Epicutaneous Administration of 17ß-Estradiol Induces Langerhans Cells Depletion.

BACKGROUND: Langerhans cells (LC) number and function in mouse vaginal mucosa are affected by 17ß-estradiol (E2) application; nonetheless, its effect on epidermal LC has not been studied. The purpose of this study was to evaluate the effect of topical administration of E2 on the number, phenotype, and migratory ability of LC in mouse skin. METHODS: Ears of adult CD1 male mice were topically treated once with several doses. Immunohistochemical staining for CD207 and TUNEL staining were performed. LC migration to lymph nodes and the effect on the expression of costimulatory molecules on cultured dendritic cells (DC) were also evaluated. RESULTS: E2 decreased the number of CD207+ LC in a dose-dependent manner. One hour after treatment, 1 and 10 µg/mL E2 significantly reduced the LC number by 21% and 26%, respectively, after two hours, the reduction was 23% and 41%, respectively. After 48 hours, LC recovered, and after 96 hours of treatment, the CD207+/MHCII+ DC numbers were increased in regional lymph nodes. However, CD86 and CD40 molecules were expressed at lower levels than in positive control. The TUNEL assay did not show apoptotic cells. Furthermore, in cultured DC, E2 promoted a decrease in CD40 and CD86 expression and an increase in CD273, CD274, MHCII, and CCR7. CONCLUSIONS: The topical administration of E2 induced a transitory local diminution of LC population and a tolerogenic phenotype. This decrease in epidermal LC suggests that E2 may affect skin immune responses, inducing an inhibitory response, which should be considered when prescribing topical E2 medications.

Volumen plaquetario medio como predictor de la mortalidad en pacientes con sepsis: revisión sistemática y metanálisis / Mean platelet volume as a predictor of mortality in patients with sepsis: systematic review and meta-analysis

Introducción: El volumen medio plaquetario (VMP) es un biomarcador utilizado en el abordaje integral de la sepsis. Objetivo: Evaluar la asociación entre VMP con la mortalidad en pacientes con sepsis. Métodos: Se realizó una revisión sistemática de estudios observacionales en cinco bases de datos. Se analizó la mortalidad asociada con la sepsis; las intervenciones consideradas fueron VMP, APACHE y lactato sérico. Resultados: Respecto a la mortalidad asociada a sepsis, se encontró un valor significativo en la VMP a las 72 horas (200 fallecidos versus 654 no fallecidos; MD 0.83 IC95% 0.53-1.13, p=< 0.0001, I2 =72.9%); así como el valor de APACHE II (220 muertos frente a 604 no fallecidos; MD 0.81 IC95% 0.62-1.0, p= 0.0001, I2 =32%). No se encontró significancia estadística para las demás variables clínicas. Conclusiones: El aumento de la VMP se asocia con mayor riesgo de mortalidad en pacientes con sepsis, especialmente después de 72 horas de evolución de las características clínicas.

Introduction: Platelet mean volume (MVP) is a biomarker used in the integral approach to sepsis. Objective: To assess the association between MVP and mortality in patients with sepsis. Methods: A systematic review of observational studies in five databases was performed. Mortality associated with sepsis was analysed; interventions considered were MPV, APACHE and serum lactate. Results: Regarding mortality associated with sepsis, a significant value was found in the MVP at 72 hours (200 deceased versus 654 not deceased; MD 0.83 IC95% 0.53-1.13, p=<0.0001, I2 =72.9%); as well as the value of APACHE II (220 dead versus 604 not deceased; MD 0.81 IC95% 0.62-1.0, p= 0.0001, I2 =32%). No statistical significance was found for the other clinical variables. Conclusions: Increased MVP is associated with increased risk of mortality in patients with sepsis, especially after 72 hours of evolution of clinical features.

In vitro study of the protective effect of manganese against vanadium-mediated nuclear and mitochondrial DNA damage.

