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.     

Host MyD88 signaling protects against acute graft-versus-host disease after allogeneic bone marrow transplantation

Recent experimental strategies to reduce graft-versus-host disease (GVHD) have focused largely on modifying innate immunity. Toll-like receptor (TLR)-driven myeloid differentiation primary response 88 (MyD88)-dependent signalling pathways that initiate adaptive immune function are also critical for the pathogenesis of GVHD. This study aimed to delineate the role of host MyD88 in the development of acute GVHD following fully major histocompatibility complex-mismatched allogeneic bone marrow transplantation (BMT). When myeloablated BALB/c MyD88 knock-out recipients were transplanted with C57BL/6 (B6) donor cells, they developed significantly more severe GVHD than wild-type (WT) BALB/c hosts. The increased morbidity and mortality in MyD88^–/– mice correlated with increased serum levels of lipopolysaccharide and elevated inflammatory cytokines in GVHD target organs. Additionally, MyD88 deficiency in BMT recipients led to increased donor T cell expansion and more donor CD11c⁺ cell intestinal infiltration with apoptotic cells but reduced proliferation of intestinal epithelial cells compared with that in WT BMT recipients. Decreased expression of tight junction mRNA in epithelial cells of MyD88^–/– mice suggested that MyD88 contributes to intestinal integrity. Cox-2 expression in the GVHD-targeted organs of WT mice is increased upon GVHD induction, but this enhanced expression was obviously inhibited by MyD88 deficiency. The present findings demonstrate an unexpected role for host MyD88 in preventing GVHD after allogeneic BMT.     

Soluble triggering receptor expressed on myeloid cells-1 in acute respiratory infections.

Levels of the soluble form of the triggering receptor expressed on myeloid cells (sTREM)-1 are elevated in severe sepsis. However, it is not known whether sTREM-1 measurements can distinguish milder bacterial infections from noninfectious inflammation. The present authors studied whether serum sTREM-1 levels differ in community-acquired pneumonia, exacerbations of chronic obstructive pulmonary disease (COPD), asthma and controls, and whether sTREM-1 may be used as a surrogate marker for the need for antibiotics. Serum sTREM-1 levels in 150 patients with pneumonia, COPD and asthma exacerbations and 62 healthy controls were measured. Serum sTREM-1 levels were significantly elevated in pneumonia (median 295.2 ng x mL(-1)), COPD (280.3 ng x mL(-1)) and asthma exacerbations (184.0 ng x mL(-1)) compared with controls (83.1 ng x mL(-1)). Levels were higher in pneumonia and Anthonisen type 1 COPD exacerbations than in type 2 and 3 COPD and asthma exacerbations. The area under the receiver operating characteristics curve for sTREM-1 as a surrogate marker for the need for antibiotics was 0.77. Serum levels of the soluble form of the triggering receptor expressed on myeloid cells-1 were elevated predominantly in pneumonia and Anthonisen type 1 COPD exacerbations versus type 2 and 3 chronic obstructive pulmonary disease exacerbations, asthma and controls. Serum levels of the soluble form of the triggering receptor expressed on myeloid cells-1 has moderate but insufficient accuracy as a surrogate marker for the need for antibiotics in lower respiratory tract infections.     

Evaluation of corticospinal tract injury with three-dimensional diffusion tensor tract in patients with acute cerebral infarction

