Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO).

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis. AIM: To evaluate in the phase III, open-label, single-arm PLUTO study the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis. METHODS: Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed. RESULTS: Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91-100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients. CONCLUSIONS: Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807].

Progression of liver fibrosis in HIV/hepatitis C virus-coinfected individuals on antiretroviral therapy with early stages of liver fibrosis at baseline.

OBJECTIVES: The aim of the study was to assess the progression of liver fibrosis in HIV/hepatitis C virus (HCV)-coinfected patients with no or mild-to-moderate fibrosis (stages F0-F2). METHODS: Liver fibrosis was reassessed by transient elastometry (TE) between January 2009 and November 2011 in HIV/HCV-coinfected patients with stage F0-F2 fibrosis in a liver biopsy performed between January 1997 and December 2007. Patients with liver stiffness at the end of follow-up < 7.1 kPa were defined as nonprogressors, and those with values ≥ 9.5 kPa or who died from liver disease were defined as progressors. Cirrhosis was defined as a cut-off of 14.6 kPa. The follow-up period was the time between liver biopsy and TE. Cox regression models adjusted for age, gender and liver fibrosis stage at baseline were applied. RESULTS: The median follow-up time was 7.8 years [interquartile range (IQR) 5.5-10 years]. The study population comprised 162 patients [115 (71%) nonprogressors and 47 (29%) progressors; 19 patients (11.7%) had cirrhosis]. The median time from the diagnosis of HCV infection to the end of follow-up was 20 years (IQR 16.3-23.1 years). Three progressors died from liver disease (1.8%). The variables associated with a lower risk of progression were age ≤ 38 years (hazard ratio (HR) 0.32; 95% confidence interval (CI) 0.16-0.62; P = 0.001], having received interferon (HR 2.18; 95% CI 1.14-4.15; P = 0.017), being hepatitis B virus surface antigen (HBsAg) negative (HR 0.20; 95% CI 0.04-0.92; P = 0.039), and baseline F0-F1 (HR 0.43; 95% CI 0.28-0.86; P = 0.017). CONCLUSIONS: A high proportion of patients with stage F0-F2 fibrosis progress to advanced liver fibrosis. Advanced liver fibrosis must be included in the list of diseases associated with aging. Our results support the recommendation to offer HCV antiviral therapy to HIV/HCV-coinfected patients at early stages of liver fibrosis.

Meta-analysis: pegylated interferon α-2a achieves higher early virological responses than α-2b in chronic hepatitis C.

BACKGROUND: A Cochrane meta-analysis established that pegylated interferon α-2a is more effective than peginterferon α-2b in terms of sustained virological response (SVR) in the treatment of chronic hepatitis C. Rapid virological response (RVR) and early virological response (EVR) are crucial to reach SVR and to make clinical decisions. AIM: To compare RVR and EVR rates of peginterferon α-2a vs. peginterferon α-2b through a meta-analysis of previously published randomised control trials (RCT). METHODS: MEDLINE, EMBASE and LILACS databases were systematically searched up to September 2011. Seven RCT that reported complete early virological response (cEVR) were selected. A meta-analysis focusing on RVR and cEVR outcomes was conducted and Relative Efficacy (RE) was calculated. RESULTS: Meta-analysis of cEVR included seven trials (n = 4359), and yielded an estimated effect in favour of peginterferon α-2a: Crude Efficacy (CEf) was 53.3% vs. 43.8%, RE = 1.118 (CI 95% = 1.039-1.203; P = 0.0028), heterogeneity Q = 8.959; I² = 33.0% (P = 0.1759). A sub-analysis of three studies with 3409 genotype-1 patients yielded CEf: 49.4% vs. 40.2%, RE = 1.151 (CI 95% = 0.968-1.369; P = 0.1124), Q = 9.802; I² = 79.6% (P = 0.0074). Meta-analysis of RVR included five trials (n = 3833) with an estimated effect in favour of peginterferon α-2a: CEf = 25.0% vs. 16.8%, RE = 1.151 (CI 95%:1.042-1.272; P = 0.0056), Q = 1.461;I² = 0.0% (P = 0.8335). Analysis of four studies reporting RVR including 3499 patients with genotypes 1 and 4 resulted in CEf: 18.3% vs. 12.7% RE = 1.206 (CI 95% = 1.059-1.374; P = 0.0048), Q = 1.116; I² = 0.0% (P = 0.7733). CONCLUSIONS: Peginterferon α-2a may be associated with a higher cEVR and RVR than peginterferon α-2b. These findings could help to achieve higher SVR rates and support clinical decision-making in the present scenario of triple combination therapy.

Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.

BACKGROUND & AIMS: Multiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs. METHODS: All cases of DILI systematically collected in the Spanish DILI Registry between 1994 and 2009 were retrieved. Data on demographics, clinical, laboratory and pathological findings, and outcome were analyzed. RESULTS: Nine patients (mean age 67 years, four women) out of 742, 1.21%, had evidence of two DILI episodes caused by different drugs. In four cases DILI was associated with structurally related drugs and in an additional two cases the drugs had a common target. In another case, unrelated antibiotics were implicated. In only two cases, the two drugs/herbals were not related in structure or function. All but one patient exhibited hepatocellular damage. The type of damage was consistent in both DILI episodes. Four cases presented as autoimmune hepatitis (AIH) in the second episode. CONCLUSIONS: Multiple episodes of DILI in association with different drugs occur infrequently. In each individual, the type of injury was similar during the two DILI episodes, regardless of the causative drug. Second episodes of DILI are more likely to be associated with features of AIH. It remains uncertain if this is drug-induced unmasking of true AIH or DILI with autoimmune features. These cases illustrate the dilemma faced by clinicians in distinguishing these possibilities.

A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4(+) CD25(+) CD127(low/-) FoxP3(+) T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment.

Resolution of hepatitis C virus (HCV) infection requires a complex interplay between innate and adaptative immune responses. The role of lymphocyte subpopulations during combined antiviral treatment remains to be defined. This study was conducted to assess the effect of pegylated interferon-alpha2a (pegIFN-α2a) and ribavirin treatment on peripheral blood lymphocytes, mainly on CD81 expression on B cells and CD4(+) CD25(+) CD127(low/-) FoxP3(+) regulatory T cells (Tregs) in patients with chronic HCV infection. Thirty-five patients with chronic HCV infection who started pegIFN-α2a and ribavirin treatment were enrolled. Peripheral blood mononuclear cells (PBMC) were obtained at baseline before treatment (BT), mid-treatment (MT), the end of treatment (ET) and 24weeks post-treatment (PT). During combined antiviral treatment, a significant decrease in the percentage of CD3(+) , CD8(+) , CD3(+) gamma/delta (γδ)(+) , CD19(+) lymphocyte subpopulations and Tregs was observed. There was also a significant increase in the percentage of the CD4(+) lymphocyte subpopulation and in CD81 expression levels on CD19(+) B cells when BT was compared with ET (all P<0.05). Seventeen patients were nonresponders (NR) and 18 had a sustained virological response (SVR). At baseline, NR patients had higher CD81 expression levels on CD19(+) B cells (P=0.017) and a higher Tregs percentage (P=0.025) than SVR patients. Our results suggest that immunomodulation fluctuates during antiviral treatment and that percentage CD81 expression levels on B cells and Tregs might be useful as an immunological prognostic factor for pegIFN-α2a and ribavirin treatment response in chronic HCV infection.

Estrategias de mejora del tratamiento de la hepatitis crónica C / No disponible

No disponible

Gene expression profiles for the human pancreas and purified islets in type 1 diabetes: new findings at clinical onset and in long-standing diabetes.

