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Immune checkpoint inhibitors (ICIs) have proven clinical benefits in various advanced cancers. However, despite their significant therapeutic efficacy, ICIs induce immune-related adverse events. Among these events, autoimmune meningoencephalitis often has severe effects on patients' outcomes, but its specific clinical features are still unclear. Here, we report two cases of ICI-associated meningoencephalitis with elevated interleukin-6 (IL-6) levels in the cerebrospinal fluid (CSF). A 47-year-old woman (Case 1) with renal cell carcinoma developed severe headache after a seventh nivolumab administration. A neurological examination revealed jolt accentuation signs and hyperreflexia in all extremities. CSF analysis revealed a high IL-6 value (6,620 pg/mL) with marked pleocytosis. A 70-year-old woman (Case 2) who received an initial administration of nivolumab plus ipilimumab for renal cell carcinoma developed alterations of consciousness. She presented with impaired consciousness, neck stiffness, and hyperreflexia in all extremities. CSF analysis demonstrated a high IL-6 value (49.3 pg/mL) with mild pleocytosis. Both patients were treated with steroid pulse therapy (methylprednisolone 1,000 mg/day, 3 days), followed by the administration of oral predonisolone. The symptoms and laboratory findings improved in both cases. CSF IL-6 values were proportional to the severity of meningoencephalitis and other clinical parameters. These findings may help elucidate the mechanisms of central nervous system complications that are caused by ICIs.

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

Aim To elucidate associations among liver disease, lipid profile, body mass index (BMI), ketonuria, and meal skipping under the influence of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) genotypes in men with alcohol dependence. Methods We investigated the associations among these variables in 1768 Japanese men with alcohol dependence. Serum lipid levels were followed up after abstinence. Results The slow-metabolizing ADH1B Arg/Arg genotype and inactive ALDH2 Glu/Lys genotype increased the age- and drinking-adjusted odds ratio or regression coefficient for fatty liver, ketonuria, and serum high-density-lipoprotein cholesterol levels (HDL-C), and decreased these for cirrhosis and serum triglyceride levels (TG). The ADH1B Arg/Arg genotype increased the adjusted regression coefficient for BMI and non-HDL-C. In addition to the positive interlinkage among fatty liver, BMI, and atherogenic dyslipidemia, positive associations were observed of fatty liver with ketonuria and meal skipping, of cirrhosis with the BMI, and of ketonuria with non-HDL-C. Negative associations were observed of cirrhosis with fatty liver, TG, non-HDL-C, and HDL-C, and of ketonuria with BMI and TG. Overall, after admission for 4 or 6 weeks, the TG and HDL-C decreased, and the serum low-density lipoprotein cholesterol levels increased. However, there was no change of the serum low-density lipoprotein in the patients with cirrhosis or of the serum TG in those with fatty liver. Conclusions These associations and the alterations in lipid profile after abstinence serve as useful information for a better understanding of the clinical features of men with alcohol dependence.

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.

Background and Aims Since 2008, a plethora of research studies has compared the efficacy of water-assisted (aided) colonoscopy (WAC) and underwater resection (UWR) of colorectal lesions with standard colonoscopy. We reviewed and graded the research evidence with potential clinical application. We conducted a modified Delphi consensus among experienced colonoscopists on definitions and practice of water immersion (WI), water exchange (WE), and UWR. Methods Major databases were searched to obtain research reports that could potentially shape clinical practice related to WAC and UWR. Pertinent references were graded (Grading of Recommendations, Assessment, Development and Evaluation). Extracted data supporting evidence-based statements were tabulated and provided to respondents. We received responses from 55 (85% surveyed) experienced colonoscopists (37 experts and 18 nonexperts in WAC) from 16 countries in 3 rounds. Voting was conducted anonymously in the second and third round, with ≥80% agreement defined as consensus. We aimed to obtain consensus in all statements. Results In the first and the second modified Delphi rounds, 20 proposed statements were decreased to 14 and then 11 statements. After the third round, the combined responses from all respondents depicted the consensus in 11 statements (S): definitions of WI (S1) and WE (S2), procedural features (S3-S5), impact on bowel cleanliness (S6), adenoma detection (S7), pain score (S8), and UWR (S9-S11). Conclusions The most important consensus statements are that WI and WE are not the same in implementation and outcomes. Because studies that could potentially shape clinical practice of WAC and UWR were chosen for review, this modified Delphi consensus supports recommendations for the use of WAC in clinical practice.

