Is the Ala138Gly alteration of MEFV gene important for amyloidosis?

Progressive systemic amyloidosis is the most important complication of familial Mediterranean fever that inevitably leads to chronic renal failure. Initial studies have suggested that the presence of the Met694Val mutation carry a significant risk for the development of amyloidosis. On the contrary, our data revealed that there was no dominance of any MEFV mutation in relation to amyloidosis. The difference between our mutation data and others led us to study a polymorphism in Turkish population that might be a risk factor for the occurrence of amyloidosis. As some of the previously reported exonic polymorphisms in other disease states found to increase the genetic susceptibility, we aimed to study Ala138Gly of the MEFV gene. Our study group consisted of 124 FMF patients, of which 47 had amyloidosis. Eighty-one individuals without any familial history of FMF were included as control group. There was no statistically significant difference between healthy controls and FMF patients for the Ala138Gly polymorphism (p=0.9). However, when FMF/amyloidosis patients (n:47) were taken as another group, the difference was significant (p= 0.01) indicating that the carriers of 138Gly are more prone to amyloidosis [odds ratio 3.1 (CI 95% 1.57-5.75)].     

北方满族人β1肾上腺素能受体基因Arg389Gly多态性分布

随着药物基因组学的发展,遗传因素在疾病发生、发展和药物反应个体差异中的作用也得到了越来越深入的阐明。受体基因的变异导致结构功能异常进而导致机体对疾病的易患性及药物的反应发生改变,所以了解不同人群中β1肾上腺素能受体基因多态性的分布,不仅为今后进一步研究不同人群中某些疾病的发生发展与β1肾上腺素能受体基因多态性间的关系提供实验依据,还可为实现以基因为导向的药物治疗和个体化用药提供可靠依据。本文对224例北方满族人β1肾上腺素能受体(adrenoreceptor,AR)基因Arg389G ly的多态性进行检测。1材料与方法1·1研究对象:2…     

纯合子Cys329Gly导致的遗传性凝血因子Ⅶ缺陷症家系基因突变分析

目的对1个姨表近亲婚配的遗传性凝血因子Ⅶ(FⅦ)缺陷症家系进行表型和F7基因突变分析,探讨其分子发病机制。方法检测先证者及其家系成员(共4代9人)凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)、血浆FⅦ活性(FⅦ:C)等来明确诊断。PCR扩增先证者全部外显子及其侧翼序列、5′和3′非翻译区及家系成员相应的突变位点区域,PCR产物纯化后直接测序,寻找突变位点,以反向测序验证所发生的突变;使用生物信息学软件(Poly Phen-2和Mutation Taster)预测突变位点对蛋白质功能的影响,利用Py MOL软件构建正常FⅦ蛋白空间模型,进行定点突变观察构型改变。结果先证者PT(36.1s)和FⅦ:C(2%)明显异常,家系中其余8位成员PT均略高于正常对照组和FⅦ:C均略低于正常对照组;基因分析显示先证者F7基因第8外显子存在c.1165 TG纯合型突变,即TGT→GGT(Cys329Gly),8位家系成员的F7基因分析均显示c.1165有杂合型突变;两种生物信息学软件都提示此突变会引起蛋白功能变化,有致病性;F7基因蛋白构型显示突变后329位点与310位点之间二硫键消失,周边静电磁场发生改变。结论该家系F7基因存在Cys329Gly突变,是引起FⅦ缺陷症的主要分子机制,推测先证者纯合Cys329Gly突变基因分别遗传自近亲结婚的杂合子父母。     

Vogt–Koyanagi–Harada syndrome

Objectives

The objectives of this study are to review our current knowledge of the aetiopathogenesis of Vogt–Koyanagi–Harada syndrome, including viral infection, genetic factors and immunomediated mechanisms, and to discuss pathogenesis and its relevance to pharmacotherapy.

Systematic review methodology

Relevant publications from 1965 to 2012 on the aetiopathogenesis and pharmacotherapy of VKHS were analysed.

