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Aims To identify determinants of hyperuricemia in alcoholics. Methods The serum uric acid (UA) levels of 1759 Japanese alcoholic men (≥40 years) were measured on their first visit or within 3 days after admission; ADH1B and ALDH2 genotyping on blood DNA samples were performed. Dipstick urinalyses for ketonuria and serum UA measurements were simultaneously performed for 621 men on their first visit. Results Serum UA levels of >416 μmol/l (7.0 mg/dl) and ≥535 μmol/l (9.0 mg/dl) were observed in 30.4 and 7.8% of the subjects, respectively. Ketonuria was positive in 35.9% of the subjects, and a multivariate analysis revealed that the ketosis level was positively associated with the UA level. The presence of the ADH1B*2 allele and the ALDH2\*1/\*1 genotype increased the odds ratio (OR; 95% confidence interval) among subjects with a high UA level of >416 μmol/l (vs. ≤416 μmol/l; 2.04 [1.58–2.65] and 1.48 [1.09–2.01], respectively) and those with a high UA level of ≥535 μmol/l (vs. ≤416 μmol/l; 2.29 [1.42–3.71] and 3.03 [1.51–6.08], respectively). The ADH1B*2 plus ALDH2\*1/\*1 combination yielded the highest ORs (2.86 [1.61–5.10] and 6.21 [1.49–25.88] for a UA level of >416 μmol/l and ≥535 μmol/l, respectively), compared with the ADH1B\*1/\*1 plus ALDH2\*1/\*2 combination. The presence of diabetes and the consumption of Japanese sake rather than beer were negatively associated with the UA levels. Conclusions The faster metabolism of ethanol and acetaldehyde by the ADH1B*2 allele and ALDH2\*1/\*1 genotype and higher ketosis levels were associated with higher UA levels in alcoholics, while diabetes and the consumption of sake were negative determinants.

Alcoholics have a high prevalence of nicotine dependence, and smoking is a major contributor to their high mortality. Three weeks after admission to an addiction center in Japan, 193 alcoholic men who were participating in an 11-week concurrent inpatient smoking cessation and alcohol abstinence programs filled out an anonymous self-report questionnaire regarding smoking and drinking, and 6 months after the completion of the programs, 83 patients were asked to respond to a mailed questionnaire about their smoking and drinking status. Of the 193 subjects, 73.3% were current smokers, but many were highly motivated in regard to both smoking cessation and alcohol abstinence. The subjects' scores on a 0 to 10 point scale for rating motivation and confidence in regard to smoking cessation and smoking urge were significantly correlated with each other and with their scores for motivation and confidence in regard to alcohol abstinence and drinking urge. Three weeks after admission, varenicline treatment was well-tolerated, and the varenicline group had a high rate of smoking cessation than the smoker group not treated with varenicline (67.7% vs. 44.6%, p = 0.012). Forty-six (55.4%) of the 83 subjects who were mailed the questionnaire responded, and the drinking category was 'totally abstinent' in 35 subjects (42.2%), and 'mostly abstinent' in another 4 subjects (4.8%). Seventeen (20.5%) of the 83 subjects were non-smokers before treatment, but after treatment, 23 (50.0%) of the 46 responders and 20 (51.3%) of the 'totally or mostly abstinent' 39 responders were total or almost non-smokers. The response rate of 'totally or mostly abstinent' was higher among the 17 non-smokers before treatment than among the 66 smokers before treatment (70.6% vs. 40.9%, p = 0.033), and the age-adjusted odds ratio (95% confidence interval) for the response of 'totally or mostly abstinent' was 3.30 (1.03-10.56) for the non-smokers before treatment (vs. the smokers before treatment). In conclusion, smoking status had a great impact on the drinking status of treatment-seeking alcoholic men, and smoking cessation should be recommended to smoking alcoholics.

The purpose of this article is to outline alcohol consumption patterns and related problems, alcohol control policy and prevention programmes in Japan, which are not well-known in other countries. In Japan, per capita alcohol consumption is no longer increasing and has even started to decrease. At the same time, diversification of drinking populations has made a rapid progress. For the last several decades, alcohol consumption in non-traditional drinking populations, such as women and young people, has been on a steep rise. Consequently, in addition to traditional drinking problems observed among adult males, the magnitude of problems among these non-traditional populations has expanded. Alcohol policy and prevention programmes, however, have not developed to adequately control these problems. Availability of alcoholic beverages, including to underage populations, remains very high. Legislation related to alcohol control has not been well enforced, with the exception of the Road Traffic Law. Tax systems on alcoholic beverages are not relevant to the suppression of alcohol consumption. Moreover, there are virtually no restrictions on advertising or sponsorship and no provisions concerning an alcohol-free environment. Prevention programmes and activities to reduce harm from drinking have been carried out, especially for underage drinking, but they are insufficient to tackle the existing problems. Comprehensive discussions on alcohol policy and implementation of effective prevention programmes with participation of all sectors concerned are necessary, in parallel with actions taken by the WHO and other organisations.

Alcohol dependence is a complex disorder with a well documented highly hereditary nature. This article reviews the recent advances in our understanding of the direct and indirect genetic influences on alcohol use and dependence.Recent findings can be summarized as follows: (a) twin studies have defined and estimated the risks of general and specific alcohol-related vulnerabilities. (b) Linkage studies have provided largely inconsistent findings, though several chromosomal regions have been implicated. (c) Quantitative trait loci analyses in animals have identified that the Mpdz gene predisposes to alcohol dependence and withdrawal. (d) Examination of family-based samples has identified several genes including GABRA2 and CHRM2 thought to be associated with alcohol dependence.Despite great advances in understanding of genetic vulnerability in alcohol use disorders, only two gene complexes, ADH and ALDH2, have been identified as having defined effects on alcohol use and liability to dependence in humans. New genes associated with increased risks for the disorder will certainly be added to this list in the near future. Neurobiological analyses of the effects of these genes will surely contribute to further understanding of the cause of alcohol dependence and the interindividual differences in risks.

