房室结慢径区域消融对迷走神经功能及心房颤动易感性的影响

Objective Atrioventricular node reentrant tachycardia (AVNRT) ablation may effect the vagal response,which is indicated by sinus tachycardia. On the other hand,atrial fibrillation (AF) ,which was found to be associated with vagal irmervation, often coexists with AVNRT. However,little is known about the im-pact of slow pathway ablation on local vagal innervation to atria. Methods In 11 dogs, bilateral cervical sympa-thovagal trunks were decentralized and metoprolol was given to block sympathetic effects. Linear lesion was per-formed from coronary sinus (CS) ostium to the middle area of Koch triangle. Atrial effective refractory period(ERP) ,vulnerability window (VW) of AF, and sinus rhythm cycle length (SCL) were measured at high fight atrium (HRA),low right atrium (LRA), distal (CSd) and proximal CS (CSp) at baseline with and without vagal stimulation before and after ablation. The histological study was also performed. Results (1) SCL during vagal stimulation remained unchanged before and after ablation(107±19)bpm vs (108±8) bpm (P > 0.05). (2) After ablation, ERP during vagal stimulation remained unchanged at HRA (55±34) ms vs (69 ±37) ms (P >0.05),and decreased slightly at CSd (42±32) ms vs (55±30) ms (P =0.08). However,at LRA and CSp,ERP was significantly decreased after ablation (19±21) ms vs (66±24) ms (P <0.001) ; and (7± 18) ms vs (46±24) ms (P < 0.001), respectively. (3) AF was difficult to be induced at baseline before and after ablation in all sites (VW close to 0). While during vagal stimulation, after ablation VW of AF significantly decreased at LRA (1±3) ms vs (49±36) ms (P < 0.005) and CSp (10±12) ms vs (45±34) ms (P < 0.05) ,decreased slightly at CSd after ablation (35±37) ms vs (57±28) ms (P =0.07) ,and remained un-changed at HRA (63±31) ms vs (63±25) ms (P > 0.05). (4) The altered architecture of individual gan-glia was histologically observed. Conclusions The decreased ERP shortening to vagal stimulation in CS and LRA induced by slow pathway ablation indicates that ablation in such area may result in the vagal dennervation in LRA and CS,thereby attenuating the susceptibility to vagal mediated AF. While unchanged SCL,ERP short-ening and VW to vagal stimulation in sinus node area and HRA indicate that slow pathway ablation did not change the vagal innervation to these sites.     

早期再灌注对急性心肌梗死患者血浆脑钠素水平的影响

目的 :探讨早期再灌注对急性心肌梗死 (AMI)患者血浆脑钠素 (BNP)水平的影响。方法 :选择AMI患者 5 6例 ,胸痛发作 12h内成功再灌注者 (38例 )为试验组 ,再灌注失败或未进行再灌注者 (18例 )为对照组。ELISA法测定入院即刻、1、2、7、14、2 8d时血浆BNP水平。结果 :AMI患者血浆BNP水平较正常人明显升高 ;试验组血浆BNP水平呈单峰曲线 ,对照组呈双峰曲线 ;再灌注可明显降低AMI患者BNP水平 ,第 7天时浓度升高不明显 ,未形成第 2个高峰。结论 :早期再灌注可明显降低血浆BNP水平。     

非风湿心房颤动脑缺血老人的脂蛋白(a)和自由基及红细胞变形

目的探讨在老年患者非风湿心房颤动(nonrheumaticatrialfibrillation,NRAf)脑缺血与血清脂蛋白(a)[lipoprote(ina),L(pa)]、脂质过氧化物酶(lipidperoxideenzyme,LPO)与红细胞变形能力(redcelldeformability,RCD)的关系。方法采用酶联免疫吸附法测定血清L(Pa)水平;采用硫代巴比妥酸法测定血清LPO;用DXC-400型测定仪检测RCD。结果脑缺血组L(pa)、非脑缺血组及对照组血清浓度44±19(n=91),24±1(5n=79),24±1(4n=83)(,×10mg/L),但脑缺血组RCD-IF较对照组升高(P<0.05);在脑缺血组和无脑缺血组患者,LPO与RCD呈正相关(r=0.672,P<0.01),而L(Pa)与LPO,RCD无相关。结论老年非风湿性慢性心房颤动患者血清L(Pa)浓度的升高可能是导致其脑缺血倾向的因素之一;氧自由基的作用是NRAf并发脑缺血发作的可能机制之一;RCD可能是评价NRAf血液高凝状态的一个敏感指标。     