Background: Adiponectin has been implicated in the pathophysiology of dementia, especially Alzheimer’s disease. However, the association between cerebrospinal fluid (CSF) adiponectin levels and positron emission tomography (PET) imaging remains unclear. Objective: To explore whether CSF adiponectin levels are associated with 11C-Pittsburgh compound B (PiB) or 18F-fluorodeoxyglucose (FDG) uptake in amnestic mild cognitive impairment (MCI) subjects. Methods: Thirty-four amnestic MCI subjects underwent PiB-PET, FDG-PET, and CSF analysis. The CSF adiponectin levels were measured using the Bio-Plex 200 suspension array system. PET uptake was assessed for the frontal and temporoparietal lobes and posterior cingulate gyrus, referenced against the cerebellar cortex. The increased brain amyloid burden was defined as a mean uptake value ratio greater than 1.4. Spearman’s rank correlation analysis and a multiple regression model were used to examine the association between CSF adiponectin levels and PiB or FDG uptake. Results: The mean age was 76.3 years; 38.2% were men, and 61.8% were women. A high amyloid burden was identified in 18 (52.9%) subjects. CSF adiponectin levels positively correlated with global FDG uptake (β = 0.45; 95% confidence interval (CI), 0.13 to 0.76, p < 0.01), especially in the parietotemporal lobe and posterior cingulate gyrus (β = 0.70; 95% CI, 0.41 to 0.99, p Conclusion: CSF adiponectin levels were associated with cortical glucose metabolism, particularly in the specific regions that connect with the medial temporal, but not brain amyloid burden in amnestic MCI subjects.

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984, His48Arg) and aldehyde dehydrogenase-2 (ALDH2; rs671, Glu504Lys) affect body weight, body fat, and lipid metabolism in individuals with alcohol dependence, and the aim of this study was to identify their determinants in relation to the development of fatty liver. We evaluated associations between the presence of fatty liver and ADH1B and ALDH2 genotypes and other factors in 1604 Japanese men who had been admitted for treatment of alcohol dependence. Fatty liver was diagnosed when ultrasonography showed both hepatorenal contrast and liver brightness. Age-adjusted usual alcohol intake did not differ according to ADH1B or ALDH2 genotypes. A multivariate analysis showed that the adjusted odds ratio (OR, 95% confidence interval) of slow-metabolizing ADH1B Arg/Arg carriers was 1.61 (1.27–2.03) for fatty liver and 1.82 (1.37–2.41) for fatty liver with deep attenuation in comparison with the ADH1B His/Arg or His/His carriers, and that the OR of inactive heterozygous ALDH2 Glu/Lys carriers was 1.43 (1.08–1.91) for fatty liver and 1.84 (1.31–2.59) for fatty liver with deep attenuation in comparison with the ALDH2 Glu/Glu carriers. Younger age, shorter interval between the last drink and the ultrasound examination, larger body mass index, and absence of cirrhosis were identified as other positive determinants for fatty liver. The ADH1B Arg/Arg genotype and the ALDH2 Glu/Lys genotype were positive determinants of fatty liver in the subjects. These results suggest that slow ethanol and acetaldehyde metabolism accelerates the development of alcoholic fatty liver in heavy drinkers.

