A -243A-->G polymorphism upstream of the gene encoding GAD65 associates with lower levels of body mass index and glycaemia in a population-based sample of 5857 middle-aged White subjects.

AIMS: The glutamate decarboxylase gene (GAD2) encodes GAD65, an enzyme catalysing the production of the gamma-aminobutyric acid (GABA) which interacts with neuropeptide Y to stimulate food intake. It has been suggested that in pancreatic islets, GABA serves as a functional regulator of pancreatic hormone release. Conflicting results have been reported concerning the potential impact of GAD2 variation on estimates of energy metabolism. The aim of this study was to elucidate potential associations between the GAD2-243A-->G polymorphism and levels of body mass index (BMI) and estimates of glycaemia. METHODS: Using high-throughput chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, the GAD2-243A-->G (rs2236418) polymorphism was genotyped in a population-based sample (Inter99) of 5857 middle-aged, unrelated Danish White subjects. RESULTS: The G-allele was associated with modestly lower BMI (P = 0.01). In a case-control study of obesity, the G-allele frequency in 2582 participants with BMI < 25 kg/m2 was 19.5% (18.4-20.6) compared with 17.1% (15.5-18.8) in 968 participants having BMI > or = 30 kg/m2 (P = 0.03), odds ratio 0.9 (0.7-1.0). Of the 5857 subjects, GG carriers had lower fasting plasma glucose levels (mmol/l) [AA (n = 3859) 5.6 +/- 0.8; AG (n = 1792) 5.5 +/- 0.8; GG (n = 206) 5.5 +/- 0.8, P = 0.008] and lower 30-min oral glucose tolerance test (OGTT)-related plasma glucose levels (AA 8.7 +/- 1.9; AG 8.6 +/- 1.9; GG 8.6 +/- 2.0, P = 0.04), adjusted for sex, age and BMI. Analysing subjects who were both normoglycaemic and glucose tolerant (n = 4431) GG carriers still had lower fasting plasma glucose concentrations: AA (n = 2895) 5.3 +/- 0.4; AG (n = 1383) 5.3 +/- 0.4; GG (n = 153) 5.2 +/- 0.4 (P = 9.10(-5)). CONCLUSION: The present study suggests that the GAD2-243A-->G polymorphism in a population of middle-aged White people associates with a modest reduction in BMI and fasting and OGTT-related plasma glucose levels.     

Diplotypes of the human serotonin 1B receptor promoter predict growth hormone responses to sumatriptan in abstinent alcohol-dependent men.

BACKGROUND: Some studies have associated alcohol dependence (AD) with the human serotonin (5-HT)(1B) receptor (HTR1B). This investigation explored the functional responsivity of HTR1B in abstinent AD men using a sumatriptan challenge, while measuring genetic heterogeneity in the HTR1B promoter. METHODS: Abstinent AD men (n = 27) and abstinent men without any alcohol use disorder (n = 19) were administered 6 mg of sumatriptan succinate, subcutaneously. Plasma samples collected over the following 2 hours were assayed for growth hormone (GH) concentrations. His DNA was genotyped for the A-161T and T-261G polymorphisms of the HTR1B promoter and diplotypes determined. RESULTS: Integrated GH responses were predicted by interactions of AD and promoter diplotypes, as well as subject ethnicity. The final model accounted for nearly 35% of the variance in GH responses. Post hoc evaluation revealed that AD was associated with a blunting of GH secretion only among individuals with the most common HTR1B diplotype (TT/TT). CONCLUSIONS: A blunting of GH responses in abstinent AD men was observed only among those with the most common HTR1B promoter diplotype. Less common promoter diplotypes appeared protective. Controlling for genetic background is a useful augmentation of case-control pharmacological challenge strategies designed to elucidate the psychobiology of AD and other complex disorders.     

