乙醛脱氢酶2（ALDH2）基因研究进展及其与饮酒行为的关系

亚洲人群中普遍存在突变型的乙醛脱氢酶2（ALDH2*2）。此酶突变后活性缺失,导致乙醛在肝脏内大量累积使突变携带者在喝酒后会有脸红等不适反应,因此这可能影响他们的饮酒行为。由于ALDH2*2等位基因与饮酒行为相关,它也可能与酒精引起的肝脏损伤及某些癌症密切相关,而且,它在不同的亚洲人群中有不同的频率分布。近年来对ALDH2*2等位基因的序列结构、表达及其重要功能等有了更深入的了解,对ALDH2的多态性在研究方法、研究群体分布范围等都有很大进展。本文还讨论了不同地理分布、不同年龄结构、性别差异条件下,中国人群中ALDH2基因型频率与饮酒行为的关系。 Abstract: An atypical allele （ALDH2*2） in low Km aldehyde dehydrogenase (ALDH2), which is highly prevalent in Asian, may influence drinking behavior because of higher production of acetaldehyde in the liver. High alcohol sensitivity such as flushing after drinking has been shown to be mainly due to the atypical ALDH2 genotypes. The atypical allele is associated with alcohol-induced liver injury and some cancers. Recently, the researches on the polymorphisms not only in the gene itself but also its frequencies in different Asian populations have been made great progress. Three factors, including different sex, age and geography, were also analyzed with the genotypes of ALDH2 in Chinese populations.     

The ALDH2 genotype, alcohol intake, and liver-function biomarkers among Japanese male workers

A highly prevalent, atypical genotype in low Km aldehyde dehydrogenase (ALDH2) may influence alcohol-induced liver injury because of higher production of acetaldehyde in the liver. In the present study, we examined relationships between the ALDH2 genotype, alcohol intake, and liver-function biomarkers among Japanese male workers. Study subjects were 385 male workers in a metal plant in Japan, who were free from hepatic viruses and did not have higher aminotransferase activities (<100). The subjects completed a questionnaire on alcohol drinking habits and other lifestyles. The ALDH2 genotype was determined by the PCR method followed by restriction-enzyme digestion. In the moderately and heavily drinking groups, those with ALDH2*1/*2 exhibited significantly lower levels than those with ALDH2*1/*1 for all three parameters of liver function, whereas no such differences were observed in the least-drinking group. Multiple linear-regression analysis, adjusting for age, obesity, and smoking habits, revealed that aspartate aminotransferase activity was positively associated with alcohol intake only in those with ALDH2*1/*1. On the other hand, alanine transferase activity was negatively associated with alcohol intake only in those with ALDH2*1/*2. The present study indicates that effects of alcohol intake on liver-function biomarkers are likely to be modified by the ALDH2 genotype in adult males.     

Trajectories of shifting of dipole sources of visual evoked potentials over the human brain

Dynamic study of 3D localization of the equivalent current dipole (ECD) sources of visual evoked potentials (EP) in the human brain was performed in 18 healthy subjects using a two-dipole model. Dipole tracing was performed for relatively early EP components (N1, P1, and N2) with 1-ms step. The analysis confirmed localization of these ECDs mainly in the right occipital cortex and revealed their successive shift over this area in the anterior-medial direction and then backwards in all subjects during generation of the EP components. Typically, some successive arch-like trajectories of the shift were revealed (75.8%); their duration was relatively standard (about 25 ms) and did not depend on the stimulus shape and EP phase. Between the 1st and the 2nd trajectories (110-120 ms after the stimulus onset) a jump in ECD coordinates in the medial direction was found in 85% of cases. Possible significance of the findings for the insight into dynamic topography of the visual feature processing in the human brain is discussed.     