Eating disorders (EDs) have a highly heterogeneous etiology and multiple genetic factors might contribute to their pathogenesis. Ghrelin, a novel growth hormone-releasing peptide, enhances appetite and increases food intake, and human ghrelin plasma levels are inversely correlated with body mass index. In the present study, we examined the 171T/C polymorphism of the ghrelin receptor (growth hormone secretagogue receptor, GHSR) gene in patients diagnosed with EDs, because the subjects having ghrelin gene polymorphism (Leu72Met) was not detected in a Japanese population, previously. In addition, beta3 adrenergic receptor gene polymorphism (Try64Arg) and cholecystokinin (CCK)-A receptor (R) gene polymorphism (-81A/G, -128G/T), which are both associated with obesity, were investigated. The subjects consisted of 228 Japanese patients with EDs [96 anorexia nervosa (AN), 116 bulimia nervosa (BN) and 16 not otherwise specified (NOS)]. The age- and gender-matched control group consisted of 284 unrelated Japanese subjects. The frequency of the CC type of the GHSR gene was significantly higher in BN subjects than in control subjects (chi(2) = 4.47, p = 0.035, odds ratio = 2.05, Bonferroni correction: p = 0.070), while the frequency in AN subjects was not different from that in controls. The distribution of neither beta3 adrenergic receptor gene nor CCK-AR polymorphism differed between EDs and control subjects. Therefore, the CC type of GHSR gene polymorphism (171T/C) is a risk factor for BN, but not for AN.

Esophageal melanosis is often observed in alcoholic Japanese men, in whom the prevalence of squamous cell dysplasia and carcinoma (SCC) in the upper aerodigestive tract are high. This study evaluated the associations of esophageal melanosis with these neoplasms, and the factors contributing to the development of esophageal melanosis in this population. Endoscopic screening was combined with esophageal iodine staining in 1535 alcoholic Japanese men (aged 40–79 years), of whom 1007 underwent aldehyde dehydrogenase-2 (ALDH2) genotyping. Fifty patients (3.3%) were diagnosed with esophageal melanosis, which had a higher incidence in those with noncancerous distinct iodine-unstained lesions (DIULs; 16/268; 6.0%), esophageal SCC (9/66; 13.6%), and oropharyngolaryngeal SCC (4/19; 21.1%) than in cancer- and DIUL-free controls (24/1182; 2.0%). The presence of esophageal melanosis was associated with higher risks for noncancerous DIULs, esophageal SCC, and oropharyngolaryngeal SCC (odds ratios, 2.81, 6.54, and 14.77, respectively). Men with the inactive ALDH2*1/2*2 genotype had a higher risk for esophageal melanosis (2.66-fold), as well as for DIULs and SCCs. The presence of esophageal melanosis in alcoholic Japanese men could indicate a high risk for DIULs and SCCs in the upper aerodigestive tract. The high incidence of esophageal melanosis may be partially linked to high acetaldehyde exposure, a consequence of drinking alcohol in persons with inactive ALDH2.

Background: Cerebrovascular disease is common in Alzheimer’s disease (AD). Elevated plasma homocysteine (pHcy) levels are reported to be associated with an increased risk of poor cognition and dementia. Objective: To determine whether high pHcy levels are associated with an increased risk of coexisting silent brain infarctions (SBIs) in AD. Methods: Study population comprising 143 outpatients with clinical diagnosis of probable AD (73.3 ± 7.0 years) were classified into 2 groups according to the presence or absence of SBIs on magnetic resonance imaging. Results: SBIs were noted in 32.9% (47/143) of the AD patients. The pHcy levels in the AD with SBIs (14.0 ± 4.5 µmol/l) were significant ly elevated compared with the AD without SBIs (11.7 ± 4.7 µmol/l, p = 0.007). After adjusting for age and gender, high pHcy (>12.4 µmol/l), but not hypertension, was associated with an increased risk of developing SBIs in AD (OR = 4.61, 95% CI = 1.74–12.2, p = 0.002). However, age at onset, cognitive function, cerebrospinal tau or amyloid β-peptide1–42 levels were not significantly correlated with pHcy levels in AD. Conclusion: SBIs commonly coexist with AD, and may be a unique vascular condition in which homocysteine plays an important role. Homocysteine-lowering therapy rather than antihypertensive medication might be an appropriate strategy to prevent stroke associated with AD.

Objective: Brain-derived neurotrophic factor (BDNF) influences dopamine and serotonin neurotransmitters that are heavily linked to addiction. A quantitative trait loci study indicated that genes localized to 11p13, where the BDNF gene is mapped (11p13–15), increase the risk for severe alcohol withdrawal. Moreover, a recent study using a pooled-sample microarray suggested that the BDNF gene locus was included in the loci that were shown to be associated with drug abuse. These lines of evidence suggested that BDNF might play some role in the development of or vulnerability to alcoholism and/or clinical characteristics of alcoholic individuals. Methods: The alcoholic subjects consisted of 377 male Japanese patients. A structured interview was used to obtain social background, drinking history, history of violence while intoxicated, history of alcohol withdrawal, and family history of alcoholism. The control group consisted of 336 nonalcoholic male subjects. Genotyping of the G196A polymorphism of the BDNF gene was done by polymerase chain reaction (PCR)–restriction fragment length polymorphism method. Results: Genotype and allele distributions of the BDNF gene polymorphism did not differ significantly between alcoholic and control subjects. However, comparing clinical characteristics across G196A genotypes, we found that alcoholic subjects with violent tendencies and a history of delirium tremens had a significantly higher frequency of AA genotypes and A allele frequencies than those without them. Moreover, alcoholic subjects with the A allele had earlier onset of the disease than those without it. Conclusions: These results indicate that BDNF gene polymorphism might modify phenotypes of alcoholism.

Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimer’s disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP) – i.e., C270T and G196A – in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, p = 0.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, p = 0.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, p = 0.035) or positive for AD family history (2.8 vs. 7.1%, p = 0.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.

Quantitative analysis of plasma phosphatidylcholine hydroperoxide (PCOOH) is an important step in evaluating the biochemical processes leading to oxidative injury. However, secondary products of lipid peroxidation are now used as indices. One hundred nine alcoholic patients, aged 22-81 years (mean +/- SEM, 52.0 +/- 1.3 years), and 21 healthy volunteers, aged 41-79 years (51.2 +/- 2.2 years), participated in this study. Plasma PCOOH was measured by HPLC with chemiluminescence detection. Plasma PCOOH concentration was significantly higher in alcoholic patients (46.1 +/- 4.1 pmol/ml) than in controls (15.6 +/- 1.8 pmol/ml). It was significantly higher in patients with blood alcohol (88.0 +/- 10.5 pmol/ml) than in those without alcohol (32.6 +/- 3.1 pmol/ml). The patients with high levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (gamma-GTP), and triglyceride (TG) showed significantly higher PCOOH concentrations than did patients with normal levels. The PCOOH level was positively correlated with levels of gamma-GTP, HDL, blood alcohol concentration, and TG. Plasma PCOOH levels in 29 alcoholic patients after a 6 week abstinence were decreased significantly (22.8 +/- 11.1 pmol/ml), which was associated with improvement on liver function tests. This is the first measurement of plasma PCOOH in alcoholic patients. These results suggest the involvement of lipid peroxidation in alcohol-induced liver damage and confirm that the PCOOH plasma concentration is a new marker of alcohol consumption as well as oxidative stress in alcoholic patients.

Several lines of evidence support possible serotonin transporter (5-HTT) involvement in modulating eating disorders (ED). The 5-HTT gene is a good candidate for genetic studies on the course of ED, despite controversy concerning the association between polymorphism in the 5-HTT gene promoter region (5-HTTLPR) and ED. Comparison of 5-HTTLPR distribution in 195 female Japanese ED patients and 290 age- and gender-matched control subjects facilitated examining the association between the course of the disease and 5-HTTLPR in 138 of 195 ED subjects. The 5-HTTLPR S allele frequency was significantly higher in subjects with anorexia nervosa (AN) than in control subjects. Among subjects observed ≥3 years, the S allele frequency was significantly higher in those diagnosed as AN at ED onset than in those diagnosed as AN in this study. The 5-HTTLPR S allele might play some role in the development of AN with persistent disease. © 2004 Wiley-Liss, Inc.

Sigma1 receptors are involved in the pathogenesis of drug abuse. Two polymorphisms (GC-241-240TT and Gln2Pro) in the sigma1 receptor gene (SIGMAR1) have been identified. To investigate the role of SIGMAR1 in conveying susceptibility to alcoholism, we performed a functional analysis of polymorphisms in the SIGMAR1 and a case-control study.We initially screened for polymorphisms in the 5'-upstream region. The effects of the polymorphisms on transcriptional activity were determined using a gene reporter assay. The distribution of SIGMAR1 polymorphisms was analyzed in 307 alcoholic and 302 control subjects.A novel T-485A polymorphism was identified. The transcriptional activity of the A-485 allele and the TT-241-240 allele was significantly reduced compared with that of the T-485 allele and the GC-241-240 allele. The frequencies of the A-485 allele (chi2=5.575, df=1, p=.0205) and the TT-241-240/Pro2 haplotype (chi2=21.464, df=1, p.0001) were significantly higher in control subjects compared with alcoholic subjects. The T-485A and the GC-241-240TT may be functional polymorphisms, and the A-485 allele and TT-241-240/Pro2 haplotype are possible protective factors for the development of alcoholism.

Nine alcoholic patients with central pontine myelinolysis (CPM),who showed a favorable prognosis, are reported. The majority of them had taken part in binge drinking and had a subsequent consciousness disturbance for 18.1+/-10.9 (mean+/-SD) days. None of the patients had had acute correction of hyponatremia. Truncal ataxia and gait instability were present in most of the patients after recovery from the disturbance of consciousness. Most of them eventually gained independence, and magnetic resonance imaging showed that their pontine lesions tended to shrink. Electrophysiological studies detected prolonged latency between the I and III waves in auditory brainstem responses and between N11 and P13/14 onsets in the somatosensory evoked potentials. These clinical, radiological and electrophysiological findings should be of use in diagnosing CPM.

