Mechanistic characterization of GS-9190 (Tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase

GS-9190 (Tegobuvir) is a novel imidazopyridine inhibitor of hepatitis C virus (HCV) RNA replication in vitro and has demonstrated potent antiviral activity in patients chronically infected with genotype 1 (GT1) HCV. GS-9190 exhibits reduced activity against GT2a (JFH1) subgenomic replicons and GT2a (J6/JFH1) infectious virus, suggesting that the compound's mechanism of action involves a genotype-specific viral component. To further investigate the GS-9190 mechanism of action, we utilized the susceptibility differences between GT1b and GT2a by constructing a series of replicon chimeras where combinations of 1b and 2a nonstructural proteins were encoded within the same replicon. The antiviral activities of GS-9190 against the chimeric replicons were reduced to levels comparable to that of the wild-type GT2a replicon in chimeras expressing GT2a NS5B. GT1b replicons in which the β-hairpin region (amino acids 435 to 455) was replaced by the corresponding sequence of GT2a were markedly less susceptible to GS-9190, indicating the importance of the thumb subdomain of the polymerase in this effect. Resistance selection in GT1b replicon cells identified several mutations in NS5B (C316Y, Y448H, Y452H, and C445F) that contributed to the drug resistance phenotype. Reintroduction of these mutations into wild-type replicons conferred resistance to GS-9190, with the number of NS5B mutations correlating with the degree of resistance. Analysis of GS-9190 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of GS-9190 is different from other nonnucleoside inhibitors. Collectively, these data demonstrate that GS-9190 represents a novel class of nonnucleoside polymerase inhibitors that interact with NS5B likely through involvement of the β-hairpin in the thumb subdomain.     

Interdisciplinary European Guidelines for Surgery for Severe (Morbid) Obesity

Foreword In 2005, for the first time, an expert panel named “The Bariatric Scientific Collaborative Group” (BSCG), was appointed through a joint effort of the major European Scientific Societies which are active in the field of obesity management. Societies that constituted this panel were: International Federation for the Surgery of Obesity – European Chapter (IFSO-EC), European Association for the Study of Obesity (EASO), European Childhood Obesity Group (ECOG) and the International Obesity Task Force (IOTF) which was represented during the completion process by its representatives. The BSCG was composed of officers representing the respective Scientific Societies (including four acting Presidents, two past Presidents, one Honorary President, and three Executive Directors). The panel was also balanced by the presence of many other opinion leaders in the field of obesity. The BSCG composition allowed coverage of the key disciplines in comprehensive obesity management, as well as being reflective of European geographic and ethnic diversity. This joint BSCG Expert Panel has convened several meetings which were entirely focused on guideline creation during the past 2 years. There was a specific effort to develop and concur on clinical guidelines which reflect current knowledge, expertise and evidence- based data on treatment of morbid obesity.     

Effects of volume and/or pressure overload secondary to congenital heart disease (tetralogy of fallot or pulmonary stenosis) on right ventricular function using cardiovascular magnetic resonance and B-type natriuretic peptide levels

The aim of this study was to analyze the effect of pressure and/or volume overload on right ventricular (RV) function and brain natriuretic peptide (BNP) levels in patients with surgically corrected congenital heart disease. Forty-two consecutive patients aged 17 to 57 years (median 30) with congenital heart disease (32 with tetralogy of Fallot and 10 with pulmonary stenosis) were examined. The RV systolic pressure was estimated using Doppler echocardiography. Cardiovascular magnetic resonance imaging was used to obtain the RV volumes, ejection fraction (EF) and corrected EF (cEF). Plasma BNP levels were determined by immunoradiometric assay. Patients were categorized as having volume overload when pulmonary regurgitation was > or =10% and pressure overload when the RV systolic pressure was >40 mm Hg. Patients with RV volume overload had a lower RVEF compared with patients with pressure overload (p = 0.02) and lower left ventricular EF (p <0.001). BNP was higher in patients with volume overload than in patients with pressure overload (p = 0.002). BNP correlated with pulmonary regurgitation, RVEF, RV cEF, and left ventricular EF. In linear regression analysis, RV cEF was an independent predictor for BNP, after adjustment for age. Without the parameter of RV cEF in the regression model, pulmonary regurgitation and RVEF were independently associated with BNP level, after adjustment for age. In conclusion, patients with RV volume overload had higher BNP levels and lower RV function than patients with RV pressure overload. BNP levels were independently associated with the degree of RV volume overload and RV function.     

急性重度有机磷农药中毒32例的救治

0引言在急性重度有机磷农药中毒(AOPP)救治过程中,早期的内科常规处理,结合抗胆碱药及复能剂的应用,并积极进行肠道水疗,血液灌流,后期营养支持等综合救治,能提高AOPP在基层医院的抢救成功率、存活率.我院2000-3/2005-03收治32例重度AOPP患者,获得满意治疗效果.     

Comparison of echocardiography with magnetic resonance imaging in the assessment of the athlete's heart

AIM: The purpose of the study was to compare the accuracy of M-modeechocardiography and two different two-dimensional echocardiographicapproaches in the assessment of left ventricular mass and volumesin endurance-trained and strength-trained athletes, using magneticresonance imaging as reference standard. METHODS AND RESULTS: We studied 19 athletes and 10 untrained control subjects, M-modeand two-dimensional echocardiography were compared to magneticresonance imaging. M-mode echocardiographic left ventricularmass was calculated using the Penn cube convention. Two-dimensionalechocardiographic left ventricular mass was calculated using(1) the area—length method as proposed by the AmericanSociety of Echocardiography (ASE) and (2) as proposed by Reichek.The best correlation between magnetic resonance imaging andechocardiographic left ventricular mass and volumes was observedwith the ASE two-dimensional echocardiographic method. The agreementbetween them (–3·4±7·6 g and 18·5±19·5ml) was better than between Reichek two-dimensional echocardiographyand magnetic resonance imaging (–39·4±15·4-gand 52·8±21·7 ml), and demonstrated lessrandom difference than M-mode echocardiography and magneticresonance imaging (3·2±21·1 g resp. 15·1±30·0ml). CONCLUSION: We conclude that the ASE two-dimensional echocardiographic approach,when using magnetic resonance imaging as a reference standard,was the most accurate estimator of left ventricular mass andvolumes in both controls and athletes.