Angiopoietin-Like Protein 8 Is a Novel Vitamin D Receptor Target Gene Involved in Nonalcoholic Fatty Liver Pathogenesis.

Hepatic vitamin D receptor (VDR) expression is increased in patients with nonalcoholic fatty liver (NAFL) and is required for liver steatosis in an NAFL mouse model. However, how hepatocyte VDR is involved in setting up steatosis remains unclear. The authors transduced human hepatocyte-derived cells with an adenoviral vector encoding human VDR and found that angiopoietin-like protein 8 (ANGPTL8) expression was increased upon VDR activation by vitamin D or lithocholic acid. The mRNA levels of hepatic VDR- and vitamin D-related genes [cytochrome P450 (CYP) 2R1, CYP27A1, and CYP3A4] were higher in NAFL patients compared with normal liver subjects. Noteworthy, hepatic ANGPTL8 mRNA and protein levels were elevated in NAFL patients, and its mRNA correlated with VDR mRNA and with the steatosis grade. Moreover, increases in serum conjugated bile acids, including the VDR agonist glycine-lithocholic acid, were observed in NAFL patients. Additionally, free fatty acids and insulin were able to up-regulate both VDR and ANGPTL8 mRNA in human hepatocytes, whereas ANGPTL8 gene knockdown attenuated free fatty acids-induced triglyceride accumulation in these cells. In conclusion, activated VDR up-regulates ANGPTL8 expression, contributing to triglyceride accumulation in human hepatocytes. Moreover, hepatic ANGPTL8 mRNA positively correlates with VDR mRNA content and the grade of steatosis in NAFL patients, suggesting that this novel pathway may play a key role in the pathogenesis of hepatosteatosis.

Prevalence and risk factors for biopsy-proven non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in a prospective cohort of adult patients with gallstones.

BACKGROUND & AIMS: Relationship between gallstones and non-alcoholic fatty liver disease (NAFLD), and largely non-alcoholic steatohepatitis (NASH), is uncertain. AIM: To determine the prevalence, non-invasive fibrosis markers profile and risk factors for biopsy-proven NAFLD and NASH among patients with gallstones. METHODS: Anthropometric and laboratory evaluation, an abdominal ultrasound and a liver biopsy were performed to 215 consecutive patients with gallstones referred for cholecystectomy. RESULTS: Prevalence of NASH was 10.2% whereas that of simple steatosis (SS) was 41.4%. In the cohort of NAFLD patients, negative predictive values for advanced fibrosis of FIB-4 and NAFLD fibrosis score were 96 and 95% respectively. Gallstone patients with NASH had a higher mean homeostatic model assessment (HOMA) score than those with SS (P = 0.015). Noteworthy, NASH was 2.5-fold more frequent in patients with gallstones who had metabolic syndrome than in those who did not (P < 0.001). Fatty liver on ultrasound was observed in 90.9% of gallstone patients with NASH compared with 61.8% of those with SS (P = 0.044). Using multivariate logistic regression, increased HOMA score (OR, 3.47; 95% CI, 1.41-8.52; P = 0.007) and fatty liver on ultrasound (OR, 23.27; 95% CI, 4.15-130.55; P < 0.001) were the only factors independently associated with NASH. CONCLUSIONS: Prevalence of NASH among patients with gallstones is lower than estimated previously, but NASH is frequent particularly in those patients with concurrent metabolic syndrome. The combination of an increased HOMA score with fatty liver on ultrasound has a good accuracy for predicting NASH in patients with gallstones.

Increased soluble CD36 is linked to advanced steatosis in nonalcoholic fatty liver disease.

BACKGROUND: Soluble CD36 (sCD36) clusters with insulin resistance, but no evidence exists on its relationship with hepatic fat content. We determined sCD36 to assess its link to steatosis in nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) patients. MATERIALS AND METHODS: Two hundred and twenty-seven NAFLD, eighty-seven CHC, and eighty-five patients with histologically normal liver (NL) were studied. Steatosis was graded by Kleiner's histological scoring system. Serum sCD36 and hepatic CD36 expression was assessed by immunoassay and immunohistochemistry, respectively. RESULTS: In NAFLD, serum sCD36 levels were significantly higher in simple steatosis than in NL (361.4 ± 286.4 vs. 173.9 ± 137.4 pg/mL, respectively; P < 0.001), but not in steatohepatitis (229.6 ± 202.5 pg/mL; P = 0.153). In CHC, serum sCD36 levels were similar regardless of the absence (428.7 ± 260.3 pg/mL) or presence of steatosis (387.2 ± 283.6 pg/mL; P = 0.173). A progressive increase in serum sCD36 values was found in NAFLD depending on the histological grade of steatosis (P < 0.001), but not in CHC (P = 0.151). Serum sCD36 concentrations were independently associated with advanced steatosis in NAFLD when adjusted by demographic and anthropometric features [odds ratio (OR), 1.001; 95% confidence interval (CI), 1.000 to 1.002; P = 0.021] and by metabolic variables (OR, 1.002; 95% CI, 1.000 to 1.003; P = 0.001). Interestingly, a significant correlation was observed between hepatic CD36 and serum sCD36 (ρ = 0.499, P < 0.001). CONCLUSIONS: Increased serum sCD36 is an independent factor associated with advanced steatosis in NAFLD.

