGROUND Capnovolumetry is of interest as a method for the diagnosis of obstructive airway diseases, requiring little cooperation from the patient. OBJECTIVE To help in the interpretation of capnovolumetric parameters, we aimed to identify their correspondence to conventional lung function indices. METHODS We studied 978 patients from a diagnostic study with complete functional data and the clinical diagnosis of asthma, chronic obstructive pulmonary disease (COPD), or no respiratory disease. Using path analysis, four capnovolumetric parameters (slope of expiratory phase 3, ratio of slopes of phases 3 and 2, volume of phase 2, and the ratio area/volume of phase 3) previously identified as predictors of airway obstruction in terms of spirometry and body ple-thysmography, were analyzed regarding their relationship to each other and the diagnostic categories of asthma or COPD versus control, or obstruction versus no obstruction. We then identified four lung function parameters showing relationships as much as pumetry. © 2020 S. Karger AG, Basel.BACKGROUND Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. OBJECTIVES To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. METHODS We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53).