Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

OBJECTIVE Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACL F development in compensated and recompensated patients. DESIGN 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACL F development. Two external cohorts (n=327) (recompensation, AD and ACL F) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1- dependent), were measured. In rats, bile duct ligationinduced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured. RESULTS Patients developing ACL F showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACL F development than compensated patients. Baseline CLIF-­C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACL F development in compensated and CLIF-­C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACL F and higher IL-1α and IL-1β detection rates in patients with ACL F were confirmed in the two external cohorts. CONCLUSION Previous AD is an important risk factor for fatal ACL F development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACL F development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosi

Early adipogenesis is repressed through the newly identified FHL2-NFAT5 signaling complex

The LIM-domain-only protein FHL2 is a modulator of signal transduction and has been shown to direct the differentiation of mesenchymal stem cells towards osteoblast and myocyte phenotypes. We hypothesized that FHL2 may simultaneously interfere with the induction of the adipocyte lineage. Therefore, we investigated the role of FHL2 in adipocyte differentiation. For these studies pre-adipocytes isolated from mouse adipose tissue and the 3T3-L1 (pre)adipocyte cell line were applied. We performed FHL2 gain of function and knockdown experiments followed by extensive RNAseq analyses and phenotypic characterization of the cells by oil-red O (ORO) lipid staining. Through affinity-purification mass spectrometry (AP-MS) novel FHL2 interacting proteins were identified. Here we report that FHL2 is expressed in pre-adipocytes and for accurate adipocyte differentiation, this protein needs to be downregulated during the early stages of adipogenesis. More specifically, constitutive overexpression of FHL2 drastically inhibits adipocyte differentiation in 3T3-L1 cells, which was demonstrated by suppressed activation of the adipogenic gene expression program as shown by RNAseq analyses, and diminished lipid accumulation. Analysis of the protein-protein interactions mediating this repressive activity of FHL2 on adipogenesis revealed the interaction of FHL2 with the Nuclear factor of activated T-cells 5 (NFAT5). NFAT5 is an established inhibitor of adipocyte differentiation and its knockdown rescued the inhibitory effect of FHL2 overexpression on 3T3-L1 differentiation, indicating that these proteins act cooperatively. We present a new regulatory function of FHL2 in early adipocyte differentiation and revealed that FHL2-mediated inhibition of pre-adipocyte differentiation is dependent on its interaction with NFAT5. FHL2 expression increases with aging, which may affect mesenchymal stem cell differentiation, more specifically inhibit adipocyte differentiation

Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure.

Acute‐on‐chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short‐term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short‐term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD. Conclusion: These data support SI as the primary driver of ACLF in cirrhosis

Іншомовні аспекти фахової між культурної комунікації в сучасній вітчизняній і зарубіжній науковій літературі

У статті розглядаються основні напрямки сучасних вітчизняних і зарубіжних наукових досліджень з іншомовної фахової міжкультурної комунікації. Aspects of the professional foreign language of intercultural communication in modern domestic and foreign scientific literature. The paper discusses the main directions of current domestic and foreign scientific research in the field of professional foreign language intercultural communication

Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death

Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

La transparencia sobre sostenibilidad en gobiernos regionales: el caso de España

En el actual contexto de crisis, los ciudadanos demandan al sector público mayor transparencia y rendición de cuentas. Este trabajo pretende avanzar en el conocimiento de las prácticas de sostenibilidad en la administración pública. Para ello proponemos comparar la divulgación de información sobre sostenibilidad realizada por distintos gobiernos regionales, analizando las webs de los mismos mediante un análisis de contenido, usando para ello un listado de ítems basado en las guías del Global Reporting Initiative (GRI). Nuestros resultados muestran que los gobiernos regionales españoles difunden dos tercios de la información requerida por el GRI, presentando la información social un nivel de respuesta mayor y la información general un menor nivel de difusión. Además, aquellos gobiernos regionales con mayor compromiso ambiental publican más información sobre sostenibilidad. De nuestras conclusiones podemos destacar que la mala situación financiera que atraviesan no parece impulsar a los gobiernos regionales españoles a divulgar información sobre sostenibilidad

E-government implementation : transparency, accessibility and usability of government websites

peerReviewe

Leukocytes from obese individuals exhibit an impaired SPM signature.

Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low-grade systemic inflammation showed reduced leukocyte production of the DHA-derived monohydroxy fatty acid 17-hydroxy-DHA (HDHA) and unbalanced formation of SPMs (in particular D-series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B4. Mechanistic studies attributed this impairment to reduced 15-lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5-LOX levels and reduced 5-LOX Ser271 phosphorylation and distinct intracellular 5-LOX redistribution. However, 15-LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of D-series Rvs was completely rescued by incubation with the intermediate precursor 17-HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis (e.g., 17-HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.-López-Vicario, C., Titos, E., Walker, M. E., Alcaraz-Quiles, J., Casulleras, M., Durán-Güell, M., Flores-Costa, R., Pérez-Romero, N., Forné, M., Dalli, J., Clària, J. Leukocytes from obese individuals exhibit an impaired SPM signature

Hip fracture co-management in the elderly in a tertiary referral hospital: A cohorts study

[ES] Introducción: La fractura de cadera del anciano es de los diagnósticos más prevalentes en los servicios de Traumatología, con gran impacto en términos clínicos, económicos y sociales. Nuestro objetivo es analizar el impacto clínico de un modelo de comanejo entre Traumatología y Medicina Interna para pacientes ancianos ingresados por fractura de cadera en un hospital de tercer nivel. Material y métodos: Cohortes retrospectivas de pacientes mayores de 65 años ingresados por fractura de cadera entre enero de 2005 y agosto de 2006 (cohorte HIST) sin modelo de comanejo, y entre enero de 2008 y agosto de 2010 (cohorte COFRAC) con dicho modelo. Se analizaron características demográficas, clínicas y quirúrgicas, incidencia de complicaciones, mortalidad y reingreso a los 30 días. Resultados: Se incluyó a 701 pacientes (471 HIST, 230 COFRAC). No hubo diferencias en edad, género, demora quirúrgica, tiempo y tipo de cirugía e intervención, estancia, deambulación al alta, consulta en urgencias ni reingreso o mortalidad a 30 días. Hubo diferencias en identificación de pluripatológicos (16,8 vs. 24,4%; p = 0,02), osteoporosis (3,9 vs. 7,6%; p = 0,03) o déficit motor (3,5 vs. 8,8%; p = 0,03), fármacos del tratamiento (3,7 ± 2,5 vs. 4,3 ± 3,2; p 0,01) y de función renal (44,5 vs. 97,3%; p < 0,01) y mortalidad intrahospitalaria (4,6 vs. 1,3%; p = 0,02). Conclusiones: El comanejo de pacientes ancianos ingresados por fractura de cadera permite mejorar la documentación de los problemas crónicos previos y el control de complicaciones hospitalarias y disminuye la mortalidad intrahospitalaria.[EN] Introduction: Hip fracture in the elderly is one of the most prevalent diagnoses in Orthopedic Surgery Departments. It has a great impact in medical, economic and social terms. Our objective is to analyze clinical impact of a co-management care model between orthopedic surgery and internal medicine departments for elderly patients admitted with hip fracture in a tertiary referral hospital. Material and methods: Retrospective cohort study of patients older than 65 years old admitted with hip fracture between January 2005-August 2006 (HIST cohort) without a co-management care model, and between January 2008-August 2010 (COFRAC cohort) with a co-manEdadment care model. Analysis of demographic, clinical and surgery characteristics, complications incidence and mortality and re-admissions at 30 days was made. Results: A total of 701 patients were included (471 HIST, 230 COFRAC). There were no differences in sex, gender, time to surgery, type of anesthesia and surgery, length of stay, ambulation at discharge and 30-days emergency room consultation, readmissions or mortality at 30 days. There were differences in identification of polypatological patients (16.8 vs. 24.4%, P = 0.02), presence of osteoporosis (3.9 vs. 7.6%, P = 0.03), motor deficit (3.5 vs. 8.8%, P = 0.03), number of chronic drugs (3.7 ± 2.5 vs. 4.3 ± 3.2, P 0.01) and renal failure at discharge (44.5 vs. 97.3%, P < 0.01) and hospital mortality (4.6 vs. 1.3%, P = 0.02). Conclusions: Co-management for elderly patients admitted with hip fracture provides a better information about previously chronic conditions, a higher control of hospital complications and decreases hospital mortality