Cardiovascular risk factors in people with different genotypes in the insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme (ACE)

The deletion (D) allele of an insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme (ACE) has been reported to be an independent risk factor for myocardial infarction (MI), particularly in people lacking traditional risk factors. Furthermore, a borderline association between Lp(a) lipoprotein level and the I/D polymorphism at the ACE locus was reported in one study. We have searched for possible "level gene" or "variability gene" effects of ACE genes on Lp(a) lipoprotein, total cholesterol (TC), high density lipoprotein (HDL) cholesterol (HDLC), low density lipoprotein (LDL) cholesterol (LDLC), triglycerides (TG), apolipoprotein B (apoB), apolipoprotein A-I (apoA-I), and body mass index (BMI). None of these variables differed significantly between genotypes in the I/D polymorphism in any of three population samples. A single population sample created by combining the three series, exhibited an insignificant trend towards individuals carrying the D-allele having a higher level of Lp(a) lipoprotein than those lacking it, and DD homozygotes had a significantly higher Lp(a) lipoprotein level than the combined group of ID/II individuals (p = 0.03). These results may indicate that the D-allele of the I/D polymorphism at the ACE locus could influence the level of Lp(a) lipoprotein.     

Human mtDNA hypervariable regions, HVR I and II, hint at deep common maternal founder and subsequent maternal gene flow in Indian population groups

We have analysed the hypervariable regions (HVR I and II) of human mitochondrial DNA (mtDNA) in individuals from Uttar Pradesh (UP), Bihar (BI) and Punjab (PUNJ), belonging to the Indo-European linguistic group, and from South India (SI), that have their linguistic roots in Dravidian language. Our analysis revealed the presence of known and novel mutations in both hypervariable regions in the studied population groups. Median joining network analyses based on mtDNA showed extensive overlap in mtDNA lineages despite the extensive cultural and linguistic diversity. MDS plot analysis based on Fst distances suggested increased maternal genetic proximity for the studied population groups compared with other world populations. Mismatch distribution curves, respective neighbour joining trees and other statistical analyses showed that there were significant expansions. The study revealed an ancient common ancestry for the studied population groups, most probably through common founder female lineage(s), and also indicated that human migrations occurred (maybe across and within the Indian subcontinent) even after the initial phase of female migration to India.     

Progressive dilated cardiomyopathy in a patient with longstanding and complete prednisone-induced hematological remission of idiopathic hypereosinophilic syndrome

Summary A female patient is described in whom the diagnosis of idiopathic hypereosinophilic syndrome (HES) with heart disease and peripheral neuropathy was made at the age of 32 years. Although prednisone induced a prompt and longstanding complete hematological remission, progressive and eventually intractable heart failure developed, and the patient died 6 years later. Endomyocardial biopsy at diagnosis showed infiltration with intact and disintegrated eosinophils and Charcot-Leyden crystals. Echocardiographic follow-up (including Doppler-Echocardiography) revealed mitral regurgitation with thickening and impaired motility of the posterior mitral leaflet, as well as progressive dilated cardiomyopathy. At autopsy, a diffuse interstitial fibrosis with patchy prominence in an eccentric hypertrophic and highly dilated heart was found. There were no significant endocardial thickening and no mural thrombi. In contrast to the findings of the initial endomyocardial biopsy, autopsy revealed no eosinophilic infiltrate.In this case, eosinophil-induced heart disease manifested as dilated cardiomyopathy, without endocardial fibrosis as originally described by Löffler. We speculate, that eosinophils have been deposited predominantly in the myocard at an early stage of disease, and — activated locally — secreted their granule proteins producing an initial damage to capillary endothelial cells and myocytes. After prednisone-induced clearance of eosinophils from blood and tissues, progressive, self-perpetuating interstitial fibrosis of the myocard and loss of myocytes eventually resulted in end-stage dilated cardiomyopathy.Abkürzungsverzeichnis HES idiopathic hypereosinophilic syndrome - UBBC unsaturated vitamin B₁₂ binding capacity - ECP eosinophil cationic protein - MBC major basic protein - EDD end-diastolic diameter of the left ventricle - LA left atrium diameter - LVEDP left ventricular end-diastolic pressure - NIH National Institutes of Health     

The rational design of TAP inhibitors using peptide substrate modifications and peptidomimetics

The major histocompatibility complex (MHC)-encoded transporter associated with antigen processing (TAP) translocates peptides from the cytosol into the lumen of the endoplasmic reticulum. This step precedes the binding of peptides to MHC class I molecules and is essential for cell surface expression of the MHC class I/peptide complex. TAP has a broad sequence specificity and a preference for peptides of around 9 amino acids. To synthesize inhibitors for TAP, we studied various alterations of the peptide substrate. The results indicate that TAP is stereospecific and that peptide bonds engineered into isosteric structures can improve translocation of the peptide. Furthermore, TAP is able to translocate peptides with large side chains that correspond to a peptide of ～ 21 amino acids in extended conformation. Peptides with longer side chains compete for the peptide binding site of TAP but fail to be translocated. Therefore, they represent the first rationally designed inhibitors of TAP.     

