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BACKGROUND Digital health technologies using mobile apps and wearable devices are a promising approach to the investigation of substance use in the real world and for the analysis of predictive factors or harms from substance use. Moreover, consecutive repeated data collection enables the development of predictive algorithms for substance use by machine learning methods. OBJECTIVE We developed a new self-monitoring mobile app to record daily substance use, triggers, and cravings. Additionally, a wearable activity tracker (Fitbit) was used to collect objective biological and behavioral data before, during, and after substance use. This study aims to describe a model using machine learning methods to determine substance use. METHODS This study is an ongoing observational study using a Fitbit and a self-monitoring app. Participants of this study were people with health risks due to alcohol or methamphetamine use. They were required to record their daily substance use and related factors on the self-monitoring app and to always wear a Fitbit for 8 weeks, which collected the following data: (1) heart rate per minute, (2) sleep duration per day, (3) sleep stages per day, (4) the number of steps per day, and (5) the amount of physical activity per day. Fitbit data will first be visualized for data analysis to confirm typical Fitbit data patterns for individual users. Next, machine learning and statistical analysis methods will be performed to create a detection model for substance use based on the combined Fitbit and self-monitoring data. The model will be tested based on 5-fold cross-validation, and further preprocessing and machine learning methods will be conducted based on the preliminary results. The usability and feasibility of this approach will also be evaluated. RESULTS Enrollment for the trial began in September 2020, and the data collection finished in April 2021. In total, 13 people with methamphetamine use disorder and 36 with alcohol problems participated in this study. The severity of methamphetamine or alcohol use disorder assessed by the Drug Abuse Screening Test-10 or the Alcohol Use Disorders Identification Test-10 was moderate to severe. The anticipated results of this study include understanding the physiological and behavioral data before, during, and after alcohol or methamphetamine use and identifying individual patterns of behavior. CONCLUSIONS Real-time data on daily life among people with substance use problems were collected in this study. This new approach to data collection might be helpful because of its high confidentiality and convenience. The findings of this study will provide data to support the development of interventions to reduce alcohol and methamphetamine use and associated negative consequences. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/44275

BACKGROUND While accumulating evidence suggests a relation between the severity of alcohol dependence and the risk of its recurrence, the impact of dependence severity on the course of the disorder has not been carefully evaluated. The present study examined the impact of several severity indices of alcohol dependence on the drinking course after inpatient treatment. METHODS This prospective study was conducted over a 12-month period following alcohol treatment at a specialized hospital. A total of 712 consecutively admitted alcohol-dependent patients were targeted for enrollment at the time of their hospitalization, with 637 patients registered and followed. The characteristics and severity of the subjects were assessed using multiple methods at admission, with their course after discharge followed continuously using mailed questionnaires that queried them regarding their drinking behavior. RESULTS Greater severity of dependence, assessed using the number of ICD-10 diagnostic criteria met, was associated with a lower rate of abstinence during the study period (p = 0.035). The rate of abstinence also decreased significantly as the baseline blood gamma-glutamyl transferase value and Alcohol Dependence Scale (ADS) score increased (p = 0.031 and p = 0.0002, respectively). In multivariate Cox proportional hazards analyses, the group with the most severe ADS scores had a significantly greater risk of relapse to drinking than the group with the least severe scores (HR = 2.67, p = 0.001). Dependence severity also associated with the drinking pattern; participants in both the controlled drinking group and the abstinence group had lower ADS scores at admission and a later age at first drinking (p = 0.001 and p

Background While several studies have revealed that neurodevelopmental disorders have a high probability of overlapping with substance use disorders, the effects of neurodevelopmental disorders on the courses of substance use disorders have hardly been examined. Methods This study targeted 637 alcohol-dependent individuals who received inpatient treatment and whose drinking situations were followed for 12 months after hospital discharge using mailed questionnaires. The comorbidity of psychiatric disorders and the characteristics associated with the neurodevelopmental disorders were assessed using several measurements at the time of hospital admission. The effects of neurodevelopmental disorders on the drinking courses of the subjects were then estimated. Results The presence of a current depressive episode or any anxiety disorder significantly lowered the abstinence rates during the follow-up period (p = 0.0195 and p = 0.0214, respectively). ADHD traits as assessed using the ADHD Self-report Scale (ASRS) predicted a significantly poorer abstinence rate (p = 0.0296). Similarly, attention-deficit characteristics assessed objectively through interviews predicted a significantly lower abstinence rate (p = 0.0346), and a sensitivity analysis enhanced these results (p = 0.0019). When the drinking patterns were classified into three groups, the subjects with attention-deficit characteristics had a significantly higher rate of “Recurrence” and lower rates of “Abstinence” and “Controlled drinking” (p = 0.013). In a multivariate proportional hazards analysis, the ASRS score was significantly correlated with the re-drinking risk (p = 0.003). Conclusion ADHD traits had significant effects on not only abstinence rates, but also on drinking pattern. The presence of ADHD traits, especially attention-deficit characteristics, influenced the drinking courses of alcohol-dependent individuals after hospital treatment.

Background Inactive aldehyde dehydrogenase-2 (ALDH2) is a well-known deterrent to the development of alcohol use disorder (AUD), and however, some individuals with inactive ALDH2 do go on to develop AUD. These alcoholics are likely to have strong risk factors for the development of this disorder. Using a model of alcoholics with inactive ALDH2 (the AIA model), we investigated the unique characteristics of alcoholics with inactive ALDH2 in an attempt to identify the risk factors for AUD. In this study, we focused on comorbid psychiatric and personality disorders as potential risk factors for AUD. Methods The subjects were 103 male alcoholics with inactive ALDH2 (AIAs), 87 age- and ADH1B genotype-matched alcoholics with active ALDH2 (AAAs) and 200 age-matched healthy men. The alcoholics were divided into 4 subgroups according to their ALDH2 and ADH1B genotypes (inactive ALDH2 vs. active ALDH2, usual ADH1B vs. superactive ADH1B). To assess the participants' comorbid psychiatric disorders, we conducted semi-structured interviews using the Japanese translation of SSAGA version 2. We compared the prevalence of comorbid psychiatric and personality disorders among groups with different combinations of the ALDH2 and ADH1B genotypes. Results The prevalence of attention-deficit/hyperactivity disorder (ADHD) was significantly higher in the AIAs with usual ADH1B than in the other 3 subgroups of alcoholics. In contrast, the prevalence rates of agoraphobia and panic disorder were significantly lower in the AIAs with superactive ADH1B than in the other 3 subgroups of alcoholics. Conclusions This study suggested that (i) ADHD is a risk factor for AUD, consistent with previous reports; (ii) agoraphobia and panic disorder may have deterrent effects against the development of AUD in individuals with inactive ALDH2, probably attributable to the similarity between the symptoms of agoraphobia and panic disorder and the adverse reactions to consumption of alcohol in subjects with inactive ALDH2.

