Eradication of HCV by DAA therapy was durable irrespective of the DAA combination used. Most of the cured patients had an excellent long-term clinical prognosis. Nevertheless, the risk of new occurrence of HCC remains worrisome and thus regular surveillance is obligatory even after clinical stabilization and improvement of the patient.
BackgroundSerotonin (5-HT) improves insulin sensitivity and glucose metabolism, however, the underlying molecular mechanism has remained elusive. Previous studies suggest that 5-HT can activate intracellular small GTPases directly by covalent binding, a process termed serotonylation. Activated small GTPases have been associated with increased GLUT4 translocation to the cell membrane. Therefore, we investigated whether serotonylation of small GTPases may be involved in improving Insulin sensitivity and glucose metabolism.MethodsUsing fully differentiated L6 rat skeletal muscle cells, we studied the effect of 5-HT in the absence or presence of insulin on glycogen synthesis, glucose uptake and GLUT4 translocation. To prove our L6 model we additionally performed preliminary experiments in C2C12 murine skeletal muscle cells.ResultsIncubation with 5-HT led to an increase in deoxyglucose uptake in a concentration-dependent fashion. Accordingly, GLUT4 translocation to the cell membrane and glycogen content were increased. These effects of 5-HT on Glucose metabolism could be augmented by co-incubation with insulin and blunted by co incubation of 5-HT with monodansylcadaverine, an inhibitor of protein serotonylation. In accordance with this observation, incubation with 5-HT resulted in serotonylation of a protein with a molecular weight of approximately 25 kDa. We identified this protein as the small GTPase Rab4, the activity of which has been shown to be stimulated by both insulin signalling and serotonylation.ConclusionOur data suggest that 5-HT elicits its beneficial effects on Glucose metabolism through serotonylation of Rab4, which likely represents the converging point between the insulin and the 5-HT signalling cascades.
Knowledge of the release of volatile organic compounds (VOCs) by cells provides important information on the origin of VOCs in exhaled breath. Muscle cells are particularly important, since their release of volatiles during the exertion of an effort contributes considerably to breath concentration profiles. Presently, the cultivation of human skeletal muscle cells is encountering a number of obstacles, necessitating the use of animal muscle cells in in vitro studies. Rat L6 skeletal muscle cells are therefore commonly used as a model for studying the molecular mechanisms of human skeletal muscle differentiation and functions, and facilitate the study of the origin and metabolic fate of the endogenously produced compounds observed in breath and skin emanations. Within this study the production and uptake of VOCs by rat L6 skeletal muscle cells were investigated using gas chromatography with mass spectrometric detection, combined with head-space needle trap extraction as the pre-concentration technique (HS-NTE-GC-MS). Seven compounds were found to be produced, whereas sixteen species were consumed (Wilcoxon signed-rank test, p < 0.05) by the cells being studied. The set of released volatiles included two ketones (2-pentanone and 2-nonanone), two volatile sulphur compounds (dimethyl sulfide and methyl 5-methyl-2-furyl sulphide), and three hydrocarbons (2-methyl 1-propene, n-pentane and isoprene). Of the metabolized species there were thirteen aldehydes (2-propenal, 2-methyl 2-propenal, 2-methyl propanal, 2-butenal, 2-methyl butanal, 3-methyl butanal, n-pentanal, 2-methyl 2-butenal, n-hexanal, benzaldehyde, n-octanal, n-nonanal and n-decanal), two esters (n-propyl propionate and n-butyl acetate), and one volatile sulphur compound (dimethyl disulfide). The possible metabolic pathways leading to the uptake and release of these compounds by L6 cells are proposed and discussed. An analysis of the VOCs showed them to have huge potential for the identification and monitoring of some molecular mechanism and conditions.
We concluded that postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes and, therefore, propose that pancreatic α cell dysfunction could be viewed, at least partly, as a postprandial phenomenon.