Trajectories of alpha rhythm dipoles shifting over the human brain cortex

Dynamic study of 3D localization of the equivalent current dipoles (ECD)--sources of the EEG alpha rhythm in the human brain was performed in seven subjects with closed eyes using a one-dipole model. An exact localization of ECDs was obtained by combination of EEG and MRI mapping that allowed tracing of ECD shifts over the cortex with 4 ms step. Our data confirmed localization of these ECDs mainly in the occipital cortex and revealed their successive shift over this area during generation of each alpha-wave. Typical trajectories of these shifts were revealed and quantitatively compared by the hierarchical cluster analysis. The data obtained directly proved periodical rhythmic alpha-wave spreading process in the human visual cortex and an external control of this process. The data are discussed in terms of the "scanning hypothesis" (Pitts W., McCulloch W.H. Bull. Math. Biophys. 1947. V. 9. P. 127) which predicted a certain functional meaning of the alpha activity for cortical processing of sensory information in the human brain.     

基于聚类分析方法的酒后人脑状态研究

目的:本文对酒精引起的人脑状态变化进行讨论。通过对客观记录的受试者摄入酒精事件的脑电图数据进行系统聚类分析,从而分析摄入酒精事件与21导联电极分类的关系,进而为有关人脑的其它研究提供实验和理论根据。方法:选取4名习惯用右手、健康的人进行实验,采用标准21个脑电极的10-20导联系统,获取受试者在安静闭眼和摄入一定量啤酒的2个事件的脑电图数据。然后进行数据分析。数据分析的方法是系统聚类分析方法。程序实现采用独立设计的脑电图分析工具箱和聚类分析程序。结果:对脑电图数据聚类分析后发现,未喝酒时脑电活动大致按前额部和中央、后头部、两侧得到3个聚类簇;摄入200毫升啤酒后,受试者P1和P2的大部分额部电极、中央部电极以及后头部电极聚类为一个簇,个别颞部、后头部电极聚类为一个簇,或单个电极独立为一簇,形成孤立点;摄入400毫升啤酒后,受试者P3和P4的大部分额极电极、额部电极、中央部电极以及后头部电极聚类为一个簇,个别额部、中央部、颞部单个电极独立为一簇,形成孤立点。结论:脑电活动对摄入酒精有显著反应。由于人在安静闭眼状态下,后头部记录到的α波较为显著,所以未喝酒时前后头部脑电信号相关性较弱,受试者前后头部的电极基本不在一个聚类簇中;摄入酒精后,受试者大部分额部、中央部和后头部电极聚类为一簇,即前后头部脑电信号的相关性增强,这说明在酒精的作用下,前头部α波增加,α波呈现扩大和增强的趋势。     

Polymorphism of aldehyde dehydrogenase and alcohol sensitivity

The metabolism of acetaldehyde has received considerable attention in the past years owing to its acute and chronic toxic effects in humans. Aldehyde dehydrogenase (ALDH) catalyzes the oxidation of acetaldehyde in liver and other organs. Two major isozymes of hepatic ALDH (ALDH I or E2 and ALDH II or E1), which differ in their structural and functional properties, have been characterized in humans. The ALDH I with a low Km for acetaldehyde is predominantly of mitochondrial origin and ALDH II which has a relatively higher Km is of cytosolic origin. An inherited deficiency of ALDH I isozyme has been found among Japanese and Chinese which is primarily responsible for producing acute alcohol sensitivity symptoms (flushing response) after drinking mild doses of alcohol. Biochemical, immunochemical and molecular genetics data indicate a structural mutation in the ALDH I isozyme gene responsible for the loss in catalytic activity. Population genetic studies indicate a wide prevalence of this ALDH polymorphism among individuals of Mongoloid race. Flushing response to alcohol shows familial resemblances and preliminary family data from Japan, China and Korea hint to an autosomal codominant inheritance for ALDH I isozyme deficiency. The ALDH polymorphism is apparently responsible for the low incidence of alcoholism in Japanese, Chinese and Koreans. Alcohol-induced sensitivity due to ALDH isozyme deficiency may act as an inhibitory factor against excessive alcohol drinking thereby imparting a protection against alcoholism.     

Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid

Nicotinic acid (niacin) is a B vitamin which is also a potent hypolipidemic agent. However, intense flushing occurs following ingestion of pharmacologic doses of niacin which greatly limits its usefulness in treating hyperlipidemias. Previous studies have demonstrated that niacin-induced flushing can be substantially attenuated by pre-treatment with cyclooxygenase inhibitors, suggesting that the vasodilation is mediated by a prostaglandin. However, the prostaglandin that presumably mediates the flush has not been conclusively determined. In this study we report the finding that ingestion of niacin evokes the release of markedly increased quantities of PGD2 in vivo in humans. PGD2 release was assessed by quantification of the PGD2 metabolite, 9 alpha, 11 beta-PGF2, in plasma by gas chromatography mass spectrometry. Following ingestion of 500 mg of niacin in three normal volunteers, intense flushing occurred and plasma levels of 9 alpha, 11 beta-PGF2 were found to increase dramatically by 800, 430, and 535-fold. Levels of 9 alpha, 11 beta-PGF2 reached a maximum between 12 and 45 min. after ingesting niacin and subsequently declined to near normal levels by 2-4 hours. Levels of 9 alpha, 11 beta-PGF2 in plasma correlated with the intensity and duration of flushing that occurred in the 3 volunteers. Release of PGD2 was not accompanied by a release of histamine which was assessed by quantification of plasma levels of the histamine metabolite, N tau-methylhistamine. This suggests that the origin of the PGD2 release is not the mast cell. Only a modest increase (approximately 2-fold) in the urinary excretion of the prostacyclin metabolite, 2,3-dinor-6-keto-PGF1 alpha, occurred following ingestion of niacin and no increase in the excretion of the major urinary metabolite of PGE2 was found. These results indicate that the major vasodilatory PG released following ingestion of niacin is PGD2. The fact that markedly increased quantities of PGD2 are released suggests that PGD2 is the mediator of niacin-induced vasodilation in humans.     

Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism.

The genes that encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1, which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, we genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. This can be accounted for by linkage disequlibrium between ADH3*1 and ADH2*2 ALDH2*2 homozygosity, regardless of the ADH2 genotypes, was fully protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (ORs 0.04-0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk associated with the ADH2*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH2*1/*2-ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that afforded by ALDH2*2.     

Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms

Ethanol is almost totally broken down by oxidative metabolism in vivo. Ethanol per se is considered to be neither carcinogenic, mutagenic nor genotoxic. However, during the metabolic conversion of ethanol to acetaldehyde and acetate, the organism is exposed to both ethanol and acetaldehyde and therefore ethanol is suspected to be co-carcinogenic. The genetic polymorphisms of alcohol dehydrogenase-2 (ADH1B) and acetaldehyde dehydrogenase-2 (ALDH2) influence the metabolism of alcohol. The ADH1B*1/*1 genotype encodes the low-activity form of ADH1B, and ALDH2*1/*2 and ALDH2*2/*2 genotype encode inactive ALDH2. The aim of this study was to test the hypothesis that polymorphisms of the ADH1B and ALDH2 genes are significantly associated with genotoxicity induced by alcohol drinking, measured using the cytokinesis-block micronucleus (CBMN) assay, an established biomarker of genome instability, in peripheral blood lymphocytes of 286 healthy Japanese men. There was a significant trend for the mean micronuclei (MN) frequency in habitual or moderate drinkers without a smoking habit to increase as the numbers of the *1 allele in ADH1B increased (P=0.039 or P=0.029) and the *2 allele in ALDH2 increased (P=0.019 or P=0.037). A logistic regression analysis showed that the number of subjects with MN frequency levels more than median value of MN (3.0) was significantly higher in the subjects with the ADH1B*1 allele as adjusted estimates (OR 2.08, 95% C.I. 1.24-3.48), when the OR for the subjects with the ADH1B*2/*2 genotype was defined as 1.00. The number of subjects with MN frequency levels more than median value of MN was also significantly higher in the subjects with the ALDH2*2 allele as adjusted estimates (OR 1.79, 95% C.I. 1.04-3.11), when the OR for the subjects with the ALDH2*1/*1 genotype was defined as 1.00. The results of this study have identified important novel associations between ADH1B/ALDH2 polymorphisms and genotoxicity in alcohol drinkers.     

