基因突变与遗传性内分泌代谢性疾病

遗传性内分泌代谢性疾病是内分泌代谢疾病中相当重要的一组疾病,临床表现复杂多变,诊治困难。遗传性内分泌代谢性疾病的分子基础是其相关基因发生突变,近年随着分子生物学技术的飞速发展,相当多的致病基因被发现,人们对此类疾病的理解逐步深入,同时也为临床诊断提供了快速准确的技术平台。本文将根据致病基因功能,对近年来遗传性内分泌代谢性疾病取得的进展进行阐述。     

肝病患者红细胞一型补受体分子基因型与数量表达的变化

目的研究肝病患者红细胞一型补体受体（complementreceptortype1,CR1）分子密度相关基因型与数量表达的变化。方法采用PCR和HindⅢ酶切技术测定红细胞CR1分子基因型,采用酶联反应法定量测定红细胞CR1分子的数量。结果各型肝病患者红细胞CR1分子密度相关基因型与正常人相比差异无显著意义。慢性活动性肝炎、肝炎后肝硬化及乙型肝炎表面抗原阳性肝癌患者红细胞CR1分子的数量表达明显低于正常健康人群（t＝10.44,P＜0.0001）,失代偿性肝炎后肝硬化患者的CR1分子数量明显低于代偿性肝炎后肝硬化患者,但肝功能正常的慢性肝炎患者红细胞CR1分子数量与正常人比较无明显变化。结论肝病患者红细胞CR1分子数量表达缺陷系后天引起,测定肝病患者红细胞CR1分子的数量对临床病情判断有重要参考价值。     

重症肝病并发侵袭性真菌病的诊治

重症肝病并发侵袭性真菌病(IFD)是影响重症肝病患者预后的重要因素,其早期诊断仍是困扰临床医生的重要问题。临床最常见的4种IFDs是念珠菌病、曲菌病、隐球菌病以及肺孢子菌肺炎,在重症肝病患者临床诊疗过程中重视并发IFD的可能,尤其对存在高危因素的患者,及早发现、及时诊断、恰当治疗,对改善危重症肝病的预后至关重要。     

腺相关病毒为载体的基因治疗在肝病应用中的进展

基因治疗是目前医学研究的热点课题。将目的基因转入细胞的方法有很多，包括脂质体包裹转染、电打孔、微注射等，最近以重组病毒为载体的基因治疗因其独特的优势受到关注。比较常用的三大病毒载体是逆转录病毒、腺病毒和腺相关病毒（adeno—associated virus，AAV）。各种病毒载体都有各自的优点和不足，在细胞和动物实验研究中均有大量的应用。但是在临床应用中，逆转录病毒为载体的基因治疗由于在法国的临床试验出现2例白血病病历，     

辅助用药在自身免疫性肝病中的应用

自身免疫性肝病是一组由自身免疫介导的肝胆系统性疾病,主要包括自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)和原发性硬化性胆管炎(PSC).由于其病因和发病机制尚未完全阐明,目前尚无治愈性药物.现简要介绍临床实践指南推荐的标准治疗方案,并讨论抗炎保肝药在自身免疫性肝病辅助治疗中的应用情况.     

乙醛脱氢酶基因多态性与酒精性肝病的关系

目的 观察乙醛脱氢酶(ALDH)基因多态性与山东地区汉族人群酒精性肝病的关系,探讨酒精性肝病遗传学的发病机制。 方法 采用聚合酶链反应结合内切酶酶切及电泳技术,检测山东地区汉族人群中酒精性肝病组、嗜酒组和对照组(各20例)中ALDH各基因型及等位基因的频率并进行比较。结果ALDH2*1、ALDH2*2两种等位基因在对照组与酒精性肝病组之间的分布差异有显著性(x2=4.80,P<0.05),对照组与无肝病嗜酒组之间差异无显著性,在嗜酒组和酒精性肝病组中以ALDH2*1/*1基因型为主,均未检出纯合子的ALDH2*2/*2。 结论 ALDH基因多态性与酒精性肝病的发生关系密切。等位基因ALDH2*2可能是本地区汉族人群中嗜酒和酒精性肝病的负性危险因素。     

肝脏疾病和心脏疾病之间的相互影响

肝脏疾病和心脏疾病共存有3种形式：即肝脏疾病影响心脏、心脏疾病影响肝脏及同一个病因导致肝脏和心脏损伤,把病人分为上述3种情况,可以缩小内科医生诊断范围,从而使临床诊断更方便。     

