Pivotal role of Interleukin-10 on microRNA-155 expression in regulation of the monocyte response in hypothermia.

This project investigated the effect of hypothermia on the monocyte response with the goal of understanding, which intracellular processes are affected by hypothermia leading to differences in cytokine secretion. A better understanding of the effects of hypothermia on the regulation of monocyte responses would allow targeted interventions and may reduce complications and death in hypothermic surgical patients. We found the following results: 1. The three major pro-inflammatory signaling pathways, Nuclear Factor Kß, p38 and c-Jun N-terminal-Kinase (JNK) of the Mitogen Activated Protein Kinases pathway, have increased and prolonged activation with hypothermia (32°C). The extracellular signal-related kinase (Erk) pathway shows increased activation at 15 minutes at 39°C. 2. The prolonged and increased activation of the pro-inflammatory signaling pathways results in a prolonged and increased expression of TNF-a messenger RNA (mRNA) and protein and microRNA-155 at 32°C. 3. Increased activation of Erk at 39°C leads to induction of Interleukin-10 mRNA and production of IL-10 protein. 4. The high IL-10 protein levels at 39°C result in suppression of the microRNA-155 expression, whereas the lack of IL-10 at 32°C prolongs microRNA-155 expression. 5. The increased and prolonged expression of microRNA-155 results in increased and prolonged TNF-a production at 32°C. The findings of our research demonstrate the importance of regulatory feedback loops in order to achieve a balanced immune response. The lack of the inhibitory IL-10 at 32°C results in a prolonged pro-inflammatory response, which may have detrimental effects on host defense with a subsequently increased susceptibility to infections and organ dysfunction. The improved understanding of the intracellular mechanisms involved in the regulation of the monocyte response may result in targeted interventions to ameliorate the detrimental effects of hypothermia

Early Serum Procalcitonin, Interleukin-6, and 24-Hour Lactate Clearance: Useful Indicators of Septic Infections in Severely Traumatized Patients

Background: Elevated lactate and interleukin-6 (IL-6) levels were shown to correlate with mortality and multiple organ dysfunction in severely traumatized patients. The purpose of this study was to test whether an association exists between 24-hour lactate clearance, IL-6 and procalcitonin (PCT) levels, and the development of infectious complications in trauma patients. Methods: A total of 1757 consecutive trauma patients with an Injury Severity Score (ISS)>16 admitted over a 10-year period were retrospectively analyzed over a 21-day period. Exclusion criteria included death within 72h of admission (24.5%), late admission>12h after injury (16%), and age3days) was 10%. Patients with insufficient 24-hour lactate clearance had a high rate of overall mortality and infections. Elevated early serum procalcitonin on days 1 to 5 after trauma was strongly associated with the subsequent development of sepsis (p<0.01) but not with nonseptic infections. The kinetics of IL-6 were similar to those of PCT but did differentiate between infected and noninfected patients after day 5. Conclusions: This study demonstrates that elevated early procalcitonin and IL-6 levels and inadequate 24-hour lactate clearance help identify trauma patients who develop septic and nonseptic infectious complications. Definition of specific cutoff values and early monitoring of these parameters may help direct early surgical and antibiotic therapy and reduce infectious mortalit

Comorbidities as an Indication for Metabolic Surgery

Metabolic diseases, comprising type 2 diabetes mellitus (T2DM), dyslipidemia, and non-alcoholic steatohepatitis (NASH), are rapidly increasing worldwide. Conservative medical therapy, including the newly available drugs, has only limited effects and does neither influence survival or the development of micro- or macrovascular complications, nor the progression of NASH to liver cirrhosis, nor the development of hepatocellular carcinomas in the NASH liver. In contrast, metabolic surgery is very effective independent of the preoperative body mass index (BMI) in reducing overall and cardiovascular mortality in patients with T2DM. Furthermore, metabolic surgery significantly reduces the development of microand macrovascular complications while being the most effective therapy in order to achieve remission of T2DM and to reach the targeted glycemic control. Importantly, even existing diabetic complications such as nephropathy as well as the features of NASH can be reversed by metabolic surgery. Here, we propose indications for metabolic surgery due to T2DM and NASH based on a simple but objective, disease-specific staging system. We outline the use of the Edmonton Obesity Staging System (EOSS) as a clinical staging system independent of the BMI that will identify patients who will benefit the most from metabolic surgery

Hochwasserschutz Sihl, Zürichsee, Limmat, Auslaufbauwerk Entlastungsstollen Thalwil

Aufsatz veröffentlicht in: "Wasserbau-Symposium 2021: Wasserbau in Zeiten von Energiewende, Gewässerschutz und Klimawandel, Zurich, Switzerland, September 15-17, 2021, Band 2" veröffentlicht unter: https://doi.org/10.3929/ethz-b-00049975

Hochwasserschutz Sihl, Zürichsee, Limmat - Einlaufbauwerk Entlastungsstollen Thalwil

Aufsatz veröffentlicht in: "Wasserbau-Symposium 2021: Wasserbau in Zeiten von Energiewende, Gewässerschutz und Klimawandel, Zurich, Switzerland, September 15-17, 2021, Band 2" veröffentlicht unter: https://doi.org/10.3929/ethz-b-00049975

Dissecting the physiology and pathophysiology of glucagon-like peptide-1

Copyright © 2018 Paternoster and Falasca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

Entlastungsstollen Thalwil - physikalische Modellversuche zum Auslaufbauwerk

ISSN:0377-905