OBJECTIVE This study sought to evaluate the impacts of interactions between the alcohol dehydrogenase-1B (rs1229984) genotype and the aldehyde dehydrogenase-2 (rs671) genotype on alcohol flushing, alcohol reeking on the day after drinking, and the age distribution in alcohol-dependent patients. METHODS The study subjects were 4107 Japanese alcohol-dependent men who underwent alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotyping: 4051 patients were asked about their current or former tendency to experience facial flushing after drinking a glass of beer, and 969 patients were asked about whether they had ever been told that they reeked of alcohol more than 12 hours after they had stopped drinking. RESULTS Current, former, and never flushing were reported in 3.5, 14.9, and 81.5%, respectively, of the subject, and alcohol reeking after more than 12 hours in 36.1% of the subjects. The fast-metabolizing ADH1B*2(+) genotype (*1/*2 or *2/*2) and the inactive ALDH2*2(+) genotype (*1/*2 or *2/*2) affected the multivariate odds ratios for current or former flushing [odds ratio, 95% confidence interval = 2.27 (1.79-2.86) and 23.0 (18.6-28.5), respectively, vs. *2(-) genotype] and for alcohol reeking [0.39 (0.29-0.52) and 1.56 (1.09-2.25), respectively, vs. *2(-) genotype]. An age-dependent decrease in the ADH1B*2(-) and ALDH2*2(-) combination from 32.3% in the 30-39-year age group to 12.5% in the 70-79-year age group and an age-dependent increase in the ADH1B*2(+) and ALDH2*2(-) combination from 52.5% in the 30-39-year age group to 70.5% in the 70-79-year age group were observed (P < 0.0001 for trend). The frequencies of the ADH1B*2(-) and ALDH2*2(+) combination (4.7-6.2%) and the ADH1B*2(+) and ALDH2*2(+) combination (8.9-12.0%) did not change markedly with increasing age. CONCLUSION Interactions between the alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes modified alcohol flushing, alcohol reeking on the day after drinking, and the age distribution. These findings support the protective roles of the ADH1B*2(+) and ALDH2*2(+) genotypes against the development of alcohol dependence.

Internet-delivered intervention may be an acceptable alternative for the more than 90% of problem gamblers who are reluctant to seek face-to-face support. Thus, we aimed to (1) develop a low-dropout unguided intervention named GAMBOT integrated with a messaging app; and (2) investigate its effect. The present study was a randomised, quadruple-blind, controlled trial. We set pre-to-post change in the Problem Gambling Severity Index (PGSI) as the primary outcome and pre-to-post change in the Gambling Symptom Assessment Scale (G-SAS) as a secondary outcome. Daily monitoring, personalised feedback, and private messages based on cognitive behavioural theory were offered to participants in the intervention group through a messaging app for 28 days (GAMBOT). Participants in the control group received biweekly messages only for assessments for 28 days (assessments only). A total of 197 problem gamblers were included in the primary analysis. We failed to demonstrate a significant between-group difference in the primary outcome (PGSI - 1.14, 95% CI - 2.75 to 0.47, p = 0.162) but in the secondary outcome (G-SAS - 3.14, 95% CI - 0.24 to - 6.04, p = 0.03). Only 6.7% of the participants dropped out during follow-up and 77% of the GAMBOT group participants (74/96) continued to participate in the intervention throughout the 28-day period. Integrating intervention into a chatbot feature on a frequently used messaging app shows promise in helping to overcome the high dropout rate of unguided internet-delivered interventions. More effective and sophisticated contents delivered by a chatbot should be sought to engage over 90% of problem gamblers who are reluctant to seek face-to-face support.

Acute alcohol administration affects functional connectivity, yet the underlying mechanism is unknown. Previous work suggested that a moderate dose of alcohol reduces the activity of gamma-aminobutyric acidergic (GABAergic) interneurons, thereby leading to a state of pyramidal disinhibition and hyperexcitability. The present study aims to relate alcohol-induced changes in functional connectivity to regional genetic markers of GABAergic interneurons. Healthy young adults (N = 15, 5 males) underwent resting state functional MRI scanning prior to alcohol administration, immediately and 90 min after alcohol administration. Functional connectivity density mapping was performed to quantify alcohol-induced changes in resting brain activity between conditions. Patterns of differences between conditions were related to regional genetic markers that express the primary GABAergic cortical interneuron subtypes (parvalbumin, somatostatin, and 5-hydroxytryptamine receptor 3A) obtained from the Allen Human Brain Atlas. Acute alcohol administration increased local functional connectivity density within the visual cortex, sensorimotor cortex, thalamus, striatum, and cerebellum. Patterns of alcohol-induced changes in local functional connectivity density inversely correlated with somatostatin cortical gene expression. These findings suggest that somatostatin-expressing interneurons modulate alcohol-induced changes in functional connectivity in healthy individuals.

Background and Objectives Altered trafficking of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed. Methods A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls. Results Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other. Conclusions and Scientific Significance The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains., Postmortem studies on AMPA receptors in patients with addiction show that the hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death, which emphasizes the need to investigate AMPA receptors in the living human brains.

