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.     

结直肠癌化疗患者营养状况及营养治疗研究进展

结直肠癌是常见的消化道肿瘤，其营养不良发生率高且严重。化疗是结直肠癌常见治疗方式之一，并与营养不良独立相关，化疗后患营养不良风险增大且营养不良进一步加重。同时，营养不良可导致患者化疗疗效差及预后不良，并增加化疗相关不良反应、影响患者生活质量及降低生存率等。营养治疗能够有效改善患者营养状况，在肿瘤综合治疗中有重要作用，且多学科团队合作是有效的营养干预模式。目前营养治疗主要包括营养咨询、口服营养补充剂、肠内营养和肠外营养等，相关指南和研究表明在营养治疗时应首选口服营养补充剂及肠内营养，仅在采用以上治疗后仍存在营养不足或无法进行肠内营养时行肠外营养。本文主要对结直肠癌患者营养状况与化疗之间关系、营养治疗的最新研究进展及相关指南进行综述，以期引起临床上对结直肠癌化疗患者营养治疗方面重视并提供参考。     

重型颅脑损伤的手术治疗

目的探讨重型颅脑损伤梯度减压的手术方法对预防术中脑膨出、降低死亡率及致残率的效果。方法对100例重型颅脑损伤患者采用分次减压手术方式及去骨瓣后，硬膜与颞肌筋膜瓣减张缝闭硬膜切口方法。结果40例脑肿胀患者术中脑嘭出6例占15．0％，死亡19例占47．5％；60例脑内血肿病人未发生脑膨出，死亡12例占20％。结论脑外伤后脑血管调节麻痹及血肿压迫继发脑水肿易造成脑膨出.术中分次减压降低了骨窗部位脑组织的顺应性，从而降低了局部的压力梯度，避免脑血管急性扩张，能有效防止脑膨出，降低死亡率及致残率。     

胃癌侵袭性对患者血清E-钙粘附素浓度的影响

探讨E-钙粘附素(E-Cd)对人胃癌侵袭性的作用。方法:应用酶联免疫吸附方法测定29例胃癌患者血清可溶性E-Cd浓度。结果:胃癌组明显高于对照组(P<0.01),浸润组或有淋巴结转移组明显高于膨胀组或无淋巴结转移组(P<0.01～0.05),切除瘤体后上述各组的血清E-Cd浓度均明显下降(P<0.01～0.05)。结论:血清可溶性E-Cd浓度可能与人胃癌的生长方式和淋巴结转移密切相关。     

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.     

重度苯妥英钠中毒的药学监护

目的首先确定中毒药物,然后通过测定血药浓度以了解中毒程度,为重度苯妥英钠中毒患者临床抢救治疗提供依据。方法间隔一定时间采集患者静脉血,萃取血中药物,在211 nm处以反相高效液相色谱法定性,明确中毒药物并测定血药浓度。结果在苯妥英中毒患者中最高血药浓度为68.94 mg.L-1,接近治疗浓度上限的3.5倍。结论患者为重度中毒,危及生命,需临床药师与临床医师积极配合,施行全程药学监护。