BackgroundIn 2016, the World Health Organization (WHO) and 69th World Health Assembly approved the first global health sector strategy (GHSS) on viral hepatitis with the goal to eliminate hepatitis C virus (HCV) infections worldwide. The aim is a 90% reduction of new infections and 65% reduction of HCV-related deaths by 2030.AimThis study reports on the epidemiology of HCV infections in the Austrian state of Tyrol (total population 750,000) and uses a predictive model to identify how the WHO strategy for elimination of HCV can be achieved.MethodsWe developed a regional disease burden model based on observed local diagnosis data from 2001 to 2016. Scenarios were developed to evaluate the impact of diagnosis and treatment on HCV-related outcomes (viremic prevalence, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths) from 2015 through 2030.ResultsIn the last 15 years, 1,721 patients living in Tyrol have been diagnosed with chronic HCV infection. When ageing, mortality and treatment were factored in, there were an estimated 2,043 viremic HCV infections in 2016, of which 1,136 cases had been diagnosed. A baseline model predicts a decrease of 588 HCV cases from 2015 to 2030, which would not translate into the significant reduction of infections needed to achieve WHO global health recommendations. A total of 1,843 infected individuals need to be identified and treated to achieve the WHO goals by 2030 (1,254 averted cases as compared to baseline model). Implementation of this strategy would avoid 523 new HCV infections and decreases HCV-related mortality by 73%.ConclusionHCV elimination and >65% reduction of associated mortality are possible for Tyrol, but requires a significant increase in new diagnoses and treatment rate. The model presented in this study could serve as an example for other regions to reliably predict regional disease burden and estimate how WHO goals can be met in the future.
Psychotropic drugs, like antipsychotics and antidepressants, are often associated with metabolic side effects such as weight gain and an increased risk of the development of diabetes and an atherogenic lipid profile. These adverse effects not only bear a high cardiovascular risk and lead to higher morbidity and mortality, but are an additional burden to mentally ill patients and can be a decisive factor for the compliance and, consequently, the success of the therapy. Second generation antipsychotics (SGAs), in particular, clozapine and olanzapine, lead to significant weight gain and impair glucose metabolism. Despite the availability of newer SGAs, such as aripiprazole, which are considered to be less prone to cause metabolic side effects, olanzapine is still one of the most prescribed SGAs worldwide. Antidepressant drugs may also induce weight again and diabetes even though the literature is contradictory, probably due to different receptor affinities. This review aims to provide an overview of the metabolic side effects caused by commonly used psychotropic drugs and give insight into underlying mechanisms.
Summary Background Only few chronic hepatitis C patients treated with interferon (IFN)‐free direct acting antiviral (DAA) combinations fail to clear the virus. Most patients can be cured by retreatment with another DAA combination; however, some still fail to eradicate the virus. So far, little is known about how to best retreat these patients. In this study we summarise our real world experience of re‐retreatments. Methods One hundred and two patients who completed a DAA‐retreatment after virological failure to an IFN‐free DAA therapy and reached at least follow‐up 12 were included in this study.Twenty‐one (20.6%) of them relapsed again after retreatment (mean age 50.0 ± 10.6, 18 male, three female, GT1a:8, GT1b:4, GT1c:1, GT3a:7; GT4:1; cirrhosis:15; resistance associated substitutions [RAS]: 17/19; relapse after:SOF/SMV:2; 3D ± RBV:4; SOF/DCV ± RBV:4; SOF/LDV ± RBV:6; SOF/VEL:3; SOF/VEL/VOX:1; EBV/GZV:1).Treatment duration and addition of RBV were at the discretion of the treating physician. These 21 patients were studied in detail. Results Seventeen of the 21 patients finished a third DAA therapy: 13 achieved SVR12, three relapsed again (cirrhosis:2; SOF/VEL/RBV:GT3a; SOF/LDV/RBV:GT1a; EBV/GZV/SOF/RBV:GT1b), one was lost to follow‐up. One (GT1a, cirrhosis) achieved SVR12 after the third retherapy with 24 weeks of 3D/SOF/RBV, and one (GT3a, cirrhosis) achieved SVR4 after 24 weeks of glecaprevir/pibrentasvir, but died shortly thereafter. Overall, 95 (93.1%) of 102 patients achieved SVR12 after one or more retreatments. Sex, cirrhosis, genotype, RAS or baseline viral load were not associated with retreatment failure. Conclusion Most patients with failure to a DAA therapy achieved SVR after retreatment with a different regimen; however, 13.7% of patients required multiple retreatments.
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