Pleiotropic genomic variants at 17q21.31 associated with bone mineral density and body fat mass: a bivariate genome-wide association analysis

Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, {"type":"entrez-nucleotide","attrs":{"text":"NC_000017.11","term_id":"568815581"}}NC_000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 10⁻⁹, replication P = 5.75 × 10⁻⁵) at the genome-wide significance level (ɑ = 5.0 × 10⁻⁸), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.Subject terms: Genome-wide association studies, Gene expression profiling     

结核分枝杆菌联合DNA疫苗初免-BCG加强的免疫效果观察

目的:研究并比较结核分枝杆菌免疫保护性抗原DNA(Ag85A和ESAT-6)疫苗联合免疫,BCG免疫以及联合DNA疫苗初免-BCG加强免疫等不同的免疫策略,诱导免疫应答效果观察.方法:健康雌性BALB/c小鼠24只,随机分成PBS 阴性对照组,DNA初免-BCG异源加强组,DNA(Ag85A和ESAT-6)初免DNA同源加强组和BCG阳性对照组,共进行3次免疫,初免2次,最后1次加强,间隔2周1次.PBS组3次均注射PBS 溶液;DNA/BCG组以质粒DNA免疫2次,最后1次以BCG加强免疫;DNA/DNA组3次均以质粒DNA进行免疫;BCG组则注射PBS溶液2次后以BCG免疫.末次免疫后4、6、8周分别分离血清测定总IgG水平,同时分离小鼠脾细胞,体外经TB-PPD刺激后进行淋巴细胞增殖实验(XTT法)并测定脾细胞培养上清中IFN-γ和IL-4水平.结果:DNA/BCG、DNA/DNA、BCG组体外经TB-PPD刺激后均检测到特异性IgG抗体产生,3组平均效价为1:120、1:160、1:80,DNA/DNA组的抗体效价高于另外2组;小鼠脾细胞体外经TB-PPD刺激后,均能产生特异性淋巴细胞增殖并诱生较强的IFN-γ反应,其中DNA/BCG组IFN-γ的分泌水平高于DNA/DNA组和BCG组(P<0.05).结论:联合DNA疫苗初免-BCG加强的免疫策略能在小鼠体内诱导较强的特异性细胞免疫反应,产生高水平的IFN-γ.     

Role of angiotensin Ⅱ and JAK2 signal pathway in transdifferentation of renal tubular cells in mice after acute ischemic followed by reperfusion

Objective To investigate the effect of angiotensin (Ang) Ⅱ and its Janns-activated kinase-2 (JAK2) signal pathway in transdifferentiation of renal tubular cells under the challenge of acute ischemic reperfusion injury.Methods Models of acute ischemic reperfusion injury were established and the level of local Ang Ⅱ ,a key element of renin-angiotensin system (RAS),in kidney was measured using radioimmunity technique.The expression of α-smooth muscle actin (α-SMA),a phenotype of mesenchymal cells,was detected by RT-PCR and inununohistochemistry methods.Renal tubule cells ( NRK-52E) were cultured with various concentration of Ang Ⅱ ,followed by blocking of PD123319,Ang U receptor 2 antagonist,and AG490,an inhibitor of JAK2 signal pathway.Results Ang 0 of kidney tissue increased immediately after acute ischemic-reperfusion injury,in time dependent fashion.Expression of α-SMA in renal tubule cells was found at 48 hours after ischemic-reperfusion injury and in NRK-52E cells treated by high concentration of Ang Ⅱ and was dose and time dependent.The peak of α-SMA expression was seen after 30 minute treatment at the dose of 10-9'mol/L,which was interrupted by both of PD123319 and AG490.Conclusions Transdifferentiarion of renal tubular epithelial cells occurs under acute ischemic- reperfusion injury.Local renin-angiotensin system may play a role in the transdifferentiation of TEC through AT2 receptor and its JAK2 signal pathway.     

The effects of sodium butyrate,an inhibitor of histone deacetylase,on the cocaine- and sucrose-maintained self-administration in rats

In order to substantiate the concept that cocaine behavioral effects may be influenced by histone modification, rats were trained to self-administer cocaine intravenously (0.75 mg/(kg injection)), and were systemically pretreated with sodium butyrate (NaBu), a potent histone deacetylase inhibitor, before the test session during the maintenance phase. The effect of NaBu on a control reinforcer (sucrose)-induced self-administration was also assessed. NaBu (100–200 mg/kg) was inactive in altering the cocaine (0.75 mg/(kg injection))-maintained responding and at the highest dose (400 mg/kg) it did increase cocaine-induced lever presses during the maintenance phase. On the other hand, sucrose-reinforcing potential was not altered when NaBu was given at the highest dose (400 mg/kg). These findings extend previous observations that changes in histone acetylation are relevant to cocaine-induced behavioral effects. Given that histone acetylase inhibitor enhances cocaine-induced behavioral plasticity, the therapeutic benefits of histone acetyltransferase inhibitors warrant further investigation in the experimental models of cocaine abuse.     