Results and conclusion

Vogt–Koyanagi–Harada syndrome (VKHS) is a rare multisystemic autoimmune disease that affects tissues containing melanin, including the eye, inner ear, meninges, and skin. The disease is characterised by bilateral uveitis associated with a varying constellation of auditory, neurological and cutaneous manifestations.The disease occurs more frequently among people with darker skin pigmentation. Asians, Native Americans, and Hispanics are most frequently affected. It predominates in patients aged between 20 and 50 years, and females are affected more frequently, with a female:male ratio of 2:1.The classic clinical course is characterised by bilateral panuveitis, hypoacusis, and meningitis, in addition to cutaneous involvement with poliosis, vitiligo, and alopecia.Although the exact cause of VKH disease remains unknown, it is thought to be a T-cell-mediated autoimmune process directed against melanocytes.VKHS classically begins with vague systemic symptoms suggestive of a viral infection, although a clear association between a specific viral agent and the disease has not been established.Genetic factors may play an important role in the loss of self-tolerance in VKHS. The HLA-DRB1*0405 allele is the main susceptibility allele for VKHS.Early and aggressive systemic corticosteroids are still the primary initial therapy for VKHS. Ocular complications may require an intravitreous injection of corticosteroids. Despite proper treatment with steroids, a number of patients experience recurrent attacks or steroid-associated complications. Thus, non steroid immunomodulatory therapy (IMT) has become necessary for the treatment of VKHS.     

纯合子p.Gly1715Ser导致的遗传性凝血因子Ⅴ缺陷症家系分析

目的 对一个由近亲婚配引起的遗传性凝血因子Ⅴ（FⅤ）缺陷症家系进行实验室表型检测与基因突变分析,初步探讨其分子发病机制。方法 检测先证者及其家系成员（3代6名成员）血浆凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、纤维蛋白原（FIB）、血浆FⅤ活性（FⅤ：C）、FⅤ抗原（FⅤ：Ag）及其他相关凝血指标进行表型诊断。通过CAT法检测凝血酶生成量。采用DNA直接测序法分析先证者F5基因的所有外显子、侧翼、5’和3’非翻译区及其家系成员相应突变位点区域,发现突变位点用反向测序证实。通过在线生物信息学软件（包括Mutation Taster、PROVEAN、SIFT及PolyPhen-2）预测和分析突变的致病性;用ClustalX-2.1-win分析突变氨基酸的保守性;利用Swiss-Pdb Viewer构建蛋白模型分析突变对蛋白质空间构象及功能的影响。结果 先证者PT和APTT均显著延长,分别为26.3 s/13.2 s和73.5 s/36.0 s;FⅤ：C和FⅤ：Ag明显降低,分别为3%和7%。先证者凝血酶生成试验峰高明显降低,延迟时间和达峰时间均显著延长,凝血酶生成潜力显著下降...     

黄体生成素β Gly102Ser基因多态性与多囊卵巢综合征的相关性研究

目的探讨黄体生成素β(Luteinizing hormoneβ-subunit,LHβ)Gly102Ser及黄体生成素受体(Luteinizing hormone receptor,LHR)基因多态性与PCOS的相关性。方法应用聚合酶链反应-限制性片段长度多态性(Polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)检测LHβGly102Ser多态性,分析LHβ基因多态性与多囊卵巢综合征(polycystic ovary syndrome,PCOS)的相关性。结果 PCOS组中LHβGly102Ser基因有14例突变型,占3.3%。对照组中3例突变,占1.1%;PCOS组LHβGly102Ser基因突变率显著高于对照组(P=0.006);LHβGly102Ser基因突变型的血清基础LH水平低于对照组(P0.05),但突变组有降低趋势;PCOS组内血清LH2mmol/L的患者,LHβ基因Gly102Ser发生突变的比例显著增加(P=0.003)。结论 PCOS人群中存在LHGly102Ser基因多态性,此多态性与PCOS有明显的相关性。LHβGly102Ser基因多态性可能是PCOS发病的危险因素之一。     

Arg389Gly β1-adrenergic receptor polymorphism and susceptibility to syncope during tilt test

Introduction

Numerous hormones, neurotransmitters, and other stimuli exert their biological effect on cellular functioning through heptahelical receptors coupled to G proteins (GPCR – G protein-coupled receptors). Adrenergic receptors that belong to this superfamily of receptors are components of the sympathetic nervous system. They play a pivotal role in blood pressure regulation and myocardial contractility. Alterations of the adrenergic receptor pathway have been suggested to be involved in the pathophysiology of vasovagal syncope (VVS). The aim of the present study was to evaluate the distribution of Arg389Gly polymorphism within the ADRB1 gene among patients with recurrent syncope.