Soft palatal melanosis can be detected by visual inspection during routine physical examination or even personally in a mirror. The aim of this study was to evaluate the association between squamous cell neoplasia in the upper aerodigestive tract (UAT) and soft palatal melanosis. We reviewed digitized records of high‐quality endoscopic images of the soft palate of 1786 Japanese alcoholic men who underwent endoscopic screening. Soft palatal melanosis was observed in 381 (21.3%) of the subjects (distinct, 6.3%). Older age, an inactive heterozygous aldehyde dehydrogenase‐2 genotype, smoking, and a high mean corpuscular volume were positively associated with the presence of soft palatal melanosis. The age‐adjusted odds ratio (95% confidence interval) for UAT neoplasia was 1.92 (1.40–2.64) in the group with melanosis and 2.51 (1.55–4.06) in the group with distinct melanosis, compared with the melanosis‐free group. A multivariate analysis showed that the presence of soft palatal melanosis was independently associated with a high risk of UAT neoplasia. We calculated the individual number of risk factors out of four easily identifiable and significant factors: age ≥55 years, current/former alcohol flushing, mean corpuscular volume ≥106 fL, and distinct soft palatal melanosis. Compared with the risk‐factor‐free condition, the odds ratio (95% confidence interval) values of UAT neoplasia for one, two, three, and four risk factors were 1.49 (0.97–2.30), 3.14 (2.02–4.88), 4.80 (2.71–8.51), and 7.80 (2.17–28.1), respectively. The presence of soft palatal melanosis provides a simple new strategy for identifying heavy drinkers with a high risk for UAT neoplasia.

Background/Aims: Colonoscopy and computed tomography (CT) are used primarily to exclude organic diseases in patients with irritable bowel syndrome (IBS), rather than to assess the pathophysiology of IBS. We aimed to evaluate colonic dysmotility and morphology in Japanese patients with IBS.Methods: One hundred eighty-four patients with IBS and 49 asymptomatic controls who underwent colonoscopy in combination with CT colonography or barium enema were retrospectively reviewed between 2008 and 2012. Water-aided colonoscopy was performed without sedation by a single endoscopist. The duration and pattern of colonic movement and cecal intubation time were recorded. To assess colonic morphology, barium enema or CT colonography were performed immediately after colonoscopy.Results: Colonic dysmotility was more frequent in the IBS group (28.8% vs. 2.0% in controls, P

Background The combination of the fast-metabolizing alcohol dehydrogenase-1B (ADH1B*2 allele) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increases susceptibility to macrocytic anemia and leukocytopenia in alcoholics due to severe acetaldehydemia. More than half of Japanese drinkers with esophageal cancer have this genotype combination. Methods To assess the recovery of hematologic abnormalities after drinking cessation, changes in blood erythrocyte indices and leukocyte count during 8-week hospital stay were evaluated in 925 Japanese alcoholic men. We used four categories in ascending order for high blood acetaldehyde exposure from drinking: A, ADH1B*1/*1 plus ALDH2*1/*1; B, ADH1B*2 plus ALDH2*1/*1; C, ADH1B*1/*1 plus ALDH2*1/*2; and D, ADH1B*2 plus ALDH2*1/*2. Results Mean values of hemoglobin and hematocrit were the lowest, and those of mean corpuscular volume (MCV) were markedly the highest in the D group on admission, and returning toward normal after abstinence, but the inter-group differences remained significant throughout the 8 weeks. The mean leukocyte count was the lowest in the D group on admission, but increased during 4-week abstinence when the inter-group differences were no longer significant. Frequencies of MCV ≥110 fl (50.5%), hemoglobin levels

