线粒体DNA点突变与心肌病关系的研究

用聚合酶链反应（ＰＣＲ）和异源双链（ＨＥＴ）凝胶电泳检测了１５例原发性扩张型心肌病（ＤＣＭ）、１３例急性心肌炎患儿及１个肥厚型心肌病（ＨＣＭ）家系中１７例成员 的外周血线粒体ＤＮＡ（ｍｔＤＮＡ）点突变。结果显示，ＤＣＭ患儿中，６例在ｍｔＤＮＡ保守区３１０８￣３７１７位存在点突变，其中１例家族性ＤＣＭ患儿及其母亲均检出点突变，提示ｍｔＤＮＡ点突变在ＤＣＭ发病中起一定作用；１３例急性心肌炎患儿中有１例     

年龄相关性黄斑变性临床观察

年龄相关性黄斑变性临床观察陈素贞，龙力年龄相关性黄斑变性（ａｇｅ－ｒｅｌａｔｅｄｍａｃｕｌａｒｄｅｇｅｎｅｒａｔｉｏｎ，ＡＭＤ）患者中，９０％为干性ＡＭＤ，１０％为湿性ＡＭＤ。后者视力下降急剧，预后较差，是老年人主要的致盲原因之一。现报道４２例湿性Ａ...     

老年性黄斑变性早期黄斑光敏度、视觉诱发电位、Amsler表检查的改变

目的了解早期老年性黄斑变性视功能的改变。方法对老年性黄斑变性（ＡＭＤ）早期患者４４例（５８只眼）进行黄斑光敏度、图形视觉诱发电位和Ａｍｓｌｅｒ表检查，并与健康人４０例（５１只眼）上述检查作对照比较。结果ＡＭＤ组黄斑阈值下降、Ｐ１００潜伏期延长和波幅下降、Ａｍｓｌｅｒ表异常发现率均较对照组明显（Ｐ＜０．０５或＜０．０１）。结论在老年性黄斑变性早期，患者视功能已有变化，这些检查对本病早期诊断有辅助意义。     

老年性黄斑变性早期黄斑光敏度,视觉诱发电位,Amsler表检查的…

目的 了解早期老年性黄斑变性视功能的改变。方法 地老年性黄斑变性（ＡＭＤ）早期患者４例（５８只眼）进行黄斑光敏度、图形视觉诱发电位和Ａｍｓｌｅｒ表检查，并与健康人４０例（５１只眼）上述检查和对照比较。结果 ＡＭＤ组黄斑阈值下降、Ｐ１００潜伏期延长和波幅下降、Ａｍｓｌｅｒ表异常发现率均较对照组明显（Ｐ〈０．０５或Ｐ〈０．０１）。结论 在老年性黄斑变性早期 患者视功能已有变化，这些检查对本病早期诊断有     

眼底荧光血管造影在老年黄斑变性诊断中应用

目的 探讨眼底荧光血管造影（ＦＦＡ）在老年黄斑变性诊断中的应用价值。方法 用Ｋｕｗａ ｆｘ－５００型眼底照相机对黄斑变性（ＡＭＤ）患者进行ＦＦＡ检查,并结合临床其他检查进行分析。结果 ５１例ＡＭＤ患者６５只眼中,萎缩型４２只眼（６４．６％）,渗出型２３只眼（３５．４％）。萎缩型表现均为点状或斑驳样透见荧光,未见荧光素渗漏。渗出型早期可见脉络膜新生血管形态（ＣＮＶ）,晚期大量荧光素渗漏,周围有出血者     