纤溶酶原激活剂抑制物-1及其基因多态性与急性心肌梗死的相关性研究

目的：研究纤溶酶原激活剂抑制物－1（PAI－1）活性及其等位基因多态性与急性心肌梗死（AMI）之间的关系，从基因水平揭示AMI发病的危险因素。方法：AMI组55例、对照组48例健康者分别应用特异性寡核苷酸点膜杂交技术，进行PAI－1启动子区4G／5G多态性分析，用发色底物法测定血浆PAI－1活性。结果：AMI组和对照组中4G／4G基因型的血浆PAI－1活性水平最高，与4G／5G基因型、5G／5G基因型比较有显著性差异（P＜0．01）。AMI组中4G／4G纯合子基因型频率明显高于对照组（P＜0．05）。结论：血浆PAI－1活性增高是AMI发病的危险因素之一，4G／4G纯合子基因型是AMI发病的危险基因型。     

Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study

Sixteen cohorts of men aged 40–59 years at entry were examined with the measurement of some risk factors and then followed-up for mortality and causes of death for 25 years. These cohorts were located in the USA (1 cohort), Finland (2), the Netherlands (1), Italy (3), the former Yugoslavia (5), Greece (2), and Japan (2), and included a total of 12,763 subjects.Large differences in age-adjusted coronary heart disease (CHD) death rates were found, with extremes of 45 per 1000 in 25 years in Tanushimaru, Japan, to 288 per 1000 in 25 years in East Finland. In general, higher rates were found in the US and Northern European cohorts as compared to the Southern European and Japanese cohorts. However, during the last 10 years of follow-up large increases of CHD death rates were found in some Yugoslavian areas. Out of 5 measured entry characteristics treated as age-adjusted levels (serum cholesterol, systolic blood pressure, cigarette smoking, body mass index and physical activity at work), only serum cholesterol was significant in explaining cohort differences in CHD death rates.Over 50% of the variance in CHD death rates in 25 years was accounted for by the difference in mean serum cholesterol. This association tended to decline with increasing length of follow-up, but this was due to the great changes in mean serum cholesterol in the two Jugoslavian cohorts of Velika Krsna and Zrenjanin. When these two cohorts were excluded the association increased with time.Changes in mean serum cholesterol between year 0 and 10 helped in explaining differences in CHD death rates from year 10 onward.It can be concluded that this study suggests that mean serum cholesterol is the major risk factor in explaining cross-cultural differences in CHD.     

The regulation of pulmonary vascular tone

1 The ability to manipulate pharmacologically pulmonary vascular tone independent of effects on systemic blood vessels is a desirable objective. Elucidation of the biochemical mechanisms underlying hypoxia-induced pulmonary vasoconstriction (HPV) may permit preferential targeting of the pulmonary circulation.
2 Here we review our studies of the role of locally synthesized candidate vasoactive factors in HPV. In addition, we present data demonstrating an attenuated pressor response to hypoxia in the pulmonary circulation of Fischer 344 rats compared with the Wistar-Kyoto (WKY) rat strain.
3 We propose that a systematic genome-wide search using the HPV phenotype and a panel of highly informative microsatellite markers will elucidate the genetic loci underlying the difference in susceptibility to HPV in these two rat strains and provide a valuable and novel insight into the factors that determine the HPV response.     

Using the polymerase chain reaction to maintain DNA probe inventories in clinical and diagnostic laboratories

Clinical and diagnostic DNA laboratories must maintain a large inventory of DNA probes for use in hybridization studies. The preparation of plasmid DNA and isolation of DNA fragments for use as probes in both expensive and time consuming. We present here a rapid and relatively inexpensive method of producing large amounts of DNA fragments from stocks, using the polymerase chain reaction (PCR). Our experience over the past year using this technique has been very positive and we believe many laboratories could benefit by employing such a labor-saving approach to maintaining DNA probes. The technique uses the bacteriophage M13 DNA sequencing primers to amplify cloned inserts contained in commonly used plasmid vectors. As examples, we illustrate the use of DNA produced in this manner as probes for linkage analysis of the fragile X syndrome and for detection of deletions in the Duchenne muscular dystrophy gene. We have also found that at least two probes can be amplified in the same PCR reaction, allowing the detection of two different restriction fragment length polymorphisms (RFLP) simultaneously. It should be possible for laboratories to devise strategies particular to their individual needs using more than one DNA probe produced in the same PCR reaction to detect RFLP's. Such strategies would need only to consider that the predicted alleles of the multiple polymorphisms do not migrate to the same position during electrophoresis. Stocks of single or multiple probes produced by the PCR could then be maintained for more rapid Southern analyses.     