肝病的中医药治疗

中医治疗肝病主要源于对中医"肝"藏血、主疏泄等功能状态的调治,其中涉及现代消化、内分泌、肠-肝-轴等系统功能,结合现代相关生理、病理和病原学形成了中医肝病治疗学。收集了近10年来中医在肝病治疗领域的临床、科研现状,采纳临床有明确疾病诊断并在核心期刊发表的论文和经过重大科研课题证实疗效的成果,力求客观反映现代中医治疗肝病的特色与优势。慢性乙型肝炎配合抗病毒治疗提高疗效;HBV携带者着力预防病情进展;慢加急性肝衰竭中西医结合治疗阻止内毒素等对肝脏的二次打击。非特异性抗炎保肝、抗肝纤维化、防治非酒精性脂肪性肝病等是中医特色,已被广为应用。对于无特效治疗方法的一些肝病,中医药治疗可发挥重要作用。对有效的理法方药的传承、发扬,创建更完善的医疗体系是我国医学界共同的责任。     

提高肝脏免疫功能认知,加强肝病细胞治疗研究

肝脏是一个重要的免疫器官,具有独特的免疫微环境,参与全身固有免疫应答和适应性免疫反应。肝脏通过肝-肠轴与系统免疫密切相连,又是免疫损伤的靶器官;肝脏在抗嗜肝病毒免疫中发挥着重要作用,但导致病毒感染慢性化机制尚不完全清楚。肝病细胞治疗包括以细胞功能替代为主的肝(干)细胞输入治疗;以抗病毒抗肿瘤为主的免疫细胞治疗和对遗传性肝病进行的以细胞为载体的基因治疗。间充质干细胞的多向分化潜能和免疫调节特性成为肝病细胞治疗的热点,体外高效扩增技术使自然杀伤细胞治疗肝癌成为可能。     

宿主因素与幽门螺杆菌感染结局的研究

幽门螺杆菌（H．pylori）感染可导致不同的l艋床结局。H．pylori细菌毒力因素和宿主遗传易感性与胃癌相关。本文论述了H．pylori毒力因子、宿主基因多态性对主要胃病表型与不同l临床结局的影响。     

Clinical Gene Therapy in Hematology: Past and Future

Gene transfer into hematopoietic cells using viral vectors has focused mostly on lymphocytes and hematopoietic stem cells (HSCs). HSCs have been considered particularly important as target cells because of their pluripotency and ability to reconstitute hematopoiesis after myeloablation and transplantation. HSCs are believed to have the ability to live a long time, perhaps a lifetime, in the recipient following bone marrow transplantation. Genetic correction of HSCs can therefore potentially last a lifetime and permanently cure hematologic disorders in which genetic deficiencies cause the pathology. Oncoretroviral vectors have been the main vectors used for HSCs because of their ability to integrate into the chromosomes of their target cells. Gene-transfer efficiency of murine HSCs is high using oncoretroviral vectors. In contrast, gene-transfer efficiency using the same viral vectors to transduce human HSCs or HSCs from large animals has been much lower. Although these difficulties may have several causes, the main reason for the low efficiency of human HSC transduction with oncoretroviral vectors is probably because of the nondividing nature of HSCs. Murine HSCs can be easily stimulated to divide in culture, whereas it is more problematic to stimulate human HSCs to divide rapidly in vitro. Because oncoretroviral vectors require dividing target cells for successful nuclear import of the preintegration complex and subsequent integration of the provirus, only the dividing fraction of the target cells can be transduced. This review focuses on gene transfer into human hematopoietic cells, particularly human HSCs. We review the clinical studies that have been reported, including the recent successful gene therapy for X-linked severe combined immunodeficiency. We discuss how the gene-transfer efficiency of human HSCs can be improved using oncoretroviral and lentiviral vectors.     