Material and methods

Arg389Gly single nucleotide polymorphism was analyzed in 205 patients with recurrent syncope. Ninety-five patients (46%) had a positive head-up tilt test (HUT) result. The control group comprised 143 non-fainting subjects. Genotyping was performed by restriction fragment length polymorphism (RFLP) with BstNI enzyme.

Results

Both analyzed groups had similar distribution of the 389Gly allele. Sixty percent of polymorphic 389Gly carriers belong to the group of syncopal patients, while 40% belong to the control group of healthy subjects.

Conclusions

An association between syncopal incidence and Arg389Gly polymorphism within the ADRB1 gene was not found. The analyzed polymorphism affecting sympathetic activity does not influence vasovagal syncope in Polish patients.     

α-内收蛋白Gly460Trp变异与中国汉族人原发性高血压的相关性研究

目的：探讨内收蛋白α亚单位（α－内收蛋白）变异与中国汉族人原发性高血压发病的关系。方法：以１８３例汉族原发性高血压患者和１２９名血压正常者为研究对象,从外周血白细胞中提取基因组ＤＮＡ,采用聚合酶链式反应、单链构象多态性分析及ＤＮＡ序列测定等分子生物学技术,对α－内收蛋白基因第１０个外显子部分序列进行基因变异检测,并对身高、体重、血压等临床资料进行测定。结果：发现在α－内收蛋白基因第１０外显子的第６１４位核苷酸存在Ｇ被Ｔ替换的变异,使其氨基酸序列第４６０位的甘氨酸（Ｇｌｙ）被色氨酸（Ｔｒｐ）取代（Ｇｌｙ４６０Ｔｒｐ）,Ｇｌｙ／Ｇｌｙ、Ｇｌｙ／Ｔｒｐ和Ｔｒｐ／Ｔｒｐ３种基因型人群中的分布符合Ｈａｒｄｙ－Ｗｅｉｎｂｅｒｇ遗传平衡。该变异在原发性高血压患者与血压正常者中的频率分布差异无显著性（Ｐ＞０．０５）,３种基因型     

β2肾上腺素受体基因Arg16Gly位点多态性与华南人群哮喘相关性研究

目的探讨β2肾上腺素受体基因(ADRB2)SNP位点rs1042713即突变位点Arg16Gly的多态性与华南汉族人群支气管哮喘发病的相关性。方法采用病例对照研究,利用基质辅助激光解吸电离飞行时间质谱技术(MALDI-TOF-MS)对rs1042713进行基因分型,对实验结果运用χ2检验和二分类Logistic回归进行统计学相关性分析。结果 rs1042713多态位点AA、AG、GG 3种基因型在哮喘患者的频率为18.7%、76.0%和5.3%,与对照组(33.8%,44.6%和21.6%)相比具有显著差异(χ2=36.28,P<0.001);对年龄和性别进行校正后,发现相对于AA+GG基因型,携带AG基因型的哮喘发病风险增加(OR=4.37,95%CI:2.64~7.23)。结论华南汉族人群哮喘的发病机制可能与SNP rs1042713位点的单核苷酸多态性有关,杂合子基因型AG为其发病的危险因素。     

DRD3基因Ser9Gly多态性与不同性别精神分裂症患者工作记忆的关联研究

目的:探讨DRD3基因Ser9Gly多态性与汉族人群不同性别精神分裂症患者工作记忆的关联.方法:选取符合美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)中精神分裂症的诊断标准的汉族患者526例和415例汉族健康对照,检测DRD3基因Ser9Gly多态性,用中国修订韦氏成人智力量表(WAIS-RC)进行智商(IQ)评定,N-back任务测量工作记忆能力.采用协方差分析等方法分析DRD3基因Ser9Gly多态性与精神分裂症工作记忆的关联.结果:在全体被试中,男性的1-back[(0.50±0.27) vs.(0.56±0.25)]和2-back[(0.25±0.22) vs.(0.28±0.22)]任务错误率小于女性(均P＜0.05).男性患者中,Ser/Ser基因型的1-back任务错误率[(0.39±0.23) vs.(0.33±0.23)]高于Gly/Ser基因型,IQ[(97.4±15.1) vs.(101.9±13.4)]低于Gly/Ser基因型(均P＜0.05);男性对照组中,不同基因型之间工作记忆及IQ得分差异无统计学意义(均P＞0.05).女性被试中,Ser9Gly多态性不同基因型的工作记忆与IQ得分差异无统计学意义(均P＞0.05).结论:精神分裂症患者的工作记忆可能存在性别差异,Ser9Gly多态性在汉族人群中与精神分裂症的工作记忆障碍有一定相关性.     