BackgroundThe presence of large or multiple esophageal distinct iodine-unstained lesions (DIULs) is a strong predictor of field cancerization in the upper aerodigestive tract. Several risk factors for DIULs, including genetic polymorphisms of alcohol and aldehyde dehydrogenases (ADH1B, rs1229984; ALDH2, rs671), have been demonstrated in Japanese alcohol-dependent men. However, few evaluations of alcohol-dependent women have been conducted in this field.MethodsUsing multiple logistic regression models, we investigated the results of screening using esophageal iodine staining and the identification of determinants for esophageal DIULs in 472 Japanese alcohol-dependent women.ResultsDIULs ≥5 mm, multiple DILUs, and both characteristics were observed in 35 (7.4%), 31 (6.6%), and 16 (3.4%) patients, respectively. DIULs ≥5 mm were histologically diagnosed as low-grade intraepithelial neoplasia in 26 patients and superficial squamous cell carcinoma in 9 patients. Although the inactive heterozygous ALDH2*1/*2 genotype was more common (33.3% vs. 11.4%, p = 0.002) in the group with DIULs ≥5 mm than in the group without DIULs ≥5 mm, no significant differences in the results of a questionnaire asking about current and past facial flushing after a glass of beer were seen between the groups with and without DIULs ≥5 mm. When individuals with current or former flushing were assumed to have inactive ALDH2, the sensitivity and specificity of current or former flushing to identify the presence of inactive ALDH2 were 50.0% and 93.5%, respectively; these values were previously reported to be 88% and 92%, respectively, in a Japanese general female population. The low sensitivity in the present study suggests that a lack of alcohol flushing may play a crucial role in the development of alcohol dependence in women with inactive ALDH2. No significant differences in age, usual alcohol consumption, or smoking habits were observed according to ADH1B and ALDH2 genotypes. Multiple logistic regression analyses showed that the slow-metabolizing ADH1B*1/*1 genotype (odds ratio [95% confidence interval], 12.5 [4.82-32.4] and 9.89 [3.50-27.9]), the inactive heterozygous ALDH2*1/*2 genotype (2.94 [1.18-7.38] and 3.79 [1.40-10.3]), a lower body mass index per -1 kg/m2 (1.17 [1.02-1.35] and 1.38 [1.14-1.67]), and a mean corpuscular volume ≥106 fl (3.70 [1.56-8.81] and 3.27 [1.24-8.64]) increased the risk of DIULs ≥5 mm and multiple DIULs, respectively. The combination of ADH1B*1/*1 and ALDH2*1/*2 markedly increased the risk of esophageal DIULs ≥5 mm (39.3 [10.6-146]).ConclusionsJapanese alcohol-dependent women shared several common risk factors for esophageal squamous cell neoplasia with alcohol-dependent men, but with considerably different magnitudes.

Aims The importance of ethanol oxidation by intestinal aerobes and facultative anaerobes under aerobic conditions in the pathogenesis of ethanol-related colorectal cancer has been proposed. However, the role of obligate anaerobes therein remains to be established, and it is still unclear which bacterial species, if any, are most important in the production and/or elimination of carcinogenic acetaldehyde under such conditions. This study was undertaken to address these issues. Methods More than 500 bacterial strains were isolated from the faeces of Japanese alcoholics and phylogenetically characterized, and their aerobic ethanol metabolism was studied in vitro to examine their ability to accumulate acetaldehyde beyond the minimum mutagenic concentration (MMC, 50 µM). Results Bacterial strains that were considered to potentially accumulate acetaldehyde beyond the MMC under aerobic conditions in the colon and rectum were identified and referred to as ‘potential acetaldehyde accumulators’ (PAAs). Ruminococcus , an obligate anaerobe, was identified as a genus that includes a large number of PAAs. Other obligate anaerobes were also found to include PAAs. The accumulation of acetaldehyde by PAAs colonizing the colorectal mucosal surface could be described, at least in part, as the response of PAAs to oxidative stress. Conclusion Ethanol oxidation by intestinal obligate anaerobes under aerobic conditions in the colon and rectum could also play an important role in the pathogenesis of ethanol-related colorectal cancer.