Hospital-based screening outperforms primary care screening as a means of achieving hepatitis C virus micro-elimination.

AIM: To assess the respective performances of a HCV screening program in a hospital setting and a HCV screening model applied concomitantly in a primary care centre. METHODS: Adult patients consecutively admitted to hospital for ambulatory surgery were screened for anti-HCV antibodies (hospital screening cohort, HPSC), as were patients receiving blood tests for medical reasons in a primary care centre (primary care screening cohort, PCSC). Serum anti-HCV and HCV RNA levels were tested by ELISA and real-time PCR, respectively. RESULTS: Seroprevalence of HCV infection was 2.2 % in the HPSC and 1.4 % in the PCSC (p = 0.044). All viraemic patients (0.2 % in HPSC and 0.1 % in PCSC) were treated with direct-acting antivirals and 85.7 % experienced a sustained virological response. CONCLUSIONS: Hospital-based HCV screening outperformed primary care-centered screening, significantly increasing HCV case findings.

[Evaluation of mitral regurgitation severity using a simplified method based on proximal flow convergence]. / Estimación de la severidad de la insuficiencia mitral según un método simplificado basado en el flujo de convergencia proximal.

INTRODUCTION AND OBJECTIVES: Calculation of the effective regurgitant orifice (ERO) is regarded as the most accurate way of assessing the severity of mitral regurgitation (MR), but the technique's complexity limits its use. Our objective was to modify and validate a previously published semiquantitative method of assessment based on measurement of the proximal isovelocity surface area (PISA) in order to adapt it to recent recommendations from American and European cardiology societies. METHODS: In the PISA method, maximum regurgitant flow (MRF) is a function of the radius and aliasing velocity (AV). Using this relationship, it is possible to construct a nomogram formed by lines of different MRF value, which can be easily derived by looking for radius values on the graph and observing where they cross with AV values. The MR severity limits on the nomogram were set to reflect the different severity grades and limits recommended for use with ERO measurements by American and European cardiology societies. RESULTS: We studied 76 patients with MR using Doppler echocardiography. There was an excellent correlation between MRF and ERO (r=0.98, P< .001). Estimates of MR severity made using the new nomogram were in good agreement with those derived from the ERO: for a scale with three severity grades, kappa was 0.951 and the standard error was 0.11; for four grades, kappa was 0.969 and the standard error, 0.11. CONCLUSIONS: Estimates of MR severity derived semiquantitatively from MRF using the nomogram proposed here were in excellent agreement with quantitative estimates obtained using the ERO, and the method was faster and easier to use.

Diagnostic and prognostic value of virologic tests in vertical transmission of hepatitis C virus infection: results of a large prospective study in pregnant women.

BACKGROUND/AIMS: This study aimed to evaluate the value of virologic tests for the diagnosis and prognosis of hepatitis C virus (HCV) vertical transmission in a large cohort of human immunodeficiency virus (HIV)-seronegative pregnant women. METHODOLOGY: HCV RNA and viral load were tested at the first and third trimester of pregnancy as well as at time of delivery, and from their newborns at birth and after 6, 12, 24, and 36 months. Viral genotype was determined in both viremic mothers and newborns. RESULTS: Antibodies to HCV were detected in 119 mothers (0.57%), whereas serum HCV RNA tested positive in 67% of them. Interestingly, presence of serum HCV RNA was only observed in 2 babies born to 80 HCV RNA-positive mothers (transmission rate: 2.4%), appearing immediately after birth and remaining positive during the entire follow-up (36 months). These two babies raised serum transaminase levels and had the same HCV genotype (1b) as their respective mothers who had intermediate or low viral load. CONCLUSIONS: Vertical HCV transmission is an infrequent event among HIV-negative HCV-infected mothers, and the presence of serum HCV RNA immediately after birth had a high diagnostic and prognostic value, as identified those newborns who developed chronic hepatitis C.