We aimed to study the effect of vanadium(V) exposure on cell viability, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) and to elucidate if these effects can be reverted by co-exposure to V and manganese (Mn). HepG2 cells were incubated with various concentrations of bis(maltolato)oxovanadium(IV) or MnCl2 for 32 h for viability study. The higher concentrations (59   µM V, 54 nM Mn and 59   µM V+54 nM Mn) were used to study DNA damage and uptake of V and Mn. Comet assay was used for the study of nDNA damage; mtDNA damage was studied by determining deletions and number of copies of the ND1/ND4 mtDNA region. Cellular content of V and Mn was determined using ICPMS. Cellular exposure to 59   µM V decreased viability (14%) and damaged nDNA and mtDNA. This effect was partially prevented by the co-exposure to V + Mn. Exposure to V increased the cellular content of V and Mn (812.3% and 153.5%, respectively). Exposure to Mn decreased the content of V and Mn (62% and 56%, respectively). Exposure to V + Mn increased V (261%) and decreased Mn (56%) content. The positive effects on cell viability and DNA damage when incubated with V + Mn could be due to the Mn-mediated inhibition of V uptake.

Global Epidemiology, Prevention, and Management of Hepatocellular Carcinoma.

The incidence rate of hepatocellular carcinoma (HCC) is rising. It is one of the most common cancers worldwide and accounts for substantial morbidity and mortality. Chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, and nonalcoholic fatty liver disease (NAFLD) are the most important etiologies of HCC, and effective screening and management strategies are crucial to reduce the HCC risk. For HBV, which accounts for the majority of HCC cases, most infections were acquired via perinatal and early horizontal transmission. Universal vaccination of newborns has led to a decline in HCC incidence compared with the pre-vaccination era. Effective antiviral therapies with nucleos(t)ide analogues or pegylated interferon reduced the incidence of HCC. For HCV, the emergence of effective direct-acting antiviral (DAA) agents has substantially improved cure rates; therefore all patients with HCV should be considered for DAA treatment. The most important obstacle in eliminating HCV is access to therapy. For NAFLD, the global incidence is increasing rapidly, thus its impact on HCC incidence may be explosive. Progression to HCC in NAFLD happens particularly in those with nonalcoholic steatohepatitis (NASH) and exacerbated by metabolic syndrome, or PNPLA3 gene polymorphism. Lifestyle changes are imperative while drug therapy has yet to demonstrate substantive protective effects on HCC prevention. For management of HCC, early diagnosis via imaging surveillance among persons with HCC risk factors remains the most important strategy to identify early-stage disease appropriate for resection or transplantation.

Thrombosis of the Portal Venous System in Cirrhotic vs. Non-Cirrhotic Patients.

INTRODUCTION AND AIM: Thrombosis is a vascular disorder of the liver often associated with significant morbidity and mortality. Cirrhosis is a predisposing factor for portal venous system thrombosis. The aim of this study is to determine differences between cirrhotics and non-cirrhotics that develop thrombosis in portal venous system and to evaluate if cirrhosis severity is related to the development of portal venous system thrombosis. MATERIAL AND METHODS: We studied patients diagnosed with portal venous system thrombosis using contrast-enhanced computed tomography scan and doppler ultrasound at Medica Sur Hospital from 2012 to 2017. They were categorized into two groups; cirrhotics and non-cirrhotics. We assessed the hepatic function by Child-Pugh score and model for end-stage liver disease. RESULTS: 67 patients with portal venous system thrombosis (25 with non-cirrhotic liver and 42 with cirrhosis) were included. The mean age (± SD) was 65 ± 9.5 years in cirrhotic group and 57 ± 13.2 years (p = 0.009) in non-cirrhotic group. Comparing non-cirrhotics and cirrhotics, 8 non-cirrhotic patients showed evidence of extra-hepatic inflammatory conditions, while in the cirrhotic group no inflammatory conditions were found (p < 0.001). 27 (64.29%) cirrhotic patients had thrombosis in the portal vein, while only 9 cases (36%) were found in non-cirrhotics (p = 0.02). CONCLUSIONS: In cirrhotic patients, hepatocellular carcinoma and cirrhosis were the strongest risk factors to develop portal venous system thrombosis. In contrast, extrahepatic inflammatory conditions were main risk factors associated in non-cirrhotics. Moreover, the portal vein was the most frequent site of thrombosis in both groups.