Acute and chronic ethanol consumption differentially impact pathways limiting hepatic protein synthesis

This review identifies the various pathways responsible for modulating hepatic protein synthesis following acute and chronic alcohol intoxication and describes the mechanism(s) responsible for these changes. Alcohol intoxication induces a defect in global protein synthetic rates that is localized to impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S preinitiation complex [controlled by eukaryotic initiation factors 2 (eIF2) and 2B (eIF2B)] and the binding of mRNA to the 40S ribosome (controlled by the eIF4F complex). To date, alcohol-induced alterations in eIF2 and eIF2B content and activity are best investigated. Ethanol decreases eIF2B activity when ingested either acutely or chronically. The reduced eIF2B activity most likely is a consequence of twofold increased phosphorylation of the alpha-subunit of eIF2 on Ser(51) following acute intoxication. The increase in eIF2alpha phosphorylation after chronic alcohol consumption is the same as that induced by acute ethanol intoxication, and protein synthesis is not further reduced by long-term alcohol ingestion despite additional reduced expression of initiation factors and elongation factors. eIF2alpha phosphorylation alone appears sufficient to maximally inhibit hepatic protein synthesis. Indeed, pretreatment with Salubrinal, an inhibitor of eIF2alpha(P) phosphatase, before ethanol treatment does not further inhibit protein synthesis or increase eIF2alpha phosphorylation, suggesting that acute ethanol intoxication causes maximal eIF2alpha phosphorylation elevation and hepatic protein synthesis inhibition. Ethanol-induced inhibition of hepatic protein synthesis is not rapidly reversed by cessation of ethanol consumption. In conclusion, sustained eIF2alpha phosphorylation is a hallmark of excessive alcohol intake leading to inhibition of protein synthesis. Enhanced phosphorylation of eIF2alpha represents a unique response of liver to alcohol intoxication, because the ethanol-induced elevation of eIF2alpha(P) is not observed in skeletal muscle or heart.     

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

Background

Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study.

Methods

From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors.

Results

Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, P for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk.

Conclusions

We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.     

Formation of acetaldehyde-derived DNA adducts due to alcohol exposure

Epidemiological studies have identified chronic alcohol consumption as a significant risk factor for cancers of the upper aerodigestive tract, including the oral cavity, pharynx, larynx and esophagus, and for cancer of the liver. Ingested ethanol is mainly oxidized by the enzymes alcohol dehydrogenase (ADH), cytochrome P-450 2E1 (CYP2E1), and catalase to form acetaldehyde, which is subsequently oxidized by aldehyde dehydrogenase 2 (ALDH2) to produce acetate. Polymorphisms of the genes which encode enzymes for ethanol metabolism affect the ethanol/acetaldehyde oxidizing capacity. ADH1B*2 allele (ADH1B, one of the enzyme in ADH family) is commonly observed in Asian population, has much higher enzymatic activity than ADH1B*1 allele. Otherwise, approximately 40% of Japanese have single nucleotide polymorphisms (SNPs) of the ALDH2 gene. The ALDH2 *2 allele encodes a protein with an amino acid change from glutamate to lysine (derived from the ALDH2*1 allele) and devoid of enzymatic activity. Neither the homozygote (ALDH2*2/*2) nor heterozygote (ALDH2*1/*2) is able to metabolize acetaldehyde promptly. Acetaldehyde is a genotoxic compound that reacts with DNA to form primarily a Schiff base N²-ethylidene-2′-deoxyguanosine (N²-ethylidene-dG) adduct, which may be converted by reducing agents to N²-ethyl-2′-deoxyguanosine (N²-ethyl-dG) in vivo, and strongly blocked translesion DNA synthesis. Several studies have demonstrated a relationship between ALDH2 genotypes and the development of certain types of cancer. On the other hand, the drinking of alcohol induces the expression of CYP2E1, resulting in an increase in reactive oxygen species (ROS) and oxidative DNA damage. This review covers the combined effects of alcohol and ALDH2 polymorphisms on cancer risk. Studies show that ALDH2*1/*2 heterozygotes who habitually consume alcohol have higher rates of cancer than ALDH2*1/*1 homozygotes. Moreover, they support that chronic alcohol consumption contributes to formation of various DNA adducts. Although some DNA adducts formation is demonstrated to be an initiation step of carcinogenesis, it is still unclear that whether these alcohol-related DNA adducts are true factors or initiators of cancer. Future studies are needed to better characterize and to validate the roles of these DNA adducts in human study.     