Selecting the best site for pacing leads after cardiac surgery by evaluating the asynchrony of myocardial deformation observed with different pacing sites.

INTRODUCTION AND OBJECTIVES: After cardiac surgery, temporary pacing leads are routinely implanted in the right ventricle (RV). The objective was to investigate the effect of different ventricular pacing locations on cardiac synchrony (by evaluating myocardial deformation, or strain) and efficiency in patients undergoing cardiac surgery. METHODS: Interventricular asynchrony (i.e. the difference in the time of onset of deformation between right and left ventricles; Tε-R/L) and intraventricular asynchrony (i.e. the standard deviation and maximum difference in the time of onset of deformation in six segments of the left ventricle [LV]; Tε-SD and Tε-MD, respectively) were assessed in 19 patients. Doppler echocardiography was used to evaluate these parameters and cardiac output after pacing in the RV and in three different LV segments. RESULTS: Pacing in the RV resulted in the greatest increases in asynchrony parameters from baseline: Tε-R/L 59.8 ms (standard deviation [SD] 40.5 ms) vs. 28.23 ms (SD 56.9 ms), P=.002; Tε-SD 53.2 ms (SD 34.4 ms) vs. 36.6 ms (SD 34.9 ms), P=.007; and Tε-MD 135.3 ms (SD 82.9 ms) vs. 90.5 ms (SD 87.4 ms), P=.007. Pacing in the LV resulted in less asynchrony: for anterior LV pacing, Tε-R/L was 17.2 ms (SD 53.8 ms), Tε-SD was 35.8 ms (SD 17.9 ms), and Tε-MD was 91.3 ms (SD 45.2). The change from baseline was not significant. Cardiac output was lower after RV pacing than after anterior LV pacing: 4.36 (SD 1) vs. 4.70 (SD 1); P=.001. CONCLUSIONS: Pacing in the LV produced less asynchrony than RV pacing. In addition, anterior LV pacing resulted in a higher cardiac output than RV pacing. These findings suggest that the location normally used for temporary leads after cardiac surgery should be changed.

Recombinant interferon-alpha2b improves immune response to hepatitis B vaccination in haemodialysis patients: results of a randomised clinical trial.

The use of adjuvants capable of improving the deficient immune response to hepatitis B virus (HBV) vaccine in haemodialysis patients is highly needed. Among potential adjuvants, type I interferons deserve a special attention in view of their known effects promoting cellular and humoral immune responses. The aim of the present trial was to evaluate the effects of recombinant interferon-alpha2b (IFN) administered as an adjuvant of HBV vaccine in unvaccinated haemodialysis patients. A significant and early enhancing effect on the antibody response was observed in patients receiving IFN. In addition, a predominance of IgG1 anti-HBs along with a transient normalization of circulating Th1 lymphocytes was only found in patients receiving IFN who achieved an early seroprotection. However, 6 months after the last vaccine dose, no significant differences were observed in the seroprotection rate achieved in patients vaccinated with IFN compared to that in patients receiving HBV vaccine alone. Mild to moderate fever, asthenia, and arthromyalgia were the most common reactions that occurred in vaccinees given IFN. In conclusion, addition of IFN to HBV vaccine, under the conditions used in this trial, is safe and achieves an earlier and higher seroprotection rate improving Th1-dependent immune response in haemodialysis patients.

Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease.

OBJECTIVES: Although chemokines seem to be important in certain inflammatory disorders, little is known about the role of these proteins in chronic hepatitis C. METHODS: Expression of selected CXC and CC chemokines and their receptors was assessed by immunohistochemistry and flow cytometry in chronic hepatitis C. Tissue samples from normal liver and that of sustained responders were also evaluated. A comparative analysis between the histological grading and the intrahepatic expression level of chemokines was performed. RESULTS: The majority of liver-derived T lymphocytes expressed CXCR3 and CCR5 chemokine receptors, representing high enrichment over levels of CXCR3 + and CCR5 + T cells in blood from chronic hepatitis C. An intense intrahepatic expression of their respective ligands, the CXC chemokine Mig, and RANTES, was detected in the same patients studied, being restricted to the sinusoidal endothelium and to hepatocytes, respectively. A statistically significant association between the intrahepatic chemokine expression level and the inflammatory activity of chronic hepatitis C was found. Of note was the marked expression of both CXCR3 and its ligand Mig on endothelial cells from portal neovessels in chronic hepatitis C. CONCLUSIONS: Intrahepatic chemokine signaling could play a key role regulating significant pathological events during chronic hepatitis C, opening new avenues for therapeutic interventions based on chemokine activities.

