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81.
Orthostatic hypotension (OH) is often reported as a significant potential adverse effect of antidepressant use but the association between phasic blood pressure (BP) and antidepressants has not yet been investigated. This cross-sectional study compares continuously measured phasic BP and prevalence of OH in a cohort of antidepressant users ≥50 years compared with an age- and sex-matched cohort not taking antidepressants. OH was defined as a drop in systolic BP ≥ 20 mm Hg or in diastolic BP ≥ 10 mm Hg at 30 seconds after standing, measured using continuous beat-to-beat finometry. Multilevel time × group interactions revealed significantly greater systolic and diastolic BP drop in antidepressant users than nonusers at 30 seconds after stand. The prevalence of OH among antidepressant users was 31% (63/206), compared with 17% in nonusers (X2 = 9.7; P = .002). Unadjusted logistic regression models demonstrated that selective serotonin reuptake inhibitor use was associated with OH at an odds ratio of 2.11 (95% confidence interval: 1.25–3.57); P = .005, and this association was not attenuated when covariates including cardiac disease and depressive symptom burden were added. There was no statistically significant association between serotonin noradrenaline reuptake inhibitor or tricyclic antidepressant use and OH in unadjusted models although the study was not powered to detect changes within these subgroups. Older people taking antidepressants have a two-fold higher prevalence of OH than nonusers, highlighting the importance of screening the older antidepressant user for OH and dizziness and rationalizing medications to reduce the risk of falls within this vulnerable cohort.  相似文献   
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AIM To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis(NASH).METHODS The effects of INT-767 on histological features of NASH were assessed in two studies using Lep~(ob/ob)(ob/ob) NASH mice fed the AMLN diet(high fat with transfat, cholesterol and fructose). In a proof-of-conceptstudy, Lep~(ob/ob)(ob/ob) NASH mice were first dosed with INT-767(3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767(3 and 10 mg/kg) to obeticholic acid(OCA)(10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57 Bl/6 mice on standard chow. C57 Bl/6 mice were orally dosed with INT-767 or OCA(1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS INT-767 dose-dependently(3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation(assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study(16 wk), the FXR agonists OCA(10 and 30 mg/kg) and INT-767(3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH.  相似文献   
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The long-term effects of disease and treatment on electrophysiologicalmeasures of neurocognitive function were studied in childrenwho had survived acute lymphoblastic leukemia (ALL) for at least4 years and were currently in remission. We report here changesin cognitive processing time as shown by the latency of theP3 wave of the auditory event-related EEG potential (ERP). P3latency was significantly prolonged in long-term ALL surivors,as well as in patients successfully trreated for solid tumors(ST)outside the CNS who received similar chemotherapy but did notreceive prophylactic treatment to the CNS. P3 latencies werestrongly correlated with measures of school performance andIQ in these individuals. The similarity in P3 latency betweenthe ALL and ST groups suggests that the treatments used on thesepateints produce changes in electrophysiological responses thatare associated with mild, but significant, cognitive deficits.  相似文献   
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Otoancorin (OTOA), encoded by OTOA, is required for the development of the tectorial membrane in the inner ear. Mutations in this gene cause nonsyndromic hearing loss (DFNB22). The molecular mechanisms underlying most DFNB22 remain poorly understood. Disruption of glycosylphosphatidylinositol (GPI) anchorage has been assumed to be the pathophysiology mandating experimental validation. From a Korean deaf family, we identified two trans OTOA variants (c.1320 + 5 G>C and p.Gln589ArgfsX55 [NM_144672.3]) . The pathogenic potential of c.1320 + 5 G>C was confirmed by a minigene splicing assay. To experimentally determine the GPI anchorage, wild‐type (WT) and mutant OTOA harboring p.Gln589ArgfsX55 were expressed in HEK293T cells. The mutant OTOA with p.Gln589ArgfsX55 resulted in an uncontrolled release of OTOA into the medium in contrast with phosphatidylinositol‐specific phospholipase C‐induced controlled release of WT OTOA from the cell surface. Together, the results of this reverse translational study confirmed GPI‐anchorage of OTOA and showed that downstream sequences from the 589th amino acid are critical for GPI‐anchorage.  相似文献   
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