A randomized study on Peg-interferon alfa-2a with or without ribavirin in liver transplant recipients with recurrent hepatitis C

BACKGROUND/AIMS: We performed a randomized trial on pegylated interferon alfa-2a (Peg-IFNalpha) monotherapy vs Peg-IFNalpha and ribavirin in non-cirrhotic liver transplant recipients with recurrent hepatitis C. METHODS: Forty-two patients transplanted for HCV-related cirrhosis 12-96 months earlier were randomized to Peg-IFNalpha monotherapy (180 microg weekly) or Peg-IFNalpha and ribavirin, up to the maximum tolerated dose, for 48 weeks. RESULTS: Early virological response (EVR, i.e., HCV-RNA2 log drop at week 12) occurred in 76% of the monotherapy and 71% of the combination groups, respectively (intention-to treat). Sustained virological response (SVR) occurred in 8 (38%) and 7 (33%) patients, respectively. EVR had a positive predictive value for SVR of 50% and 47%, respectively, and a 100% negative predictive value in both groups. Six drop-outs occurred in the monotherapy (including 3 rejections) and 7 in the combination groups (including one rejection). Peg-INFalpha dose was reduced in 7 and 8 patients, respectively. The average daily dose of ribavirin was 435 mg/day. CONCLUSIONS: Peg-IFNalpha-2a, with or without ribavirin, induces SVR in one-third of transplant recipients with recurrent hepatitis C. Treatment cessation is indicated in patients without EVR. The low SVR rate is mainly due to inability to sustain full doses of antivirals and lack of the booster effect of ribavirin.     

The use of the antifungal agent miconazole as an inhibitor of Blastocystis hominis growth in Entamoeba histolytica/E. dispar cultures

In regions with high prevalence, Blastocystis hominis is frequently found in association with Entamoeba histolytica/E. dispar in xenic cultures. Its exacerbated growth is often superimposed on the growth of amebas, thus impeding the continuation of the amebas in the culture, within a few generations. The present study reports on the excellent efficacy (100%) of the antifungal agent miconazole in eliminating B. hominis from cultures of E. histolytica/E. dispar, thereby maintaining the integrity of the trophozoites of the amebas. Nystatin presented low efficacy (33.3%).     

Acute pulmonary embolism is an independent predictor of adverse events in severe decompensated heart failure patients

BACKGROUND: Congestive heart failure (CHF) is a well-recognized risk factor for venous thromboembolism (VTE) and is associated with higher mortality in patients with an acute pulmonary embolism (PE). There are very few data on how acute PE affects the clinical course of patients with heart failure. The purpose of this study was to determine the impact of an acute PE on the short-term prognosis of patients hospitalized for decompensated CHF. METHODS: This was a prospective cohort study of 198 patients admitted to a coronary care unit between July 2001 and March 2003 with severe decompensated CHF. The primary outcome measure was death or rehospitalization at 3 months. RESULTS: PE was confirmed in 18 of 198 patients enrolled (9.1%). The groups with and without PE were comparable with regards to demographics, the prevalence of comorbid conditions, and severity of CHF (p > 0.05). The prevalence of cancer (p = 0.0001), previous VTE (p = 0.003), and right ventricular overload (p = 0.006) was higher in the PE group. The presence of PE was also associated with a longer hospital stay (37.5 +/- 71.6 days vs 15.4 +/- 15.0 days, p = 0.001) [mean +/- SD] and a higher incidence of death or rehospitalization at 3 months (72.2% vs 43.9%, p = 0.02). In a multiple logistic regression analysis, PE remained an independent predictor of death or rehospitalization at 3 months (odds ratio, 4.0; 95% confidence interval, 1.1 to 15.1; p = 0.038). CONCLUSIONS: Acute PE commonly complicates the hospital course of patients with severe CHF, increasing the length of hospital stay and the chance of death or rehospitalization at 3 months.     

Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, placebo-controlled study

CONTEXT: Genistein, a soy isoflavone, has received wide attention over the last few years because of its potential preventive role for cardiovascular disease. OBJECTIVE: Our objective was to assess the effects of genistein administration (54 mg/d) on some predictors of cardiovascular risk in osteopenic, postmenopausal women. DESIGN AND SETTING: We conducted a randomized, double-blind, placebo-controlled trial at three Italian university medical centers. INTERVENTION: After a 4-wk stabilization on a standard isocaloric, fat-reduced diet, participants were randomly assigned to receive genistein (n = 198) or placebo (n = 191) daily for 24 months. Both intervention and placebo contained calcium and vitamin D(3). OUTCOME MEASURES: Blood lipid profiles, fasting glucose and insulin, homeostasis model assessment for insulin resistance, fibrinogen, soluble intercellular adhesion molecule-1, soluble vascular cellular adhesion molecule-1, F2-isoprostanes, and osteoprotegerin at baseline and after 12 and 24 months of treatment were measured. RESULTS: Compared with placebo, genistein significantly reduced fasting glucose and insulin as well as homeostasis model assessment for insulin resistance after both 12 and 24 months of treatment. By contrast, genistein administration did not affect blood lipid levels although fibrinogen, F2-isoprostanes, soluble intercellular adhesion molecule-1, and soluble vascular cellular adhesion molecule-1 decreased significantly compared with placebo after 24 months. Serum osteoprotegerin was higher in the genistein group compared with placebo. At 24 months, the genistein group showed no change in endometrial thickness compared with placebo. Most treatment-related adverse events were moderate and composed of gastrointestinal side effects [genistein, n = 37 (19%); placebo, n = 15 (8%)]. CONCLUSIONS: These results suggest that 54 mg genistein plus calcium, vitamin D(3), and a healthy diet was associated with favorable effects on both glycemic control and some cardiovascular risk markers in a cohort of osteopenic, postmenopausal women.     

Racial difference in endothelial function: role of the infective burden

There is much evidence to suggest the existence of racial differences between blacks and whites in the behaviour of endothelial function. Infective state, sustained by viral or bacterial agents, may injure the endothelial surface favouring the onset and progression of atherosclerotic process, mainly by an inflammatory mechanism. The aim of the study was to investigate endothelial function, expressed as brachial flow-mediated vasodilation (FMV), in black and white healthy subjects, along with antibody titer to cytomegalovirus, hepatitis virus (B, C), herpes virus-1 and 2, Epstein-Barr, Chlamydia pneumoniae and the expression of adhesion molecules. We enrolled 22 young (mean age 27+/-8 years) healthy subjects of black race (10 males) and 20 healthy young subjects (10 males, mean age 28+/-9 years) of white race. Total infectious burden (TIB) was defined as the number of serological positive infections. Black subjects have a reduced brachial FMV (6.9+/-3.5% versus 11.6+/-3.0%, p<0.01) and increased values of hsCRP (0.35+/-0.15 mg/dL versus 0.07+/-0.08 mg/dL, p<0.05), white cells (8578+/-1041/mmc versus 5833+/-998/mmc, p<0.01) and adhesion molecules (respectively: sVCAM-1 945+/-142 versus 779+/-93, sICAM-1 534+/-107 ng/mL versus 325+/-80 ng/mL; both p<0.01) in comparison to white subjects. The total infectious burden in black race was significantly higher than in white race (5+/-1 versus 2+/-1, p<0.01). At the univariate analysis, brachial FMV was significantly related to the levels of adhesion molecules (respectively: sVCAM-1 r=-0.49; sICAM-1 r=-0.50, both p<0.05), hsCRP (r=-0.47, p<0.05) and white blood cells (r=-0.43, p<0.05). TIB was associated with brachial FMV (r=-0.64, p<0.05), sVCAM-1 (r=0.55, p<0.05) and hsCRP (r=0.47, p<0.05). At the multivariate analysis the only predictive variables for brachial FMV were hsCRP, TIB and brachial diameter (respectively: beta=-0.49, -0.19, -0.54, all p<0.05). This study confirms that endothelial reactivity is impaired in young African black patients; moreover its behavior is strictly related to the inflammatory state and to the total infectious burden.     

