盐酸埃他卡林选择性降压作用的研究

目的 :在清醒正常血压犬和“两肾一夹”肾性高血压犬 (RHD)上 ,观察不同剂量盐酸埃他卡林(iptakalimhydrochloride,Ipt)的降压作用特征 ;在清醒正常血压的Wistar大鼠和脑卒中易感型自发性高血压大鼠 (stroke pronespontaneouslyhypertensiverat,SHRsp)上 ,采用无创心功能监测方法 ,观察Ipt对心功能和血流动力学的作用特征 ,以判断其降压作用和对心功能及血流动力学的影响是否具有选择性。方法 :给清醒正常血压犬和RHD口服不同剂量的Ipt,用听诊法测量移于皮鞘内的颈总动脉血压 ,用触诊法测量心率 ,同时记录Ⅱ导联心电图。给清醒正常血压大鼠和SHRsp静脉注射相同剂量的Ipt,采用清醒无创心功能血流动力学实验方法 ,观察Ipt对对心功能和血流动力学的影响。结果 :在RHD模型上 ,单次口服Ipt0 .1 2 5、0 .2 5、0 .5、1 .0mg·kg- 1 后 ,产生剂量依赖性的降压作用 ,0 .5h开始起效 ,2～ 3h达效应峰值 ,其最大降低SBP幅度分别为 1 3、2 3、2 5、3 6mmHg,降压作用维持时间分别为 4、6、6、1 2h。在清醒正常血压犬上 ,单次口服Ipt 0 .8,3 .2 ,1 2 .8mg·kg- 1 ,其中剂量为 0 .8和 3 .2mg·kg- 1 时 ,血压和心率均无明显变化 ,剂量增至 1 2 .8mg·kg- 1 时 ,在给药后 5h之内可以显著降低收缩压和舒张压 ,其最大降低SB     

What are the roles of the many different types of potassium channel expressed in cerebellar granule cells?

Potassium (K) channels have a key role in the regulation of neuronal excitability. Over a hundred different subunits encoding distinct K channel subtypes have been identified so far. A major challenge is to relate these many different channel subunits to the functional K currents observed in native neurons. In this review, we have concentrated on cerebellar granule neurons (CGNs). We have considered each of the three principal super families of K channels in turn, namely, the six transmembrane domain, voltage-gated super family, the two transmembrane domain, inward-rectifier super family and the four transmembrane domain, leak channel super family. For each super family, we have identified the subunits that are expressed in CGNs and related the properties of these expressed channel subunits to the functional currents seen in electrophysiological recordings from these neurons. In some cases, there are strong molecular candidates for proteins underlying observed currents. In other cases the correlation is less clear. We show that at least 26 potassium channel alpha subunits are moderately or strongly expressed in CGNs. Nevertheless, a good empirical model of CGN function has been obtained with just six distinct K conductances. The transient KA current in CGNs, seems due to expression of Kv4.2 channels or Kv4.2/4.3 heteromers, while the KCa current is due to expression of large-conductance slo channels. The G-protein activated KIR current is probably due to heteromeric expression of KIR3.1 and KIR3.2. Perhaps KIR2.2 subunits underlie the KIR current when it is constitutively active. The leak conductance can be attributed to TASK-1 and or TASK-3 channels. With less certainty, the IK-slow current may be due to expression of one or more members of the KCNQ or EAG family. Lastly, the delayed-rectifier Kv current has as many as six different potential contributors from the extensive Kv family of alpha subunits. Since many of these subunits are highly regulated by neurotransmitters, physiological regulators and, often, auxiliary subunits, the resulting electrical properties of CGNs may be highly dynamic and subject to constant fine-tuning.     

BRD7交互作用蛋白基因BRD2、BRD3在鼻咽癌组织中的表达

背景与目的：BRD7基因是通过cDNA代表性差异分析获得的一个鼻咽癌（nasopharyngeal carcinoma,NPC）密切相关基因。采用酵母双杂交技术,已从人胎脑的cDNA文库中筛选到了两个与BRD7蛋白存在交互作用且包含溴区结构域（bromodomain)的蛋白BRD2、BRD3。本研究的目的在于进一步证实BRD7蛋白与BRD2、BRD3蛋白之间的交互作用,探讨BRD2、BRD3基因在鼻咽癌中的表达和作用模式。方法：将BRD2、BRD3基因分别与BRD7基因共转化酵母Y187后将菌落影印到尼龙膜,X－Gal检测酵母中报告基因LacZ的表达,推断BRD2、BRD3与BRD7蛋白之间的交互作用。RT－PCR方法检测BRD2、BRD3基因在正常鼻咽上皮组织和鼻咽癌活检组织中的差异表达以及在BRD7基因稳定转染的鼻咽癌细胞株（HNE1）中,BRD7基因的重表达对BRD2、BRD3基因表达水平的影响。结果：通过特异性酵母双杂交技术,发现酵母转化子的颜色呈蓝色,进一步证实BRD2、BRD3蛋白能分别与BRD7蛋白发生交互作用。RT－PCR结果显示,在鼻咽癌组织中,BRD2和BRD3基因表达下调或缺失;在BRD7基因稳定转染的HNE1细胞株中,随着BRD7基因表达的增强,BRD2、BRD3基因的表达存在明显的上调。结论：BRD7蛋白能分别与BRD2、BRD3蛋白发生交互作用,且在mRNA水平存在一定程度的协同表达作用,彼此可能形成二聚体或三聚体,共同参与鼻咽癌的发病过程。     

Hepatobiliary elimination of bile acid-modified oligodeoxynucleotides in Wistar and TR- rats: evidence for mrp2 as carrier for oligodeoxynucleotides

As therapeutic antisense tools, oligonucleotides (ODNs) must enter cells to bind to their target structures. ODNs distribute in nearly each tissue with relatively high concentrations in kidney and liver from where excretion into urine and bile occurs. To investigate mechanisms involved in hepatic ODN transport, normal mixed backbone phosphodiester/phosphorothioate ODNs (n-ODN) and two different bile acid-conjugated mixed backbone ODNs (1BA-ODN and 2BA-ODN) were applied to two different rat strains, normal Wistar rats and Wistar TR- rats. In normal Wistar rats, concentration-dependent hepatobiliary elimination of the ODNs was observed with a remarkable increase of excretion of the cholic acid BA-ODN conjugates. In contrast to normal Wistar rats, n-ODN excretion into bile by TR- rats, a mutant Wistar rat strain lacking a functional multidrug resistance-associated protein 2 (mrp2) at the canalicular membrane, was strongly diminished, whereas these rats excreted an ODN conjugated with two cholic acid molecules (2BA-ODN) into bile. Concomitant application of substrates transported by mrp2 such as bromosulfophthalein (BSP) or the synthetic chlorogenic acid derivative S 3025 significantly reduced the biliary appearance of normal ODN and 2BA-ODN in Wistar rats and also in TR- rats. To inhibit the expression of cRNA derived from the Na+ -dependent taurocholate cotransporting polypeptide (Ntcp), antisense ODNs were constructed which fully retained the antisense properties when coupled with two bile acid molecules. The results indicate that ODNs are secreted via the mrp2 into bile. In the absence of mrp2, further excretory transport systems with affinity for bile acids seem to be relevant for their excretion. The results further indicate that bile acid tagged ODNs are useful tools for liver specific antisense therapy.     

Multipoint analysis using affected sib pairs: incorporating linkage evidence from unlinked regions

In this paper, we proposed a multipoint method to assess evidence of linkage to one region by incorporating linkage evidence from another region. This approach uses affected sib pairs in which the number of alleles shared identical by descent (IBD) is the primary statistic. This generalized estimating equation (GEE) approach is robust in that no assumption about the mode of inheritance is required, other than assuming the two regions being considered are unlinked and that there is no more than one susceptibility gene in each region. The method proposed here uses data from all available families to simultaneously test the hypothesis of statistical interaction between regions and to estimate the location of the susceptibility gene in the target region. As an illustration, we have applied this GEE method to an asthma sib pair study (Wjst et al. [1999] Genomics 58:1-8), which earlier reported evidence of linkage to chromosome 6 but showed no evidence for chromosome 20. Our results yield strong evidence to chromosome 20 (P value = 0.0001) after incorporating linkage information from chromosome 6. Furthermore, it estimates with 95% certainty that the map location of the susceptibility gene is flanked by markers D20S186 and D20S101, which are approximately 16.3 cM apart.     

