Pharmacologic treatment of portal hypertension in the prevention of community-acquired spontaneous bacterial peritonitis

INTRODUCTION: Given that beta-blockers reduce the incidence of bacterial translocation in cirrhotic rats, the aim of this study was to compare the long-term incidence of spontaneous bacterial peritonitis in cirrhotic patients submitted to pharmacologic versus endoscopic treatment to prevent variceal rebleeding. PATIENTS AND METHODS: Two hundred and thirty patients with variceal hemorrhage were included in two previous randomized trials performed to compare the efficacy of medication (nadolol plus isosorbide mononitrate, n=115) versus endoscopic treatment (n=115) with sclerotherapy or ligation for the prevention of rebleeding. RESULTS: The mean follow-up was 23+/-1.4 months. The characteristics of the patients and the number of patients on long-term prophylaxis with norfloxacin were similar in both groups. The incidence of spontaneous bacterial peritonitis was lower in the medication group (9 versus 14.7%, P=NS). The probability of spontaneous bacterial peritonitis was also lower in the medication group (6 versus 12% at 1 year, 22 versus 36% at 5 years; P=0.08), due to a significantly lower probability of community-acquired spontaneous bacterial peritonitis in this group (1 versus 10% at 1 year, 18 versus 32% at 5 years; P=0.02). Patients with no hemodynamic response to therapy had a significantly higher probability to develop community-acquired spontaneous bacterial peritonitis during follow-up than hemodynamic responders (P<0.03). Long-term probability of developing community-acquired spontaneous bacterial peritonitis is lower in patients submitted to pharmacologic treatment for preventing variceal rebleeding than in those submitted to endoscopic treatment. CONCLUSION: Long-term pharmacologic prophylaxis of variceal rebleeding contributes to the prevention of community-acquired spontaneous bacterial peritonitis.     

Relation of circulating C-reactive protein to progression of aortic valve stenosis

C-reactive protein (CRP) is a marker of inflammation and predicts outcome in apparently healthy subjects and patients with coronary artery disease. Systemic inflammation is present in patients with aortic valve stenosis (AS). The aim of this prospective study was to assess whether CRP levels predict the progression of AS severity. Blood samples for high-sensitivity CRP measurements and echocardiographic data were obtained in 43 patients (70% men; mean age 73 +/- 8 years) with asymptomatic degenerative AS at study entry. On the basis of repeat echocardiographic assessment at 6 months, patients were grouped as (1) slow progressors (a decrease in aortic valve area [AVA] <0.05 cm2 and/or an increase in aortic peak velocity <0.15 m/s) and (2) rapid progressors (a decrease in AVA > or =0.05 cm2 and/or an increase in aortic peak velocity > or =0.15 m/s). Plasma CRP levels were significantly higher in rapid progressors than slow progressors (median 5.1 [range 2.3 to 11.3] vs 2.1 [range 1.0 to 3.1] mg/L, p = 0.007). In multivariate analysis, CRP levels >3 mg/L were independently associated with rapid AS progression (odds ratio 9.1, 95% confidence interval 2.2 to 37.3). In conclusion, CRP levels are higher in patients with degenerative AS who show rapid valve disease progression. These findings suggest that inflammation may have a pathogenic role in degenerative AS.     

A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells

Many key regulatory proteins, including members of the Ras family of GTPases, are modified at their C terminus by a process termed prenylation. This processing is initiated by the addition of an isoprenoid lipid, and the proteins are further modified by a proteolytic event and methylation of the C-terminal prenylcysteine. Although the biological consequences of prenylation have been characterized extensively, the contributions of prenylcysteine methylation to the functions of the modified proteins are not well understood. This reaction is catalyzed by the enzyme isoprenylcysteine carboxyl methyltransferase (Icmt). Recent genetic disruption studies have provided strong evidence that blocking Icmt activity has profound consequences on oncogenic transformation. Here, we report the identification of a selective small-molecule inhibitor of Icmt, 2-[5-(3-methylphenyl)-1-octyl-1H-indol-3-yl]acetamide (cysmethynil). Cysmethynil treatment results in inhibition of cell growth in an Icmt-dependent fashion, demonstrating mechanism-based activity of the compound. Treatment of cancer cells with cysmethynil results in mislocalization of Ras and impaired epidermal growth factor signaling. In a human colon cancer cell line, cysmethynil treatment blocks anchorage-independent growth, and this effect is reversed by overexpression of Icmt. These findings provide a compelling rationale for development of Icmt inhibitors as another approach to anticancer drug development.     

Is the Val16Ala manganese superoxide dismutase polymorphism associated with the aging process?