Type 1 diabetes (T1D) is caused by the selective destruction of the insulin-producing beta cells of the pancreas by an autoimmune response. Due to ethical and practical difficulties, the features of the destructive process are known from a small number of observations, and transcriptomic data are remarkably missing. Here we report whole genome transcript analysis validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and correlated with immunohistological observations for four T1D pancreases (collected 5 days, 9 months, 8 and 10 years after diagnosis) and for purified islets from two of them. Collectively, the expression profile of immune response and inflammatory genes confirmed the current views on the immunopathogenesis of diabetes and showed similarities with other autoimmune diseases; for example, an interferon signature was detected. The data also supported the concept that the autoimmune process is maintained and balanced partially by regeneration and regulatory pathway activation, e.g. non-classical class I human leucocyte antigen and leucocyte immunoglobulin-like receptor, subfamily B1 (LILRB1). Changes in gene expression in islets were confined mainly to endocrine and neural genes, some of which are T1D autoantigens. By contrast, these islets showed only a few overexpressed immune system genes, among which bioinformatic analysis pointed to chemokine (C-C motif) receptor 5 (CCR5) and chemokine (CXC motif) receptor 4) (CXCR4) chemokine pathway activation. Remarkably, the expression of genes of innate immunity, complement, chemokines, immunoglobulin and regeneration genes was maintained or even increased in the long-standing cases. Transcriptomic data favour the view that T1D is caused by a chronic inflammatory process with a strong participation of innate immunity that progresses in spite of the regulatory and regenerative mechanisms.

Endoscopist experience as a risk factor for colonoscopic complications.

AIM: We aimed to determine the incidence of colonic perforation (CP) following colonoscopy and postpolypectomy bleeding (PPB) in a teaching hospital, assessing the influence of endoscopist experience as a risk factor. METHOD: All colonoscopies performed between 1995 and 2008 were reviewed. Demographic data, endoscopic procedure information, incidence of CP and PPB, and endoscopist experience were recorded. RESULTS: In the 14-year period, 25,214 endoscopic colonic procedures were performed, and 3991 patients underwent polypectomy. The overall CP risk was 0.51/1000 procedures; and PPB 14.7/1000. The relative risk (RR) ratio of complications was 2.8/1000 procedures. The RR rate was highest for endoscopists performing less than 591 procedures per year (4.0/1000 [95% CI, 3.7-4.3] vs 2.9/1000 [95% CI, 2.6-3.2]), P < 0.001). CONCLUSION: The complication rate after colonoscopy was comparable to that previously reported. Colonoscopy carried out by a low-volume endoscopist was independently associated with bleeding and perforation.

Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes.

Dendritic cells (DCs) are powerful antigen-presenting cells capable of maintaining peripheral tolerance. The possibility to generate tolerogenic DCs opens new therapeutic approaches in the prevention or remission of autoimmunity. There is currently no treatment inducing long-term tolerance and remission in type 1 diabetes (T1D), a disease caused by autoimmunity towards beta cells. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow islet regeneration. Apoptotic cells--a source of autoantigens--are cleared rapidly by macrophages and DCs through an immunologically silent process that contributes to maintaining tolerance. Our aims were to prevent T1D and to evaluate the re-establishment of peripheral tolerance using autologous DCs pulsed in vitro with apoptotic bodies from beta cells. Immature DCs derived from bone marrow of non-obese diabetic (NOD) mice were obtained and pulsed with antigen-specific apoptotic bodies from the beta cell line NIT-1. Those DCs that phagocytosed apoptotic cells diminished the expression of co-stimulatory molecules CD40 and CD86 and reduced secretion of proinflammatory cytokines. Moreover, these cells were resistant to increase the expression of co-stimulatory molecules after lipopolysaccharide activation. The administration of these cells to NOD transgenic mice expressing interferon-beta in their insulin-producing cells, a model of accelerated autoimmune diabetes, decreased diabetes incidence significantly and correlated positively with insulitis reduction. DCs pulsed with apoptotic cells that express disease-associated antigens constitutes a promising strategy to prevent T1D.

