A Powerful Approach to Test an Optimally Weighted Combination of Rare Variants in Admixed Populations

Population stratification has long been recognized as an issue in genetic association studies because unrecognized population stratification can lead to both false‐positive and false‐negative findings and can obscure true association signals if not appropriately corrected. This issue can be even worse in rare variant association analyses because rare variants often demonstrate stronger and potentially different patterns of stratification than common variants. To correct for population stratification in genetic association studies, we proposed a novel method to Test the effect of an Optimally Weighted combination of variants in Admixed populations (TOWA) in which the analytically derived optimal weights can be calculated from existing phenotype and genotype data. TOWA up weights rare variants and those variants that have strong associations with the phenotype. Additionally, it can adjust for the direction of the association, and allows for local ancestry difference among study subjects. Extensive simulations show that the type I error rate of TOWA is under control in the presence of population stratification and it is more powerful than existing methods. We have also applied TOWA to a real sequencing data. Our simulation studies as well as real data analysis results indicate that TOWA is a useful tool for rare variant association analyses in admixed populations.     

2001—2012年河北省新发矽肺病病例特征及趋势研究

目的了解河北省新发矽肺病例的特征和流行趋势,为建立矽肺病监测、预警数学模型,制定河北省矽肺防治对策提供依据。方法整合2001年1月1日—2012年12月31日全省职业病网络报告数据并建立数据库,采用SPSS 17.0对矽肺新发病例的时间、地区、行业、工种进行统计描述;对矽肺新发病例的企业、经济类型的期别的构成进行χ2检验,对矽肺新发病例发病年龄、发病工龄的中位数进行H检验,对矽肺时间、发病工龄的变化趋势进行分析。结果 2001年-2012年河北省累计报告新发矽肺病例2 679例,主要集中在承德、张家口和唐山,分别为870(32.5%)、662(24.7%)和656例(24.5%)。唐山、承德和张家口各年度矽肺病例数与总矽肺例数变化趋势基本一致。矽肺病例主要集中在冶金(1 041例,38.86%)、有色金属(655例,24.45%)和煤炭(323例,12.06%)行业。2006年后,煤炭、有色金属行业发病例数明显高于2005年之前。有色金属、煤炭和冶金行业贰、叁期矽肺病例数所占比例依次减少,分别为44.58%、31.06%和24.90%。矽肺病例主要集中在凿岩工(41.10%)、破碎工(8.17%)和采矿工(7.54%);凿岩工、主掘进工和破碎工的贰、叁期矽肺检出率较高。矽肺期别与大、中、小型企业之间构成比比较,差异有统计学意义(χ2=235.80,P0.01),矽肺期别与企业规模之间呈正相关(r=0.29)。矽肺期别与国有经济、集体经济和私有经济3者构成比比较,差异有统计学意义(χ2=41.98,P0.01),经济类型与矽肺期别之间呈正相关(r=0.15)。矽肺发病年龄中位数变化趋于平缓(M=48.89,43.38,55.38);发病年龄总体分布比较,差异有统计学意义(χ2=81.38,P0.01)。发病工龄呈明显下降趋势,2010年矽肺发病工龄最短为9a;2001—2012年发病工龄总体分布比较,差异有统计学意义(χ2=239.38,P0.01)。结论矽肺病发病形势依然严峻,主要表现为:新发矽肺病例数仍呈逐年增长趋势,矽肺发病工龄呈现明显缩短趋势,贰期及以上新发病例达30%以上;新发矽肺病呈现明显的地区、行业、工种和企业规模的集聚性或集中趋势。     

长期注射水杨酸钠对大鼠下丘GAD67和GABAAα1、c-fos表达的影响

目的通过观察长期注射水杨酸钠对大鼠听性脑干反应(ABR)及下丘GAD67和GABAAα1、c-fos表达的影响,探讨大鼠下丘GAD67、GABAAα1、c-fos表达的改变在水杨酸钠耳毒性中的可能机制。方法将24只成年健康Wistar大鼠随机分为2组:水杨酸钠组(肌肉注射10%水杨酸钠175 mg/kg,2次/d,连续28 d)、对照组(每天相同时间注射等量生理盐水,连续28 d)。两组大鼠在处死前进行ABR检测并观察ABR反应阈及波Ⅲ潜伏期的变化,然后将大鼠断头处死并迅速剥离下丘,采用实时荧光定量PCR(real-time PCR)、蛋白质印迹(Western blot)方法检测下丘GAD67、GABAAα1、c-fos mRNA及蛋白表达的变化。结果 1药物注射28 d后,水杨酸钠组较注射前以及对照组ABR反应阈明显升高,波Ⅲ潜伏期明显延长,差异有统计学意义(P<0.01);2水杨酸钠组GAD67、GABAAα1、c-fos mRNA及其蛋白表达水平较对照组明显升高,差异有统计学意义(P<0.01)。结论GAD67、GABAAα1、c-fos均不同程度参与了水杨酸钠耳毒性的发生发展过程,c-fos表达的上调则可能与水杨酸钠作用于机体后引起听觉中枢神经活动增强有关。     