AIMS To investigate the acute effects of intravenous alcohol and its metabolite acetaldehyde on cognitive function in healthy individuals. DESIGN Experimental pre-test/post-test design. SETTING Kurihama Medical and Addiction Center, Japan. PARTICIPANTS A total of 298 healthy Japanese people age 20 to 24 years. MEASUREMENTS Participants underwent an intravenous alcohol infusion with a target blood alcohol concentration (BAC) of 0.50 mg/mL for 180 minutes. Participants completed the continuous performance test (CPT) for sustained attention, the paced auditory serial addition test (PASAT) for working memory, and the reaction time test (RTT) for speed/accuracy, along with the blood test for BAC and blood acetaldehyde concentration (BAAC) at baseline, 60 and 180 minutes. FINDINGS Although the target BAC was maintained during the infusion, BAAC peaked at 30 minutes and then gradually declined (η2 = 0.18, P < 0.01). The CPT scores worsened, and the changes between 0 and 60 minutes were correlated with BAAC (correct detection, η2 = 0.09, P < 0.01; r = -0.34, P < 0.01; omission errors, η2 = 0.08, P < 0.01; r = 0.34, P < 0.01). PASAT scores improved through 180 minutes, whereas the changes between 0 and 60 minutes were negatively correlated with BAAC (task one, η2 = 0.02, P < 0.01; r = -0.25, P < 0.01; task two, η2 = 0.03, P < 0.01; r = -0.28, P < 0.01). Although RTTs worsened, they were not associated with BAC or BAAC. None of these comparisons maintained the time effect after controlling for body height. CONCLUSIONS Acetaldehyde exposure following acute intravenous alcohol appears to have a negative impact on sustained attention and working memory, whereas there seems to be only a minor effect of moderate alcohol concentration on speed and accuracy.

Background In areas affected by the tsunami of the great East Japan Earthquake, smoking behavior may have deteriorated due to high stress and drastic changes in living environment. Surveys were conducted to reveal changes in smoking behaviors among victims. Methods A population-based random-sample home-visit interview survey of victims in Iwate and Miyagi Prefectures affected by the tsunami disaster was conducted in 2012 (n = 1978), while a population-based nationwide survey was conducted in 2013 (n = 1082). A panel survey in 2014 was conducted with respondents of the 2012 survey (n = 930). Multiple logistic regression analysis was performed to reveal factors related to smoking status after the disaster. Results There was high smoking prevalence of both sexes in the tsunami disaster area (current smoking rate in coastal area, 50.0% for male, 21.4% for female; inland area, 34.7% for male, 7.6% for female). Low prevalence of male quitters was observed (quitter rate in coastal area, 20.8% for male, 8.0% for female; inland area, 23.4% for male, 5.5% for female). The prevalence of nicotine-dependent people assessed by FTND (Fagerström Test for Nicotine Dependence) in the coastal area was also higher than in the inland area or other areas of Japan. Smoking behavior among victims worsened after the disaster and did not improve 3 years from the disaster. Post-disaster factors related to smoking were living in coastal area, complete destruction of house, and living in temporary housing. Conclusions Smoking prevalence and the level of nicotine dependence of tsunami victims were still high even 3 years after the disaster. It is important to emphasize measures for smoking control in the disaster areas for an extended time period.

Additional file 1. Table a. Propotion of nicotine dependence accessed by TSD, by area (disaster area in 2012, All Japan in 2013). Table b. Change of nicotine dependence status accessed by TSD from 2012 to 2014 (Panel survey in disaster areas). Table c. Factors associated with nicotine dependence assessed by FTND score. Table d. Factors associated with nicotine dependence assessed by TDS score

Objective The risk of alcohol dependence (AD) in Japanese men and women was evaluated according to combinations of alcohol flushing and aldehyde dehydrogenase-2 (ALDH2, rs671) and alcohol dehydrogenase-1B (ADH1B, rs1229984) genotypes, all of which are known to determine AD susceptibility in Asians. Previous studies have focused on men, since women account for a smaller proportion of AD subjects. Methods Case control studies were conducted between 3721 male and 335 female AD Japanese and 610 male and 406 female controls who were asked about their current or former tendency to experience facial flushing after drinking a glass of beer and underwent ALDH2 and ADH1B genotyping. The time at which alcohol-induced facial flushing tendencies had disappeared in former-flushing AD subjects was also evaluated. Results Current alcohol flushing, the inactive ALDH2*1/*2 genotype, and the fast-metabolizing ADH1B*2 allele were less frequently found in the AD groups. Although alcohol flushing was strongly influenced by the ALDH2 and ADH1B genotypes, multiple logistic model showed that never or former flushing and the genotype combinations were independent strong risk factors of AD in men and women. Never or former flushing (vs. current flushing) markedly increased the odds ratios of AD in carriers of each of the ALDH2 and ADH1B genotype combinations. The temporal profiles for drinking and flushing in former-flushing AD subjects revealed that the flushing response disappeared soon after or before the start of habitual drinking during young adulthood, regardless of the ALDH2 genotype. Conclusion Although alcohol flushing is influenced by the ALDH2 and ADH1B genotypes, constitutional or acquired flushing tolerance is an independent susceptibility trait for AD. The combination of the alcohol flushing status and the ALDH2 and ADH1B genotypes can provide a better new strategy for AD risk assessment than the alcohol flushing status alone or the genotypes alone in Asian men and women.

