Short-term effects of propranolol on portal venous pressure

The present study was designed to investigate the effect of propranolol on portal pressure of patients with alcoholic cirrhosis and portal hypertension and to correlate these effects with clinical and laboratory parameters. The mean baseline hepatic venous pressure gradient in the 50 patients studied was of 18.2 +/- 4.1 mm Hg. It decreased significantly 2 hr after the oral administration of 40 mg of propranolol to 15.7 +/- 4.2 mm Hg (a mean reduction of 13.4 +/- 17%). This reduction in hepatic venous pressure gradient resulted mainly from a decrease in mean wedged hepatic venous pressure. There was no correlation between the decrease in hepatic venous pressure gradient and the decrease in heart rate. When results were analyzed individually, only 15 (30%) showed a large decrease in hepatic venous pressure gradient (greater than 20%), 15 (30%) showed a moderate decrease (10 to 19%), and in 20 patients (40%) there was no reduction or an increase in hepatic venous pressure gradient. Comparison of "responders" (those that reduced hepatic venous pressure gradient greater than 10%) and "nonresponders" (hepatic venous pressure gradient reduction less than 10%) showed no significant differences in baseline laboratory and hemodynamic parameters, in the severity of the liver disease, in the heart rate and blood pressure response to propranolol, nor in the propranolol plasma levels achieved 2 hr after propranolol administration. Propranolol plasma levels correlated with the reduction in heart rate but not with the reduction in hepatic venous pressure gradient. Of 14 nonresponders to 40 mg of propranolol who received additional doses, six showed a reduction in hepatic venous pressure gradient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Inducers and Epoxide Hydrase on the Metabolism of Benzo[a]pyrene by Liver Microsomes and a Reconstituted System: Analysis by High Pressure Liquid Chromatography

The mobilities of 24 potential metabolites of benzo[a]pyrene were examined with high pressure liquid chromatography. Twelve phenols, five quinones, four dihydrodiols, and three oxides were studied. The chromatographic procedure employed allowed the separation and quantitation of benzopyrene metabolites into three major groups consisting of phenols, quinones, and dihydrodiols. Two of the benzopyrene oxides were unstable during chromatography, whereas the third oxide was more stable and chromatographed in the quinone fraction.Treatment of rats with phenobarbital or 3-methylcholanthrene enhanced the metabolism of benzopyrene by liver microsomes and altered the relative amounts of the various metabolites formed. In the absence of epoxide hydrase (EC 4.2.1.63), benzopyrene was metabolized primarily to phenols and quinones but was not appreciably metabolized to dihydrodiols by a solubilized, reconstituted cytochrome P-448 monooxygenase system. Addition of partially purified epoxide hydrase resulted in the formation of benzopyrene dihydrodiols with a concomitant decrease in the formation of phenolic metabolites, indicating that benzopyrene undergoes metabolism via arene oxides that are precursors for dihydrodiols and phenols.     

Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery

Ureaplasma urealyticum is the microorganism most frequently isolated from the amniotic fluid of women in preterm labor. The relationship between intra-amniotic U. urealyticum in healthy second-trimester pregnant women and subsequent pregnancy outcome was investigated. Transabdominal amniotic fluid obtained from 254 asymptomatic women at 15-17 weeks' gestation were tested by polymerase chain reaction (PCR). U. urealyticum was identified in 29 subjects (11.4%). A subsequent preterm labor occurred in 17 U. urealyticum-positive women (58.6%), compared with 10 (4.4%) U. urealyticum-negative women (P<.0001). Preterm birth was documented in 7 (24.1%) U. urealyticum-positive women compared with only 1 U. urealyticum-negative woman (0.4%) (P<.0001). U. urealyticum-positive women also had a higher prevalence of preterm labor in a prior pregnancy (20.7%) than did the negative women (2.7%; P=.0008). PCR testing of second-trimester amniotic fluid for U. urealyticum can identify women at risk for subsequent preterm labor and delivery.     

Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors

Genomic DNA copy number alterations are key genetic events in the development and progression of human cancers. Here we report a genome-wide microarray comparative genomic hybridization (array CGH) analysis of DNA copy number variation in a series of primary human breast tumors. We have profiled DNA copy number alteration across 6,691 mapped human genes, in 44 predominantly advanced, primary breast tumors and 10 breast cancer cell lines. While the overall patterns of DNA amplification and deletion corroborate previous cytogenetic studies, the high-resolution (gene-by-gene) mapping of amplicon boundaries and the quantitative analysis of amplicon shape provide significant improvement in the localization of candidate oncogenes. Parallel microarray measurements of mRNA levels reveal the remarkable degree to which variation in gene copy number contributes to variation in gene expression in tumor cells. Specifically, we find that 62% of highly amplified genes show moderately or highly elevated expression, that DNA copy number influences gene expression across a wide range of DNA copy number alterations (deletion, low-, mid- and high-level amplification), that on average, a 2-fold change in DNA copy number is associated with a corresponding 1.5-fold change in mRNA levels, and that overall, at least 12% of all the variation in gene expression among the breast tumors is directly attributable to underlying variation in gene copy number. These findings provide evidence that widespread DNA copy number alteration can lead directly to global deregulation of gene expression, which may contribute to the development or progression of cancer.     

