Genes and Hypertension: Where we are and where we Should Go

Our understanding of the genetics of hypertension is incomplete, A great deal has, however, been learned about the role of several »candidate« genes by altering their expression in transgenic and knockout models. Crosses of inbred strains, analyzed in F₂ generations, have demonstrated consistent quantitative trait loci, particularly on chromosomes 1, 2 and 10, suggesting significant contributions of some genes in distinct models of rodent hypertension. The effect of these loci has been tested in congenic strains and their interaction underlined in double congenics. The weakness of testing individual animals from F₂ crosses is overcome in recombinant inbred strains. In humans, Mendelian models of hypertension have contributed to progress in our understanding of this disease, but have not yet revealed any major gene of essential hypertension. Many association as well as linkage studies of humans have provided useful though somewhat contradictory data. Our renewed effort is oriented towards the discovery of genetic determinants of environmental interaction in hypertension as well as towards the future of pharmacogenomics. This progress will be the basis of future individualized treatment and prevention.     

Characterization of Listeria monocytogenes isolated from Ganges water,human clinical and milk samples at Varanasi,India

Listeria monocytogenes isolated from Ganges water, human clinical and milk samples were characterized by antibiotic susceptibility, serotype identification, detection of virulence genes and ERIC- and REP-PCR fingerprint analyses. All isolates were uniformly resistant to ampicillin, except two isolates, and showed variable resistance to gentamicin, cotrimoxazole, ofloxacin, rifampicin and tetracycline. Of the 20 isolates found positive for pathogens, seven (four human and three water isolates) belong to serogroups 4b, 4d and 4e; six (one human and five water isolates) belong to serogroups 1/2c and 3c; four milk isolates belong to serogroups 1/2b and 3b; and three milk isolates belong to serogroups 1/2a and 3a. Two water isolates, all human isolates, except one (Pb1) lacking inlJ gene, and three milk isolates possess inlA, inlC, plcA, prfA, actA, hlyA and iap genes. The remaining water and milk isolates showed variable presence of inlJ, plcA, prfA, and iap genes. ERIC- and REP-PCR based analyses collectively indicated that isolates of human clinical samples belong to identical or similar clone and isolates of water and milk samples belong to different clones. Overall study demonstrates the prevalence of pathogenic L. monocytogenes species in the environmental and clinical samples. Most of the isolates were resistant to commonly used antibiotics.     

Joint analysis of individual participants’ data from 17 studies on the association of the IL6 variant -174G>C with circulating glucose levels,interleukin-6 levels,and body mass index

Background. Several studies have investigated associations between the -174G>C single nucleotide polymorphism (rs1800795) of the IL6 gene and phenotypes related to type 2 diabetes mellitus (T2DM) but presented inconsistent results.

Aims. This joint analysis aimed to clarify whether IL6 -174G>C was associated with glucose and circulating interleukin-6 concentrations as well as body mass index (BMI).

Methods. Individual-level data from all studies of the IL6-T2DM consortium on Caucasian subjects with available BMI were collected. As study-specific estimates did not show heterogeneity (P>0.1), they were combined by using the inverse-variance fixed-effect model.

Results. The main analysis included 9440, 7398, 24,117, or 5659 non-diabetic and manifest T2DM subjects for fasting glucose, 2-hour glucose, BMI, or circulating interleukin-6 levels, respectively. IL6 -174 C-allele carriers had significantly lower fasting glucose (?0.091 mmol/L, P=0.014). There was no evidence for association between IL6 -174G>C and BMI or interleukin-6 levels, except in some subgroups.

Conclusions. Our data suggest that C-allele carriers of the IL6 -174G>C polymorphism have lower fasting glucose levels on average, which substantiates previous findings of decreased T2DM risk of these subjects.     

Adenoviral gene therapy of gastrointestinal tumour metastases in the liver

Summary

Gastrointestinal cancers are the second most common cause of cancer death. Once metastasised, 5 year survival is < 5% in gastrointestinal cancer. Because the liver is the preferred site for distant organ metastasis of colon cancer, treatment of hepatic metastases remains a challenge for experimental cancer therapy approaches. Gene therapy provides tools to combat cancer on a molecular level. In contrast to conventional chemotherapy, vectors are used to insert DNA into tumour cells, neighbouring parenchymal cells, or cells involved in the cellular immune defense. The shuttle vectors are of nonviral or viral origin. Adenoviral vectors have been developed for high efficiency in vivo gene transfer and expression. The incorporation of foreign DNA can result in direct tumour cell killing, using suicide genes. Cytokine genes, or genes encoding for tumour-specific antigens recognised by the cellular host immune system, can result in anti-tumoral immune stimulation. Experimental suicide-gene expression in hepatic metastasis of gastrointestinal tumours, utilising thymidine kinase and cytosine deaminase, results in significant tumour necrosis and regression. Intratumoral interleukin-2 and interleukin-12 gene expression can induce a systemic cellular antitumoral immune response, with long-term survival demonstrating the potential of this new therapeutic approach in cancer therapy.     

