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.     

Off pump coronary artery bypass (OPCAB) in critical left mainstem stenosis—Our experience

Background Beating heart surgery has now become the commonest technique of doing Coronary Artery Bypass Graft Surgery (CABG) in our country. It is being used even in such high risk situations like diffuse coronary disease and Critical Left Main stem Stenosis (LMCS) with good results. The aim of this study is to retrospectively review our results in Off-Pump Coronary Artery Bypass Surgery (OPCAB) in patients with critical left main stem stenosis. Methods This study is a retrospective analysis of the data of patients who underwent primary coronary artery bypass surgery. During the period from April 2003 to September 2005 a total of 64 patients underwent OPCAB procedure for critical LMCS. During the same period 10 patients underwent CABG on Cardio Pulmonary Bypass (CPB). The age range was 36–77yrs. The sex distribution was M: F 53∶10. Ten patients were done as emergency. 2 of them were on Intra Aortic Balloon Pump (IABP) support preoperatively. 10 patients were high risk with a Euro score of ≥5. Results Left Internal Mammary Artery (LIMA) was used in 78% of cases. Average grafts per patient was 2.96. The median ventilation time was 5.91 hrs. New IABP insertion in postoperative period was required in 1 patient. One patient was reexplored for bleeding. There was one perioperative myocardial infarction. 57% of patients did not need any blood transfusion. There was no conversion to CPB. There was no operative mortality. Inotropes were used in ten cases. Conclusions OPCAB is a safe method of revascularization in patients with critical LMCS. Preoperative IABP is useful in patients with cardiogenic shock. However, there is a place for CPB in patients needing additional procedures like Mitral Valve repair (MV repair) or Dor's procedure or when the vessels are very diffusely diseased. Those patients who are unstable despite IABP support may be managed by Beating heart On Pump (BHOP) technique.     

Experience with a metered-dose inhaler with a spacer in the pediatric emergency department

Studies of adults suggest that metered-dose inhalers with spacers are as effective as hand-held nebulizers for bronchodilator delivery. We studied 13 children with acute asthma. They received two puffs every 2 minutes from metered-dose inhalers with spacers (range, 4 to 14 puffs) titrated until improvement stopped. Peak expiratory flow increased 34% for metered-dose inhalers with spacers after the first 2 puffs and increased 87% for metered-dose inhalers with spacers after dose titration. After titration, respiratory rate decreased by 12%, heart rate increased by 2%, and breath sounds improved in 92% of the patients. We concluded that the metered-dose inhalers with spacers are an effective device for the treatment of asthma in the pediatric emergency department and that the use of metered-dose inhalers with spacers with titration can achieve significant bronchodilation in the treatment of patients with acute asthma.     

氟西汀与阿米替林治疗105例抑郁障碍病人的双盲对照试验

目的：评价国产氟西汀的抗抑郁作用及安全性。方法：采用随机、双盲对照、多中心研究，分为国产氟西汀组５７例（男性２２例，女性３５例；年龄４０±ｓ１３ａ），口服氟西汀２０ｍｇ，ｑｄ，阿米替林５７例（男性２７例，女性３０例；年龄４０±１４ａ），口服阿米替林７５ｍｇ，ｂｉｄ，疗程６ｗｋ。结果：氟西汀治疗抑郁障碍的疗效与阿米替林相当，总有效率分别为８５％及９２％（Ｐ＞０．０５）；氟西汀组的主要副作用有口干、便秘、恶心、心动过速等，但较之阿米替林程度轻且发生率低。结论：氟西汀的抗抑郁作用与阿米替林相当，副作用少，服用方便。     

Challenges in accessing multidisciplinary pain treatment facilities in Canada

PURPOSE: The objective of this survey was to examine the services offered by multidisciplinary pain treatment facilities (MPTFs) across Canada and to compare access to care at these MPTFs. METHODS: A MPTF was defined as a clinic that advertised specialized multidisciplinary services for the diagnosis and management of patients with chronic pain, having a minimum of three different health care disciplines (including at least one medical speciality) available and integrated within the facility. The search method included approaching all hospital and rehabilitation centre administrators in Canada, the Insurance Bureau of Canada, the Workplace Safety and Insurance Board or similar body in each province. Designated investigators were responsible for confirming and supplementing MPTFs from the preliminary list for each province. Administrative leads at each eligible MPTF were asked to complete a detailed questionnaire regarding their MPTF infrastructure, clinical, research, teaching and administrative activities. RESULTS: Completed survey forms were received from 102 MPTFs (response rate 85%) with 80% concentrated in major cities, and none in Prince Edward Island and the Territories. The MPTFs offer a wide variety of treatments including non-pharmacological modalities such as interventional, physical and psychological therapy. The median wait time for a first appointment in public MPTFs is six months, which is approximately 12 times longer than non-public MPTFs. Eighteen pain fellowship programs exist in Canadian MPTFs and 64% engage in some form of research activities CONCLUSION: Canadian MPTFs are unable to meet clinical demands of patients suffering from chronic pain, both in terms of regional accessibility and reasonable wait time for patients' first appointment.