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Mehta G.,University College London | Gustot T.,Laboratory of Experimental Gastroenterology | Mookerjee R.P.,University College London | Garcia-Pagan J.C.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS | And 5 more authors.
Journal of Hepatology

Summary Portal hypertension has traditionally been viewed as a progressive process, involving ultrastructural changes including fibrosis, nodule formation, and vascular thrombosis, leading to increased intrahepatic resistance to flow. However, it is increasingly recognized that a significant component of this vascular resistance results from a dynamic process, regulated by complex interactions between the injured hepatocyte, the sinusoidal endothelial cell, the Kupffer cell and the hepatic stellate cell, which impact on sinusoidal calibre. Recent findings suggest these haemodynamic findings are most marked in patients with superimposed inflammation. The precise mechanisms for vascular dysfunction in cirrhosis with superimposed inflammation remain to be fully elucidated but several studies over the past decade have started to generate the hypothesis that inflammation may be a key mediator of the pathogenesis and severity of portal hypertension in this context. This review provides a comprehensive overview of the biological mechanisms for inflammation playing a key role in the severity of portal hypertension, and illustrates potential novel therapies that act by modifying these processes. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

Vidal J.,Hospital Clinic Universitari | Vidal J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Vidal J.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS | Jimenez A.,Hospital Clinic Universitari
Current Atherosclerosis Reports

The parallel occurrence of improved glucose tolerance and increased glucagon-like peptide 1 (GLP-1) response to meal intake following metabolic surgery (MS) demonstrated in several studies has led to the notion that GLP-1 is the culprit for the impressive rates of remission of type 2 diabetes mellitus (T2DM) following MS. In this article, we critically review current evidence supporting this view. Recent studies specifically designed to elucidate a causative role of GLP-1 in the antidiabetic effects of MS call into question GLP-1 as a key player for T2DM outcome following MS procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy in morbidly obese subjects. Whether GLP-1 plays a more prominent role in the remission of T2DM following MS in subjects with moderate obesity warrants further studies. Appraisal of the mechanisms involved in the amelioration of hyperglycemia following MS is a priority, as it could help in the battle against the current combined epidemics of obesity and T2DM. © 2013 Springer Science+Business Media New York. Source

Acevedo J.,Hospital of Calella | Fernandez J.,University of Barcelona | Fernandez J.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS | Fernandez J.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehed
World Journal of Gastroenterology

Despite major advances in the knowledge and management of liver diseases achieved in recent decades, decompensation of cirrhosis still carries a high burden of morbidity and mortality. Bacterial infections are one of the main causes of decompensation. It is very important for clinical management to be aware of the population with the highest risk of poor outcome. This review deals with the new determinants of prognosis in patients with cirrhosis and bacterial infections reported recently. Emergence of multiresistant bacteria has led to an increasing failure rate of the standard empirical antibiotic therapy recommended by international guidelines. Moreover, it has been recently reported that endothelial dysfunction is associated with the degree of liver dysfunction and, in infected patients, with the degree of sepsis. It has also been reported that relative adrenal insufficiency is frequent in the non-critically ill cirrhotic population and it is associated with a higher risk of developing infection, severe sepsis, hepatorenal syndrome and death. We advise a change in the standard empirical antibiotic therapy in patients with high risk for multiresistant infections and also to take into account endothelial and adrenal dysfunction in prognostic models in hospitalized patients with decompensated cirrhosis. © 2014 Baishideng Publishing Group Inc. All rights reserved. Source

Angeli P.,University of Padua | Gines P.,University of Barcelona | Gines P.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS
Journal of Hepatology

Hepatorenal syndrome (HRS) is a severe complication of cirrhosis that is associated with poor survival. A rapid diagnosis of HRS and a prompt initiation of the treatment with terlipressin and albumin are mandatory because this leads to an improvement of prognosis. This review covers the predictive value of HRS on 3-month mortality beyond the MELD score and its consequential impact on the prioritization policy to liver transplantation (LT). Moreover, it analyzes the impact of the response to pharmacological treatment on the MELD score, its possible delaying effect on the timing of LT, and suggests a way of overcoming the paradoxical effect of terlipressin and albumin on the priority to LT in responders. Finally, the review discusses the appropriate use of combined liver-kidney transplantation (CLKT) in patients with HRS who do not respond to treatment with terlipressin and albumin. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

Gambus P.L.,Systems Pharmacology Effect Control and Modeling SPEC M Research Group | Gambus P.L.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS | Gambus P.L.,University of California at San Francisco | Troconiz I.F.,University of Navarra
British Journal of Clinical Pharmacology

Anaesthesiologists adjust drug dosing, administration system and kind of drug to the characteristics of the patient. They then observe the expected response and adjust dosing to the specific requirements according to the difference between observed response, expected response and the context of the surgery and the patient. The approach above can be achieved because on one hand quantification technology has made significant advances allowing the anaesthesiologist to measure almost any effect by using noninvasive, continuous measuring systems. On the other the knowledge on the relations between dosing, concentration, biophase dynamics and effect as well as detection of variability sources has been achieved as being the benchmark specialty for pharmacokinetic-pharmacodynamic (PKPD) modelling. The aim of the review is to revisit the most common PKPD models applied in the field of anaesthesia (i.e. effect compartmental, turnover, drug-receptor binding and drug interaction models) through representative examples. The effect compartmental model has been widely used in this field and there are multiple applications and examples. The use of turnover models has been limited mainly to describe respiratory effects. Similarly, cases in which the dissociation process of the drug-receptor complex is slow compared with other processes relevant to the time course of the anaesthetic effect are not frequent in anaesthesia, where in addition to a rapid onset, a fast offset of the response is required. With respect to the characterization of PD drug interactions different response surface models are discussed. Relevant applications that have changed the way modern anaesthesia is practiced are also provided. © 2013 The British Pharmacological Society. Source

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