Background and Objectives Epidemiological studies consistently find that Asian populations report lower rates of alcohol use disorders (AUD) compared with other racial groups. These differences result from a variety of biological, genetic, and environmental influences, some of which are related to the metabolism of alcohol. We will review several studies of these metabolic factors, including several alcohol clamping studies conducted in our laboratory, that provide further insight into the role of the alcohol metabolizing genes and drinking behavior among Japanese drinkers. Methods This manuscript reviewed studies investigating genetic variations of alcohol metabolizing enzymes among Asians and several mechanisms by which these genes are thought to give rise to differences in rates of alcohol dependence. Results The inactive aldehyde dehydrogenase 2 (ALDH2) and highly active alcohol dehydrogenase-1B (ADH1B) genes are protective factors for the development of AUD. The inactive ALDH2 provides its protective effect through the accumulation of acetaldehyde after consuming alcohol, resulting in unpleasant effects, and heightened sensitivity to alcohol. However, the suppressive effects of inactive ALDH2 and highly active ADH1B for AUDs are only partial and interact with other factors, such as personality traits, psychiatric comorbidities, and environmental factors. Discussion and Conclusions While Asians are excellent models for the study of certain genetic effects on the development and consequences of AUD, few clinical studies of this population have been conducted. Further exploration of the interactions between various genetic, individual, and environmental factors influencing drinking behavior and, thus affecting the risk of AUD, would enhance our understanding of how alcohol-related problems develop. Scientific Significance The heterozygous ALDH2*1/*2 genotype has only partial effects on limiting drinking behavior, suggesting the potential interaction with other factors. Therefore AUD patients with inactive ALDH2 may be a useful model to identify and to test a variety of other risk factors of AUD. (Am J Addict 2017;XX:1–8)

Heavy drinking leads to premature aging and precipitates the onset of age-related diseases. Acetaldehyde (AcH), a toxic metabolite of ethanol, has been implicated in various types of cancer. However, whether alcohol accelerates biological aging at a cellular level is controversial and the mechanism involved is unclear. We addressed these questions by measuring telomere length (TL) in peripheral blood leukocytes of Japanese patients with alcohol dependence (AD) and examined the association between TL, genetic variants of alcohol dehydrogenase (ADH)1B and aldehyde dehydrogenase (ALDH)2, and other clinical characteristics. A total of 134 male AD patients and 121 age- and sex-matched healthy controls were evaluated. All patients received endoscopic screening for cancer of the upper aerodigestive tract (UADT). TL was almost 50% shorter in AD patients relative to controls. There were no significant differences in TL between AD patients with and without UADT cancer, and no associations between ADH1B and ALDH2 genotypes and TL. AD patients with thiamine (vitamin B1) deficiency at admission had significantly shorter TL than those with normal thiamine status. Although the exact mechanism underlying the shorter TL in AD patients remain unclear, our findings suggest that alcohol rather than AcH is associated with telomere shortening in AD, which may be accelerated by thiamine deficiency. Future studies should also focus on the association between telomere shortening and TD in the context of oxidative stress.

Aims: Alcoholic ketosis and ketoacidosis are metabolic abnormalities often diagnosed in alcoholics in emergency departments. We attempted to identify determinants or factors associated with alcoholic ketosis. Methods: The subjects of this cross-sectional survey were 1588 Japanese alcoholic men (≥40 years) who came to an addiction center within 14 days of their last drink. Results: The results of the dipstick urinalyses revealed a prevalence of ketosis of 34.0% (±, 21.5%; +, 8.9%; and 2+/3+; 3.6%) in the alcoholics. Higher urine ketone levels were associated with higher serum total bilirubin, aspartate transaminase (AST), alanine transaminase and gamma-glutamyl transpeptidase levels. A multivariate analysis by the proportional odds model showed that the odds ratio (95% confidence interval) for an increase in ketosis by one category was 0.94 (0.84–1.06) per 10-year increase in age, 0.93 (0.89–0.97) per 1-day increase in interval since the last drink, 1.78 (1.41–2.26) in the presence of slow-metabolizing alcohol dehydrogenase-1B ( ADH1B\*1/\*1 ), 1.61 (1.10–2.36) and 1.30 (1.03–1.65) when the beverage of choice was whiskey and shochu, respectively (distilled no-carbohydrate beverages vs. the other beverages), 2.05 (1.27–3.32) in the presence of hypoglycemia

Background Oxidation of ethanol by alcohol dehydrogenase (ADH) generates acetaldehyde (AcH), which is converted to acetate by aldehyde dehydrogenase-2 (ALDH2). Roughly 40% of East Asians are ALDH2-deficient due to an inactive enzyme encoded by the ALDH2*2 allele. ALDH2-deficient individuals have a dramatically elevated risk of esophageal cancer from alcohol consumption. Methods We investigated the relationship between ALDH2*2, ADH1B*2 (encoding a highly active ADH) and erythrocyte abnormalities, in a population of Japanese alcoholic men (N = 1,238). Results Macrocytosis (mean corpuscular volume [MCV] ≥100 fl) and macrocytic anemia (MCV ≥100 fl and hemoglobin

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) affect ethanol (EtOH) metabolism and susceptibility to alcoholism.We evaluated associations between ADH1B/ALDH2 genotypes and the blood EtOH levels of 805 Japanese alcoholic men in the morning after they had drunk within the previous 34 h.Age-adjusted usual alcohol consumption did not differ according to ADH1B/ALDH2 genotypes. Higher blood EtOH levels persisted for longer periods in the ADH1B*1/*1 carriers (n = 246) than in the ADH1B*2 carriers (n = 559). Blood EtOH levels did not differ by ALDH2 genotype. The blood EtOH levels ≥ 0.3 mg/ml (criterion for drunk driving in Japanese law) were observed (40% vs. 14-17%, P0.0001) in a higher proportion of the ADH1B*1/*1 carriers than of the ADH1B*2 carriers after a 12.1-to-18-h interval since the last drink. Multivariate analyses showed that the EtOH levels heightened by 0.500 mg/ml in the presence of ADH1B*1*1 and by 0.248 mg/ml in the presence of cirrhosis, and lowered by 0.120 mg/ml per 10-year age increase, by 0.087 mg/ml per 10-kg body-weight increase and by 0.673 mg/ml per 10-h interval since the last drink. The odds ratio (95% confidence interval) for an EtOH level ≥ 0.3 mg/ml was 3.44 (2.34-5.04) in the presence of ADH1B*1/*1, 2.01 (1.28-3.14) in the presence of cirrhosis, 0.59 (0.49-0.71) per 10-year age increase, 0.80 (0.68-0.95) per 10-kg body-weight increase and 0.10 (0.07-0.15) per 10-h interval since the last drink.The longer-than-expected EtOH lingering in the blood of the ADH1B*1/*1 alcoholics may exacerbate alcohol-related problems, including drunk driving.