Background: Cholecystokinin (CCK) plays an important role in the function of the central nervous system by interacting with dopamine and other neurotransmitters. We previously reported genetic variations in the promoter and coding regions of the CCKA receptor (CCKAR), CCKBR, and CCK genes and a possible association between polymorphisms of the CCKAR gene and alcoholism. In this study, association analyses were re-examined between the polymorphisms of the promoter region of the CCKAR gene and patients with alcohol withdrawal symptoms, in addition to patients with alcoholic liver injury. Methods: A total of 131 Japanese male patients with alcohol withdrawal symptoms, 70 Japanese patients with alcoholic liver injury, and 98 age-matched Japanese male controls (nonhabitual drinkers) were examined using polymerase chain reaction-based single strand conformational polymorphism and sequencing analyses. Results: Significant differences between patients with hallucination and controls were found in the allele frequencies at the -388 and -85 loci of the CCKAR gene (p = 0.0095, p = 0.0087, respectively), but these differences were not significant after Bonferroni correction for multiple testing. In contrast, the frequency of the homozygous genotype -85CC was significantly higher in hallucination-positive patients than in controls (p = 0.0031) and in patients with hallucination accompanying delirium tremens than in controls (p = 0.0022), and these differences were significant after Bonferroni correction. Conclusions: The data from the case control suggest that polymorphisms of the promoter region of the CCKAR gene do not play a major role in the pathogenesis of alcohol withdrawal symptoms or alcoholic liver injury. However, a significant association was found between polymorphism at the -85 locus of the CCKAR gene and patients with hallucination, and especially patients with hallucination accompanying delirium tremens.

The level of response to alcohol, which reflects individual differences in sensitivity to the pharmacologic effects of alcohol, is considered to be an important endophenotype of alcohol use disorder (AUD). By comparing monozygotic and dizygotic twins, the heritability of the level of response to alcohol has been estimated to be 60%. Many genes have been implicated as potential contributors toward heavy drinking, alcohol-related problems, and AUD through a low level of response to alcohol, each with a small effect. Identified are genes for gamma-aminobutyric acid (GABA) receptors, serotonin transporter, opioid receptor, and nicotinic acetylcholine receptor, but the most well-characterized genes that have a strong impact on the level of response to alcohol are those for alcohol-metabolizing enzymes. Although two genetic variations in alcohol and aldehyde dehydrogenases, which have been the most intensively studied, exist almost exclusively in Asian populations, studies on the effect of genetic variations in alcohol-metabolizing enzymes on the response to alcohol are gradually expanding in non-Asian populations. In this chapter, we focus on genetic studies in humans. After analyzing the overall influence of genetic factors on the response to alcohol, we explore individual genes that may influence the response to alcohol. Lastly, we review studies examining the effects of genetic variations in alcohol-metabolizing enzymes on the level of response to alcohol.

BACKGROUND: Alcohol is well established as a risk factor for cancer development in many organ sites. To assess the reliability and validity of the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) for detecting alcohol use disorders or risky drinking in Japanese adults the present study was conducted. MATERIALS AND METHODS: A test-retest method was applied with a 2-week interval with 113 health care employees. The ??coefficient, Cronbach's coefficient alpha, Spearman's correlation coefficient, and intraclass correlation coefficient (ICC) were determined and the validity of the AUDIT-C was analyzed using the data from a nationwide survey on adult alcohol use conducted in 2008 (n=4,123). RESULTS: The reliability of the AUDIT-C score was high (??coefficient=0.63, Cronbach's alpha=0.98, correlation coefficient=0.95, and ICC=0.95). According to the likelihood ratio and Youden index, appropriate cutoffs for the AUDIT-C were ≥5points in men and ≥4 points in women. The sensitivity and specificity of these cutoffs for identifying ≥8 points on the AUDIT were 0.88 and 0.80, respectively, for men (positive likelihood ratio [LR+]=4.5) and 0.96 and 0.87, respectively, for women (LR+=7.7). The sensitivity and specificity of the cutoffs for identifying ≥12 points on the AUDIT were 0.90 and 0.84, respectively, for men (LR+=5.8) and 0.93 and 0.94, respectively, for women (LR+=15.8). The sensitivity and specificity of the cutoffs for identifying ≥16 points on the AUDIT were 0.93 and 0.80, respectively, for men (LR+=4.7) and 0.92 and 0.98, respectively, for women (LR+=55.6). With higher scores on the AUDIT, the specificity decreased and false-positives increased. The appropriate cutoffs for identifying risky drinking were the same for both genders. CONCLUSIONS: The reliability and validity of the AUDIT-C are high, indicating that it is useful for identifying alcohol use disorders or risky drinking among the general population in Japan, a group at high risk of cancer development. Language: en

Aims: This study evaluated the acceptance of controlled drinking (CD) goals among physicians specializing in the treatment of alcohol dependence (AD) in Japan. Methods: A mailed questionnaire survey was sent to physician members of the Japanese Society of Alcohol-Related Problems ( n = 232) who were specialists in the treatment of AD in Japan. The evaluated items included the acceptance of CD goals, the definition of CD, the reasons for accepting or rejecting CD and the patient factors used to make treatment-goal decisions. Results: CD as an interim goal on the way toward abstinence was accepted by about two-thirds of the specialists, while CD as a final goal was accepted by about one-third of specialists. Specialists supported harm-free drinking and a satisfactory quality of life, rather than alcohol consumption limits, as the definition of CD. Of note, a significantly higher percentage of specialists who rejected CD, compared with those who accepted CD, supported the disease model of AD as grounds for their decision. Specialists who accepted CD relied mostly on factors such as the severity of dependence, attitude toward CD and abstinence, and the level of psychological dependence and social stability, when making treatment-goal decisions. Conclusion: CD was accepted as an interim goal by two-thirds and as a final goal by one-third of Japanese physician specialists. Despite differences in drinking cultures and treatment circumstances, great similarities were found between this study and those conducted in Europe and North America with regard to the reasoning of treatment providers and the use of patient characteristics to make treatment-goal decisions.