The Changing Face of the Diagnosis of Chronic and Malignant Liver Diseases: Potential New Biomarkers.

The early diagnosis of primary sclerosing cholangitis, hepatocellular carcinoma, and cholangiocarcinoma is often challenging. In a recent study in 134 patients (Arbelaiz, Hepatology 2017; 66:1125-1143), it was reported that specific proteins found in serum extracellular vesicles of patients with primary sclerosing cholangitis, hepatocellular carcinoma,orcholangiocarcinomamay be useful as noninvasive diagnostic and prognostic tools. This current article critically appraises this study.

Bile Acids in Nonalcoholic Fatty Liver Disease: New Concepts and therapeutic advances.

Nonalcoholic liver disease (NAFLD) is a major emerging health burden that is a common cause of illness and death worldwide. NAFLD can progress into nonalcoholic steatohepatitis (NASH) which is a severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism of the progression from simple steatosis to NASH is unclear. However, there are theories and hypothesis which support the link between disruption of the bile acids homeostasis and the progression of this disorder. Previous studies have been demonstrated that alterations to these pathways can lead to dysregulation of energy balance and increased liver inflammation and fibrosis. In this review, we summarized the current knowledge of the interaction between BA and the process related to the development of NAFLD, besides, the potential targets for novel therapies.

Prevalence, Risk Factors, and Survival of Patients with Intrahepatic Cholangiocarcinoma.

PURPOSE: To investigate the prevalence, related risk factors, and survival of intrahepatic cholangiocarcinoma in a Mexican population. MATERIAL AND METHODS: We conducted a cross-sectional study at Medica Sur Hospital in Mexico City with approval of the local research ethics committee. We found cases by reviewing all clinical records of in-patients between October 2005 and January 2016 who had been diagnosed with malignant liver tumors. Clinical characteristics and comorbidities were obtained to evaluate the probable risk factors and the Charlson index. The cases were staged based on the TNM staging system for bile duct tumors used by the American Joint Committee on Cancer and median patient survival rates were calculated using the Kaplan-Meier method. RESULTS: We reviewed 233 cases of hepatic cancer. Amongst these, hepatocellular carcinomas represented 19.3% (n = 45), followed by intrahepatic cholangiocarcinomas, which accounted for 7.7% (n = 18). The median age of patients with intrahepatic cholangiocarcinoma was 63 years, and most of them presented with cholestasis and intrahepatic biliary ductal dilation. Unfortunately, 89% (n = 16) of them were in an advanced stage and 80% had multicentric tumors. Median survival was 286 days among patients with advanced stage tumors (25th-75th interquartile range, 174-645 days). No correlation was found between the presence of comorbidities defined by the Charlson index, and survival. We evaluated the presence of definite and probable risk factors for the development of intrahepatic cholangiocarcinoma, that is, smoking, alcohol consumption, and primary sclerosing cholangitis. DISCUSSION: We found an overall prevalence of intrahepatic cholangiocarcinoma of 7.7%; unfortunately, these patients were diagnosed at advanced stages. Smoking and primary sclerosing cholangitis were the positive risk factors for its development in this population.

The Direct-Acting Antivirals for Hepatitis C Virus and the Risk for Hepatocellular Carcinoma.