Oxidative stress has been related to aging. Recent evidences suggest that a genetic dimorphism that encodes for either alanine or valine in superoxide dismutase (SOD2) is involved with oxidative stress. However, the current literature is still controversial, and the potential role of the Ala16Val polymorphism in human aging needs to be established. Here we investigated the role of the SOD2 polymorphism in: a) age-related mortality, b) morbidity (breast and prostate cancer), c) immunological markers, and d) DNA damage in peripheral blood cells. We did not find an association between SOD2 polymorphisms and mortality. However, the AA genotype was associated with increased risk for prostate and breast cancer, immunosenescence profile, as well as DNA damage. These data suggest that SOD2 presents characteristics that support the free radical theory of aging.     

Acute dilatation to phytoestrogens and estrogen receptor subtypes expression in small arteries from women with coronary heart disease

We tested if endothelial function and estrogen receptor (ER) expression differs between resistance arteries in subcutaneous circulation from postmenopausal women with coronary heart disease (CHD, congruent with 1 year after myocardial infarction, n=12) and aged matched controls (n=14); and if acute effects of phytoestrogens (genistein, resveratrol) could be of relevance for vascular protection. We utilized ex vivo small artery ( congruent with 350 microm) bioassays and found no difference in bradykinin (BK)-mediated dilatation between the groups. One-hour incubation with phytoestrogens (natural ER beta agonists), propyl-pyrazole-triol-trisphenol (PPT-selective ER alpha agonist) and 17beta-estradiol (17beta-E(2)-ER alpha/beta agonist) at 0.01 microM/L had no effect on BK-induced responses. Concentration-response curves (0.01-30 microM/L) to investigated compounds were also obtained and compared in separate arteries. We found that dilatation to phytoestrogens was enhanced in CHD if compared to controls (p<0.05), while responses to 17beta-E(2) remained similar. The dilatation to phytoestrogens was also higher if compared to 17beta-E(2) (p<0.05) in CHD. In controls, only responses to PPT, but not to phytoestrogens, were enhanced in comparison to 17beta-E(2) (p<0.05). Inhibition of NO synthase had no effect on dilatation induced by increasing concentrations of investigated compounds. ER beta expression was enhanced in the vascular wall from CHD women, while ER alpha predominated in the controls (p<0.05). We suggest that diet supplementation by phytoestrogens may provide cardiovascular benefit for postmenopausal women with CHD. The selective targeting of one of the ER subtype may have implications for women's cardiovascular health.     

Prognostic value of a new cardiopulmonary exercise testing parameter in chronic heart failure: oxygen uptake efficiency at peak exercise - comparison with oxygen uptake efficiency slope

IntroductionA growing body of evidence shows the prognostic value of oxygen uptake efficiency slope (OUES), a cardiopulmonary exercise test (CPET) parameter derived from the logarithmic relationship between O₂ consumption (VO₂) and minute ventilation (VE) in patients with chronic heart failure (CHF).ObjectiveTo evaluate the prognostic value of a new CPET parameter — peak oxygen uptake efficiency (POUE) — and to compare it with OUES in patients with CHF.MethodsWe prospectively studied 206 consecutive patients with stable CHF due to dilated cardiomyopathy — 153 male, aged 53.3 ± 13.0 years, 35.4% of ischemic etiology, left ventricular ejection fraction 27.7 ± 8.0%, 81.1% in sinus rhythm, 97.1% receiving ACE-Is or ARBs, 78.2% beta-blockers and 60.2% spironolactone — who performed a first maximal symptom-limited treadmill CPET, using the modified Bruce protocol. In 33% of patients an cardioverterdefibrillator (ICD) or cardiac resynchronization therapy device (CRT-D) was implanted during follow-up.Peak VO₂, percentage of predicted peak VO₂, VE/VCO₂ slope, OUES and POUE were analyzed. OUES was calculated using the formula VO₂ (l/min) = OUES (log₁₀VE) + b. POUE was calculated as pVO₂ (l/min) / log₁₀peakVE (l/min). Correlation coefficients between the studied parameters were obtained. The prognosis of each variable adjusted for age was evaluated through Cox proportional hazard models and R2 percent (R2%) and V index (V6) were used as measures of the predictive accuracy of events of each of these variables. Receiver operating characteristic (ROC) curves from logistic regression models were used to determine the cut-offs for OUES and POUE.ResultspVO₂: 20.5 ± 5.9; percentage of predicted peak VO₂: 68.6 ± 18.2; VE/VCO₂ slope: 30.6 ± 8.3; OUES: 1.85 ± 0.61; POUE: 0.88 ± 0.27. During a mean follow-up of 33.1 ± 14.8 months, 45 (21.8%) patients died, 10 (4.9%) underwent urgent heart transplantation and in three patients (1.5%) a left ventricular assist device was implanted. All variables proved to be independent predictors of this combined event; however, VE/VCO2 slope was most strongly associated with events (HR 11.14). In this population, POUE was associated with a higher risk of events than OUES (HR 9.61 vs. 7.01), and was also a better predictor of events (R2: 28.91 vs. 22.37).ConclusionPOUE was more strongly associated with death, urgent heart transplantation and implantation of a left ventricular assist device and proved to be a better predictor of events than OUES. These results suggest that this new parameter can increase the prognostic value of CPET in patients with CHF.     