Arg—Gly—Asp—Ser序列肽抗血小板聚集及抑制血栓形成的作用

本研究采集精氨酰－甘氨酰－天冬氨酸（Ａｒｇ－Ｇｌｙ－Ａｓｐ，ＲＧＤ）序列肽精氨酰－甘氨酰－天冬氨酰－丝氨酸四肽（Ａｒｇ－Ｇｌｙ－Ａｓｐ－Ｓｅｒ，ＲＧＤＳ）观察其小血板聚集功能，实验性血栓形成以及对纤维蛋白溶解系统的影响，结果表明ＲＧＤＳ显著抑制了血小板聚集功能，一分钟聚集抑制率，最大聚集抑制率随药物体外作用浓度增加而增加（０．０５～１．０ｍｍｏｌ／Ｌ）同时聚集速率显著下降，体内给予ＲＧＤＳ（８μｍ     

Density–property relationships in collagen–glycosaminoglycan scaffolds

Collagen–glycosaminoglycan scaffolds for the regeneration of skin have previously been fabricated by freeze-drying a slurry containing a co-precipitate of collagen and glycosaminoglycan. The mechanical properties of the scaffold are low (e.g. the dry compressive Young’s modulus is roughly 30 kPa and the dry compressive strength is roughly 5 kPa). There is interest in using these scaffolds for tendon and ligament regeneration where there is a need for improved mechanical properties. Previous attempts to increase the mechanical properties of the scaffold by increasing the solid volume fraction of the scaffolds were limited by the increasing viscosity of the slurry, making it more difficult to mix and giving inhomogeneous scaffolds. Our recent work on mineralized collagen–glycosaminoglycan scaffolds used a vacuum filtration technique to increase the volume fraction of solids in the slurry, thereby increasing the density and mechanical properties of the scaffolds. In this work, we used this technique to fabricate collagen–glycosaminoglycan scaffolds with dry densities between 0.0076 and 0.0311 g cm^?3 and pore sizes between 250 and 350 μm, values appropriate for soft tissue growth. The compressive Young’s modulus and strength in the dry state increased from 32 to 127 kPa and from 5 to 19 kPa, respectively, with increasing density. The tensile Young’s modulus in the dry state increased from 295 to 3.1 MPa with increasing density. Finally, we showed that the attachment of cells onto the scaffold was directly proportional to the specific surface area of the scaffold, which defines the total internal surface area per volume of scaffold.     

[Gly14]-Humanin对Aβ25-35诱导PC12细胞凋亡的影响

目的:探讨神经保护肽[Gly14]-Humanin过表达对Aβ25-35诱导的PC12细胞凋亡的影响.方法:采用脂质体法将重组真核表达载体pcDNA3.1(-)/HNG-FLAG转入PC12细胞,G418筛选获得抗性亚克隆细胞株,免疫细胞化学法分析[Gly14]-Humanin基因的表达.用25μmol/L Aβ25-35作用细胞24 h,MTT法分析细胞存活率,流式细胞术(FCM)监测细胞凋亡,Hoechst 33258染色观察凋亡细胞核形态改变.结果:建立了稳定过表达[Gly14]-Humanin的PC12细胞系.经25 μmol/L Aβ25-35作用后,稳定表达[Gly14]-Humanin的PC12细胞存活率较空质粒转染组明显提高(P<0.05),凋亡率显著降低(P<0.05).Hoechst 33258染色结果表明,空质粒转染组细胞核出现浓缩及断裂等凋亡形态,而过表达[Gly14]-Humanin组细胞核形态正常.结论:过表达[Gly14]-Humanin能够抑制Aβ25-35诱导的PC12细胞凋亡.     