老年胃十二指肠急性穿孔诊治分析

目的 总结老年胃十二指肠穿孔的特点及临床治疗经验。方法 回顾性分析我院1990年至2002年经手术治疗的142例60岁以上胃十二指肠溃疡或肿瘤穿孔病人的临床资料。结果 行穿孔修补术96例，胃大部切除术46例；治愈127例；死亡11例；其它4例。结论 对老年人的急性穿孔，一旦确诊尽早手术，如年龄大并存病多，也不应成为手术的禁忌证。术后的并存病治疗及营养代谢的支持是降低病死率的重要因素。     

HBeAg时间分辨荧光免疫分析法的建立

采用平衡饱和法建立了乙型肝炎病毒e抗原(HBeAg)时间分辨荧光免疫分析法.以针对HBeAg的单克隆抗体G8包被板,双功能螯合剂异氰酸苄基二乙烯三胺四乙酸络合Eu3+及标记C4单抗,发光增强系统为以β-二酮体为主的增强液.数据采用Log-Logit法函数和四参数Logitc函数数据处理程序处理.结果表明方法的批内和批间CV分别为2.39%和5.28%,平均回收率为97.62%,灵敏度为0.58NCU/mL,可测范围为12.01-529.84NCU/mL,ED20、ED50和ED80分别为6.36NCU/mL、26.85NCU/mL和136.7NCU/mL.本方法与HBsAg有13.1%的交叉反应.Eu3+标记抗体-30℃保存6个月免疫反应性基本无损失,同批试剂连续5个月应用分析结果稳定.HBeAg时间分辨荧光免疫分析的质量参数优于EIA和IRMA.     

脂多糖对人脐静脉内皮细胞ET-1、eNOS、iNOS mRNA表达的影响

目的：观察脂多糖（LPS）对人脐静脉内皮细胞ET-1、eNOS、iNOSmRNA表达的影响，在分子水平上进一步探讨LPS影响人脐静脉内皮细胞分泌ET-1、NO的机制。方法：选用体外培养的第3代人脐静脉内皮细胞，以100 μg/L浓度的LPS与之共孵育6 h。提取总RNA，运用半定量RT-RCR的方法，对ET-1、eNOS、iNOS mRNA的表达情况进行分析。结果：ET-1的灰度比值分别为：正常对照组0.82，LPS组1.32；eNOS的灰度比值分别为：正常对照组1.20，LPS组0.65；iNOS组的灰度比值分别为：正常对照组0.20，LPS组0.19。结论：低浓度的LPS对人脐静脉内皮细胞ET-1 mRNA的表达有促进作用，对eNOS mRNA的表达有抑制作用，对iNOS mRNA的表达则无显著作用。     

血浆凝血酶调节蛋白在评估血管病变和并发症中的意义

目的探讨血浆凝血酶调节蛋白(PTM)在评估血管病变和并发症中的意义。方法用ELISA检测PTM。结果大血管病变的心脑血管疾病(冠心病、脑梗死和脑出血),PTM为轻度升高,平均水平均在35μg/L以下。微血管病变性疾病(原发性慢性肾小球疾病、SLE尿蛋白阳性者、糖尿病微血管病变、多脏器功能不全综合征和D IC),PTM中重度升高,平均水平全在40μg/L以上,分别与大血管病变的各组疾病比较有显著性差异(P<0.01)。分析病情进展和并发症PTM水平,原发性肾小球慢性疾病的肾功能衰竭组显著高于无肾功能衰竭组(P<0.01),SLE尿蛋白阳性组高于阴性组(P<0.01),糖尿病微血管病变组高于大血管病变组(P<0.01),D IC的PTM水平更是显著高于其他所有组别(P<0.01)。结论检测PTM可评估大小血管病变和并发症,有实用的临床指导意义,并为研究病理生理与血管病变的关系提供新的思路。     

脆性X综合征的快速PCR筛查

目的建立一种简便、快速、经济的脆性X综合征基因筛查PCR方法.方法通过提高预变性温度联合应用betaine扩增FMR1基因的三核苷酸重复序列.结果本方法扩增正常等位基因效率高,重复性好.结论该方法简便、价廉,可用于高危人群的快速筛查.     

L-精氨酸脂质体对慢性低O2高CO2肺血管L-精氨酸转运的影响

目的:探讨慢性低O₂高CO₂对大鼠肺动脉L-精氨酸(L-Arg)转运的影响与L-Arg脂质体的作用。方法:雄性SD大鼠40只,随机分成4组,正常对照组(NC)、单纯低O₂高CO₂组(HH)、低O₂高CO2加L-Arg组(HL)和低O₂高CO₂加L-Arg脂质体组(HP)。将肺动脉孵育,测定其对[³H]-L-Arg的摄取率,同时光镜下观察肺细小动脉显微结构的变化。结果:(1)肺动脉平均压(mPAP)、右心室(RV)和左心室加室间隔(LV+S)重量比值(RV/LV+S)比较:HH组明显高于NC组(P<0.05),HP组明显低于HH组及HL组(P<0.01);HL组与HH组相比无显著差别(P>0.05)。(2)肺动脉薄片对0.005mmol/L、0.01mmol/L、0.02mmol/L、0.05mmol/L、0.1mmol/L和0.2mmol/L[³H]-L-Arg摄取率比较:HH组明显低于NC组,HL组明显高于HH组;HP组显著高于HH组及HL组(P<0.01)。(3)光镜下HH组肺细小动脉内弹力板扭曲,中膜平滑肌细胞增生,管腔明显狭窄;HP组肺细小动脉内弹力板扭曲明显减轻,中膜平滑肌层变薄,管壁较均匀一致。结论:慢性低O₂高CO₂大鼠肺血管存在L-Arg的转运障碍,用脂质体作为载体可显著提高肺血管对L-Arg的跨膜转运,L-Arg脂质体治疗慢性肺动脉高压具有潜在临床应用价值。