The increase of incidences of Hepatocellular Carcinoma (HCC) will continue in the next decades. The therapies about hepatitis C infection has been questioned as a risk factor. Some authors emphasized that sustained virologic response (SVR) with interferon-based therapy reduced the risk of developing HCC. In contrast, some publications that to suggest an increasing risk of HCC in patients treated with Direct-Acting Antivirals (DAA). Whether these therapies are associated with an increased risk of HCC remains to be studied and continued long-term observational studies will be needed. The goal in HCV care needs to go beyond merely achieving an SVR.

Costo efectividad de un programa de rehabilitación cardiovascular para personas post infarto agudo al miocardio: un análisis teórico / Cardiovascular rehabilitation program in post myocardial infarction: a theoretical analysis of cost effectiveness

Pese a que la efectividad de los programas de prevención secundaria en pacientes con enfermedades cardiovasculares (ECV) ha sido ampliamente demostrada, su implementación tanto Chile como a nivel internacional ha sido pobre. Objetivo: Determinar la tasa costo-efectividad de una propuesta teórica de Programa de Rehabilitación cardiovascular (PRC) basada en la evidencia y validada por expertos, en personas post Infarto Agudo al Miocardio (IAM) en el nivel secundario de atención en salud, pertenecientes al Servicio de Salud Metropolitano Norte, Región Metropolitana. Método: Se elaboró un protocolo teórico de un PRC integral basado en las guías clínicas internacionales (AHA, AACVPD, NICE, ESC, NHMRC, Victoria), ajustado a la realidad chilena, el cual fue costeado. Luego se estimó los años de vida por muerte prematura con y sin participación en un PRC, para obtener finalmente los Años de Vida Ganados (AVG). Con ello se calculó la tasa de costo-efectividad. Resultados: El costo anual del centro de rehabilitación cardíaca es de $64.407.065 CLP. La Razón Incremental de Costo Efectividad (ICER), considerando una reducción de la mortalidad tardía del 25%, es de CLP$475.209,72/AVG. Valor que al ser menor al Producto Interno Bruto per cápita, se considera como una intervención muy costo efectiva. Conclusión: Un programa de rehabilitación cardiaca integral post-IAM parece muy costo-efectivo.

Although the effectiveness of secondary prevention programs in patients with cardiovascular disease (CVD) has been widely demons-trated, its implementation both in Chile and other countries has been scarce. Aim: To determine the cost-effectiveness of an evidence-based theoretical comprehensive cardiac rehabilitation (CCR), validated by experts, for post-acute myocardial infarction (AMI) patients at the secondary level from the Chilean Public Health System. Methods: A theoretical protocol of a CCR program based on recommendations from international guidelines (AHA, AACVPD, NICE, ESC, NHMRC, Victoria) was elaborated and adjusted to the Chilean conditions. A cost analysis was performed. Life years due to premature death were estimated with and without participation in the cardiac rehabilitation program (CRP). We obtained gained life-years, and calculated the ratio of cost-effectiveness. Results: The annual cost of the cardiac rehabilitation center is $ 64,407,065 CLP. The Incremental Cost Effectiveness Ratio (ICER) considering a reduction in late mortality of 25%, is CLP$475.209,72/ AVG. Since it is less than one per capita gross domestic product, it is considered as a very cost-effective intervention. Conclusion: A comprehensive cardiac rehabilitation program post AMI is very cost-effective for use in a in public health service. It should be considered to review Optimal frequency and intensity of exercise in order to achieve optimal results should be determined.

Potential probiotic yeasts isolated from the fish gut protect zebrafish (Danio rerio) from a Vibrio anguillarum challenge.