Hepatotoxicidad secundaria a “productos naturales”: análisis de los casos notificados al Registro Español de Hepatotoxicidad / No disponible

Introducción: la toxicidad hepática asociada al uso crecientede productos de “remedios naturales” es un fenómeno emergente.Objetivos: valoración de las características epidemiológicas,clínicas y demográficas de los casos de hepatotoxicidad secundariosa productos herbales (PH) y suplementos dietéticos(SD).Pacientes y métodos: análisis de los casos de hepatotoxicidaddebida a PH y SD incluidos en el Registro Español de Hepatotoxicidad.Resultados: trece casos de un total de 521 casos (2%) dereacciones adversas hepáticas incluidas en el registro entre1994 y 2006, eran secundarios a PH/SD, representando el décimogrupo terapéutico responsable por orden de frecuencia,por delante de analgésicos, ansiolíticos y antipsicóticos. Nuevepacientes (69%) eran mujeres y la edad media fue de 45 años.Nueve pacientes (69%) presentaron ictericia. El tipo de dañomás frecuente fue el hepatocelular (12; 92%) y un 31% de loscasos presentaron datos de hipersensibilidad. La sustancia máscomúnmente involucrada en los casos de daño hepático fue laCamellia sinensis (23%) seguida de Rhamnus purshianus eisoflavonas (Fitosoja®, Biosoja®) con dos casos cada uno (15%).Tres casos (23%) presentaron re-exposición positiva.Conclusiones: la hepatotoxicidad originada por PH/SD noes excepcional, y su perfil es la hepatitis aguda hepatocelular ictéricapredominantemente en mujeres. La frecuente ocurrenciade reexposición positiva en estos pacientes indica un bajo índicede sospecha y un retraso o ausencia de diagnóstico de estetipo de reacción adversa

Background: toxic liver damage associated with the use ofnatural remedies is a growing health problem.Objectives: to analyze the demographics, and clinical andepidemiological characteristics of patients developing liver injuryrelated to these remedies.Patients and methods: all DILI cases associated with the useof herbal remedies (HR) or dietary supplements (DS) submitted tothe Spanish Registry were analyzed. Type of liver damage, severity,and outcome were specifically evaluated.Results: thirteen cases out of 521 DILI cases (2%) submittedto the Spanish Liver Toxicity Registry between 1994 and2006 were related to HR/DS, which ranked as the 10th therapeuticgroup with a greater number of cases and above painkillers, anxiolytics, and antipsychotic drugs. Nine patients (69%)were female (mean age 45 years). Nine cases (69%) had jaundiceat presentation. The predominating type of liver damagewas hepatocellular (12; 92%), and 31% of cases exhibited thecommon features of hypersensitivity. Camellia sinensis (3,23%) was the main causative herb, followed by Rhamnus purshianusand isoflavones (Fitosoja®, Biosoja®) (2 cases each,15%). Three cases (23%) were rechallenged with the offendingproduct.Conclusions: the incidence of hepatic damage related toHR/DS is not so rare, the most common profile of affected patientsbeing a woman with acute hepatocellular hepatitis. Lowsuspicion regarding the putative role of herbs in hepatotoxicitymakes diagnosis more difficult, and probably increases the incidenceof inadvertent rechallenge in these patients

Natural killer cells are required for accelerated type 1 diabetes driven by interferon-beta.

The destruction of beta cells by the islet infiltrating lymphocytes causes type 1 diabetes. Transgenic mice models expressing interferon (IFN)-beta in beta cells, in the non-obese diabetic (NOD) strain and in a diabetes-free, major histocompatibility complex-matched, homologous strain, the non-obese resistant (NOR) mice, developed accelerated type 1 diabetes after 3 weeks of age. Our aim was to determine if natural killer (NK) cells could affect the acceleration of the disease. We determined the amount of NK cells in the pancreas, spleen and lymph nodes from NOD rat insulin promoter (RIP)-IFN-beta mice. Pancreatic cytokines were assessed by quantitative real-time polymerase chain reaction and protein arrays. To confirm the relevance of NK cells in the acceleration of autoimmune diabetes this subset was depleted with anti-asialo GM1 antibodies. An increase of intrapancreatic NK cells characterized the accelerated onset of diabetes both in NOD and NOR RIP-IFN-beta transgenic models. Cytokines involved in NK function and migration were found to be hyperexpressed in the pancreas from accelerated diabetic mice. Interestingly, the depletion of NK cells in vivo abolished completely the acceleration of diabetes. NK cells connect innate to adaptive immunity and might play a role in autoimmunity. We report here that NK cells are required critically in the pancreas for accelerated diabetes. This model links inflammation to acceleration of beta cell-specific autoimmunity mediated by NK cells.