Background The presence of the less-active form of alcohol dehydrogenase-1B encoded by ADH1B*1/*1 (vs. *2 allele) and active form of aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH2*1/*1 (vs. *2 allele) increases the risk of alcoholism in East Asians. Methods The subjects in this cross-sectional survey were 1,902 Japanese alcoholic men (≥40 years) who underwent ADH1B/ALDH2 genotyping. Results Age-adjusted daily alcohol consumption did not differ according to the ADH1B/ALDH2 genotypes. The age-adjusted odds ratios (AORs; 95% confidence interval) for liver cirrhosis (LC; n = 359, 1.58 [1.19 to 2.09]), chronic calcific pancreatitis (CP; n = 80, 2.24 [1.20 to 4.20]), and diabetes mellitus (DM; n = 383, 1.51 [1.15 to 1.99]) were higher in the ADH1B*2 allele carriers than in the ADH1B*1/*1 carriers. The AORs for LC (1.43 [1.01 to 2.02]), CP (1.68 [0.80 to 3.53]), DM (1.63 [1.15 to 2.30]), and hypertension (HT; n = 495, 1.52 [1.11 to 2.07]) were higher in the ALDH2*1/*1 carriers than in the ALDH2*1/*2 carriers. The ADH1B*2-associated AOR for LC was 2.08 (1.46 to 2.94) among those aged 40 to 59 years, but 0.89 (0.56 to 1.43) among those aged 60 years or over, and the interaction between ADH1B genotype and age on the LC risk was significant (p = 0.009). When the group with non-LC and no/mild fibrosis was used as controls, the ADH1B*2-associated AORs increased according to the severity of their liver disease: 1.67 (1.32 to 2.11) for the group with non-LC and serum type IV collagen values ≥200 ng/ml, 1.81 (1.24 to 2.63) for the group of Child-Pugh class A LC, and 3.17 (1.98 to 5.07) for the group with Child-Pugh class B/C LC. Anti-hepatitis C virus (HCV) antibody was positive in 103 patients, and the groups with a high anti-HCV antibody titer and either the ADH1B*2/*2 genotype or the ALDH2*1/*1 genotype had the highest AORs (8.83 and 4.90, respectively). The population attributable fraction (PAF) due to the ADH1B*2 allele was 29% for LC, 47% for CP, and 27% for DM, and the PAF due to the ALDH2*1/*1 genotype was 26% for LC, 34% for DM, and 30% for HT. Conclusions The ADH1B*2 allele increased the AORs for LC, CP, and DM of the alcoholics, and the ALDH2*1/*1 genotype increased their AORs for LC, DM, and HT. HCV infection and genetic susceptibility had a synergistic effect on the AOR for LC.

Background The calories in alcoholic beverages consumed by alcoholics are a major energy source and a strong modifier of their body weight. Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) affect susceptibility to alcoholism and may affect body weight via gene-associated differences in fuel utilization in alcoholics. Methods We evaluated associations between ADH1B/ALDH2 genotypes and the body weight and body mass index (BMI) of 1,301 Japanese alcoholic men at the time of their first visit to an addiction center. Results Median (25th to 75th) caloric intake in the form of alcoholic beverages was 864 (588 to 1,176) kcal/d. Age-adjusted caloric intake did not differ according to ADH1B/ALDH2 genotypes. The body weight and BMI values showed that the ADH1B*2/*2 and *1/*2 carriers (n = 939) were significantly leaner than the ADH1B*1/*1 carriers (n = 362) irrespective of age, drinking, smoking, and dietary habits. The age-adjusted body weight values of the ADH1B*2/*2, ADH1B*1/*2, and ADH1B*1/*1 carriers were 58.4 ± 0.4, 58.7 ± 0.5, and 63.6 ± 0.5 kg, respectively (ADH1B*2 vs. ADH1B*1/*1 carriers, p

Aims: The life-time drinking profiles of Japanese alcoholics have shown that gastrectomy increases susceptibility to alcoholism. We investigated the trends in gastrectomy and alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) genotypes and their interactions in alcoholics. Methods: This survey was conducted on 4879 Japanese alcoholic men 40 years of age or older who underwent routine gastrointestinal endoscopic screening during the period 1996–2010. ADH1B/ALDH2 genotyping was performed in 3702 patients. Results: A history of gastrectomy was found in 508 (10.4%) patients. The reason for the gastrectomy was peptic ulcer in 317 patients and gastric cancer in 187 patients. The frequency of gastrectomy had gradually decreased from 13.3% in 1996–2000 to 10.5% in 2001–2005 and to 7.8% in 2006–2010 ( P < 0.0001). ADH1B\*1/\*1 was less frequent in the gastrectomy group than in the non-gastrectomy group (age-adjusted prevalence: 20.4 vs. 27.6%, P = 0.006). ALDH2 genotype distribution did not differ between the two groups. The frequency of inactive ALDH2\*1/\*2 heterozygotes increased slightly from 13.0% in 1996–2000 to 14.0% in 2001–2005 and to 15.4% in 2006–2010 ( P < 0.08). Two alcoholism-susceptibility genotypes, ADH1B\*1/\*1 and ALDH2\*1/\*1 , modestly but significantly tended not to occur in the same individual ( P = 0.026). The frequency of ADH1B\*1/\*1 decreased with ascending age groups. Conclusions: The high frequency of history of gastrectomy suggested that gastrectomy is still a risk factor for alcoholism, although the percentage decreased during the period. The alcoholism-susceptibility genotype ADH1B\*1/\*1 was less frequent in the gastrectomy group, suggesting a competitive gene–gastrectomy interaction for alcoholism. A gene–gene interaction and gene–age interactions regarding the ADH1B genotype were observed.