高密度cDNA微阵列技术检测乳腺癌差异表达基因

目的 描绘乳腺癌的基因差异表达谱，以寻找乳腺癌新的肿瘤相关候选基因和分子标志。方法 用含14000个cDNA克隆的表达微阵列检测乳腺癌组织、乳腺癌旁组织及乳腺非癌组织的mRNA表达，并分析其表达的差异。结果 乳腺癌组织与乳腺非癌组织比较有80个差异表达基因，乳腺癌组织与乳腺癌旁组织比较有57个差异表达基因，乳腺癌旁组织与乳腺非癌组织比较有29个差异表达基因，在乳腺癌组织与乳腺非癌组织和乳腺癌旁组织比较中有14个差异表达基因是一致的。结论 用微阵列技术对乳腺癌的肿瘤相关基因和分子标志作初步探索，为了解中国女性乳腺癌发生发展的分子机制、发展新的诊断和治疗手段提供了信息。     

New type of spinocerebellar degeneration syndrome in a northern Swedish population

A follow-up investigation of 24 patients with hereditary spasticity in a geographically isolated northern Swedish population, first examined by Böök (1953), was performed. Fifteen of them were dead. During the period from 1950–1972 five new cases of spastic syndromes were diagnosed in this population. The patterns of clinical symptoms and the genetic associations between the new and 24 previously reported patients with spastic syndromes were analyzed. Three of the five new cases had a specific syndrome. This starts in the first years of life with ataxia, which is followed by dysarthria, spasticity and jerky intention tremor. Initially the patients are mentally normal, but there seems to be slight mental deterioration through the years. The disorder is a progressive spinocerebellar degeneration with autosomal recessive inheritance.     

5岁以下健康儿童流感嗜血杆菌携带状态的研究

[目的]流感嗜血杆菌(Hi)是引起儿童细菌性感染的主要病原菌,国内对Hi携带的研究资料较少,本文对石家庄市5岁以下健康儿童Hi感染的流行病学分布情况进行了研究,为制订防治对策提供参考依据。[方法]在石家庄市区整群随机抽样,调查1045例5岁以下健康儿童,取鼻咽拭子标本,用改良巧克力培养基,常规Hi培养并鉴定菌型。[结果](1)Hi携带率为15.6%,生物型Ⅰ、Ⅱ、Ⅲ型共98例(70.5%)为优势菌型。(2)经Logistic多元回归分析显示Hi携带与年龄、出生时身高、家庭人均经济收入和裂纹舌有关。[结论]石家庄市5岁以下正常儿童Hi携带率为15.6%,6个月至2岁儿童Hi携带率最高(22.4%)。Hi携带可能受遗传等综合因素影响。把中医舌诊试用于Hi携带的观察研究,显示了裂纹舌与Hi感染有关,为中西医结合提供参考依据。     

Molecular staging of head and neck squamous carcinoma

The staging system of head and neck cancer is a Tumor-Node-Metastases system that was developed by the American Joint Committee on Cancer. The stage of the head and neck cancer defines the extent of the lesion and is determined by physical examination, radiologic studies, and pathologic examination. Accurate staging of head and neck cancer is critical since it will determine the treatment modalities used to cure the disease. Recent advances in the field of molecular genetics have allowed clinicians to detect occult cancer cells previously missed by physical examination and standard histopathologic techniques. Molecular assays are 500 times more sensitive in identifying cancer cells than standard techniques and provide more objective analyses with fewer sampling errors. Consequently, these techniques are currently being used to perform molecular staging of head and neck cancer patients. Preliminary results show that molecular staging will accurately identify those patients at significantly increased risk for recurrence of their head and neck cancer.