Incidência de arritmias ventriculares em doentes com disfunção sistólica ventricular esquerda grave: existe benefício após terapêutica de ressincronização cardíaca

BackgroundCardiac resynchronization therapy (CRT) has significant benefits in selected patients (P). The impact of this modality in the incidence of ventricular tachyarrhythmias remains controversial. We analysed the occurrence of appropriate therapies in P submitted to CRT combined with a cardioverter-defibrillator (ICD).MethodsStudy of 123 P with left ventricular ejection fraction (LVEF) <35%, submitted to successful implantation of CRT-ICD or ICD alone (primary prevention).ResultsMean age was 63±12 years, LVEF of 25±6%, median follow-up of 372 days. CRT-ICD implanted in 63P (group A) and ICD alone in 60P (group B). Group A has 86% of clinical responders, lower prevalence of ischemic cardiomyopathy (30% vs. 72%), and more P in class III of the NYHA before device implantation (90% vs. 7%) compared with ICD alone patients. There were no differences in the incidence of appropriate therapies (19% vs. 12%) or in the time for first therapy (305 days vs. 293 days). Total mortality was 11% in group A and 12% in group B. Kaplan-Meier curves for arrhythmic events in patients with CRT showed no significant differences (HR 3.02, 95% CI 0.82 – 11.09, p=NS) when compared to patients without CRT.ConclusionsIn P submitted to CRT-ICD for primary prevention, despite a higher rate of responders, the incidence of appropriate therapies is not different from those with an ICD alone.     

Impaired glucose tolerance and reduced beta-cell function in overweight Latino children with a positive family history for type 2 diabetes

The objective of this study was to examine relationships between impaired glucose tolerance (IGT) and body composition and insulin-related phenotypes in 150 overweight Latino children with a family history of type 2 diabetes. Glucose tolerance was assessed by an oral glucose challenge. Body composition was assessed by dual energy x-ray absorptiometry and magnetic resonance imaging. Insulin sensitivity, the acute insulin response, and the disposition index (DI), as an index of beta-cell function, were determined by an iv glucose tolerance test and compared between normal glucose-tolerant and IGT children. IGT was present in 28% of children, and was similar across obesity groups, but higher in children exposed to gestational diabetes mellitus (41% IGT). There were no significant differences in body composition, fat distribution, insulin sensitivity, or acute insulin response, but DI was significantly lower in IGT children by 16% (P < 0.02), and DI was inversely related to age. In conclusion, IGT is present in 28% of overweight Latino children with a family history of type 2 diabetes, is not influenced by obesity, is more prevalent in children exposed to gestational diabetes mellitus, and is related to poor beta-cell function, which shows signs of deterioration with age in this population.     

The influence of lipoprotein lipase gene variation on postprandial lipoprotein metabolism

Lipoprotein lipase (LPL) is one of the key enzymes in the metabolism of triacylglycerol-rich lipoproteins (TRL). We evaluated whether the association of LPL HindIII (H1/H2) and Serine447-Stop (S447X) polymorphisms may explain the interindividual variability observed during postprandial lipemia. Fifty-one healthy male volunteers (26 with the H2S447 genotype, 15 with the H1X447 genotype, and 10 with the H1S447 genotype) were subjected to a vitamin A-fat load test consisting of 1 g fat/kg body weight and 60,000 IU vitamin A. Blood was drawn every hour until the 6th hour and every 2 h and 30 min until the 11th hour. Data revealed that subjects that are homozygous for the H2 allele (H2H2) showed a higher postprandial response for small TRL, retinyl palmitate (RP), large TRL-RP, large TRL-B48, and small TRL-B48 levels. Furthermore, in the case of the S447X polymorphism, 447Ter carriers had a lower postprandial response for small TRL-RP, large TRL-B48, and small TRL-RP. Subjects with the LPL H2S447 genotype had higher plasma triacylglycerol, large TRL-triacylglycerol, large TRL-RP, small TRL-RP, and large TRL-B48 (P < 0.037) than H1X447 subjects. The modifications observed in postprandial lipoprotein metabolism in young normolipemic males with LPL polymorphism could be involved in the lower risk of coronary artery disease associated with the H1X447 genotype.