原发性干燥综合征与人类组织相容性抗原—DRβ基因

原发性干燥综合征（ＰＳＳ）的病因未明，其中可能涉及遗传因素。用序列特异性引物聚合酶链反应（ＰＣＲ－ＳＳＰ）法对７０例ＰＳＳ患者和１３６名正常人进行人类组织相容性抗原（ＨＬＡ）－ＤＲβ基因分型。发现ＰＳＳ患者群体的ＨＬＡ－ＤＲ３、ＤＲ５２及ＤＲ２的基因频率明显高于正常对照组，而ＨＬＡ－ＤＲ５及ＤＲ９的基因频率则相反，提示ＰＳＳ的发病与ＤＲ３、ＤＲ５２及ＤＲ２呈正相关；而和ＤＲ９、ＤＲ５呈负相关。２个ＰＳＳ患者家族的姐妹与患者具有相同的遗传因素，且和ＰＳＳ患者群体测定的正相关基因相一致。ＰＳＳ患者的主要自身抗体（抗ＳＳＡ抗体及抗ＳＳＢ抗体）与ＨＬＡ－ＤＲ５２之间有明显的相关性，因而表明ＰＳＳ的发病和遗传因素有关。     

NIDDM致病候选基因的分子流行病学研究进展

综述了ＮＩＤＤＭ致病候选基因的分子流行病学研究近况。其中，己糖激酶Ⅱ（ＨＫⅡ）基因，激素原转化酶３（ＰＣ３）基因被认为不大可能是ＮＩＤＤＭ的主要致病基因；线粒体ｔＲＮＡ（ｍｔＲＮＡ）基因突变与ＮＩＤＤＭ的一个亚型有关；ｒａｄ基因与ＮＩＤＤＭ有关，但有争议；β细胞ＡＴＰ敏感钾通道（ＡＴＰ－Ｋ＋）基因的ＢＩＲ和ＳＵＲ亚单位与日本人ＮＩＤＤＭ遗传易患性无关，ＳＵＲ基因缺陷可能是北欧白人ＮＩＤＤＭ发病的主要遗传基础；胰高血糖素受体（ＧＣ）基因突变与法国人ＮＩＤＤＭ有关     

老年急性心肌梗塞心率变异时域分析

目的分析急性心肌梗塞（ＡＭＩ）后老年患者心率变异（ＨＲＶ）时域指标，了解ＡＭＩ后ＨＲＶ变化。方法以多单位协作方式对１５７例ＡＭＩ后２周的老年患者行动态心电图检测ＨＲＶ时域法５项指标，并与健康老年组对比分析。数据经ＥｐｉＩｎｆｏ（６．０）统计软件处理。结果①ＡＭＩ患者的正常Ｒ－Ｒ间期标准差（ＳＤＮＮ）、平均值的标准差（ＳＤＡＮＮ）和标准差的平均值（ＳＤＮＮＩｎｄｅｘ）低于对照组（Ｐ＜０．０１），而相邻正常Ｒ－Ｒ间期差值的均方根（ＲＭＳＳＤ）和相邻正常Ｒ－Ｒ差值大于５０ｍｓ记数占总Ｒ－Ｒ间期数的百分比（ＰＮＮ５０）虽低于对照组，但无显著差异（Ｐ＞０．０５）。②ＡＭＩ后ＨＲＶ时域５项指标男、女性别间无显著性差异（Ｐ＞０．０５）。③ＳＤＮＮ、ＳＤＡＮＮ和ＳＤＮＮＩｎ－ｄｅｘ在心肌梗塞各部位间无显著差异（Ｐ＞０．０５），ＲＭＳＳＤ和ＰＮＮ５０前间壁低于下壁心肌梗塞（Ｐ＜０．０５）。结论老年人ＡＭＩ后ＨＲＶ降低。反映交感神经活性的ＳＤＮＮ、ＳＤＡＮＮ和ＳＤＮＮＩｎｄｅｘ和反映迷走神经活性的ＲＭＳＳＤ和ＰＮＮ５０２组指标变化不相同。     

