Background: The C terminus of the serotonin transporter (SERT) is required for folding.Results: Replacing C-terminal residues (Phe604, Ile608, and Ile612 by Gln and Glu615 by Lys) caused misfolding of SERT. A charge reversal (R152E) rescued SERT-E615K.Conclusion: An amphipathic C-terminal helix interacts with the first intracellular loop to facilitate folding of SERT.Significance: These data provide insights into the folding trajectory of SERT and related transporters.
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Portal hypertension (PHT) in advanced chronic liver disease (ACLD) results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition (structural component) and intrahepatic vasoconstriction (functional component). PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding. Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns (PAMPs) that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways. Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability: The intestinal barrier function is affected by impaired microcirculation, neoangiogenesis, and abnormal vascular and mucosal permeability. The close bidirectional relationship between the gut and the liver has been termed “gut-liver axis”. Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function, intestinal barrier integrity, as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects. The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments, however, further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed. In this review, we summarize the clinical impact of PHT on the course of liver disease, discuss the underlying pathophysiological link of PHT to gut-liver axis signaling, and provide insight into molecular mechanisms that may represent novel therapeutic targets.
G adoxetic acid-enhanced MRI is used to depict and help characterize focal liver nodules (1,2) in patients with chronic liver diseases (CLDs) (3,4), including nonalcoholic steatohepatitis (5) and chronic hepatitis C (5,6). Gadoxetic acid-enhanced MRI has been shown to help predict both liver failure after subtotal hepatectomy and graft survival after liver transplant (7-9).As laboratory and clinical estimators of liver disease severity, the albumin-bilirubin index, the Model for End-Stage Liver Disease, and the Child-Turcotte-Pugh score correlate well with gadoxetic acid uptake in the liver in the hepatobiliary phase (ie, 20 minutes after contrast agent administration of gadoxetic acid) (10,11). Previously described methods to assess hepatobiliary phase uptake include the relative liver enhancement, the hepatic uptake index, the contrast enhancement index, and T1 values (12). These methods all require complex computations and have vendor, field-strength, and sequence dependencies that complicate their clinical application.Recently, Bastati et al ( 13) introduced the functional liver imaging score (FLIS), derived from the three hepatobiliary phase features of gadoxetic acid-enhanced MRI and each scored on an ordinal 0-2 scale. The three features included in the FLIS semiquantitatively assess the enhancement
Background&Aims:The COVID-19 pandemic necessitated down-scaling of in-hospital care to prohibit the spread of severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2). We (i)assessed patient perceptions on quality of care by tele-survey(cohort 1) and written questionnaire(cohort 2) and (ii)analyzed trends in elective and non-elective admissions prior to (12/2019- 02/2020) and during (03/2020-05/2020) the COVID-19 pandemic in Austria. Methods:Two-hundred seventy-nine outpatients were recruited into cohort 1 and 138 patients into cohort 2. All admissions from 12/2019 to 05/2020 to the Division of Gastroenterology/Hepatology at the Vienna General Hospital were analyzed. Results:Thirty-two point six percent (n=91/279) of cohort 1 and 72.5%(n=95/131) of cohort 2 had tele-medical contact, while 59.5%(n=166/279)and 68.2%(n=90/132) had face-to-face visits. 24.1%(n=32/133) needed acute medical help during healthcare restrictions, however, 57.3%(n=51/89) reported that contacting their physician during COVID-19 was difficult or impossible. Patient-reported satisfaction with treatment decreased significantly during restrictions in cohort 1 (visual analog scale[VAS] 0-
ObjectiveSystemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment initiation impacts biomarkers of systemic inflammation and (2) whether these changes in systemic inflammation predict complications and mortality.DesignBiomarkers of systemic inflammation, that is, white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) were determined at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB and under stable NSBB intake. The influence of NSBB-related changes in systemic inflammation on the risk of decompensation and liver-related death was analysed using competing risk regression.ResultsOur study comprised 307 stable patients with ACLD (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17–24) mm Hg) including 231 (75.2%) with decompensated disease.WBC significantly decreased upon NSBB therapy initiation (median: −2 (IQR −19;+13)%, p=0.011) in the overall cohort. NSBB-related reductions of WBC (Child-C: −16 (−30;+3)% vs Child-B: −2 (−16;+16)% vs Child-A: +3 (−7;+13)%, p<0.001) and of CRP (Child-C: −26 (−56,+8)% vs Child-B: −16 (−46;+13)% vs Child-A: ±0 (−33;+33)%, p<0.001) were more pronounced in advanced stages of cirrhosis. The NSBB-associated changes in WBC correlated with changes in CRP (Spearman’s ρ=0.228, p<0.001), PCT (ρ=0.470, p=0.002) and IL-6 (ρ=0.501, p=0.001), but not with changes in HVPG (ρ=0.097, p=0.088).An NSBB-related decrease in systemic inflammation (ie, WBC reduction ≥15%) was achieved by n=91 (29.6%) patients and was found to be an independent protective factor of further decompensation (subdistribution HR, sHR: 0.694 (0.49–0.98), p=0.038) in decompensated patients and of liver-related mortality in the overall patient cohort (sHR: 0.561 (0.356–0.883), p=0.013).ConclusionNSBB therapy seems to exert systemic anti-inflammatory activity as evidenced by reductions of WBC and CRP levels. Interestingly, this effect was most pronounced in Child-C and independent of HVPG response. An NSBB-related WBC reduction by ≥15% was associated with a decreased risk of further decompensation and death.
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