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

Background and Aim Although intestinal obstruction as a result of sigmoid volvulus (SV) may be successfully resolved using endoscopic detorsion, surgical treatment remains the main therapeutic strategy. We evaluated the endoscopic detorsion procedure using unsedated water-immersion colonoscopy for the treatment of SV. Methods A retrospective chart review was conducted on the clinical background and prognosis of 21 SV patients who underwent 71 endoscopic detorsion procedures using unsedated, water-immersion colonoscopy. Results In all, 14 (67%) male and seven (33%) female patients, with a mean age of 73 years (range, 54–95 years) were enrolled; 86% were >70 years of age. Among these patients, 90% had a background of key predisposing factors. In the 21 patients, endoscopic detorsion was successfully done using unsedated water-immersion colonoscopy. SV recurred in 10 patients at a median of 180 days. Endoscopic detorsion for recurrent SV was successfully achieved in all cases, and none of the secondary cases became severe. Only male patients were observed to experience three or more recurrent episodes of SV. Conclusions SV occurred most commonly in elderly patients with a surgical risk. Our experience suggests that conservative endoscopic treatment using unsedated water-immersion colonoscopy is a safe, reasonable, conservative endoscopic approach for elderly patients in the absence of necrotic findings. We currently use this procedure in most of our cases.

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.

Aims Alcohol consumption increases the risk of colorectal adenoma and cancer. The fecal immunochemical test (FIT) is a widely used screening method for detecting colorectal neoplasia. We evaluated the results of screening and risk factors for colorectal neoplasia in individuals with alcohol dependence. Methods Total colonoscopic screening was performed for 1006 Japanese men with alcohol dependence (462 FIT-positive and 544 FIT-negative). Advanced neoplasia was defined as neoplasia ≥10 mm, villous or tubulovillous adenoma, high-grade adenoma, or carcinoma. Results The detection rates for non-advanced adenoma, advanced neoplasia and intramucosal or invasive carcinoma were 38.7%, 39.4% and 9.7% for the FIT-positive group, and 33.3%, 10.8% and 2.2% for the FIT-negative group, respectively. Advanced neoplasia, especially carcinoma, was detected more frequently in the distal colon than in the proximal colon in the FIT-positive group. The respective multivariate odds ratios (ORs; 95% confidence interval) for non-advanced adenoma and advanced neoplasia were 2.83 (2.06–3.88) and 9.13 (6.19–13.5) for a positive FIT (vs. negative), 1.68 (1.39–2.02) and 1.83 (1.45–2.30) for age (per +10 years), 1.54 (1.06–2.23) and 1.88 (1.17–3.03) for current smoking (vs. non-smokers), and 1.35 (0.96–1.92) and 1.59 (1.02–2.48) for the presence of marked macrocytosis (mean corpuscular volume ≥106 fl vs.

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.

Chronic consumption of excess ethanol increases the risk of colorectal cancer. The pathogenesis of ethanol-related colorectal cancer (ER-CRC) is thought to be partly mediated by gut microbes. Specifically, bacteria in the colon and rectum convert ethanol to acetaldehyde (AcH), which is carcinogenic. However, the effects of chronic ethanol consumption on the human gut microbiome are poorly understood and the role of gut microbes in the proposed AcH-mediated pathogenesis of ER-CRC remains to be elaborated. Here we analyse and compare the gut microbiota structures of non-alcoholics and alcoholics. The gut microbiotas of alcoholics were diminished in dominant obligate anaerobes (e.g., Bacteroides and Ruminococcus) and enriched in Streptococcus and other minor species. This alteration might be exacerbated by habitual smoking. These observations could at least partly be explained by the susceptibility of obligate anaerobes to reactive oxygen species, which are increased by chronic exposure of the gut mucosa to ethanol. The AcH productivity from ethanol was much lower in the faeces of alcoholic patients than in faeces of non-alcoholic subjects. The faecal phenotype of the alcoholics could be rationalised based on their gut microbiota structures and the ability of gut bacteria to accumulate AcH from ethanol.

症例は74歳女性．平成15年頃に肝硬変（C型）と糖尿病を指摘された．平成18年に肝細胞癌を発症し，以後4回肝動脈化学塞栓療法（TACE）を施行した．その後の腹部CTで左葉外側区と肝S8に約2 cmの肝細胞癌再発が疑われた．平成19年10月30日，血管造影検査にて肝細胞癌と診断され，TACEを施行された．術後より頻回の嘔吐と心窩部痛，術後4日目より38度台の発熱を認め，対症療法を行った．術後6日目深夜に心肺停止状態で発見され，心肺蘇生術に反応せず死亡した．急変時は著明な貧血と黄疸を示しており，同日病理解剖を行った． マクロ所見では明らかな臓器出血は認めなかったが，大動脈は赤褐色を呈していた．ミクロ所見では全身の各臓器にグラム陽性桿菌の増殖を認めた．術後5日目の血液培養よりClostridium perfringens（C. perfringens）が検出され，同菌による敗血症と発作性溶血が今回の死因と考えられた．TACE後にC. perfringens敗血症となり，急激な溶血を伴った症例の報告は少なく，今回若干の文献的考察も加えて報告する．