Excessive alcohol use is associated with health problems for the elderly in combination with their chronic conditions. One such complication, alcohol-related dementia (ARD) is brought about by direct or indirect ethanol intoxication, and coexisting nutritional deficiency, liver disease, cerebrovascular disease and traumatic brain injury. The elderly people with ARD have been underestimated and underdiagnosed. In these older alcoholics, atrophic changes, lacunar infarcts and deep white matter lesions of the brain are evident and are associated not only with their cognitive decline, but also with their frailty, leading to high morbidity and mortality ratio. Although lifelong abstinence can recover patients with ARD to temporally lull, aging, the severity of alcohol dependence, and the concomitant nutritional, physical and environmental factors can all impact negatively their outcome. Therefore, a comprehensive approach to lifestyle factors is recommended so that they can minimize preventable risks and maintain health status. Nursing home placement may be an appropriate treatment option for some refractory, long-term patients with ARD.

The level of response to alcohol, which reflects individual differences in sensitivity to the pharmacologic effects of alcohol, is considered to be an important endophenotype of alcohol use disorder (AUD). By comparing monozygotic and dizygotic twins, the heritability of the level of response to alcohol has been estimated to be 60%. Many genes have been implicated as potential contributors toward heavy drinking, alcohol-related problems, and AUD through a low level of response to alcohol, each with a small effect. Identified are genes for gamma-aminobutyric acid (GABA) receptors, serotonin transporter, opioid receptor, and nicotinic acetylcholine receptor, but the most well-characterized genes that have a strong impact on the level of response to alcohol are those for alcohol-metabolizing enzymes. Although two genetic variations in alcohol and aldehyde dehydrogenases, which have been the most intensively studied, exist almost exclusively in Asian populations, studies on the effect of genetic variations in alcohol-metabolizing enzymes on the response to alcohol are gradually expanding in non-Asian populations. In this chapter, we focus on genetic studies in humans. After analyzing the overall influence of genetic factors on the response to alcohol, we explore individual genes that may influence the response to alcohol. Lastly, we review studies examining the effects of genetic variations in alcohol-metabolizing enzymes on the level of response to alcohol.

Background: Evidence from family and twin studies suggests a genetic contribution to the etiology of eating disorders (EDs). Recently, researchers have reported genetic associations between the MspI polymorphism (-1438A/G) of the promoter region of the 5HT2A receptor gene and EDs; however, reports of evidence against these findings make the association controversial. Methods: The authors examined the prevalence of the -1438A/G polymorphism of the 5HT2A receptor gene among 182 Japanese patients with EDs and 374 normal control subjects. Interactions of the association of this polymorphism with subtypes of anorexia nervosa (AN), bulimia nervosa (BN), and various clinical characteristics were also assessed. Results: In contrast to previous studies reporting elevated A allele frequencies in patients with AN, the G allele had a significantly higher frequency in patients with BN but not in patients with AN, than in control subjects. Examination of the interactions revealed that the presence of the binge eating and/or purging behavior and comorbid borderline personality disorder (BPD) tended to be associated with increased frequency of the G allele. Conclusions: Though preliminary, these results can be interpreted as suggesting that the G allele of the 5HT2A receptor gene -1438A/G polymorphism may be associated with pathological features that EDs and BPD have in common, especially disinhibition in eating behavior and personality trait.

Among many candidate genes for the genetically heterogeneous Alzheimer’s disease (AD), only apolipoprotein E (ApoE) has been confirmed. Another candidate is the dihydrolipoyl succinyltransferase (DLST) gene, one of three components of thiamine-dependent mitochondrial α-ketoglutarate dehydrogenase complex (KGDHC), because KGDHC activity is reported reduced in AD patients. Also characterized by reduced KGDHC activity is another neuropsychiatric disease, Wernicke-Korsakoff syndrome (WKS), which results from thiamine deficiency. Examination of specific DLST gene polymorphism in 247 Japanese AD patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and AD.

Previous studies have indicated associations between a functional biallelic repetitive element in the 5' regulatory region of the serotonin transporter gene (5-HTTLPR) and alcoholic subjects who have either dissocial personality disorder or severe withdrawal symptoms. To replicate these associations under the hypothesis that genetic polymorphism plays some role in the susceptibility or vulnerability of some subgroup of alcoholics, the associations between alcoholic subjects' genetic polymorphisms, clinical characteristics, and personality traits were examined. This case control study comprised 697 alcoholic and 270 control subjects. A questionnaire focusing on family and social background, history of drinking and alcohol withdrawal, DSM-III-R criteria for the evaluation of psychiatric conditions, and Feighner's criteria for the lifetime diagnosis and assessment of overall severity of alcoholism was administered to 373 alcoholic subjects. Temperament and Character Inventory (TCI) and Sensation Seeking Scale (SSS) were used to evaluate the other 324 alcoholics. The frequency of the homozygous short allele was significantly higher in alcoholic binge drinkers than in nonbinge drinking alcoholics. There were no significant differences in the frequencies of either the 5-HTTLPR genotype or the short vs. long allele in alcoholic and control subjects. The alcoholics' 5-HTTLPR genotype and allele frequencies did not differ significantly by the severity of withdrawal symptoms or by the number of positive Feighner's diagnostic criteria. Although these results indicate an association between 5-HTTLPR and a subgroup of alcoholics characterized by binge drinking, the authors found no differences in SSS and TCI subscale scores for alcoholics with different 5-HTTLPR genotypes. Future studies of the association in other alcoholic population should take into account personality traits.