Thrombocytopenia during intoxication, rebound thrombocytosis during 1 to 3 weeks of abstinence, and subsequent normalization of the platelet count are common in alcoholics.We evaluated 989 Japanese alcoholic men to identify the effects of genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) on platelet counts during an 8-week in-hospital abstinence period.Thrombocytopenia (15 × 10In alcoholics, the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission and of a rebound platelet increase 2 weeks thereafter, while the ALDH2*1/*1 genotype was associated with lower platelet counts throughout the 8-week hospital stay.

This article reviews studies examining the relationship between alcohol consumption and dementia. Several studies have found that light to moderate alcohol consumption might be associated with decreased dementia risk compared to alcohol abstention. However, not all studies drew the same conclusion and there is no consensus regarding decreased dementia risk related to light to moderate alcohol consumption. The methodological limitations of these studies also need to be considered. For example, definition of alcohol consumption varies with studies. Some studies defined no drinking as never consuming alcohol, while other studies defined it as currently not consuming alcohol. Estimates of dementia risk related to alcohol consumption should be significantly altered by these definitions. Therefore, based on the current evidence, alcohol should not be used as a means to decrease the risk of developing dementia. This article also describes the pathophysiology of alcohol-related dementia, the relationship between Wernicke-Korsakoff syndrome and alcohol-related dementia, clinical characteristics, and the prevalence of alcohol-related dementia. Finally, we document a couple of articles examining the relationship between mortality and alcohol consumption in patients with mild Alzheimer's disease and the impact of alcohol abstention on cognitive decline in patients with Alzheimer's disease.

Aim: The aim of this study was to identify risk factors for suicide in Japanese substance use disorder (SUD) patients, adjusting for age and sex, and to examine sex differences in suicide risk among these patients. Methods: A self-reporting questionnaire on age, sex, types of abused substances, current depression, and suicidality was administered to 1420 SUD patients who consecutively visited seven hospitals specializing in SUD treatment during the month of December 2009. Unadjusted/adjusted odds ratios of factors associated with suicidality were calculated for each sex. Results: The multivariate analysis using the total sample identified younger age, female sex, and current depression as risk factors for severe suicidality in SUD patients. The multivariate analysis by each sex demonstrated that younger age and current depression were associated with severe suicidality in male SUD patients. Only current depression was associated with severe suicidality in female patients. Conclusion: Current depression is a risk factor for suicide in SUD patients common in both Western countries and Japan, although in Japanese SUD patients both younger age and female sex were more closely associated with severe suicidality than aspects of SUD. Additionally, young male SUD patients are speculated to have psychosocial features associated with suicidality in common with female SUD patients.

Background: Gender differences are known to exist in the prevalence, characteristics, and course of alcohol dependence. Elucidating gender differences in the characteristics of alcohol dependence is important in gender-based medicine and may improve treatment outcomes. Many studies have shown that genetic factors are associated with the risk of alcohol dependence in both genders. Polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) are strong genetic determinants of alcohol dependence. This study aimed to clarify gender differences in the effects of ADH1B and ALDH2 polymorphism on the development of alcohol dependence. Methods: Subjects were 200 female alcoholics and 415 male alcoholics hospitalized in Kurihama Alcoholism Center. Clinical information and background data were obtained by chart review. ALDH2 and ADH1B genotyping was performed by the polymerase chain reaction–restriction fragment length polymorphism method. Results: The onset age of female alcoholics with inactive ALDH2 genotype was significantly lower than those with active ALDH2 genotype, but the onset age did not differ between the inactive and active ALDH2 group in male alcoholics. The difference in onset age between the ADH1B genotype groups did not reach significant levels. The prevalence of comorbid psychiatric disorders, including major depression, eating disorder, panic disorder, and borderline personality disorder, was significantly higher in female alcoholics with inactive ALDH2 or superactive ADH1B than in those with active ALDH2 or normal ADH1B. Conclusions: ALDH2 polymorphism appears to have contrasting effects on the development of alcoholism in women and men. One possible reason for this gender difference may be the high prevalence of psychiatric comorbidities in female alcoholics with inactive ALDH2.

The present study sought to determine whether the co-occurrence of problem drinking heightens suicide risk in individuals with depression in Japan, using a sample of 784 outpatients (287 men and 497 women) with depressive disorder. Female subjects with at least a moderate problem drinking showed significantly more severe depression and suicidality than those without, but no such difference was identified in men.