老年急性心肌梗塞患者脂蛋白（a）、脂质过氧化物及红细胞变形能力的变化

观察老年急性心肌梗塞（ＡＭＩ）患者３２例、心绞痛患者４５例和对照组５０例的血清脂蛋白（ａ）［Ｌｐ（ａ）］、过氧化脂质（ＬＰＯ）及红细胞变形能力（ＲＣＤ）的变化．结果表明：ＡＭＩ组的血清Ｌｐ（ａ）、ＬＰＯ及ＲＣＤ均高于其他两组，且具明显性差异。相关分析表明，Ｌｐ（ａ）的变化与ＬＰＯ、ＲＣＤ无关，而ＬＰＯ的升高与ＲＣＤ的降低呈一定的线性相关（Ｐ＜０．０１），进一步证实了Ｌｐ（ａ）是冠心病的独立危险因素，ＬＰＯ、ＲＣＤ的变化亦是冠心病加重的重要因素。Ｌｐ（ａ）、ＬＰＯ及ＲＣＤ的检测对ＡＭＩ的诊断及预防有一定的指导意义。降低Ｌｐ（ａ）、清除ＬＰＯ、改善ＲＣＤ是治疗ＡＭＩ及改善其预后的重要手段。     

NIDDM致病候选基因的分子流行病学研究进展

综述了ＮＩＤＤＭ致病候选基因的分子流行病学研究近况。其中，已糖激酶Ⅱ（ＨＫⅡ）基因，激素原转化酶３（ＰＣ３）基因被认为不大可能是ＮＩＤＤＭ的主要致病基因；线粒体ｔＲＮＡ（ｍｔＲＮＡ）基因突变与ＮＩＤＤＭ的一个亚型有关；ｒａｄ基因与ＮＩＤＤＭ有关，但有争议，β细胞ＡＴＰ细胞敏感钾通道基因的ＢＩＲ和ＳＵＲ亚单位与日本人ＮＩＤＤＭ遗传易患性无关，ＳＵＲ基因缺陷可能是北欧白人ＮＩＤＤＭ发病的主要遗传基础；     

老年人黄斑变性的荧光和吲哚青绿血管造影特征比较

目的 对渗出型老年黄斑变性(ARMD)的荧光血管造影和吲哚青绿血管造影特征进行比较和临床评价。方法 诊断为渗出型ARMD患者25例，35只眼，年龄60～81岁，视力：指数／30cm～1．0。所有患者均进行彩色眼底照相、荧光血管造影和吲哚青绿血管造影，比较和分析图像特征。结果 诊断为典型脉络膜新生血管的20只眼，其中荧光血管造影5只眼(14．3％)，吲哚青绿血管造影15只眼(42．9％)。在荧光血管造影诊断为隐匿型脉络膜新生血管的20只眼中，吲哚青绿血管造影诊断为典型脉络膜新生血管的为7只眼。荧光血管造影诊断为浆液性色素上皮脱离(PED)不伴脉络膜新生血管的3只眼中，吲哚青绿血管造影证实其诊断仅1只眼，其中2只眼为典型脉络膜新生血管。荧光血管造影诊断为浆液性PED伴脉络膜新生血管1只眼，而吲哚青绿血管造影诊断为隐匿型脉络膜新生血管。结论与荧光血管造影比较，吲哚青绿血管造影提高了对ARMD的脉络膜新生血管检出率和准确性，为临床早期治疗ARMD提供了帮助。     

Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye

Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis that the subretinal transplantation of genetically modified autologous IPE cells expressing biological therapeutics might be a promising strategy for the treatment of ARMD and other retinal disorders. Pigment epithelium-derived factor (PEDF) has strong antiangiogenic and neuroprotective activities in the eye. Subretinal transplantation of PEDF expressing IPE cells inhibited pathological choroidal neovascularization in rat models of laser-induced rupture of Bruch's membrane and of oxygen induced ischemic retinopathy. PEDF expressing IPE transplants also increased the survival and preserved rhodopsin expression of photoreceptor cells in the RCS rat, a model of retinal degeneration. These findings suggest a promising concept for the treatment of ARMD and other retinal disorders.     