呼出气一氧化氮在儿童哮喘缓解期的应用价值

目的：探讨呼出气一氧化氮检测用于评估临床缓解期哮喘儿童病情的价值。方法选取214例处于临床缓解期哮喘儿童,按照有无进行规范化治疗分为治疗组和对照组。同时记录FeNO及PC20 FEV1数值。结果治疗组与对照组平均FeNO值分别为22．63×10－9 ppb和39．67×10－9 ppb ,差异有统计学意义（ P＜0．01）。治疗组与对照组平均 PC20 FEV1数值分别为（7．43±6．16）和（6．78±5．83）,差异无统计学意义（P＞0．05）。FeNO与PC20 FEV1呈负相关性（r＝－0．372,P＜0．01）,直线回归方程为Y＝35．883－1．074X（X表示PC20 FEV1,Y 表示FeNO）。结论 FeNO数值可以作为哮喘患儿非特异性气道炎症控制状况的可靠指标。呼出气一氧化氮检测与支气管激发试验联合,可显著提高临床缓解期哮喘患儿的诊断率。     

Role for engagement of β‐arrestin2 by the transactivated EGFR in agonist‐specific regulation of δ receptor activation of ERK1/2

Background and Purpose

β‐Arrestins function as signal transducers linking GPCRs to ERK1/2 signalling either by scaffolding members of ERK1/2s cascades or by transactivating receptor tyrosine kinases through Src‐mediated release of transactivating factor. Recruitment of β‐arrestins to the activated GPCRs is required for ERK1/2 activation. Our previous studies showed that δ receptors activate ERK1/2 through a β‐arrestin‐dependent mechanism without inducing β‐arrestin binding to the δ receptors. However, the precise mechanisms involved remain to be established.

Experimental Approach

ERK1/2 activation by δ receptor ligands was assessed using HEK293 cells in vitro and male Sprague Dawley rats in vivo. Immunoprecipitation, immunoblotting, siRNA transfection, intracerebroventricular injection and immunohistochemistry were used to elucidate the underlying mechanism.

Key Results

We identified a new signalling pathway in which recruitment of β‐arrestin2 to the EGFR rather than δ receptor was required for its role in δ receptor‐mediated ERK1/2 activation in response to H‐Tyr–Tic–Phe–Phe–OH (TIPP) or morphine stimulation. Stimulation of the δ receptor with ligands leads to the phosphorylation of PKCδ, which acts upstream of EGFR transactivation and is needed for the release of the EGFR‐activating factor, whereas β‐arrestin2 was found to act downstream of the EGFR transactivation. Moreover, we demonstrated that coupling of the PKCδ/EGFR/β‐arrestin2 transactivation pathway to δ receptor‐mediated ERK1/2 activation was ligand‐specific and the Ser³⁶³ of δ receptors was crucial for ligand‐specific implementation of this ERK1/2 activation pathway.

Conclusions and Implications

The δ receptor‐mediated activation of ERK1/2 is via ligand‐specific transactivation of EGFR. This study adds new insights into the mechanism by which δ receptors activate ERK1/2.

Abbreviations

DPDPE

[D‐Pen2, D‐Pen5] enkephalin

HB‐EGF

heparin‐binding EGF‐like growth factor

IGFR

insulin‐like growth factor receptor

NG108‐15

cell mouse neuroblastoma x rat glioma hybrid cell

RTK

receptor tyrosine kinase

TIPP

H‐Tyr‐Tic‐Phe‐Phe‐OH

     