Análisis inicial de eficiencia en la aplicación clínica de las nuevas recomendaciones para la prevención secundaria del cáncer de cuello de útero / Initial evaluation of the efficiency of the clinical application of the new cervical cancer screening recommendations

OBJETIVO: Evaluar la eficiencia de la aplicación de las nuevas recomendaciones de cribado del cáncer de cuello de útero auspiciadas por la Sociedad Española de Ginecología y Obstetricia. MATERIAL Y MÉTODOS: Seiscientas treintaiuna mujeres de 30 años o más que consultaron para prevención del cáncer de cuello del útero en una consulta de ginecología del Hospital de Santa Cristina de Madrid recibieron, como estrategia preventiva, una citología y una prueba de VPH (captura híbrida 2). RESULTADOS: Aplicados los costes asistenciales propios del hospital, la nueva estrategia preventiva genera un ahorro estimado de 198,47 € por mujer sometida a prevención secundaria del cáncer de cuello de útero. CONCLUSIONES: Las nuevas recomendaciones de cribado del cáncer de cuello de útero, auspiciadas por la Sociedad Española de Ginecología y Obstetricia, son altamente eficientes (AU)

AIM: To evaluate the efficiency of the application of the new cervical cancer screening recommendations sponsored by the Spanish Society of Obstetrics and Gynecology. MATERIAL AND METHODS: A total of 631 women, aged 30 years or older, who attended the Gynecology Unit of the Santa Cristina Hospital, Madrid, for cervical cancer screening underwent cervical cytology and DNA/human papilloma virus determination (Hybrid Capture 2). RESULTS: Analysis of the hospital's costs showed that the new prevention strategy generated an estimated saving of 198.47 € per woman undergoing cervical cancer screening. CONCLUSIONS: The new cervical cancer screening recommendations sponsored by the Spanish Society of Gynecology and Obstetrics are highly efficient (AU)

Selección del mejor lugar de estimulación tras cirugía cardiaca evaluando la asincronía con strain tras diferentes estimulaciones / Selecting the best site for pacing leads after cardiac surgery by evaluating the asynchrony of myocardial deformation observed with different pacing sites

Introducción y objetivos. Implantar electrodos transitorios en ventrículo derecho (VD) tras cirugía cardiaca es habitual. El objetivo es estudiar en pacientes intervenidos el efecto de la estimulación en diferentes localizaciones ventriculares en la sincronía, analizando la deformación miocárdica (strain), y en la eficacia cardiaca. Métodos. En 19 pacientes se midió la asincronía interventricular (diferencia en el tiempo al comienzo del strain entre VD y ventrículo izquierdo [VI]: TE DI) y la intraventricular (desviación estándar [TE DE] y máxima diferencia en el tiempo de comienzo del strain en las seis caras del VI [TE MD]). Estas estimaciones y el gasto cardiaco (GC) mediante Doppler se determinaron tras la estimulación en VD en tres diferentes segmentos del VI. Resultados. La estimulación en VD fue la que más aumentó los parámetros de asincronía respecto al estudio basal: TE DI, 59,8 ± 40,5 frente a 28,23 ± 56,9 ms (p = 0,002); TE DE, 53,2 ± 34,4 frente a 36,6 ± 34,9 ms (p = 0,007); TE MD, 135,3 ± 82,9 frente a 90,5 ± 87,4 ms (p = 0,007). La estimulación en VI produjo menos asincronía (estimulación en segmento anterior del VI: TE DI, 17,2 ± 53,8 ms; TE DE, 35,8 ± 17,9 ms; TE MD, 91,3 ± 45,2 ms (sin significación estadística respecto a basal). El GC tras la estimulación en VD fue menor que tras estimulación en la cara anterior del VI: 4,36 ± 1 frente a 4,7 ± 1 (p = 0,001). Conclusiones. La estimulación en VI produce menos asincronía que en VD. Asimismo, la estimulación en la cara anterior del VI consigue mayor GC que la estimulación en VD. Estos datos indican que se debería modificar la localización de los electrodos transitorios tras cirugía cardiaca (AU)