Three-dimensional diffusion tensor tract (DTT) is the newest imaging to describe the structure of white matter fiber in three-dimensions, it has great significance in dividing the concrete anatomic site of gray and white matter lesions, displaying the correlation with fibrous band and judging clinical prognosis, which is incomparable by other imagings.OBJECTTVE: To observe the conditions of corticospinal tract (CST) in acute cerebral ischemic stroke patients,and analyze the relationship between motor function and the severity of CST injury.DESIGN: A case-control observation.SETTTNG: Department of Medical Imaging, Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA.PARTTCTPANTS: Fifteen patients with acute cerebral infarction were selected from Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA from February to December in 2005. They all suffered from acute attack and motor disorder of hemiplegic limbs to different extent, and were conformed by CT or MRI.There were 9 males and 6 females, aging 16-87 years old, the median age was 51.7 years, and all were right handed. Fifteen right-handed normal subjects, who were matched by age and sex with the patients in the cerebral infarction group, were selected from the relatives of patients and physicians of the Imaging Department as the control group. All the subjects were informed and agreed with the study.METHODS: The patients with acute cerebral infarction and subjects in the control group received MR diffusion tensor imaging (DTI) with GE 1.5 T nuclear magnetic resonance system, fiber tracking with the software of dTV- Ⅱ. Fractional anisotropy (FA) maps and three-dimensional tractography of bilateral CST of all patients were created. Displacement, continuity and destroy of fibrous bands were observed. At the same time, muscle strength of ipsilateral hand of patients with cerebral infarction was measured with Brunnstrom standard. The correlation between the severity of CST injury and the muscle strength of ipsilateral hand was analyzed with spearman correlation analysis.MAIN OUTCOME MEASURES: ① FA values in the infarcted sites and those in the contralateral corresponding sites of patients with cerebral infarction; ② CST manifestations in the patients with cerebral infarction and the control group.RESULTS: All the 30 testees were involved in the analysis of results. ① The FA values in infarcted sites of white matter were significantly lower than those in the contralateral ones (t =4.570, P ＜ 0.001 ). ② In the control group, bilateral CST were reconstructed, they originated from precentral gyrus, went downwards to internal capsule, and extended to pontine and medulla oblongata, each fiber had good uniformity in continuous form. In the patients with cerebral infarction, the forms of contralateral CST were consistent with those in the control group with good continuity. Due to the involvement by the infarcted site to different extents, the ipsilateral CST manifested as continuous interruption and loss of uniformity in anatomic structure and form. The CST involvements were divided into three grades: integrated CST for grade I (n =2); integrated CST but compressed or displaced for grade 2 (n =5); interrupted CST for grade 3 (n =8). ③ The severity of CST injury was obviously correlated with the muscle strength of the ipsilateral hand (r=0.888, P＜ 0.05＝.CONCLUSION: ① CST is injured to different extents in patients with acute cerebral infarction, and the severity of injury is associated with muscle strength. It is indicated that it can be used to judge the prognosis of rehabilitative treatment. ②DTT can directly display the status of pyramidal tract more three-dimensionally.     

Body weight and comorbidity predict mortality in COPD patients treated with oxygen therapy.

The aim of this study was to investigate the association between clinical variables and all-cause and respiratory mortality in patients with chronic obstructive pulmonary disease (COPD) undergoing long-term oxygen therapy (LTOT). The authors retrospectively studied a historic cohort of 128 patients with COPD (126 males, mean age+/-SD 68.9+/-9.7 yrs, body mass index (BMI) 25.1+/-4.5 kg.m-2, and forced expiratory volume in one second 25.4+/-8.8% predicted), who were being treated with long-term oxygen therapy in a tertiary teaching hospital between 1992 and 1999. Comorbidity, assessed with the Charlson Index, was present in 38% of the patients. Vital status and cause of death were assessed through the population death registry. A total of 78 patients (61%) had died by the end of follow-up. Three-year survival was 55%. Death was due to respiratory causes in 77% of cases. On Cox analysis, BMI<25 kg.m-2, comorbid conditions, age>or=70 yrs and cor pulmonale were associated with all-cause mortality. The BMI and comorbidity were the only significant predictive factors when the analysis was restricted to respiratory mortality. In conclusion, body mass index<25 kg.m-2 and comorbidity were predictors of all-cause and respiratory mortality in a cohort of chronic obstructive pulmonary disease patients treated with long-term oxygen therapy. These factors should be taken into account when considering the management and prognosis of these patients.     

骨髓移植术后急性肠道移植物抗宿主病内镜及病理学诊断研究

目的评价内镜和病理学诊断在急性肠道移植物抗宿主病(GVHD)中的作用。方法回顾性总结和分析2001—2005年北京大学人民医院血液病学研究所临床已确诊的23例急性肠道GVHD患者的内镜及病理学资料。结果内镜下表现可分为:黏膜大致正常、血管纹理模糊或消失、弥漫性黏膜充血、水肿和脆性增加,重者出现糜烂、溃疡,甚至黏膜脱落或出血;病理学表现提示:隐窝上皮细胞凋亡、缺失,隐窝结构破坏,上皮和黏膜固有层不同程度的淋巴细胞浸润。结论内镜和病理学检查可以用于急性肠道GVHD的诊断,尤其是内镜在急性肠道GVHD的早期诊断方面具有重要作用,同时结合病理学检查最终确立诊断。