We investigated the development of esophageal neoplasia in biopsy specimens of the distinct iodine-unstained lesions (DIULs) ≥ 5 mm detected in 280 of 2,115 Japanese alcoholic men who underwent screening by esophageal iodine staining. Low-grade intraepithelial neoplasia (LGIN) was diagnosed in 155 of them, high-grade intraepithelial neoplasia (HGIN) in 57, and invasive SCC in 35. The size of the DIULs increased with the degree of neoplasia. Most LGINs were flat and were missed before iodine staining. Some DIULs became a light pink color (PC) about 2 min after staining, and 2.6, 56.1 and 96.0% of the LGIN, HGIN and invasive SCC lesions, respectively, were PC-sign-positive. Multiple DIULs of any size markedly increased the risk of LGIN [adjusted OR (95%CI) = 10.1 (7.12-14.5)], HGIN [27.9 (14.6-53.4)] and invasive SCC [21.6 (10.1-46.4)], and were strongly associated with the presence vs. absence of DIULs ≥ 5 mm [13.3 (9.21-19.1)], inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) vs. ALDH2*1/*1 [2.60 (1.79-3.78)], and less-active alcohol dehydrogenase-1B (ADH1B*1/*1) vs. ADH1B*2 allele [2.61 (1.87-3.64)]. The combination of ALDH2*1/*2 and ADH1B*1/*1 synergistically increased the risk of LGIN [4.53 (2.17-9.47)], HGIN [10.4 (4.34-24.7)] and invasive SCC [21.7 (7.96-59.3)]. Esophageal neoplasia developed at earlier ages in those with ALDH2*1/*2. Biopsy-proven HGIN was diagnosed as invasive SCC in 15 (39.5%) of 38 patients after endoscopic mucosectomy or surgery. In conclusion, large size, non-flat appearance, positive PC sign and multiplicity of DIULs and ALDH2*1/*2 and ADH1B*1/*1 were associated with development of esophageal neoplasia in Japanese alcoholics. Biopsy-proven HGIN should be totally resected for both diagnostic and therapeutic purposes.

Large colonic polyps have large vessels, which often cause post-polypectomy hemorrhage. Some of the stalks of large pedunculated polyps are formed by the weight of the polyps and disappear after polypectomy. There are some reports suggesting that pre-ligation with Endoloop(R) may minimize the risk of post-polypectomy hemorrhage. However, the current density increases more at the site of pre-ligation as compared with that at the site of polypectomy, because polypectomy is carried out with gradual snaring. This implies that burn injury may also occur at the site of pre-ligation, causing the loss of pre-ligation and, consequently, post-polypectomy hemorrhage. Ligation of stalks after polypectomy is very difficult. The Endoloop(R) rolls back when it is tightened, because of the lack of torsional stiffness. We have developed a simple and improved post-polypectomy ligation technique using the Anchor clip. Before polypectomy, an Endoclip(R) is placed partially at the base of the pedunculated polyp. When the stalk is tightened completely with the Endoclip(R) before polypectomy, burn injury occurs around the Endoclip(R) . The Anchor clip at the base of the pedunculated polyp holds the stalk after polypectomy and the constricted part formed by the Anchor clip prevents the rolling up of the Endoloop(R) and helps in easy ligation of the stalk. We have used the Anchor clip for 50 patients. Application of the Endoloop(R) after polypectomy was impossible in two patients. The remaining 48 patients underwent Endoloop(R) -assisted polypectomy with the Anchor clip, and in none of the cases did bleeding occur after polypectomy.