Introduction and objectives. After cardiac surgery, temporary pacing leads are routinely implanted in the right ventricle (RV). The objective was to investigate the effect of different ventricular pacing locations on cardiac synchrony (by evaluating myocardial deformation, or strain) and efficiency in patients undergoing cardiac surgery. Methods. Interventricular asynchrony (i.e. the difference in the time of onset of deformation between right and left ventricles; TE-R/L) and intraventricular asynchrony (i.e. the standard deviation and maximum difference in the time of onset of deformation in six segments of the left ventricle [LV]; TE-SD and TE-MD, respectively) were assessed in 19 patients. Doppler echocardiography was used to evaluate these parameters and cardiac output after pacing in the RV and in three different LV segments. Results. Pacing in the RV resulted in the greatest increases in asynchrony parameters from baseline: TE- R/L 59.8 ms (standard deviation [SD] 40.5 ms) vs. 28.23 ms (SD 56.9 ms), P=.002; TE-SD 53.2 ms (SD 34.4 ms) vs. 36.6 ms (SD 34.9 ms), P=.007; and TE-MD 135.3 ms (SD 82.9 ms) vs. 90.5 ms (SD 87.4 ms), P=.007. Pacing in the LV resulted in less asynchrony: for anterior LV pacing, TE-R/L was 17.2 ms (SD 53.8 ms), TE-SD was 35.8 ms (SD 17.9 ms), and TE-MD was 91.3 ms (SD 45.2). The change from baseline was not significant. Cardiac output was lower after RV pacing than after anterior LV pacing: 4.36 (SD 1) vs. 4.70 (SD 1); P=.001. Conclusions. Pacing in the LV produced less asynchrony than RV pacing. In addition, anterior LV pacing resulted in a higher cardiac output than RV pacing. These findings suggest that the location normally used for temporary leads after cardiac surgery should be changed (AU)

Estimación de la severidad de la insuficiencia mitral según un método simplificado basado en el flujo de convergencia proximal / Evaluation of mitral regurgitation severity using a simplified method based on proximal flow convergence

Introducción y objetivos. El cálculo del orificio regurgitante efectivo (ORE) se considera el método más fiable para estimar la severidad de la insuficiencia mitral (IM), pero es poco usado por su complejidad. El objetivo fue modificar y validar un método semicuantitativo basado en la proximal isovelocity surface area (PISA), previamente publicado, para adaptarlo a las recientes recomendaciones de las sociedades americana y europea de cardiología. Métodos. Cuando usamos el método PISA, el flujo regurgitante máximo (FRM) es una función del radio y la velocidad de aliasing (Va). Esta relación permite la creación de un normograma formado por líneas de diferentes valores de FRM que se pueden obtener con facilidad al buscar en el gráfico los valores del radio y su cruce con los de Va. Los límites de severidad en esa tabla se han adaptado para que reflejen los grados y los límites de severidad recomendados por las sociedades americana y europea de cardiología según el valor de ORE. Resultados. Estudiamos a 76 pacientes con IM mediante eco-Doppler. Se encontró una correlación excelente entre FRM y ORE (r = 0,98; p < 0,001). La estimación de severidad mediante el nuevo normograma mostró una concordancia excelente con la determinada mediante el ORE, con un valor de kappa de 0,951 y un error estándar de 0,11 para una escala en 3 grados, y un valor de kappa de 0,969 y error estándar de 0,11 para la escala en 4 grados. Conclusiones. La estimación semicuantitativa de la severidad de la IM mediante el FRM mediante el normograma propuesto tiene un acuerdo excelente con la estimación cuantitativa por ORE, pero es mucho más simple y rápida

Introduction and objectives. Calculation of the effective regurgitant orifice (ERO) is regarded as the most accurate way of assessing the severity of mitral regurgitation (MR), but the technique's complexity limits its use. Our objective was to modify and validate a previously published semiquantitative method of assessment based on measurement of the proximal isovelocity surface area (PISA) in order to adapt it to recent recommendations from American and European cardiology societies. Methods. In the PISA method, maximum regurgitant flow (MRF) is a function of the radius and aliasing velocity (AV). Using this relationship, it is possible to construct a nomogram formed by lines of different MRF value, which can be easily derived by looking for radius values on the graph and observing where they cross with AV values. The MR severity limits on the nomogram were set to reflect the different severity grades and limits recommended for use with ERO measurements by American and European cardiology societies. Results. We studied 76 patients with MR using Doppler echocardiography. There was an excellent correlation between MRF and ERO (r=0.98, P<.001). Estimates of MR severity made using the new nomogram were in good agreement with those derived from the ERO: for a scale with three severity grades, kappa was 0.951 and the standard error was 0.11; for four grades, kappa was 0.969 and the standard error, 0.11. Conclusions. Estimates of MR severity derived semiquantitatively from MRF using the nomogram proposed here were in excellent agreement with quantitative estimates obtained using the ERO, and the method was faster and easier to use