DADS诱导人白血病细胞分化中的代谢变化

目的 研究二烯丙基二硫诱导人髓性白血病HL-60细胞分化过程中蛋白质组的差异表达.方法 运用蛋白质组学方法(双向凝胶电泳、质谱分析、生物信息学方法)分析鉴定DADS诱导HL-60细胞分化的差异表达蛋白质.结果 初步鉴定的差异表达蛋白质点中二型碳酸酐酶、磷酸丙糖异构酶、醛缩酶A在处理组中均表达下调,其功能与细胞代谢调节有关.结论 DADS可通过抑制二型碳酸酐酶表达和抑制糖酵解途径,抑制HL-60细胞增殖,诱导其分化.     

中医药治疗老年性白内障的临床研究

目的:观察二百味草花液治疗早中期白内障的临床疗效.方法:50例老年性白内障患者,采用电离子透入加二百味草花液治疗.结果:治疗组用二百味草花液电离子透入治疗后患者视力显著提高,有效率86.42%,经统计学处理t=19.305,P＜0.01,有显著性意义.结论:二百味草花液中所含的多种成分借助于电疗机使眼周围皮肤、粘膜血管扩张,改善局部微循环功能,促进药物吸收,使药物通过血-眼屏障促进组织新陈代谢,疗效确切,不失为治疗早中期老年性白内障的一种有效的治疗方法.     

二孔法腹腔镜阑尾切除术的探讨

目的探讨二孔法腹腔镜阑尾切除术(laparoscopic appendectomy, LA)的应用价值。方法回顾分析3年来我院阑尾切除术161例的临床资料。行LA 的94例与常规开腹手术(open appendectomy, OA)67例进行对比。比较两组手术时间,住院时间,术后排气时间,住院费用及并发症等。结果LA组手术平均时间,术后住院时间,术后排气时间较OA组明显缩短(P<0.01)。住院费用无明显差异(P>0.05)。LA组无并发症,OA组切口感染6例。结论二孔法LA较OA创伤轻,康复快,住院时间短,并发症少,但住院费用无明显差异,值得临床推广应用。     

迭代二步法估算维拉帕米的群体药动学参数

目的 :为临床合理应用维拉帕米提供依据。方法 :53例高血压患者口服维拉帕米片 ,采用荧光分光光度法测定血浆中维拉帕米浓度 ,用迭代二步法估算维拉帕米的群体药动学参数 ,并与传统二步法的结果比较。结果 :迭代二步法估算维拉帕米的CL为(189 3±59 3)ml/(h·kg) ,Vd 为 (1 420±0 231)L/kg ,T1/2 为 (5 74±1 90)h ,与传统二步法拟合的结果基本一致。结论 :迭代二步法能较好地估算出维拉帕米的群体及个体药动学参数 ,可用于预测血药浓度及优化个体给药方案。     

Two-stage instrumental variable methods for estimating the causal odds ratio: analysis of bias

We present closed-form expressions of asymptotic bias for the causal odds ratio from two estimation approaches of instrumental variable logistic regression: (i) the two-stage predictor substitution (2SPS) method and (ii) the two-stage residual inclusion (2SRI) approach. Under the 2SPS approach, the first stage model yields the predicted value of treatment as a function of an instrument and covariates, and in the second stage model for the outcome, this predicted value replaces the observed value of treatment as a covariate. Under the 2SRI approach, the first stage is the same, but the residual term of the first stage regression is included in the second stage regression, retaining the observed treatment as a covariate. Our bias assessment is for a different context from that of Terza (J. Health Econ. 2008; 27(3):531-543), who focused on the causal odds ratio conditional on the unmeasured confounder, whereas we focus on the causal odds ratio among compliers under the principal stratification framework. Our closed-form bias results show that the 2SPS logistic regression generates asymptotically biased estimates of this causal odds ratio when there is no unmeasured confounding and that this bias increases with increasing unmeasured confounding. The 2SRI logistic regression is asymptotically unbiased when there is no unmeasured confounding, but when there is unmeasured confounding, there is bias and it increases with increasing unmeasured confounding. The closed-form bias results provide guidance for using these IV logistic regression methods. Our simulation results are consistent with our closed-form analytic results under different combinations of parameter settings.