The potential health challenges of TiO2 nanomaterials

Titanium dioxide (TiO₂) nanomaterials (NMs) have found widespread applications owing to their attractive physical and chemical properties. As a result, the potential adverse impacts of nano‐TiO₂ exposure on humans have become a matter of concern. This review presents the state‐of‐the‐art advances on the investigations of the adverse effects of NMs, including the potential exposure routes of nano‐TiO₂ (e.g. respiratory system, skin absorption and digestive system), the physico‐chemical characterizations of nano‐TiO₂ (e.g. crystal structure, shape,size, zeta potential, treatment media, aggregation and agglomeration tendency, surface characteristics and coatings), risk evaluation of nanotoxicity (e.g. cytotoxicity, ecotoxicity, phototoxicity, and phytotoxicity) and potential mechanisms of adverse effects (e.g. generation of reactive oxygen species, oxidative stress and organelle dysfunction). The review aims to facilitate scientific assessments of health risks to nano‐TiO₂, which would guide the safe applications of NMs in our daily life. Copyright © 2015 John Wiley & Sons, Ltd.     

Tandem autologous hematopoietic stem cell transplantation for treatment of adult T-cell lymphoblastic lymphoma: a multiple center prospective study in China

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive form of lymphoma with poor clinical outcomes and no standard treatment regimen. In this study, we assessed the safety and efficacy of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) for adult T-LBL and evaluated prognostic factors affecting survival. A total of 181 newly-diagnosed adult T-LBL patients were enrolled: 89 patients were treated with chemotherapy alone, 46 were allocated to the single auto-HSCT group, 46 were treated with tandem auto-HSCT. Median follow-up time was 37 months; the 3-year progression/relapse rate of the tandem auto- HSCT group was significantly lower than that of the single auto-HSCT and chemotherapy groups (26.5% vs. 53.1% and 54.8%). The 3-year progression- free survival (PFS) and overall survival (OS) rates of the tandem auto- HSCT group (73.5% and 76.3%) were significantly higher than those of the single auto-HSCT group (46.9% and 58.3%) and the chemotherapy group (45.1% and 57.1%). In the tandem auto-HSCT group, age and disease status after the first transplant impacted OS and PFS. Multivariate analysis identified that disease status after the first transplant was the only independent prognostic factor for patients treated with tandem-HSCT. In addition, diagnostic models of the initial CD8⁺CD28⁺/CD8⁺CD28^– T-cell ratio in predicting the disease status were found to be significant. Taken together, tandem auto- HSCT can be considered an optimal strategy for adult T-LBL patients. (Study registered at: ChiCTR-ONN-16008480).     

江苏省医院非技术服务质量评价指标体系的研究

非技术性服务质量对于现代医院来讲意义重大。评价指标体系是对其进行评价而改进其质量为前提和关键。该研究从指标体系的构建、指标体系的确立以及指标体系的考核三个方面研究了江苏省医院非技术服务质量评价指标体系。     

PDCA循环与系统追踪在围手术期质量管理中的应用研究

围手术期的医疗质量一直是医院医疗质量与安全的重中之重。如何才能管理好围手术期医疗质量,一直是让人棘手的问题。南通大学附属医院借鉴三级医院等级评审中广泛使用的PDCA质量管理循环及系统追踪并将其灵活运用,在医院围手术期质量管理中起到良好的效果。     

胰腺脓肿及胰腺坏死感染15例分析

目的:分析比较胰腺脓肿及胰腺坏死感染的临床特点、病原学特征、诊治措施和转归,以期改善其预后.方法:对1991年1月～2002年12月北京协和医院诊治的胰腺脓肿患者13例,胰腺坏死感染患者2例进行回顾性分析,比较其临床特点、诊断和治疗结果及预后.结果:(1)腴腺脓肿和胰腺坏死感染的好发因素有重症胰腺炎、手术后胰腺炎、囊肿穿刺引流.(2)所有患者病程中均有持续发热或体温降而复升,可伴或不伴腹痛、血白细胞和淀粉酶升高.(3)引流液细菌培养阳性率100%,由高到低依次为肠杆菌、绿脓杆菌、肠球菌、葡萄球菌和类酵母菌等,73.3%(11/15)为混合感染.(4)在内科支持治疗基础上全部患者行局部穿刺置管或手术清创引流,80%(12/15)好转出院,20%(3/15)死亡或放弃治疗.结论:(1)对持续中等度以上发热大于3周或体温下降后再次上升者,适时进行胰腺穿刺可以获得早期诊断.(2)积极的外科或介入治疗,同时密切监护、加强抗感染和全身支持治疗,有可能改善患者的预后.(3)与手术相比,介入治疗在胰腺脓肿中的应用前景有待进一步研究.