[Liver injury induced by "natural remedies": an analysis of cases submitted to the Spanish Liver Toxicity Registry]. / Hepatotoxicidad secundaria a "productos naturales": análisis de los casos notificados al Reigstro Español de Hepatotoxicidad.

BACKGROUND: toxic liver damage associated with the use of natural remedies is a growing health problem. OBJECTIVES: to analyze the demographics, and clinical and epidemiological characteristics of patients developing liver injury related to these remedies. PATIENTS AND METHODS: all DILI cases associated with the use of herbal remedies (HR) or dietary supplements (DS) submitted to the Spanish Registry were analyzed. Type of liver damage, severity, and outcome were specifically evaluated. RESULTS: thirteen cases out of 521 DILI cases (2%) submitted to the Spanish Liver Toxicity Registry between 1994 and 2006 were related to HR/DS, which ranked as the 10th therapeutic group with a greater number of cases and above pain killers, anxiolytics, and antipsychotic drugs. Nine patients (69%) were female (mean age 45 years). Nine cases (69%) had jaundice at presentation. The predominating type of liver damage was hepatocellular (12; 92%), and 31% of cases exhibited the common features of hypersensitivity. Camellia sinensis (3, 23%) was the main causative herb, followed by Rhamnus purshianus and isoflavones (Fitosoja(R), Biosoja(R)) (2 cases each, 15%). Three cases (23%) were rechallenged with the offending product. CONCLUSIONS: the incidence of hepatic damage related to HR/DS is not so rare, the most common profile of affected patients being a woman with acute hepatocellular hepatitis. Low suspicion regarding the putative role of herbs in hepatotoxicity makes diagnosis more difficult, and probably increases the incidence of inadvertent rechallenge in these patients.

De novo depression and anxiety disorders and influence on adherence during peginterferon-alpha-2a and ribavirin treatment in patients with hepatitis C.

BACKGROUND: Depression and anxiety have been associated with interferon treatment and low treatment adherence. AIM: To study the incidence and associated risk factors of depressive and anxiety disorders during pegylated interferon plus ribavirin and treatment adherence in a prospective cohort of 176 patients with chronic hepatitis C patients. METHODS: Patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV Mental Disorders and the Patient Health Questionnaire and the Hospital Anxiety and Depression Scale were completed. Both questionnaires were completed also after 4, 12 and 24 weeks of treatment. RESULTS: De novo depressive and/or anxiety disorders were diagnosed in 53 (36%) patients, in whom antidepressants and/or anxiolytics were administered. Higher baseline depression-subscale score (OR = 27.8, 95% CI = 2.82-333), primary education level (OR = 3.1, 95% CI = 1.40-7.03) and being an immigrant (OR = 3.2, 95% CI = 1.12-9.47) were predictors of psychiatric disorders during anti-viral therapy. The percentage of patients with good adherence was lower in those with depression and/or anxiety (79% vs. 90%, P < 0.04). Only one patient (1%) discontinued treatment because of a major depressive episode. Depression and/or anxiety disorders had no effect on attainment of sustained virological response. CONCLUSION: Early detection and treatment of depressive and anxiety disorders favours good adherence to anti-viral treatment in hepatitis C.

Safety and efficacy of an induction dose of pegylated interferon alpha-2a on early hepatitis C virus kinetics in HIV/HCV co-infected patients: the CORAL-1 multicentre pilot study.