原发性肝细胞癌患者血清抗p53抗体的检测及意义探讨

目的 研究抗p53抗体检测以及与甲胎蛋白(AFP)联合检测对原发性肝细胞癌(HCC)诊断的效能。 方法 分别采用ELISA法与电化学发光法检测50例HCC、50例肝脏良性病变(LBL)、50例健康对照(HC)患者的血清抗p53抗体与AFP。 结果 HCC组血清抗p53抗体的水平和阳性率均明显高于LBL组(P<0.05)和HC组(P<0.01)。抗p53抗体对HCC的敏感性为36.0%,特异性为91.0%,ROC曲线下面积(AUC)为0.630(95% CI 0.547～0.707); AFP对HCC的敏感性为54.0%,特异性为83.0%,AUC为0.685(95%CI 0.604～0.758); 抗p53抗体与AFP联合检测可将对HCC敏感性提高至76.0%(特异性80.0%),AUC提高至0.770(95% CI 0.694～0.835)。 结论 抗p53抗体对HCC具有理想诊断价值; 抗p53抗体与AFP联合检测有助于提高对HCC的诊断效能(在保证特异性的前提下,提高敏感性)。     

血浆K-ras突变联合CA19-9检测对胰腺癌的诊断价值

目的: 探讨血浆K-ras基因突变联合CA19-9检测对胰腺癌的诊断价值.方法: 对连续58例疑为胰腺肿瘤患者,入院时抽取外周静脉血,分离血浆并提取DNA.采用突变富集PCR-RFLP法分析K-ras基因密码子12突变,用放射免疫法测定血清CA19-9.所有病例的血标本分析均在术前完成,并将检测结果与手术探查、病理诊断进行比较.结果: 41例胰腺癌患者中,血浆K-ras基因突变者29例(占70.7%),血清CA19-9升高者30例(占73.2%).联合K-ras与CA19-9检测胰腺癌的敏感性为90.2%(37/41).在其他17例非胰腺癌患者中,有3例血浆K-ras突变,8例血清CA19-9有升高.结论: 血浆K-ras突变可能是诊断胰腺癌的一个有价值的指标,若同时测定血清CA19-9,可提高检测胰腺癌的敏感性.     

大肠癌中DCC基因与蛋白激酶C的表达与预后

目的 探讨大肠癌组织中 DCC（Deleted in Colorectal Carcinoma）基因和蛋白激酶 C（Protein Ki-nase C）的表达与预后的关系。方法 采用免疫组化 En VisionTM法,对91例大肠癌组织中的DCC蛋白及PKC表达状态进行检测,并对其结果与各临床病理因素和生存期的关系进行相关的统计分析。结果 91例大肠癌中DCC阴性率为43.9％,PKC阴性率为51.6％,两者的表达水平呈正相关（相关系数r=0.041,P=0.005）。其中DCC的表达与肿瘤分化程度、术后有无脏器的转移、5年生存率有统计学相关性（P<0.05）;而PKC的表达仅与肿瘤组织分化程度有统计学相关性（P=0.019）。利用Cox回归模型进行单因素和多因素分析,发现只有分期与DCC表达水平可做为大肠癌独立的预后因素。结论　DCC基因的表达缺失可以作为判断大肠癌转移潜能及预后的独立指标。     

Staged Fontan procedure for mitral atresia associated with severe tricuspid regurgitation, pulmonary hypertension, and pulmonary artery distortion

Optimal initial palliation and a subsequent staged approach is mandatory for high-risk Fontan candidates. We describe the case of mitral atresia with severe tricuspid regurgitation and pulmonary hypertension successfully managed by repeated palliation from the neonatal period and 2-stage Fontan surgery. A 1-month-old boy diagnosed with mitral atresia and double-outlet right ventricle underwent pulmonary artery banding at 1 month of age, followed by repeated pulmonary artery banding accompanied by tricuspid annuloplasty and atrial septal defect enlargement at 6 months. Because of the presence of pulmonary artery distortion, right ventricular dysfunction, and borderline pulmonary vascular resistance, a hemi-Fontan procedure was conducted with extended pulmonary artery plasty when the boy was 3 years and 8 months old. Cardiac catheterization done 3 months after showed improvement in risk factors, and the final Fontan operation (total cavopulmonary connection) was successfully done in conjunction with repeated tricuspid annuloplasty when the boy was 4 years and 5 months old. The patient remains in excellent clinical condition at the last follow-up 5 years after the final Fontan procedure with sinus rhythm and good ventricular function.     

抑癌基因ING1mRNA在大肠癌中的表达、突变分析及其意义

目的 探讨人大肠癌组织中ING1基因表达及突变水平与大肠癌临床病理特征的关系。方法 选择人大肠癌组织标本及正常对照52例，应用逆转录PCR法检测ING1mRNA的表达，用DNA单链多态性分析法检测基因突变情况；同时应用免疫组化方法检测大肠癌中p53蛋白的表达情况。结果 ING1mRNA在大肠癌中的表达较正常组织明显减弱，其低表达与肿瘤的Dukes分期及淋巴结转移显著相关（P≤0.01),ING1mRNA的表达水平与p53蛋白表达呈显著正相关（P≤0.01),ING1基因在大肠癌中的突变率极低。结论 ING1可能通过降低表达而不是通过突变在大肠癌发生发展中起重要调节作用。