Two genetic markers of the plasma protein alpha2-macroglobulin, a 5 bp deletion/insertion at the 5' splice site of exon 18 (A2MI) and the GTC/ATC (VaIIO00IIe) in exon 24 (A2M2), may have roles in the development of Alzheimer's disease (AD). Genotyping and linkage analysis of these markers in 426 Japanese sporadic AD patients, 85 autopsy-confirmed Caucasian AD cases, and, as controls, 382 Japanese and 65 Caucasians who were cognitively normal and 140 Japanese Parkinson's disease patients showed racial diversity in the frequencies and relationship of the two markers. Comparison of genotype and allele frequencies, stratification of the samples by the presence of the apolipoprotein E epsilon4 allele, and logistic regression analysis revealed no association of these markers with AD in either racial group.

Background: Previous studies have suggested a genetic predisposition to the development of Wernicke-Korsakoff syndrome (WKS), a neuropsychiatric syndrome commonly associated with alcoholism; however, little is known about this genetic risk factor. Methods: To test the hypothesis that altered alcohol or aldehyde regulation is related to the development of WKS, the genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-2 (ADH2) were examined in 47 alcoholic subjects with WKS and compared with those of 342 alcoholic subjects without any WKS symptoms and 175 nonalcoholic controls. Results: Although the frequencies of the ALDH2 genotypes and alleles did not differ significantly between alcoholic subjects with WKS and alcoholics without WKS, the ADH2 * 1/2 * 1 genotype and ADH2 * 1 allele were significantly increased in WKS. Conclusions: These findings suggest that the ADH2 * 1/2 * 1 genotype is a risk factor for the development of WKS in alcoholic patients.

Apolipoprotein E (APOE) is a plasma protein that plays an important role in cholesterol transport. The protein exists in 3 different isoforms coded for by alleles e2, e3 and e4. Recent studies have shown that the frequency of the APOE e4 allele is much greater among individuals with Alzheimer’s disease than age-matched healthy controls [an approximate 4-fold increase (36.6 vs 9.4%) in one recent study]. However, due to an insufficient sensitivity of the APOE e4 allele in detecting patients with Alzheimer’s disease and the presence of this allele in demented and nondemented individuals, APOE genotyping should not be used alone as a sole diagnostic test for Alzheimer’s disease. An additional recent findings that central muscarinic receptor binding, as revealed by positron emission tomography (PET) and [11C]benztropine, declines with the progression of Alzheimer’s disease regardless of the presence or absence of APOE e4 allele. These findings suggest that measures of acetylcholine neurotransmission in the living Alzheimer’s disease brain by PET help to visualise altered cholinergic function during the clinical course of Alzheimer’s disease and to identify appropriate individuals who are more likely to respond to emerging cholinergic interventions

Inactive aldehyde dehydrogenase-2 (ALDH2) is known as a genetic negative risk factor for the development of alcoholism. In alcoholics with inactive ALDH2, unidentified factors that overcome the adverse reactions of high blood acetaldehyde concentration after drinking may increase such persons' susceptibility to alcoholism. Comparison of clinical characteristics, including sociofamilial backgrounds and psychopathologies, failed to show significant differences between alcoholics with inactive ALDH2 (inactive group) and those with active ALDH2 (active group). Examination of the temporal profile of disease development showed that the inactive group experienced each stage or event in the history of drinking and alcoholism 1 to 5 years later in life than the active group; however, not all comparisons reached statistically significant levels. Although preliminary, these results suggest that an inactive ALDH2-mediated delay in the occurrence of alcohol-related problems seems to contribute to the suppression of alcoholism development.

In a study of the relationship between the flushing response and drinking behavior, the Adolescent Alcohol Involvement Scale was used to survey 932 male and female Japanese high school students identified by the ethanol patch test as flushers (338; 36.3%) and nonflushers (594; 63.7%). The goal was to clarify whether the flushing response inhibits adolescent drinking. Students with the flushing response reported drinking significantly less than nonflushers with respect to both frequency and amount. Although the flushing response was associated with less drinking, the flushers and nonflushers had similar drinking partners and reasons for drinking, and their total Adolescent Alcohol Involvement Scale scores did not differ significantly. The survey showed that many flushers were seeking the pleasures of alcohol despite the discomforts it caused, suggesting that Japanese adolescents need more education on the risks of adolescent drinking.

The proportion of alcoholic patients aged 60 years or older is about 25% of the patients who visit medical institutions specializing in alcohol-related problems, and this rate has tended to increase gradually. Alcohol-use disorders among elderly people are frequently underdetected, but the Short Michigan Alcoholism Screening Test-Geriatric Version (SMAST-G) is reported to be a valid screening tool for elderly people. Alcohol withdrawal symptoms among the elderly are not conspicuous since comorbidities, such as amnesic syndrome and cancer, are more common in the elderly than among younger patients. Elderly alcoholics have better treatment outcomes than younger alcoholics, with a higher abstinent rate and a lower recurrence rate.