To evaluate the safety and efficacy of an induction dose of pegylated interferon alpha 2a (IFN-alpha2a) on the 12-week hepatitis C virus (HCV) kinetics in human immunodeficiency virus (HIV) patients co-infected with HCV. One hundred sixteen HIV/HCV co-infected patients from nine hospitals in Spain were randomized to receive 270 microg/week of pegylated IFN-alpha2a for 4 weeks followed by 180 microg/week for 8 weeks or 180 microg/week for 12 weeks. Ribavirin was given at a daily dose of 1000 or 1200 mg. The main outcome measure was the percentage of patients achieving an HCV-RNA below 50 IU/mL or a decrease of 2 or more log(10) at week 12 (early virologic response, EVR). HCV-RNA was measured at baseline, weekly, for the first 4 weeks and monthly thereafter. We observed no difference in the percentage of patients achieving an EVR between arms (on-treatment, 74% in both arms; intention-to-treat, 70% in the induction arm and 67% in the control arm), nor were there differences in the percentage achieving an undetectable HCV qualitative polymerase chain reaction at any time points or in the decrease in HCV-RNA from baseline. No differences were found between arms in the percentage of dropouts (8% in the whole study population). Our study failed to find a benefit of an induction dose of 270 microg/week of pegylated IFN-alpha2a for 4 weeks on the EVR in co-infected patients who are treatment naive. Despite the lack of benefit with this regimen, induction therapy with this schedule was safe and well tolerated in co-infected patients.

Treatment of chronic he1patitis C genotype 1 with peginterferon-alpha2a (40 kDa) plus ribavirin under routine clinical practice in Spain: early prediction of sustained virological response rate.

BACKGROUND: Sustained virological response rates of up to 52% have been obtained with peginterferon alpha2a (40 kDa) plus ribavirin in patients suffering from chronic hepatitis C genotype 1 in randomized-controlled trials. AIM: To assess early virological response and its clinical utility in predicting an sustained virological response in patients suffering from chronic hepatitis C genotype 1 in routine clinical practice in Spain. METHODS: Treatment-naïve patients received pegylated interferon alpha2a (40 kDa) 180 microg/week plus ribavirin 1000/1200 mg/day for 48 weeks, and were followed for a further 24 weeks. Overall, 475 patients received at least one dose of medication and were included in the efficacy population. RESULTS: The overall sustained virological response rate was 48%. Of those with week 12 virological data, 83% had an early virological response. The negative predictive value of an early virological response was 93%. CONCLUSION: If sustained virological response is the goal, a treatment-decision based on a 12-week evaluation during routine clinical practice is feasible.

Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNbeta.

AIMS/HYPOTHESIS: The expression of IFNbeta in beta cells results in accelerated type 1 diabetes. The REG family of beta cell proliferation factors have been described as autoantigens in autoimmune diabetes. The aim of this study was to determine the effect of IFNbeta on Reg expression, and the implications of this in terms of autoimmunity. METHODS: Reg gene expression was determined in islets from non-obese diabetic (NOD) RIP-HuIFNbeta mice by cDNA microarray, quantitative real-time PCR and immunohistochemistry. The effect of IFNbeta on Reg1 and Reg2 expression was assessed in the NOD insulinoma cell line NIT-1. IL-6, known to induce Reg expression, was measured in the insulitis microenvironment. Morphological studies were carried out to determine islet enlargement in this model. RESULTS: Reg2 was upregulated in islets from the NOD RIP-HuIFNbeta mice at the onset of the autoimmune attack. IFNbeta upregulates Reg1 and Reg2 genes in NIT-1 cells. The expression of Il6 was increased in islets from transgenic mice and in NIT-1 cells exposed to HuIFNbeta. Moreover, islets from transgenic mice were enlarged compared with those from wild-type mice. CONCLUSIONS/INTERPRETATION: Reg overexpression correlates well with the acceleration of diabetes in this model. The upregulation of Reg suggests that islets try to improve hyperglycaemia by regenerating the cells lost in the autoimmune attack. Reg expression is regulated by several factors such as inflammation. Therefore, the overexpression of an IFNbeta-induced autoantigen (REG) in the islets during inflammation might contribute to the premature onset of diabetes.