洛阳市汉族群体ADH2和ALDH2的基因多态性研究

为研究洛阳市汉族群体ADH2和ALDH2基因的多态性分布,应用聚合酶链反应-扩增片段长度多态性（PCR-APLP）分析法,对ADH2基因外显子3和ALDH2基因外显子12的特定片段同时进行特异性扩增,用非变性的聚丙烯酰胺垂直凝胶电泳和DNA银染方法判定基因型。ADH2*1和ADH2*2等位基因频率分别为42.86%和57.14%,ADH2*1/*1、*1/*2和*2/*2的基因型频率分别为22.86%、40.00%和37.14%;ALDH2*1和ALDH2*2的等位基因频率分别为85.24%和14.76%,ALDH2*1/*1、*1/*2和*2/*2的基因型频率分别为71.43%、27.62%和0.95%。洛阳市汉族群体ADH2和ALDH2的等位基因频率和基因型频率不同于台湾人和上海人,ALDH2*1/*1基因型频率明显高于上海人和台湾人的。因而,洛阳市居民对酒精的耐受性比上海人和台湾人强。 Studies of Genetic Polymorphisms of ADH2 and ALDH2 among the Han Population in Luoyang China ZHANG Zhu-mei1,LIU Cha-zhen1,BIAN Jian-chao1,TANG Bo-ming2,JIANG Feng1,WANG Qi-jun2,WANG Qi-min2,ZHU Xin2,SHEN Fu-min1 1.Department of Epidemiology,Public Health School of Fudan University,Shanghai 200032,China; 2.Section Office of Epidemiology,Luoyang Hygiene and Anti-epidemic Center,Luoyang 471000,China Abstract:In order to investigate genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang City,portions of exon 3 of ADH2 and exon 12 of ALDH gene were amplified by using polymerase chain reaction.The amplified products were electrophoresed on 10% undenatured vertical polyacrylamide gels and stained with argentine.Frequencies of ADH2*1 and ADH2*2 alleles are 42.86% and 57.14%.Frequencies of three genotypes of ADH2 are 22.86%、40.00% and 37.14%,respectively.Frequencies of ALDH2*1 and ALDH2*2 alleles are 85.24% and 14.76%.Genotype frequencies of ALDH2 loci are 71.43%、27.62% and 0.95%,respectively.Genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang City are different from those among Taiwanese and Shanghainese.Frequency of ALDH2*1/*1 in Luoyang people is higher than those in Shanghai and Taiwan.Therefore,there is a higher resistance to alcohol drinking in the Han population in Luoyang. Key words：polymerase chain reaction-amplified products length polymorphism; alcohol dehydrogenase 2; aldehyde dehydrogenase 2; genetic     

Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.     

Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.

The liver enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. An allele encoding an inactive form of the mitochondrial ALDH2 is known to reduce the likelihood of alcoholism in Japanese. We hypothesized that the polymorphisms of both ALDH and ADH modify the predisposition to development of alcoholism. Therefore, we determined the genotypes of the ADH2, ADH3, and ALDH2 loci of alcoholic and nonalcoholic Chinese men living in Taiwan, using leukocyte DNA amplified by the PCR and allele-specific oligonucleotides. The alcoholics had significantly lower frequencies of the ADH2*2, ADH3*1, and ALDH2*2 alleles than did the nonalcoholics, suggesting that genetic variation in both ADH and ALDH, by modulating the rate of metabolism of ethanol and acetaldehyde, influences drinking behavior and the risk of developing alcoholism.     