Variations in frequencies of drug resistance in Plasmodium falciparum

Continual exposure of malarial parasite populations to different drugs may have selected not only for resistance to individual drugs but also for genetic traits that favor initiation of resistance to novel unrelated antimalarials. To test this hypothesis, different Plasmodium falciparum clones having varying numbers of preexisting resistance mechanisms were treated with two new antimalarial agents: 5-fluoroorotate and atovaquone. All parasite populations were equally susceptible in small numbers. However, when large populations of these clones were challenged with either of the two compounds, significant variations in frequencies of resistance became apparent. On one extreme, clone D6 from West Africa, which was sensitive to all traditional antimalarial agents, failed to develop resistance under simple nonmutagenic conditions in vitro. In sharp contrast, the Indochina clone W2, which was known to be resistant to all traditional antimalarial drugs, independently acquired resistance to both new compounds as much as a 1,000 times more frequently than D6. Additional clones that were resistant to some (but not all) traditional antimalarial agents acquired resistance to atovaquone at high frequency, but not to 5-fluoroorotate. These findings were unexpected and surprising based on current views of the evolution of drug resistance in P. falciparum populations. Such new phenotypes, named accelerated resistance to multiple drugs (ARMD), raise important questions about the genetic and biochemical mechanisms related to the initiation of drug resistance in malarial parasites. Some potential mechanisms underlying ARMD phenotypes have public health implications that are ominous.     

Combined factor VIII and IX deficiency in a family

A family with combined deficiency of factor VIII and factor IX is reported. Family study showed that the father and his nephew had mild factor VIII deficiency with normal von Willebrand factor antigen and factor IX levels while his two sons had a reduced level of factor IX and normal factor VIII levels. His wife was found to have marginally reduced factor IX levels, whereas his daughter had reduced or normal levels of both factors VIII and IX. DNA analysis using the intra- and extragenic markers of factor VIII and IX genes showed that mother is a carrier of haemophilia B and the daughter is a carrier for both haemophilia A and B. Thus, the combined deficiency observed was due to a chance association of two distinct genetic defects.     

Homozygotes for prothrombin gene 20210 A allele in a thrombophilic family without clinical manifestations of venous thromboembolism.

BACKGROUND AND OBJECTIVE: A new genetic risk factor for venous thromboembolism has recently been described which involves a G to A transition at position 20210 in the 3' untranslated region of the prothrombin gene. To date, only a few homozygotes for this mutation have been reported and in most of cases, they suffered from thrombotic disease. Here, we describe a pedigree including both heterozygous and homozygous subjects for prothrombin (PT) 20210 A. DESIGN AND METHODS: This family was recruited in 1996 as part of our GAIT (Genetic Analysis of Idiopathic Thrombophilia) project. To qualify for the GAIT study, a pedigree was required to have at least 10 living individuals in three or more generations (i.e. extended pedigree). The pedigrees were selected through probands with idiopathic thrombophilia. A complete set of plasma and DNA determinations related to hemostasis was performed on this family. RESULTS: The plasma studies yielded normal results in all of the individuals. The family members who had a history of thromboembolism were heterozygous carriers of the PT 20210 A variant. In addition, 4 relatives who were heterozygous, and two who were homozygous for this A allele, failed to show clinical manifestations. These two homozygotes were 51 and 19 years old. INTERPRETATION AND CONCLUSIONS: This case exemplifies the complexity of thrombotic disease since individuals homozygous for a mutant gene do not exhibit symptoms while heterozygous individuals often do exhibit the disease. This case suggests that the new genetic risk factor for thrombosis (i.e. PT 20210 A) may not be as strong as most of the previously described genetic risk factors.     