The postnatal development of thalamocortical projections from the pulvinar in the cat

Summary The postnatal development of thalamocortical projections from the pulvinar to an association cortex of the cat, the crown of the middle suprasylvian gyrus, was studied by using both HRP and evoked field potentials. From birth onward, the pulvinar sends dense fibres to this cortical area, but the cortical laminar distribution of the afferents was found to change markedly with aging. An orthograde HRP study showed that at birth and up to 2 weeks of age, the terminals are distributed mainly in layer I, whereas in adult cats and kittens older than 1 month, the terminals are found largely in and around layer IV and only sparsely in layer I. After HRP injections exclusively into layer I of the crown, numerous thalamic neurones were retrogradely labelled in both the ventroanterior-ventrolateral complex (VA-VL) and the pulvinar in 5-day-old kittens, but in the VAVL alone in 2-month-old kittens. In agreement with these anatomical findings, stimulation of the pulvinar elicited a surface-negative, depth-positive potential in 1-week-old kittens, indicating the existence of a large current sink in layer I; however, it induced a surface-positive, depth-negative potential in 1month-old kittens, reflecting the presence of a strong current sink in the deep cortical layers.     

PCR－RFLP用于Ⅰ型脊髓灰质炎病毒野毒株与疫苗相关株的鉴别

利用互补于Ⅰ型脊髓灰质炎病毒ＶＰ１区的一对引物，扩增病毒核酸中约２６８ｂｐ的片段。产物经ＨａｅⅢ、ＲｓａⅠ、ＸｂａⅠ三种限制性内切酶切割后，用２％琼脂糖凝胶电泳检测，观察各分离株与ＳａｂｉｎⅠ型株酶切图谱的异同。在所检测的１３株病毒分离株中，只有１株的酶切图谱与ＳａｂｉｎⅠ型株的相同，为疫苗相关株，其它的１２株均为野毒株。本实验的结果表明从不同地区、不同年份所得的Ⅰ型脊髓灰质炎病毒分离株的碱基组成是有差异的。     

An integrative approach to CTL epitope prediction: a combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have also been developed for predicting the antigen-processing steps preceding MHC class I binding, including proteasomal cleavage and transporter associated with antigen processing (TAP) transport efficiency. Here, we use a dataset obtained from the SYFPEITHI database to show that a method integrating predictions of MHC class I binding affinity, TAP transport efficiency, and C-terminal proteasomal cleavage outperforms any of the individual methods. Using an independent evaluation dataset of HIV epitopes from the Los Alamos database, the validity of the integrated method is confirmed. The performance of the integrated method is found to be significantly higher than that of the two publicly available prediction methods BIMAS and SYFPEITHI. To identify 85% of the epitopes in the HIV dataset, 9% and 10% of all possible nonamers in the HIV proteins must be tested when using the BIMAS and SYFPEITHI methods, respectively, for the selection of candidate epitopes. This number is reduced to 7% when using the integrated method. In practical terms, this means that the experimental effort needed to identify an epitope in a hypothetical protein with 85% probability is reduced by 20-30% when using the integrated method.The method is available at http://www.cbs.dtu.dk/services/NetCTL. Supplementary material is available at http://www.cbs.dtu.dk/suppl/immunology/CTL.php.     

2型糖尿病患者血清von Willebrand因子变化与微血管并发症的关系

目的 :探讨 2型糖尿病患者的微血管内皮细胞功能损伤与微血管并发症之间的关系。方法 :从 3 3 4名 2型糖尿病患者中选择合并微血管并发症但未合并大血管并发症者 3 2人作为微血管并发症组 ,并选择年龄与之匹配的无大血管及微血管并发症 55人作为无并发症组 ,观察二组患者血清vonWillebrand因子 (vWF)水平 ,并与年龄相接近的正常对照组 ( 4 0例 )比较。结果 :血清vWF水平正常对照组 0 .92U± 0 .44U/ml;无并发症组 1.15U± 0 .42U /ml ;微血管并发症组 1.3 7U± 0 .44U/ml;三组之间均有显著性差异 (P <0 .0 5～ 0 .0 1)。多因素Logistic回归分析表明vWF、空腹血糖分别与糖尿病人是否合并微血管病变显著相关 (ExpB分别为 3 .0 2 3 ,1.3 3 7,P <0 .0 5～ 0 .0 1) ,以vWF为应变量的多元逐步回归分析表明年龄、糖尿病病程、甘油三酯分别与vWF呈显著独立正相关 (B =0 .53 ,0 .3 5,0 .2 9,P <0 .0 5～ 0 .0 1)。结论 :在糖尿病患者中存在不同程度的微血管内皮细胞的损伤 ,此变化随着微血管并发症的进展呈进行性加重。以vWF升高所反映的微血管内皮细胞损伤是一项值得临床推广的研究方法     

检测体内异种II型胶原异体移植引起的细胞毒反应

检测用猪II型胶原免疫新西兰大白兔的异种异体细胞免疫反应。用II型胶原免疫新西兰大白兔60 d,定期抽取血浆检测抗II型胶原抗体;第60 d取兔的外周血淋巴细胞、兔脾细胞、淋巴结分别分离淋巴细胞,进行体外二次II型胶原刺激,检测由此引起的反应性的细胞增殖规律。实验分为二组,第一组加入不同浓度植物血凝素(PHA)作阳性对照,并测定非特异性免疫;第二组加入不同浓度II型胶原,检测特异性免疫。正常兔的淋巴细胞在PHA剌激下发生增殖,但对II型胶原的第一次剌激不发生增殖,而免疫兔对PHA和II型胶原的剌激均能发生显著的增殖。表明异种II型胶原在一定浓度下,可以引起免疫兔的抗II型胶原抗体的升高,并可引起兔脾、外周血淋巴细胞增殖,异种II型胶原能在体内引起细胞免疫反应。