白细胞介素-6基因多态性对冠心病发病易感性的影响及其机制

目的了解白细胞介素-6（IL-6）基因-597G／A及-572C／G多态性对冠心病（CHD）发病易感性的影响及其影响机制。方法 应用聚合酶链反应．限制性片段长度多态性（PCR-RFLP）分析方法,测定245例CHD患者和260例正常对照者的IL-6基因型,探讨其与CHD的相关关系;观察基因型对血清IL-6水平的影响,并采用logistic回归分析法了解基因型与CHD其他危险因素间的相互作用。结果 两组研究对象中-597位点均仅发现GG基因型。-572C／G基因型和等位基因频率在两组间存在明显统计学差异（P均〈0．01）,CHD组GG基因型和G等位基因频率均显著高于对照组（P均〈0．01）;CG、GG基因型人群患CHD的风险分别为CC基因型人群的1．46倍（95％CI：1．01～2．10,P〈0．05）和5．19倍（95％CI：1．69～15．89,P〈0．01）;不同基因型患者间血清IL-6水平无统计学差异（P〉0．05）;-572C／G基因型与总胆固醇、甘油三酯间存在一定的交互作用,OR值分别为1．76（95％CI：1．05～3．16,P〈0．05）、2．51（95％CI：1．04～6．45,P〈0．05）。结论 IL-6基因-597G／A多态性可能与中国汉族人群CHD发病易感性无关,而-572C／G多态性可能是该人群CHD发病的易感基因之一,其可能通过对组织IL-6水平的影响及与血脂的协同作用参与CHD的发生。     

白细胞介素-6基因-572C/G多态性与冠心病的关系及对血清IL-6水平的影响

目的:了解白细胞介素-6(IL-6)基因-572C/G多态性对冠心病(CHD)发病易感性及血清IL-6水平的影响。方法:应用聚合酶链反应-限制性片段长度多态性分析方法,测定245例CHD患者(CHD组)和260例正常对照者(对照组)的IL-6基因-572C/G多态性,探讨其与CHD的相关关系;并应用酶联免疫吸附试验法检测研究人群血清IL-6水平,观察基因型对血清IL-6水平的影响。结果:IL-6基因-572C/G基因型和等位基因频率在2组间分布差异有统计学意义,CHD组GG基因型和G等位基因频率均显著高于对照组(P<0.01);相对于CC基因型,暴露于CG、GG基因型的相对危险度分别为1.46(95%CI:1.01~2.10,P<0.05)和5.19(95%CI:1.69~15.89,P<0.01);不同基因型患者间血清IL-6水平差异无统计学意义(P>0.05)。结论:IL-6基因-572C/G多态性可能是中国汉族人群CHD发病的遗传危险因素之一,但该多态性对血清IL-6水平无影响。     

B超引导下PICC置管在肝病患者中的应用效果分析

目的 探讨提高肝病患者经外周静脉置入中心静脉导管(peripherally inserted central catheter,PICC)置管成功率,以及如何减少局部渗血及机械性静脉炎等并发症的方法.方法 将选择普通PICC置管和B超引导下PICC置管的284例肝病患者分为对照组(146例)和试验组(138例),由固定人员操作,统一评估标准,并对比2组的置管成功率、局部渗血及机械性静脉炎的发生率.结果 对照组和试验组的置管成功率分别为91.2％和100％,置管后Ⅲ度渗血发生率分别为11.6％和4.3％,机械性静脉炎的发生率分别为13.7％和0(P均＜0.05).结论 B超引导下PICC置管可有效提高肝病患者PICC置管成功率,明显降低置管后局部渗血和机械性静脉炎的发生率.     

Autoimmune liver diseases

The liver was one of the earliest recognized sites among autoimmune diseases yet autoimmune hepatitis,primary biliary cirrhosis,primary sclerosing cholangitis,and their overlap forms,are still problematic in diagnosis and causation.The contributions herein comprise ＇pairs of articles＇ on clinical characteristics,and concepts of etiopathogenesis,for each of the above diseases,together with childhood autoimmune liver disease,overlaps,interpretations of diagnostic serology,and liver transplantation.This issue is timely,since we are witnessing an ever increasing applicability of immunology to a wide variety of chronic diseases,hepatic and non-hepatic,in both developed and developing countries.The 11 invited expert review articles capture the changing features over recent years of the autoimmune liver diseases,the underlying immunomolecular mechanisms of development,the potent albeit still unexplained genetic influences,the expanding repertoire of immunoserological diagnostic markers,and the increasingly effective therapeutic possibilities.     