Alcohol use disorder is a common and complex disorder with a well-documented highly hereditary nature (Higuchi et al., 2006; Roh et al., 2008). Subjective response to alcohol is also known to be a genetically influenced characteristic (Schuckit et al., 2007; Viken et al., 2003). This suggests that genetic influences on individual variation in subjective response to alcohol may underlie the effects of genes on alcohol-related disorders. A low level of response to the acute effects of alcohol has been associated with an increased risk of both excessive alcohol intake (Hinckers et al., 2006; Schuckit et al., 2007) and alcohol dependence (Schuckit, 1994; Schuckit and Smith, 1996; Schuckit et al., 2004), which are well known to be highly heritable (Kendler, 2001). There is consistent evidence that the GABAA receptor regulates the alcohol self-administration in animal models, probably by stimulating reward circuitry in the mesolimbic system (Chester and Cunningham, 2002; Eiler and June, 2007; Harvey et al., 2002; June et al., 2003). Several GABAA receptor subunits have been implicated in alcohol effects, so that the specific subunit composition of the receptor may be an important determinant of alcohol’s CNS effects. The α2 subunit of the GABAA receptor mediates the anxiolytic effects of benzodiazepines (Low et al., 2000; Rudolph et al., 1999) and enhances the hypnotic, but not the sedative, effects of combined exposure to alcohol and benzodiazepines (Tauber et al., 2003). Two genome-wide scans in humans have provided evidence of linkage of alcohol dependence to a region of chromosome 4p that includes a cluster of 4 genes encoding γ-aminobutyric acid A (GABAA) receptor subunits (Long et al., 1998; Reich et al., 1998). A previous study (Edenberg et al., 2004) found that 31 single nucleotide polymorphisms (SNPs) in GABAA receptor α2 subunit gene (GABRA2), but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcohol dependence. Additional studies have provided the replication of this association in a region of GABRA2 among various ethnic groups (Covault et al., 2004; Fehr et al., 2006; Lappalainen et al., 2005; Soyka et al., 2008); though, there is a negative association study between GABRA2 and alcohol dependence (Matthews et al., 2007). Previous studies have also provided evidence that GABAA receptors mediate several behavioral effects of alcohol such as ethanol self-administration and motor impairment (Davies, 2003; Grobin et al., 1998; Hanchar et al., 2005). GABRA2 gene was associated with the differences in the subjective effects of alcohol including blushing sensations, stimulant and sedative effects (Pierucci-Lagha et al., 2005), and the variance in drinking behavior (Bauer et al., 2007). In the former study (Pierucci-Lagha et al., 2005), the more common A allele of the rs279858 SNP within the GABRA2 gene showed greater subjective effects of alcohol than did individuals with 1 or 2 copies of the alcohol dependence–associated G allele. These findings underscore the potential contributions of variation at GABRA2 to the differences in the subjective responses to alcohol, the variance of drinking behavior, and the risk for alcohol dependence. This study examined the moderating effects of GABRA2 alleles on subjective and physiologic effects of alcohol in healthy social drinkers. We used the alcohol clamp method for alcohol administration, which uses an intravenous infusion of alcohol at rates adjusted online to close the gap between measurements of breath alcohol concentration (BrAC) and the target concentration. The clamp method reduces experimental variance in BrAC (O’Connor et al., 1998) which can be caused by the substantial pharmacokinetic variability following oral alcohol administration. Therefore, the alcohol clamp used in this study is a more exhaustive objective measure than the oral loading of alcohol that was used in the previous study of the effects of GABRA2 on the subjective effects of alcohol assessed only during the ascending limb of the BrAC (Pierucci-Lagha et al., 2005). Our method allowed the evaluation of the initial response to alcohol following the ascending limb of the BrAC as well as the adaptive response to alcohol during the clamped BrAC interval. Based on the previous studies, we hypothesized that GABRA2 alleles would moderate the subjective responses to alcohol measured during not only the ascending limb of BrAC curve but also the clamped BrAC interval. As we expected, subjects with ALDH2*1/*2 showed higher initial response than those with ALDH2*1/*1 (Matsushita et al., manuscript in preparation). Therefore, we divided subjects by ALDH2 genotype and performed further analyses separately in each ALDH2 genotypic group.

Background: Heavy alcohol drinking is implicated in osteoporosis. Although abstinence is rapidly followed by a restoration of osteoblastic activity, little is known about the contributions of alcohol-related factors or the effectiveness of a lifestyle modification program (LMP) on bone density. Methods: We conducted a study of 138 male alcoholic patients to investigate whether drinking history and concurrent factors were associated with the bone density of the calcaneus. A 2.5-months LMP in an institutionalized setting was completed by 20 of them, and its effect on bone density, serum parathyroid hormone (PTH), and 1.25-(OH)2 vitamin D levels were assessed. Results: The patients had a high prevalence of daytime drinking (93.5%), continuous drinking (84.1%), and current smoking (82.0%) with mean duration of alcohol abuse of 30.0 ± 12.8 years. The patients had lower bone density than a reference control group (Z-scores: −0.45 ± 1.02). Multiple stepwise regression analysis identified age, poor activities of daily living (ADL), continuous drinking, absence of liver cirrhosis, depression, and dementia as determinants of low bone density. The bone density of the 20 participants in the LMP improved 2.3% (p = 0.0003) with a more ameliorating effect on bone density than a conventional abstinence therapy (p = 0.014 for interventional effect). The upper normal range of PTH levels at baseline were significantly decreased, and 1.25-(OH)2 vitamin D levels also had a trend toward decrease during the abstinence. Conclusions: Alcoholic patients may have many complications such as poor ADL and dementia, which are independently associated with decreased bone density. The results of this study support the idea that comprehensive approach to lifestyle factors to minimize risk of osteoporosis is the best way to improve bone density.

Objective: Limited neuronal cell loss is seen in the neuropathology of Wernicke’s encephalopathy (WE), but the extent of neuronal damage has not been well studied. Moreover, there is still a debate as to whether alcohol itself causes brain damage in humans. Although, it is difficult to examine the extent of neuronal damage in living patients, recent studies have revealed that total tau protein levels in the cerebrospinal fluid (CSF) reflect the rate of neuronal degeneration. Therefore, we hypothesized that the elevated CSF total tau in patients with WE was due to neuronal damage and thus we examined CSF total tau protein in patients with WE, as well as in those with alcohol withdrawal delirium (WD) and Korsakoff syndrome (KS). We also examined CSF total tau in nonalcohol dependent patients with Alzheimer’s disease (AD) as a disease control. Methods: CSF samples were obtained from 13 acute WE patients with alcohol dependence, 9 WD patients with alcohol dependence and 16 KS patients with alcohol dependence, and from 20 nonalcohol dependent AD patients. CSF was also obtained from 10 of the WE patients after their disease had progressed to the chronic stage. CSF tau protein levels in all samples were determined by sandwich enzyme-linked immunosorbent assay. Tau phosphorylated at threonine 181 (p-tau181) and amyloid β-protein ending at amino acid 42 (Aβ42) in CSF were also determined for comparison between acute WE with AD. Results: Total tau was significantly elevated in acute WE and decreased on long-term follow-up, but was not elevated in WD or KS. The patterns of p-tau181 and Aβ42 differed between acute WE and AD. Conclusions: Intense neuronal cell death occurs transiently in WE, and the mechanism differs from that in AD. Neuronal damage is generally unaccompanied in WD. These results suggest that CSF total tau is a useful biological marker for WE.