Polymorphisms of alcohol metabolizing enzyme and cytochrome P4502E1 genes in mongolian population

Although the genetic polymorphism of the alcohol-metabolizing enzymes was extensively studied at the molecular level by many investigators, the genetic polymorphism studies for ethanolmetabolizing enzymes in Mongolians are very rare. The present study was therefore performed to determine the genetic distribution of various forms of alcohol-metabolizing enzymes such as alcohol dehydrogenase 2 (ADH2, currently accepted nomenclature ADH1B), ADH3 (ADH1C), aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1) in 300 healthy Mongolian males. Genetic polymorphisms were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. The allele frequencies ofADH2 *1 andADH2 *2 were 0.24 and 0.76;ADH3 *1 andADH3 *2 were 0.92 and 0.08;ALDH2 *1 andALDH2 *2 were 0.96 and 0.04; andCYP2E1 *C andCYP2E1 *D were 0.15 and 0.85, respectively. Compared to the results reported by other investigators, the allele frequencies ofALDH2 *2 andCYP2E1 *C among Mongolian subjects were much lower than among East Asians (Korean, Japanese, and/or Han-Chinese), while those ofADH2 andADH3 were more similar. Interestingly, this study shows that the ineffectiveALDH2 gene (ALDH2*2 allele) among Mongolians is not as common as among East Asians.     

Dipole models of alpha-rhythm generators

Different hypothesis of the alpha rhythm origin were tested by dipole simulation of the alpha rhythm sources. EEG was recorded during driving photic stimulation in order to increase the signal-to-noise ratio. Models with fixed and moving dipoles were analyzed. Dipole sources were compared with magnetic resonance imaging (MRI) scans to find the exact location of oscillations in brain anatomical structures. A two-level multiple dipole model was found to fit the EEG most adequately. The first level was represented by two oscillators localized in the thalamic reticular nuclei, and the second level is associated with two modality-specific oscillators localized in the respective cortical areas.     

Strong protective effect of the aldehyde dehydrogenase gene (<Emphasis Type="Italic">ALDH2</Emphasis>) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians

Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case–control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3 × 10⁻⁵⁶ and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys–lys + lys–glu vs. glu–glu) also showed strong association with P value of 1 × 10⁻⁴⁴ and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2 × 10⁻²⁸ for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians.     

Dipole tracing of visual evoked potentials in human brain

3D tracing of equivalent current dipoles (ECDs) of averaged human visual evoked potentials (VEP) by their distribution across a 34-electrode array was obtained under short presentation of pattern-onset stimuli (sets of 45 horizontal, vertical bars or crosses). Using a 2-dipole spherical three-layer model, we dynamically (step of 1 ms) localized dipoles in four healthy subjects. Dipole locations were matched to anatomical brain regions visualized in structural MRI. Best-fitting source parameters were superimposed on MR images of each subject to identify the anatomical structures giving rise to the surface patterns. It was found that during 50-300 ms following the onset of the stimuli, the ECDs in all subjects were localized in the occipital cortex and demonstrated reliable systematic shift in localization. Two local (1-2 cm3) zones of the preferable dipole attendance were found at 5-6 cm behind zero line: the first one was localized near the midline of the brain, whereas the other zone was situated in the right hemisphere at a distance of 6-7 cm from the first zone. Their localization and strength of activation were reliably different for crosses and lines and changed during VEP generation. Zones of relatively rare dipole attendance were found also. The data are discussed in relation to localization of initial and endpoint of ECDs trajectories, as well as with sensitivity of the visual cortex to line crossing and branching.     

Microglial AGE-Albumin Is Critical in Promoting Alcohol-Induced Neurodegeneration in Rats and Humans

Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration.