Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

Primary Prevention of Sudden Cardiac Death: Can We Afford the Cost of Cardioverter-Defibrillators? Data from the Search-MI Registry-Italian Sub-study

Background: Large randomized trials show that in appropriately selected patients with left ventricular dysfunction, implantable cardioverter-defibrillators (ICDs) can improve overall survival at 2–5 years. Since direct implementation of the criteria used in the MADIT II and SCD-HeFT will lead to a marked rise in ICD implants, there is a growing fear that increased use of ICDs may cause a dramatic burden to health care systems. The ICD has traditionally been seen as an expensive form of treatment, which is difficult to accept at the first look. This is mainly due to the nonlinear character of the ICD investment, characterized by high initial expenditure, followed by a deferred pay-off in terms of clinical benefits. Cost-effectiveness analysis may help provide a different perspective on the problem of ICD cost, as may estimation of the daily cost of ICD treatment, assuming a time horizon of 5–7 years—a particularly interesting subject for further registry studies.
Methods and Results: Based on real expenditure data from 2002 to 2005, as recorded in the Search-MI Registry-Italian Sub-study of patients implanted on MADIT II indications, we estimated the daily costs associated with the device and leads. Over a 5–7 year time horizon, the average daily cost was estimated to be €4.60–€6.70. Translation of these figures into U.S. market conditions suggests a daily cost of around $7.90–$11.40.
Conclusions: These findings appear useful to help evaluate the affordability of ICD in comparison with other therapeutic options in a context of limited available economic resources.     

含左氧氟沙星及卷曲霉素方案治疗耐多药肺结核近期疗效分析

目的　观察和评价含左氧氟沙星和卷曲霉素联合化疗方案在耐多药肺结核 (MDR PTB)治疗中的疗效。方法　将 177例MDR PTB患者分为治疗组 88例和对照组 89例。化疗方案 :治疗组以左氧氟沙星和卷曲霉素为主 ,联合利福喷汀、异烟肼、对氨基水杨酸钠、吡嗪酰胺 ;对照组用链霉素、乙胺丁醇 ,联用药物同治疗组 ,疗程均为 2 1个月。结果　共有 16 1例患者完成化疗疗程 ,治疗组 82例 ,痰菌阴转率 83% ;对照组 79例 ,痰菌阴转率 5 8% ;痰菌阴转率治疗组明显高于对照组 (P <0 0 1) ;治疗组病灶显效率 5 0 % ,空洞闭合率 6 3% ,治疗组优于对照组 (P <0 0 1) ;治疗组的药物不良反应率为 31% ,对照组为 35 % ,两组比较差异无显著性 (P >0 0 5 )。结论　含左氧氟沙星和卷曲霉素的方案治疗MDR PTB ,有助于痰菌阴转和病变吸收好转 ,药物不良反应低 ,值得在临床上推广应用     

Prevention of Bone Loss by Clodronate in Early Postmenopausal Women with Vertebral Osteopenia: A Dose-Finding Study

This double-masked, placebo-controlled study was undertaken to determine the efficacy and safety of oral clodronate in the prevention of bone loss in early postmenopausal women with vertebral osteopenia. Altogether 610 women with a mean age of 53 years were recruited for the study. They were 1–5 years postmenopausal and their lumbar spine bone mineral density (BMD) was at least 1 standard deviation below the mean of premenopausal women (T-score ≤−1). The subjects were randomized into five study groups to receive either placebo, clodronate 65 mg, 400 mg or 800 mg daily, or intermittent clodronate in 3 month cycles with 400 mg daily for 15 days followed with no treatment for 75 days for 3 years. One hundred and eighty-seven of 509 women who completed the primary study continued in the extension study of 2 years in which previous placebo users were switched to clodronate 800 mg daily, while previous users of 400 mg or 800 mg of clodronate used either placebo or 800 mg of clodronate daily. In the primary study clodronate was administered in the evening, and in the extension 1 h before breakfast on an empty stomach. In the primary study mean changes in lumbar spine BMD were −3.4% in the placebo group and +0.4% in 800 mg clodronate group [difference between groups at 3 years 3.8% (95% CI 2.7% to 4.9%, p<0.0001)], and in the trochanter area BMD −1.1% in the placebo group, and + 0.4% in the 800 mg clodronate group [difference between groups at 3 years 1.5% (95% CI 0.05% to 2.9%)]. During the extension study mean changes in lumbar spine BMD were +1.5% in the clodronate group and −0.2 % in the placebo group [difference between groups 1.7% (CI 0.4% to 3.0%, p = 0.010)] and in trochanter BMD were +2.5% in the clodronate group and no change in the placebo group [difference between groups 2.1% (CI 0.3% to 3.9%, p = 0.007)]. No statistically significant differences between the placebo and 800 mg clodronate groups were found in the femoral neck BMD. In the primary study the urinary excretion of type I collagen aminoterminal telopeptide (NTX) decreased by 44% (p<0.0001 compared with placebo) and that of deoxypyridinoline by 18% (p<0.0001) in the clodronate 800 mg group. In the extension study urinary NTX decreased by 51% (p<0.0001) in those who were switched to 800 mg of clodronate and increased by 67% (p<0.0001) in those who stopped using that dose. There was no difference in the frequency of gastrointestinal complaints between clodronate- and placebo-treated patients in the primary study, but they were more common among women who received clodronate in the extension phase. Clodronate in daily doses of 400–800 mg caused a slight elevation of aminotransferase levels, usually within the reference range. In bone biopsies no defect in mineralization was found. In conclusion, clodronate in a daily dose of 800 mg prevents early postmenopausal bone loss at the sites of the skeleton in which cancellous bone predominates. It effectively reduces bone resorption and bone turnover rate. Antifracture efficacy of clodronate remains to be established by prospective, placebo-controlled trials. Received: 4 March 2002 / Accepted: 9 July 2002     

Influence of Lung Aeration on Pulmonary Concentrations of Nebulized and Intravenous Amikacin in Ventilated Piglets with Severe Bronchopneumonia

Background: Pulmonary concentrations of aminoglycosides administered intravenously are usually low in the infected lung parenchyma. Nebulization represents an alternative to increase pulmonary concentrations, although the obstruction of bronchioles by purulent plugs may impair lung deposition by decreasing lung aeration.

Methods: An experimental bronchopneumonia was induced in anesthetized piglets by inoculating lower lobes with a suspension of 106 cfu/ml Escherichia coli. After 24 h of mechanical ventilation, 7 animals received two intravenous injections of 15 mg/kg amikacin, and 11 animals received two nebulizations of 40 mg/kg amikacin at 24-h intervals. One hour following the second administration, animals were killed, and multiple lung specimens were sampled for assessing amikacin pulmonary concentrations and quantifying lung aeration on histologic sections.

Results: Thirty-eight percent of the nebulized amikacin (15 mg/kg) reached the tracheobronchial tree. Amikacin pulmonary concentrations were always higher after nebulization than after intravenous administration, decreased with the extension of parenchymal infection, and were significantly influenced by lung aeration: 197 +/- 165 versus 6 +/- 5 [mu]g/g in lung segments with focal bronchopneumonia (P = 0.03), 40 +/- 62 versus 5 +/- 3 [mu]g/g in lung segments with confluent bronchopneumonia (P = 0.001), 18 +/- 7 versus 7 +/- 4 [mu]g/g in lung segments with lung aeration of 30% or less, and 65 +/- 9 versus 2 +/- 3 [mu]g/g in lung segments with lung aeration of 50% or more.