In this study, 1,000 Japanese male alcoholics were consecutively screened by upper gastrointestinal endoscopy with esophageal iodine staining. Associations among cancer-detection rates, drinking and smoking habits, and aldehyde dehydrogenase-2 (ALDH2) genotypes were evaluated. A total of 53 patients (5.3%) had histologically confirmed cancer. Esophageal cancer was diagnosed in 36, gastric cancer in 17, and oropharyngolaryngeal cancer in 9 patients: 8 of the esophageal-cancer patients were multiple-cancer patients, with additional cancer(s) in the stomach and/or oropharyngolaryngeal region. Multiple logistic regression revealed that use of stronger alcoholic beverages (whisky or shochu) in contrast with lighter beverages (sake or beer) and smoking of 50 pack-years or more increased the risks for esophageal (odds ratio 3.2 and 2.8 respectively), oropharyngolaryngeal (4.8 and 5.1 respectively) and multiple cancer (10.5 and 11.8 respectively). The inactive form of ALDH2, encoded by the gene ALDH2*1/2*2 prevalent in Orientals, exposes them to higher blood levels of acetaldehyde, a recognized animal carcinogen, after drinking. This inactive ALDH2 was detected in 19/36 (52.8%) patients with esophageal cancer, in 5/9 (55.6%) patients with oropharyngolaryngeal cancer, and in 7/8 (87.5%) patients with multiple cancer. All of these gene frequencies far exceeded that in a large alcoholic cohort (80/655, 12.2%). The triple combination of the risk factors of the inactive ALDH2, stronger alcoholic beverages and heavy smoking was more commonly associated with multiple-cancer patients than with patients with esophageal cancer alone (62.5% vs. 7.1%). These results show that the 3 risk factors are important for the development of upper-aerodigestive-tract cancer in Japanese alcoholics. For these high-risk drinkers, regimented screening appears to be indicated. © 1996 Wiley-Liss, Inc.

Brains from 21 patients with Alzheimer's disease (AD), nine with diffuse Lewy body disease (DLBD), six with progressive supranuclear palsy (PSP) and five with Parkinson's disease (PD) as well as 20 normal subjects were examined to detect apolipoprotein E (ApoE) by immunohistochemistry and immunoblotting. ApoE antigenicity was optimally preserved in Bouin-fixed tissues compared with those fixed in neutral-buffered formalin, 70% ethanol or denatured by microwave energy. ApoE immunoreactivity was prominent in senile plaques and in intra- and extra-neuronal tangles, as well as in a diverse neurones and their processes and astroglial cells. Notably, tangles in PSP and Lewy bodies in PD and DLBD were both devoid of ApoE immunoreactivity. Western blots of cerebral cortex revealed an immunoreactive ApoE band with mol. wt of 34 kDa. Our results suggest that ApoE is not a crucial factor in the development of neuronal inclusions in DLBD, PSP and PD.

BACKGROUND Multiple intraesophageal primary cancer and upper aerodigestive tract (UADT) cancer associated with esophageal cancer are common diseases, especially in heavy drinkers. They are often explained by the concept of field cancerization, which suggests a similar etiology. However, little is known about the nature of the hypothesized etiology. METHODS Among 901 Japanese male alcoholics systematically screened by upper gastrointestinal endoscopy (with esophageal iodine staining), 33 had squamous cell carcinoma of the esophagus. The multiplicity of their esophageal carcinoma and their concurrent UADT cancer was compared with their genotype for aldehyde dehydrogenase-2 (ALDH2), the major determinant of blood acetaldehyde concentration after drinking. RESULTS Of 17 patients with inactive ALDH2, 13 (76.5%) had multiple primary carcinoma of the esophagus, whereas 5 of 16 (31.3%) with active ALDH2 had multiple carcinomas (P < 0.01). The prevalence of concurrent UADT cancer was 29.4% in those patients with inactive ALDH2, compared with 6.3% in those patients with active ALDH2. CONCLUSIONS Inactive ALDH2 is a risk factor for multiple carcinoma of the esophagus in alcoholics. Acetaldehyde, a recognized animal carcinogen, appears to play a critical role in field cancerization. Cancer 1996;77:1986-90.

The effects of the genotype of alcohol dehydrogenase-2 (ADH2) and mitochondrial aldehyde dehydrogenase (ALDH2) on drinking behavior were investigated in a population of 451 Japanese. Although the ALDH2*2 allele had a significant inhibitory effect on alcohol consumption, hence on drinking problems, the apparent association was not confirmed between ADH2 genotype and overall drinking patterns for either males or females. However, the frequency of the ADH2*2 allele was significantly lower in male Japanese classified as alcoholic on the basis of the Kurihama Alcoholism Screening Test than in nonalcoholic males. These results corroborate a previous study that revealed a significantly lower ADH2*2 allele frequency in hospitalized Japanese alcoholics than in the general population. Together, these studies suggest that the ALDH2*2 allele has an inhibitory effect on drinking behavior, irrespective of the level of alcohol consumption, whereas the effect of the ADH2 polymorphism only becomes apparent in individuals with higher alcohol consumption, such as alcoholics.

Several lines of evidence have suggested that naturally occurring alterations in cholecystokinin (CCK) systems could contribute to the development of panic disorder (PD). Among recent investigations, polymorphisms of the CCK and CCK-B receptor (R) genes were investigated, but the results were inconclusive. We recently cloned the genomic structures of human CCK-AR, and determined the transcriptional start site of the human CCK-AR gene. Two sequence changes were detected in the promoter region: a G to T change in nucleotide −128 and an A to G change in nucleotide −81 (GenBank database under accession number D85606). The frequencies of the genotypes and haplotypes of these two polymorphisms were compared in 109 Japanese patients with PD and 400 age- and gender-matched normal Japanese control subjects. The frequency of variant genotypes (−81A/G, −128G/T; G/G, G/T, and G/G, T/T) having variant haplotype (−81G/−128T) was significantly higher in PD than in controls (P