Due to the negative consequences associated with the use of antibiotics, researchers, and food producers have studied alternatives, such as probiotics, for the control of fish diseases. The probiotic properties of yeasts in aquaculture have been scarcely considered. The present study investigated the probiotic properties of local yeast strains for aquaculture application in the protection of bacterial diseases. Yeast strains (n = 15), previously isolated from the intestinal gut of healthy salmonids, yellowtail, and croaker, were evaluated for their protection of zebrafish larvae following a Vibrio anguillarum challenge. We developed an infection model on zebrafish larvae with V. anguillarum, observing rapid mortality (≥50%) 5 days post-immersion challenge. Infection of Tg(Lyz:DsRed)(nz50) larvae with fluorescent-marked V. anguillarum showed the oro-intestinal as the natural route of infection concomitant with an inflammatory response of the larvae reflected by neutrophil migration outside the hematopoietic tissue. Thirteen of 15 strains increased the percentage of larvae survival after the V. anguillarum challenge, although no yeast showed in vitro anti-V. anguillarum activity. In a subset of yeasts, we explored yeast-larvae interactions using fluorescent yeast and evaluated larvae colonization by culture analysis. All fluorescent yeasts were located in the gastrointestinal tract until 5 days post-inoculation (dpi). Yeasts reached 10(3) CFU/larvae at 0 dpi, although the persistence until 5 dpi of the viable yeast in the gut was different among the strains. These results reveal that some yeasts isolated from the gut of fish could be potential probiotics, reducing the mortality associated to V. anguillarum challenge, and suggest that gut colonization could be involved in the protective effect. Future studies should elucidate other mechanisms involved in yeast protection and verify the beneficial effects of probiotic use in commercial fish species.

Transformaciones del sistema de salud público post reforma AUGE-GES en Valparaíso / Health system transformations following AUGE-GESreform in Valparaiso, Ch

La Reforma de Salud emprendida en el año 2005 tiene como su principal componente el Plan AUGE-GES. Pese a que su propósito fundamental ha sido mejorar la equidad en el acceso a la atención, esta política no ha sido evaluada de manera integral. El presente estudio forma parte de una investigación mayor de carácter nacional, con el objetivo de caracterizar la implementación de la política de salud desde la perspectiva regional, a nivel de servicios de salud, de hospitales y otros organismos en relación a la reorganización estructural. Para ello se utilizó metodología de investigación cualitativa, efectuándose42 entrevistas semiestructuradas a informantes clave (regionales y locales)a las cuales se realizó análisis de contenido. Los resultados señalan que la implementación de la Reforma AUGEGES en Valparaíso es valorada positivamente por todos los actores al compararla con la situación previa a la Reforma. Tanto las garantías no cumplidas como las listas de espera NO GES son resultados criticados. Se percibe una “augización” de la política. Los equipos de los tres niveles de atención han sido tensionados y enfocados a la atención curativa, postergando las actividades de prevención y promoción de la salud. El GES se visualiza como una estrategia de priorización que ha aumentado la exclusión de grupos poblacionales. Los derechos de las personas son restringidos a los derechos propios de consumidores. En base a estos resultados, es posible concluir que la Reforma AUGE-GES no ha cumplido cabalmente con la finalidad de promover el acceso equitativo a la atención en salud.

Introduction. Health Reform launched in Chile in 2005 has as its main component the AUGE-GES Plan. Although its main purpose has been to improve equity in access to care, this policy has not been evaluated comprehensively. The present study is part of a larger national investigation with the objective to characterize the implementation of health policy from a regional perspective, at the level of health services, hospitals and other agencies, in relation to structural reorganization. Methodology. The present study employed qualitative research methodology where 42semi-structured interviews to key informants (local and regional) were conducted, and content analysis was performed. Results: The results show that the implementation of the GES Reform in Valparaiso is highly valued by all stakeholders when compared to the previous situation. Unfulfilled guarantees and Non-GES waiting lists are both criticized results. GES is perceived as extremely focused public policy. Health teams have been stressed and have focused primarily on curative care, postponing prevention and health promotion. GES is seen as a prioritization strategy that has increased the exclusion of certain groups of the population. The rights of persons are restricted to their rights as consumers. Conclusion. Based on the present analysis, one can conclude that the AUGE-GES Reform has not fully complied with the objective to promote equitable access to health care.