防御素与肺炎症性疾病

防御素是富含半胱氨酸,带正电的小分子抗微生物肽,具有广谱的抗微生物活性,包括细菌,真菌和一些包膜病毒,在肺的固有免疫中起重要作用。防御素也可以起到趋化因子的作用,这突出了防御素在宿主免疫和炎症反应中的重要作用。防御素或组成性表达或被细菌和炎症介质所诱导。防御素功能的改变可能会导致疾病。     

非家族性心房颤动与血管紧张素基因I/D多态性关系的研究

目的探讨肾素血管紧张素系统(RAS)中的血管紧张素转换酶(angiotensin 1-converting enzyme,ACE)基因多态性与黑龙江地区人群非家族性房颤的发生关系。方法选取ACE基因I/D位点进行分析。采用病例-对照实验设计,研究对象共400例,均来自黑龙江省,包括非家族性房颤者200例和对照组200例。本研究采用聚合酶链反应(polymerase chain reaction,PCR)技术。结果ACEI/D位点与房颤发生显著相关,疾病组中的ACE-D等位频率显著高于对照组。结论RAS基因可能不仅是高血压病的候选基因,也有可能是非家族性房颤的候选基因。     

FDA “肽类药物产品临床药理学的考虑的供企业用的指导原则草案” 及其启示

美国食品药品管理局（FDA）于2023年9月发布了“肽类药物产品临床药理学的考虑的供企业用的指导原则草案”。该指导原则描述了FDA对肽类药物产品开发方案的临床药理学的建议,包括肝损害、药物-药物相互作用评估、心电图按心率校正的QT间期（QTc）延长风险评估以及免疫原性风险及其对药动学、安全性和有效性评估的影响。详细介绍FDA该指导原则的主要内容,期望对我国肽类药物产品临床药理学研究和监管有所启示。     

新疆汉族与维吾尔族心房颤动患者钠通道基因多态性与心房颤动易感性的相关性研究

目的 探究新疆汉族与维吾尔族心房颤动(房颤)患者钠通道基因的多态性与房颤易感性的相关性.方法 选取2016年6月至2018年6月在新疆医科大学第一附属医院诊断及治疗的汉族及维吾尔族房颤患者各100例,纳入房颤组;选择同时期非房颤的汉族及维吾尔族健康体检者各100例,纳入对照组.比较两组患者一般资料,包括:性别、年龄、血压、血脂、病史等情况,并进行钠离子通道(SCN5A)H558R位点基因多态性检测,使用多因素Logistic回归模型分析房颤的危险因素.结果 汉族及维吾尔族患者房颤组和非房颤组间年龄、总胆固醇和低密度脂蛋白胆固醇水平(LDL-C)的差异均具有统计学意义(P<0.05);SCN5A H558R位点基因符合Hardy-Weinberg平衡,汉族及维吾尔族房颤患者G等位基因频率均显著高于非房颤组,且基因型频率也与非房颤患者具有显著差异;多因素Logistic回归显示,汉族患者显性模型中(AG+GG)基因型(OR=2.72,P=0.012),共显性模型中AG基因型(OR=2.77,P=0.014)是房颤发生的独立危险因素;维吾尔族患者显性模型中(AG+GG)基因型(OR=2.37,P=0.012),共显性模型中AG基因型(OR=2.65,P=0.006)是房颤发生的独立危险因素;入组总患者显性模型中(AG+GG)基因型(OR=2.19,P=0.001),共显性模型中AG基因型(OR=2.20,P=0.001)是房颤发生的独立危险因素.结论 新疆汉族与维吾尔族房颤患者钠通道基因多态性与房颤均存在显著相关性,值得进一步深入研究.     