中国人内源性高甘油三酯血症患者β2肾上腺素受体基因Arg16Gly多态性的研究

目的 研究β2肾上腺素受体(β2-adrenergic receptor,β2AR)基因Arg16Gly多态性是否与中国人内源性高甘油三酯血症(hypertriglyceridemia,HTG)有关联,为探讨本病的分子遗传基础提供依据.方法 应用聚合酶链反应.限制性片段长度多态性分析法,对成都地区341名汉族人(241名正常人及100例HTG患者)β2AR基因Arg16Gly多态性位点进行分析.结果 中国人β2AR基因Arg16Gly多态位点Gly等位基因频率为0.446,与日本人的0.505相近,较美国白人的0.248显著增高,而低于欧洲波兰人的0.633.HTG组和对照组之间β2AR基因Arg16Gly位点Gly等位基因的频率差异无统计学意义(0.490 vs 0.427,P》0.05).在正常对照组,Arg/Arg基因型携带者血清TG水平显著高于Arg/Gly基因型携带者[(1.24±0.36)mmol/L vs(1.13±0.34)mmol/L,P《0.05],而与Gly/Gly基因型携带者比较,其血清apoB100显著增高(P《0.01),apoAⅡ显著降低(P《0.05).HTG组Arg/Arg基因型携带者血清TC及低密度脂蛋白胆固醇水平较Gly/Gly基因型者显著升高[(5.36±0.74)mmol/L vs(4.77±1.07)mmol/L,P《0.05;(3.03±0.70)mmol/L vs(2.38±1.10)mmol/L,P《0.05].结论 β2AR基因Arg16Gly多态性不仅与成都地区正常汉族人血清TG、apoB100和apoAⅡ含量有关,而且还与内源性高甘油三酯血症患者血清TC和低密度脂蛋白胆固醇水平相关联,Arg16Gly多态性可能在影响中国汉族人血清甘油三酯和(或)胆固醇的代谢中起一定的作用.     

冠心病患者内皮脂肪酶基因Thr111Ile和Gly26Ser多态性与脂蛋白代谢的关系

目的: 探讨冠心病（CHD）患者内皮脂肪酶基因（LIPG）Thr111Ile和Gly26Ser 的多态性与脂蛋白代谢的关系。 方法: 438例冠状动脉造影患者，根据造影结果分为CHD组（242例）和对照组（196 例）。应用酶法测定患者的总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-c）、低密度脂蛋白胆固醇（LDL-c）水平。同时应用聚合酶链反应-限制性内切酶片段长度多态性（PCR-RELP）核苷酸分型技术检测Thr111Ile和Gly26Ser多态性，进行统计学分析。 结果: Thr111Ile在本研究人群中的基因频率分布为CC 76.7％、CT 23.3％、TT 0.0％，等位基因频率为C 88.3％、T 11.7%。CT组HDL-c水平高于CC组（P<0.05），经多因素逻辑回归分析，CT基因仍与高HDL-c水平呈显著相关（P<0.05），CHD与Thr111Ile多态性无显著相关（P>0.05）。未发现Gly26Ser基因变异。结论: 中国汉族人群中存在LIPG基因的Thr111Ile多态性。Thr111Ile多态性中的CT基因致HDL-c水平升高，但未发现其与CHD直接相关。本研究未发现Gly26Ser多态性。     

Infant–mother and infant–sibling attachment in Zambia

This study, the first in Zambia using the Strange Situation Procedure (SSP) to observe attachment relationships and the “very first” observational study of infant–sibling attachment, examined patterns of infant–mother and infant–sibling attachment, and tested their association. We included siblings who were substantially involved in caregiving activities with their younger siblings. We hypothesized that infants would develop attachment relationships to both mothers and siblings; the majority of infants would be classified as securely attached to both caregivers, and infant–mother and infant–sibling attachment would be unrelated. The sample included 88 low-income families in Lusaka, Zambia (average of 3.5 children; SD = 1.5). The SSP distributions (infant–mother) were 59% secure, 24% avoidant and 17% resistant, and 46% secure, 20% avoidant, 5% resistant and 29% disorganized for three- and four-way classifications, respectively. The infant–sibling classifications were 42% secure, 23% avoidant and 35% resistant, and 35% secure, 23% avoidant, 9% resistant and 33% disorganized for three- and four-way classifications, respectively. Infant–mother and infant–sibling attachment relationships were not associated.