Tolerance, Autoimmunity and Immune Regulation: Report from the Keystone Symposia, Breckenridge, Colorado (USA)

Los grupos internacionales más relevantes en tolerancia inmunológica y autoinmunidad participaron en el Simposio Keystone ‘Tolerancia, Autoinmunidad y Regulación Inmunológica’ en Breckenridge, Colorado, entre el 21 y el 26 de marzo de 2006. Las ponencias describieron los avances en la investigación en el campo de la tolerancia y la autoinmunidad. En este resumen se ha organizado la información en cinco áreas: 1) Genes y señalización en la regulación del sistema inmune, 2) Desencadenantes extrínsecos y aspectos intrínsecos de la autoinmunidad, 3) Supresión y regulación del sistema inmune, 4) Ensayos clínicos de inmunotolerancia, 5) Debate y reconocimientos a la trayectoria científica. Los resultados presentados en el simposio demuestran los continuos avances en el conocimiento de la tolerancia y ponen de manifiesto la necesidad de continuar investigando en esta línea. Esto contribuiría al desarrollo de ensayos clínicos de prevención de enfermedades autoinmunes en sujetos de riesgo

The most relevant international groups working in immunological tolerance and autoimmunity participated in the Keystone Symposia ‘Tolerance, Autoimmunity and Immune Regulation’ in Breckenridge, Colorado, between the 21st and 26th of March 2006. Lectures and abstracts described new research work and advances relevant to tolerance and autoimmunity. In this report, the information is organized in five areas: 1) Genes and signals in immune regulation, 2) Extrinsic triggers and intrinsic drivers of autoimmunity, 3) Suppression and regulation of the immune system, 4) Translating tolerance to the clinic, 5) Debate and awards. The results presented in the meeting demonstrate the continuous advances in the knowledge of tolerance and prove the need to pursue research on this field. This may help to develop clinical trials to prevent autoimmune diseases in at risk subjects

Insulin-like growth factor I improves intestinal barrier function in cirrhotic rats.

BACKGROUND AND AIMS: In liver cirrhosis, disruption of the intestinal barrier facilitates bacterial translocation and spontaneous bacterial peritonitis. Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesised by hepatocytes that displays hepatoprotective activities and trophic effects on the intestine. The aim of this study was to investigate the effect of IGF-I on intestinal barrier function in cirrhotic rats. METHODS: In rats with carbon tetrachloride induced cirrhosis, we investigated the effect of IGF-I therapy on: (a) portal pressure; (b) intestinal histology and permeability to endotoxin and bacteria; (c) intestinal expression of cyclooxygenase 2 (COX-2) and tumour necrosis factor alpha (TNF-alpha), two factors that influence in a positive and negative manner, respectively, the integrity of the intestinal barrier; (d) intestinal permeability to 3H-mannitol in rats with bile duct ligation (BDL); and (e) transepithelial electrical resistance (TER) of polarised monolayers of rat small intestine epithelial cells. RESULTS: IGF-I therapy reduced liver collagen expression and portal pressure in cirrhotic rats, induced improvement in intestinal histology, and caused a reduction in bacterial translocation and endotoxaemia. These changes were associated with diminished TNF-alpha expression and elevated COX-2 levels in the intestine. IGF-I reduced intestinal permeability in BDL rats and enhanced barrier function of the monolayers of epithelial intestinal cells where lipopolysaccharide (LPS) caused a decrease in TER that was reversed by IGF-I. This effect of IGF-I was associated with upregulation of COX-2 in LPS treated enterocytes. CONCLUSIONS: IGF-I enhances intestinal barrier function and reduces endotoxaemia and bacterial translocation in cirrhotic rats. IGF-I therapy might be useful in the prevention of spontaneous bacterial peritonitis in liver cirrhosis.

[Atypical presentation of distant metastases from hepatocarcinoma]. / Presentación atípica de metástasis a distancia de hepatocarcinoma.

Hepatocarcinoma (HCC) is the most frequent primary malignant hepatic tumour. These tumours usually develop in cirrhotic liver; for this reason, periodic screening using alphafetoprotein determination and abdominal ultrasonography is considered in cirrhotic patients with preserved hepatocellular function. This strategy allows early detection of HCC, increasing the proportion of curable tumours. The most frequent metastasic dissemination is portal vein neoplasic thrombosis, being unusual the occurrence of spread metastases in other organs. We present 3 cases of atypical HCC metastasis with non specific clinical manifestations which initial diagnosis was wrong. Because of a longer survival of these patients in recent years, spread metastasis might be considered in patients with known HCC and non specific symptoms.