Alcohol-related dementia (ARD) is one of the most common dementing disorders in middle-aged people and occurs in heavy drinkers who are estimated to be 10 - 15 % of the adult men in a community. While the concept of ARD is multifactorial and includes all cognitive deficits in alcoholics, the central clinical manifestations are exemplified by Korsakoff's syndrome (KS), a persistent neuropsychiatric syndrome, characterized by amnesia and disorientation that is caused by thiamine deficiency along with excessive alcohol consumption. Antemortem detection of intracranial changes has been made possible by MRI and many studies have revealed that alcoholics have atrophic changes in frontal lobe, cerebellum, medial temporal lobe and hippocampus. However, these brain regions are vulnerable to excessive alcohol and seem to be independent of cognitive deficits in alcoholics. This review shows the regional differences in gray matter volumes between cognitively normal alcoholics and patients with KS. By employing a 3-dimensional MRI method for voxel-based morphometry that enables an automated, unbiased, comprehensive assessment, we demonstrate that parahippocampal/hippocampal atrophy is specific to KS and thalamic atrophy and the third ventricle enlargement are more severe in patients with KS than in cognitively normal alcoholics.

The present study used a self-reporting questionnaire to compare suicide risk in outpatients being treated for substance use disorder at specialized hospitals to suicide risk in outpatients being treated for depressive disorder at general psychiatric clinics. Although patients in both groups exhibited an equal severity of depression, the patients with drug use disorder had a higher suicide risk than those with depressive disorder. These findings indicate that drug-abusing patients at specialized hospitals may have a severe risk of committing suicide, suggesting that carefully assessing the comorbidity of depression with drug abuse may be required for preventing suicide in drug-abusing patients.

The Kurihama Medical and Addiction Center began to conduct research and to provide medical care for alcohol-related problems in 1963, when special alcoholism treatment wards were established in Japan for the first time. At first, the provision of medical care to patients was prioritized. However, training courses for specialists were initiated in 1975, and the Department of Clinical Research was established in 1984, which led to the formation of the present management structure in which the centre's staff are shared by three departments: Medical Care, Clinical Research and Education and Information. The Department of Medical Care provides specialized treatment for alcohol use disorders and medical services for other conditions, including behavioural addictions such as internet addiction and gambling disorder, as well as dementia and other psychiatric disorders. The Departments of Clinical Research and Education and Information are engaged mainly in specialized activities related to alcohol. The Department of Clinical Research conducts research on the epidemiology of alcohol use, the effects of alcohol on health and the treatment of alcohol use disorders in Japan, in cooperation with universities and other research institutions. The Department of Education and Information fosters the human capacity to achieve the primary, secondary and tertiary prevention of alcohol-related problems and the dissemination of information on alcohol. The centre also performs alcohol-related problem prevention activities, government consultations and international collaborative research and personal exchanges, thereby functioning as a central institution for alcohol policy-based medical services and research in Japan.

This article reports the first longitudinal cohort study on Japanese adolescent alcohol use and abuse from 1997 to 2007. The purpose of the cohort study is to show that factors which promote adolescent problem drinking, will develop into the early alcohol dependence syndrome. A total of 802 subjects with a mean age 13.5 years old was recruited from four junior high schools in Kanagawa prefecture. The survey was conducted annually by mail using self-reported questionnaires concerning drinking status and alcohol-related problems. In the 2007 survey at 10 years after the first survey, the respondents numbered 493 with a mean age of 23.8 years old, and the follow-up rate was 61.5%. In the 2007 survey, 25.2% of male and 14.3% of female subjects were found to be problem drinkers from the scores of the Alcohol Use Disorder Identification Test (AUDIT). We divided the subjects into two groups according to the AUDIT scores, problem drinkers and non-problem drinkers. The two groups were compared concerning family relationships, first drinking age and drinking status of parents with the respons- es of the 1997 survey. A multiple regression analysis was performed to determine problem drink promoting factors. The factors determined were fathers with moderate to heavy drinking in male subjects and having drinking experiences at 13.5 years old at the start of the survey in female subjects. Furthermore, we confirmed a continuity of problem drinking from adolescents to young adults. Problem drinkers in the 2002 survey had significantly increased in the 2007 survey when compared with non-problem drinkers in the 2002 survey. We concluded that first drinking in junior high school and having moderate to heavy drinking fathers promote adult problem drinking, and problem drinking continued from adolescents to young adults.

Human fetal spinal cords and other non-neural tissues from cases with gestational age from 6 to 21 weeks were examined with a panel of antibodies to different domains of beta-amyloid precursor proteins (beta-APPs). In the early developmental stages, the beta-APPs were expressed in three distinct layers, i.e., primitive neuroepithelial cell layer, mantle layer and marginal layer. beta-APP immunoreactivity was most prominent in cell bodies of putative neuroblasts located in the outer ventral part of the mantle layer. beta-APP expression diminished as the spinal cord matured and a weak residual immunoreactivity was detected exclusively in a subset of the anterior horn cells by 21 weeks gestational age. Throughout the gestational ages examined, no convincing beta/A4 immunostaining was seen in any of the spinal cord regions. Outside the spinal cord, beta-APP immunostaining was consistently present in (1) cell bodies and proximal nerves of immature neurons of dorsal root ganglia and in (2) myotubules, although these cells were devoid of beta/A4 immunoreactivity. Western blot analysis of fetal spinal cord revealed immunoreactive bands with apparent molecular weight between 100 and 140 kDa in the membrane-associated fraction, while soluble proteins with a molecular mass centered on 115 kDa were detected in the cytosolic fraction. Our results indicate that: (1) one or more isoforms of full length beta-APPs are expressed at very early gestational ages in the developing human spinal cord; (2) the normal metabolism of beta-APPs does not result in accumulations of beta/A4 fragments.