Screening of TNFR1 Binding Peptides from Deinagkistrodon acutus Venom through Phage Display

The venomous species Deinagkistrodon acutus has been used as anti-inflammatory medicine in China for a long time. It has been proven to have anti-inflammatory activity, but its specific anti-inflammatory components have not yet been fully elucidated. Tumor necrosis factor receptor-1 (TNFR1), which participates in important intracellular signaling pathways, mediates apoptosis, and functions as a regulator of inflammation, is often used as the target to develop anti-inflammatory drugs. The small peptides of snake venom have the advantages of weak immunogenicity and strong activity. To obtain the specific TNFR1 binding peptides, we constructed a T7 phage library of D. acutus venom glands, and then performed biopanning against TNFR1 on the constructed library. After biopanning three times, several sequences with potential binding capacity were obtained and one 41-amino acid peptide was selected through a series of biological analyses including sequence length, solubility, and simulated affinity, named DAvp-1. After synthesis, the binding capacity of DAvp-1 and TNFR1 was verified using surface plasmon resonance technology (SPR). Conclusively, by applying phage display technology, this work depicts the successful screening of a promising peptide DAvp-1 from D. acutus venom that binds to TNFR1. Additionally, our study emphasizes the usefulness of phage display technology for studies on screening natural product components.     

Variability in the Spatial Structure of the Central Loop in Cobra Cytotoxins Revealed by X-ray Analysis and Molecular Modeling

Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and “membrane” conformations of the central loop (loop-2) were determined by X-ray crystallography. The “water” conformation of the loop was frequently observed. It was similar to the structure of loop-2 of numerous CTs, determined by either NMR spectroscopy in aqueous solution, or the X-ray method. The “membrane” conformation is rare one and, to date has only been observed by NMR for a single cytotoxin 1 from N. oxiana (CT1No) in detergent micelle. Both CT13Nn and CT1No are S-type CTs. Membrane-binding of these CTs probably involves an additional step—the conformational transformation of the loop-2. To confirm this suggestion, we conducted molecular dynamics simulations of both CT1No and CT13Nn in the Highly Mimetic Membrane Model of palmitoiloleoylphosphatidylglycerol, starting with their “water” NMR models. We found that the both toxins transform their “water” conformation of loop-2 into the “membrane” one during the insertion process. This supports the hypothesis that the S-type CTs, unlike their P-type counterparts, require conformational adaptation of loop-2 during interaction with lipid membranes.     

腺病毒介导的NT4p53(N15)Ant异源融合基因对肝癌细胞的杀伤作用

目的 构建包括神经营养因子4(NT4)信号肽,p53氨基端短活性肽(12～26位氨基酸)及蛋白质转导结构域-黑腹果蝇触足肽(Ant)序列在内的异源融合基因,并以腺病毒作为基因转移载体观察NT4p53(N15)Ant基因在体外对肝癌细胞系HepG2的杀伤效应.方法 应用互为模板的引物PCR技术及T载体克隆法获得p53(N15)Ant基因克隆,经酶切后连入pBV220/NT4质粒,再将融合基因NT4p53(N15)Ant亚克隆至腺病毒的穿梭质粒内,与辅助质粒pJM17共转染HEK293细胞,通过同源重组获得重组腺病毒,经PCR鉴定后,NT4p53(N15)Ant重组腺病毒感染HepG2细胞,用MTT比色法和PI染色流式细胞计数仪分析Ad.NT4p53(N15)Ant对肿瘤细胞和正常细胞的杀伤效应及凋亡率.结果 克隆出NT4p53(N15)Ant基因,得到高滴度的重组腺病毒,提取病毒DNA经PCR证实含目的基因.MTT测定结果显示,与平行对照病毒Ad.GFP相比,Ad.NT4p53(N15)Ant对HepG2细胞有强烈的杀伤效应,且以病毒感染后48 h作用最为明显,对肿瘤细胞抑制率达到63.3%,而对正常细胞NIH3T3的影响很小.Ad.NT4p53(N15)Ant感染HepG2细胞30 h后的流式细胞仪分析结果显示:Ad.NT4p53(N15)Ant可使HepG2细胞发生凋亡,凋亡率为18.16%.结论 通过分子克隆体外重组技术我们首次成功制备了NT4p53(N15)Ant复制缺陷型重组腺病毒;初步的研究发现Ad.NT4p53(N15)Ant对HepG2细胞有强烈的杀伤效应,这种效应部分是通过诱导HepG2细胞的凋亡而实现的.