R&D studies on the performance as well as on the gas properties of the microMEGAS-based time projection chamber with standard readout were carried out in June 2005 using 4 GeV/c pion beam in a magnetic field from 0 to 1 T at the proton synchrotron beam line at KEK, Japan. Analysis of the electron drift velocity, diffusion constant and point resolution of padrow measurement for MicroMEGAS TPC filled with 95% argon and 5% isobutane gas are presented. The underlying physical mechanism which determines the optimal TPC performance are briefly discussed. Preliminary measurements of gas properties and spatial resolution in close agreement with the analytical calculation and MAGBOLTZ simulation are summarized and presented in this paper.

Aims The purpose of this paper is to outline alcohol availability, alcohol consumption and related harm, alcohol control policy and prevention programmes in Japan, few of which have been discussed in either the Japanese or English literature. Methods Data were collected primarily from the following two sources: statistics and survey results issued by the national government, including surveys funded by the government; and papers published since 2000, identified by searching the MEDLINE and Igaku-Chuo-Zasshi databases. These data were assessed regarding their quality and summarized. Some data presented here were produced specifically for this review. Results Although per capita alcohol consumption has tended to decline for more than 10 years, it has remained at a high level. Diversification of the drinking population has progressed rapidly, specifically in women, among whom alcohol consumption has increased sharply. Cross-sectional data suggest that alcohol consumption is associated with serious health and social consequences. Existing longitudinal data suggest that alcohol-related problems, especially health problems, have increased steadily over the past several decades, with few exceptions, including alcohol-related fatal road traffic accidents. Alcohol policy and prevention programmes have not developed to a level that can control these problems adequately. Specifically, the high availability of alcoholic beverages, including the lack of restrictions on sales and advertising and decreasing prices, are noted. Conclusions This review provides basic information regarding alcohol availability and alcohol consumption and related harm that may facilitate the improvement of existing alcohol control measures in Japan and encourage the development of new alcohol control measures. This research revealed the scarcity of longitudinal data regarding alcohol consumption and its consequences, and the lack of several important variables, such as disability adjusted life years, for improving our understanding of the comprehensive status of alcohol in Japan. Language: en

Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR = 4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.

Background: Gastric carcinoma occurs at a high rate in alcoholic Japanese men. Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/2*2) and macrocytosis (mean corpuscular volume [MCV] ≥ 106 fl) enhance the risk for esophageal carcinoma, which frequently occurs with gastric carcinoma in this population. Whether alcoholism affects Helicobacter pylori-induced chronic atrophic gastritis (CAG) is unknown. Methods: This study of Japanese alcoholic men with (n = 45) and without (n = 281) gastric carcinoma included assessment of H. pylori IgG antibody, serum pepsinogen-confirmed CAG, MCV, and ALDH2 genotype. Results: The gastric carcinoma cases had a significantly higher age-adjusted prevalence of H. pylori-positivity (78%vs 57%), CAG (78%vs 42%), ALDH2*1/2*2 (36%vs 14%), MCV ≥106 fl (38%vs 20%), and concurrent esophageal/oropharyngolaryngeal carcinoma (18%vs 5%) than controls. Among gastric cancer-free controls, the prevalence of CAG was higher than generally reported in Japan, regardless of H. pylori status (H. pylori-positive, 56%vs 35–36% for Japanese general population; H. pylori-negative, 8%vs 1–3%). Alcoholism may accelerate the progression of CAG. Each of these factors increased the risk of gastric carcinoma (ORs = 3.7 for H. pylori-positive, 2.7 for non-severe CAG, 8.7 for severe CAG, 3.5 for ALDH2*1/2*2, 2.5 for MCV ≥106 fl, and 3.7 for concurrent carcinoma). A multivariate analysis showed that CAG and ALDH2*1/2*2 were independently related to the risk of gastric carcinoma. Combinations of CAG and ALDH2*1/2*2 showed greater risks of gastric carcinoma (ORs = 4.0 for non-severe CAG alone, 17.6 for severe CAG alone, 9.7 for ALDH2*1/2*2 alone, 17.1 for non-severe CAG plus ALDH2*1/2*2, and 39.2 for severe CAG plus ALDH2*1/2*2). Conclusions: Combining blood tests for H. pylori, CAG, MCV and ALDH2 genotype could offer a new means of predicting risk of gastric carcinoma in Japanese alcoholic men.

Coping skills training (CST) and cue exposure treatment (CET) have yielded favorable outcomes when used to treat alcoholics. We conducted 6-week inpatient programs that consisted of 9 CST group sessions (n = 117) during 2005-2009 and 9 CST group sessions plus 4 CET group sessions (n = 49) during 2009-2011 and subsequent 1-year letter therapy for Japanese alcoholic men who had relapsed and been readmitted after standard cognitive-behavioral inpatient therapy. When patients received a letter containing encouraging words every 2 weeks, they were asked to reread their CST and CET records and to respond to the letter by marking drinking days on a calendar and naming the skills on a list of the 9 CST themes and CET that were useful for maintaining abstinence during that 2-week period. The estimated percentages of achievement of 30 or fewer drinking days during the one year of letter therapy were 36.1 - 45.8%. 'Non-smoking', '2nd admission', and 'After age-limit job retirement' were significant factors in achieving good outcomes. The 'usefulness' responses for 'Increasing pleasant activities', 'CET', 'Anger management', ' Managing negative thinking', 'Problem solving', and ' Seemingly irrelevant decisions' as percentages of overall responses to the letters were significantly higher, in order of decreasing percentages, in the achiever group than in the non-achiever group, but the differences between the groups in ' Managing urges to drink', ' Drink refusal skills', ' Planning for emergencies', and ' Receiving criticism about drinking' were not significant. The odds ratios for achievement of 30 or fewer drinking days during the 1-year period increased significantly by 1.15 -1.31 fold per 10% increment in the 'usefulness' ratio for 'Increasing pleasant activities'. The difference in percentage achievement between the group treated by CST alone and the group treated by CST plus CET was not significant. In conclusion, some coping skills were more useful for relapse prevention than others in this study population, and addition of CET to CST and subsequent letter therapy did not improve outcomes.

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.