Nearly identical strains of human herpesvirus 8 in couples discordant for Kaposi's sarcoma

Transmission of human herpesvirus 8 (HHV-8) may occur through various routes including breastfeeding and sexual intercourse. We attempted to detect HHV-8 infection in nine HIV-positive couples discordant for Kaposi's sarcoma who maintained a monogamous sexual relationship for at least one year. By quantitative real-time polymerase chain reaction and HHV-8 genotyping we provide strong evidence for the sexual transmission of HHV-8 in this unique cohort.     

Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection

The functional impairment of HCV-specific T cell responses is believed to be an important determinant of HCV persistence, but the functional T cell defects of patients with chronic hepatitis C (CH-C) are only partially defined. CD8 responses to HLA-A2-restricted epitopes of HCV and other unrelated viruses were studied in 23 HLA-A2-positive patients both ex vivo and after in vitro culture. Degranulation capacity, intracellular perforin, and granzyme-A content and cytokine production (IFN-gamma, TNF-alpha) by HCV- and non-HCV-specific CD8 cells were tested both ex vivo and in vitro, whereas cytolytic activity was studied after 10 days' expansion in vitro. Memory maturation and role of exhaustion were assessed ex vivo by HCV-specific CD8 staining for CD127 and PD-1, and in vitro after peripheral blood mononuclear cells (PBMC) culture in the presence of anti-PD-L1 monoclonal antibodies. IFN-gamma production and cytolytic activity were expressed less efficiently by HCV-specific than by non-HCV specific CD8 cells derived from the same CH-C patients. The amount of stored granzyme-A within single cells was always lower in HCV-specific CD8 cells, which were less efficient also in the release of lytic granules and in the production of TNF-alpha. The CD8 dysfunction was associated with high PD-1 expression by most HCV-specific CD8 cells, and PD-1/PD-L1 blockade by anti-PD-L1 antibodies in vitro was able to improve the HCV-specific CD8 function. CONCLUSION: Our study characterizes CD8 defects that may be important in maintaining HCV persistence; identification of strategies to correct these defects may help to define novel approaches to treat HCV infection.     

Optimizing fat oxidation through exercise in severely obese Caucasian adolescents

OBJECTIVE: To measure the contribution of substrate oxidation to energy expenditure during cycling at different workloads and to identify the exercise intensity that elicits the maximum fat oxidation rate in groups of severely obese or nonobese Caucasian adolescents. DESIGN: A total of 30 severely obese subjects (mean body mass index, BMI = 34.7 kg/m2; fat-mass = 39.9%) and 30 nonobese sedentary adolescents (mean BMI = 22.7 kg/m2; fat-mass = 21.8%) aged 14-16 years, participated in this study. Body composition was assessed by bioelectrical impedance. Peak oxygen uptake (VO2peak) and maximal fat oxidation rate were determined with indirect calorimetry by using a graded exercise test on an electromagnetically braked cycle ergometer. RESULTS: Predicted VO2max were expressed in absolute (l/min) and relative (ml/kg FFM/min) values, and maximal work rates were not significantly different between obese and nonobese adolescents, but were significantly higher in boys than in girls. No significant differences in fat oxidation rates were found in obese and nonobese sedentary adolescents during the graded exercise test. Maximal fat oxidation was observed at an exercise intensity corresponding to (mean +/- SD) 41 +/- 3%VO2max or 58 +/- 3% HRmax. At this exercise intensity, fat oxidation rates were higher in boys than in girls (0.32 +/- 0.02 g/min vs. 0.25 +/- 0.02 g/min, P < 0.001). CONCLUSIONS: Severely obese and sedentary nonobese adolescents reached maximal fat oxidation rates at 41%VO2max, which corresponds to 58% HRmax. At this exercise intensity, fat oxidation rates were higher in boys than in girls probably due to higher VO2max and absolute workload during the exercise steps for boys compared with those for girls.