Genetic and environmental contributions to hay fever among young adult twins

BACKGROUND: The susceptibility to develop hay fever is putatively the result both of genetic and environmental causes. We estimated the significance and magnitude of genetic and environmental contributions to hay fever among young adult twins. METHODS: From the birth cohorts 1953-82 of The Danish Twin Registry 11,750 twin pairs were identified through a nationwide questionnaire survey. Subjects were regarded hay fever cases when responding affirmatively to the question 'Do you have, or have you ever had hay fever?' Latent factor models of genetic and environmental effects were fitted to the observed data using maximum likelihood methods. RESULTS: The overall cumulative prevalence of hay fever was 12.6%. Identical twins were significantly more likely to be concordant for hay fever than were fraternal twins (P<0.001). Additive genetic effects accounted for 71% and non-shared environmental effects accounted for 29% of the individual susceptibility to hay fever. The same genes contributed to the susceptibility to hay fever both in males and in females. In families with asthma, the susceptibility to develop hay fever was, in addition to genes, to a great extent ascribable to family environment, whereas the aetiology of 'sporadic' hay fever was mainly genetic. CONCLUSIONS: The susceptibility to develop hay fever is attributable to major genetic influences. However, effects of family environment and upbringing are also of importance in families where asthma is present. These results indicate that different sub-forms of hay fever may have different aetiologies.     

An Electrophoretic and Quantitative Analysis of Coagulation Factor XIII in Normal and Deficient Subjects

S ummary Previous electrophoretic studies of the A and B subunits of factor XIII have revealed considerable genetic heterogeneity. The present work investigates the electrophoretic forms and quantitates the A and B subunits in a family with inherited factor XIII deficiency. The data indicate that the deficiency in this family is due to a null allele at the locus controlling the A subunit. All family members were found to have decreased levels of B subunit. The data also indicate that there is no difference in thrombin activated transamidase activity between normal individuals with the three commonly occurring electrophoretic phenotypes of the A subunit.     

The Y402H variant of complement factor H is associated with age‐related macular degeneration but not with diabetic retinal disease in the Go‐DARTS study

Aims The Y402H variant of complement factor H (CFH) is associated with risk of age‐related macular degeneration (ARMD). In common with ARMD, diabetic retinal disease also appears to involve complement activation. The aim was to investigate the impact of Y402H on both retinal pathologies in patients with Type 2 diabetes (T2DM) undergoing systematic eye screening. Methods Patients with T2DM (n = 2350) were genotyped for the CFH Y402H variant. The association of genotype with retinal disease was determined in both retrospective and prospective models. Results The retrospective study demonstrated that the HH genotype was associated with an age‐adjusted odds ratio of 7.4 for ARMD (P = 2.9 × 10^?11). In a longitudinal study in the disease‐free cohort, the age‐adjusted hazard ratio was 2.8 (P = 2.4 × 10^?7). The life‐time hazard ratio was 3.4 (P = 2.1 × 10^?16). We found no association of Y402H with development of referable diabetic retinal disease. Conclusion The ARMD‐associated Y402H variant in CFH does not appear to be associated with diabetic retinal disease, although complement activation is involved in the pathoaetiology of both conditions.     

The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study

Aims/hypothesis

Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association.

Methods

A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created.

Results

A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history.

Conclusions/interpretation

Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.     

Psychosocial adaptation to visual impairment and its relationship to depressive affect in older adults with age-related macular degeneration

PURPOSE: In this study we examined psychosocial adaptation to vision loss and its relationship to depressive symptomatology in legally blind older adults with age-related macular degeneration (ARMD). DESIGN AND METHODS: The 144 study participants were outpatients of a large regional vision clinic that specializes in the diagnosis and treatment of ARMD in older adults. They were administered a battery of cognitive and psychological screening instruments including the Adaptation to Vision Loss Scale, the Short Portable Mental Status Questionnaire, and the short form of the Geriatric Depression Scale. RESULTS: A principal components analysis of the Adaptation to Vision Loss Scale identified three distinct adaptation factors, namely, acceptance of vision loss, negative impact on relationships, and attitudes toward compensation. Of these, acceptance of vision loss and attitudes toward compensation were positively associated with depressive affect. In addition, self-reported use of outpatient rehabilitative services was less frequent in those reporting greater depressive symptomatology. IMPLICATIONS: These findings support the contention that depressive symptomatology as measured by self-report in older adults with ARMD is mediated by one's perceived sense of individual control as it relates to intrapersonal factors underlying adaptation to profound vision loss in old age caused by ARMD.