Serum dolichols in chronic cholestatic liver diseases

BACKGROUND/AIMS: Dolichols are long-chain polyisoprenoid alcohols. It has been suggested that they modify membrane fluidity, stability and permeability. Some lysosomal diseases are associated with elevated serum dolichol levels. Liver has been suggested to play an important role in the regulation of serum dolichol levels and biliary excretion of dolichols has been proposed to be the main elimination route for dolichols from the body. The possible effect of liver diseases on serum dolichol, however, is not known. METHODS: We therefore studied the effect of early or intermediate primary biliary cirrhosis, primary sclerosing cholangitis and alcoholic liver cirrhosis on serum dolichol concentration. Furthermore, serum dolichol content was measured in patients with end-stage primary biliary cirrhosis, primary sclerosing cholangitis and chronic active hepatitis, waiting to be transplanted. RESULTS: As compared to age-adjusted controls, serum dolichol was significantly increased in early and intermediate primary biliary cirrhosis (451+/-56 ng/ml vs. 225+/-13 ng/ml, p<0.0001) and primary sclerosing cholangitis (315+/-16 ng/ml vs. 224+/-7 ng/ml, p<0.0001). However, in alcoholic liver cirrhosis serum dolichol was unaffected. Serum dolichol content was also significantly elevated in patients with end-stage primary biliary cirrhosis (844+/-210 ng/ml vs. 225+/-13, p<0.001) and chronic active hepatitis (594+/-198 vs. 224+/-7 ng/ml, p<0.02). Furthermore, in patients with liver diseases serum dolichol concentration correlated positively with serum high density lipoprotein (HDL)-cholesterol (r = +0.50, p<0.0001). CONCLUSIONS: Serum dolichol levels are elevated in all stages of chronic cholestatic liver diseases but not in alcoholic liver cirrhosis. Impaired biliary excretion of dolichols appears to be the primary explanation for this finding.     

产前序贯性筛查遗传性耳聋基因携带者的临床意义分析

［摘要］　目的　分析产前序贯性筛查遗传性耳聋基因携带者的临床意义。方法　选择2022年5月至12月于首都医科大学附属北京妇产医院进行遗传性耳聋基因突变位点筛查的孕妇9 391例,采用微流控芯片法检测遗传性耳聋基因,分析其在孕妇人群中的携带率。对检出GJB2基因和SLC26A4基因变异的孕妇配偶采用靶向高通量测序进行相同致病基因筛查,当夫妻双方均检出同一基因致病变异时建议对胎儿进行致病基因的产前诊断。对于检出GJB3基因变异孕妇,建议其进行听力学评估和遗传咨询及随访。对检出线粒体12S rRNA基因变异孕妇进行遗传咨询及用药指导。结果　9 391例孕妇中检出遗传性耳聋基因突变携带者1 002例,携带率为10.67%;GJB2、SLC26A4、GJB3及线粒体12S rRNA突变的携带率分别为7.93%、1.99%、0.28%和0.15%。突变经Sanger测序验证,符合率达99.80%。293例GJB2基因或SLC26A4基因突变携带者的配偶进行了序贯性筛查,其中4对夫妇双方检出携带相同基因上的致病突变位点,经羊水细胞测序,1例为GJB2 c.235 del C纯合突变,1例为SLC26A4 c.919-2 A>G纯合突变,其余2例均为杂合突变。结论　产前序贯性筛查耳聋基因携带者筛查不仅可以遗传性耳聋基因突变的携带者,还可以发现药物性耳聋敏感性个体,从而实现耳聋胎儿早期诊断、早期干预和及时预警。     

Genome-wide linkage analysis of electrocardiographic and echocardiographic left ventricular hypertrophy in families with hypertension.

AIMS: To localize chromosomal regions (or quantitative trait loci) that harbour genetic variants influencing the variability of electrocardiographic (ECG) and echocardiographic left ventricular hypertrophy (LVH). METHODS AND RESULTS: We evaluated genetic linkage to ECG Sokolow-Lyon voltage, ECG Cornell voltage product, ECG left ventricular (LV) mass, and to echocardiographic septal wall thickness, LV cavity size, and LV mass in 868 members of 224 white British families. A genome-wide scan was performed with microsatellite markers that covered the genome at 10-cM intervals and linkage was assessed by variance components analysis. We identified chromosomal regions suggestive of linkage for Sokolow-Lyon voltage on chromosome 10q23.1 [log(10) of the odds (LOD = 2.21, P = 0.0007)], for ECG Cornell voltage product on chromosome 17p13.3 (LOD = 2.67; P = 0.0002), and for ECG LV mass on chromosome 12q14.1 (LOD = 2.19; P = 0.0007). There was a single region of possible linkage for echocardiographic LV mass on chromosome 5p14.1 (LOD = 1.6; P = 0.003). CONCLUSION: Stronger genetic signals for LVH were found using electrocardiographic than echocardiographic measurements, and the genetic determinants of each of these appear to be distinct. Chromosomes 10, 12, and 17 are likely to harbour genetic loci that exert a major influence on electrocardiographic LVH.