Safety and efficacy of radiofrequency energy catheter ablation of atrial fibrillation in patients with pacemakers and implantable cardiac defibrillators

BACKGROUND: Catheter ablation has significantly transformed the clinical management of atrial fibrillation (AF). The safety and efficacy of this procedure are not well understood in patients with pacemakers and defibrillators. OBJECTIVES: The purpose of this study was to study the impact of radiofrequency catheter ablation of AF in patients with pacemakers and implantable cardiac defibrillators. METHODS: We studied 86 patients with pacemakers and defibrillators (group I) and a similar number of age- and gender-matched controls (group II) who underwent AF ablation between 1999 and 2004. Clinical and procedural variables were compared between the two groups. In group I, various generator and lead parameters were compared before and after the procedure. Resurgence of clinical AF after 2 months was considered recurrence. RESULTS: Both groups were similar with regard to age, gender, body mass index, and type of AF. Group I had a higher incidence of diabetes (17% vs 6%, P = .03), coronary artery disease (25% vs 13%, P = .05), less prolonged AF (31 +/- 21 vs 45 +/- 30 months, P <.001), lower left ventricular ejection fraction (49 +/- 13% vs 52 +/- 9%, P = .03), and left ventricular end-diastolic dimensions (4.97 +/- 0.81 vs 4.72 +/- 0.67, P = .03). No changes in the sensing and pacing thresholds, impedance of atrial and ventricular leads, or defibrillator coil impedance after AF ablation were observed in group I. Atrial lead dislodgment was seen in two patients. Transient abnormal but "expected" pulse generator behavior was seen in 25% of patients without permanent malfunction. Stroke (1% vs 1%, P = 1.000), pulmonary vein stenosis (2% vs 1%, P = .77), and AF recurrence rates at 12 months were similar between groups I and II, respectively (19% vs 21%, P = .73). CONCLUSION: AF ablation is safe and efficacious in patients with pacemakers and defibrillators.     

G-protein-coupled receptor kinase activity in human heart failure: effects of beta-adrenoceptor blockade

OBJECTIVES: In human end-stage heart failure as well as in experimental animal models of heart failure, G-protein-coupled receptor kinase activity (GRK) is increased while beta-adrenoceptor responsiveness is diminished. In animal studies, beta-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial beta-adrenoceptors. The aim of this study was to investigate whether alterations in GRK activity are an early or late accompaniment of human heart failure and whether also in humans beta-adrenoceptor blocker treatment is able to influence myocardial GRK activity. METHODS: We assessed in right atria, obtained from patients at different stages of heart failure, treated with or not treated with beta-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, beta-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and GRK activity (by an in vitro rhodopsin phosphorylation assay). RESULTS: With increasing severity of heart failure, plasma noradrenaline levels increased while myocardial beta-adrenoceptor density decreased with a maximum in GRK activity in end-stage heart failure. However, in relation to the progression of heart failure, we found that GRK activity transiently increased at an early stage of heart failure (NYHA I and II) but decreased back to control values in patients at NYHA III and IV. beta-Adrenoceptor blockers were able to reduce the early increase in GRK activity at NYHA I and II to control levels, whereas in those patients who did not have increased GRK activity (NYHA III and IV), they had only a marginal effect. CONCLUSION: According to our results, an increase in GRK activity is an early and transient event in the course of heart failure that can be prevented by beta-adrenoceptor blocker treatment.     

A prospective evaluation of computerized tomographic (CT) scanning as a screening modality for esophageal varices

Patients with cirrhosis require endoscopic screening for large esophageal varices. The aims of this study were to determine the cost-effectiveness and patient preferences of a strategy employing abdominal computerized tomography (CT) as the initial screening test for identifying large esophageal varices. In a prospective evaluation,102 patients underwent both CT and endoscopic screening for gastroesophageal varices. Two radiologists read each CT independently; standard upper gastrointestinal endoscopy was the reference standard. Agreement between radiologists, and between endoscopists regarding size of varices was determined using kappa statistic. Cost-effectiveness analysis was performed to determine the optimal screening strategy for varices. Patient preference was assessed by questionnaire. CT was found to have approximately 90% sensitivity in the identification of esophageal varices determined to be large on endoscopy, but only about 50% specificity. The sensitivity of CT in detecting gastric varices was 87%. In addition, a significant number of gastric varices, peri-esophageal varices, and extraluminal pathology were identified by CT that were not identified by endoscopy. Patients overwhelmingly preferred CT over endoscopy. Agreement between radiologists was good regarding the size of varices (Kappa = 0.56), and exceeded agreement between endoscopists (Kappa = 0.36). Use of CT as the initial screening modality for the detection of varices was significantly more cost-effective compared to endoscopy irrespective of the prevalence of large varices. CONCLUSION: Abdominal CT as the initial screening test for varices could be cost-effective. CT also permits evaluation of extra-luminal pathology that impacts management.     

Fractional Flow Reserve Derived From Computed Tomographic Angiography in Patients With Multivessel CAD

Background

The functional SYNTAX score (FSS) has been shown to improve the discrimination for major adverse cardiac events compared with the anatomic SYNTAX score (SS) while reducing interobserver variability. However, evidence supporting the noninvasive FSS in patients with multivessel coronary artery disease (CAD) is scarce.