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.

Colonoscopy is a difficult examination to conduct for inexperienced examiners. In an attempt to improve the view, there is often a tendency to overinsufflate air, which causes elongation or acute angulations of the colon and makes passage of the scope difficult. Sakai et al. were the first to describe a simple colonoscopic technique using water infusion instead of air insufflation. We have modified this technique to simplify the procedure further by combining water infusion using disposable syringes with complete air suction from the rectum to the descending colon. With the resultant elimination of the boundary lines between water and air, a good view of the lumen is obtained though the transparent water. With the patient in the left lateral position, this procedure allows the water to flow straight down into the descending colon through the ‘collapsed’ lumen, and the scope to be easily negotiated through the straightened recto-sigmoid colon and sigmoid-descending colon junction with minimum discomfort. Measurements of the patients’ abdominal circumference during colonoscopy showed that colonic distension hardly occurred. Under supervision by the author, six complete novices were allowed to insert the colonoscope within 10 min by this method for one patient per week, as long as the patients did not complain of pain. The average trial number for the first cecal intubation within 10 min was 3.3, and the average success rate during the first 3 months was 58.6%. We believe that this ‘collapse-submergence method’ is easy to master, even for inexperienced examiners.

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.

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.

1542 Background: Squamous cell dysplasia and carcinoma in the upper aerodigestive tract (UAT) was frequently accompanied by melanosis in the UAT. Soft palatal melanosis can be detected by visual inspection during routine physical examination or even personally in a mirror. Methods: We reviewed digitalized records of high-quality endoscopic images of the soft palate of 1786 Japanese alcoholic men who underwent endoscopic screening combined with esophageal iodine staining and evaluated to what extent the presence of soft palatal melanosis combined with other risk factors can predict the risk of UAT neoplasia. Results: Soft palatal melanosis was observed in 381 (21·3%) of the subjects (mild, 15·0%; distinct, 6·3%). An older age, an inactive heterozygous aldehyde dehydrogenase-2 genotype, smoking, and a high mean corpuscular volume (MCV) were positively associated with the presence of soft palatal melanosis. The age-adjusted odds ratio (OR [95% CI]) for neoplasia in the UAT was 1·92 [1·40–2·64] in the group with melanosis and 2·51 (1·55–4·06) in the group with distinct melanosis, compared with the melanosis-free group. A multiple logistic analysis including the alcohol and aldehyde dehydrogenases genotypes and non-genetic risk factors showed that the presence of soft palatal melanosis was independently associated with a high risk of neoplasia in the UAT. We calculated the individual number of risk factors out of four easily identifiable and significant factors: age ≥55 years, current/former alcohol flushing, MCV ≥106 fl, and distinct soft palatal melanosis. Compared with the risk-factor-free condition, the OR (95% CI) values of UAT neoplasia for one, two, three and four risk factors were 1·49 (0·97–2·30), 3·14 (2·02–4·88), 4·80 (2·71–8·51) and 7·80 (2·17–28·1), respectively. Conclusions: Soft palatal melanosis combined with other simple risk assessments provides a simple new strategy for identifying heavy drinkers with a high risk for UAT neoplasia.

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) modulate exposure levels to ethanol/acetaldehyde. Endoscopic screening of 6,014 Japanese alcoholics yielded high detection rates of esophageal squamous cell carcinoma (SCC; 4.1%) and head and neck SCC (1.0%). The risks of upper aerodigestive tract SCC/dysplasia, especially of multiple SCC/dysplasia, were increased in a multiplicative fashion by the presence of a combination of slow-metabolizing ADH1B*1/*1 and inactive heterozygous ALDH2*1/*2 because of prolonged exposure to higher concentrations of ethanol/acetaldehyde. A questionnaire asking about current and past facial flushing after drinking a glass (≈180 mL) of beer is a reliable tool for detecting the presence of inactive ALDH2. We invented a health-risk appraisal (HRA) model including the flushing questionnaire and drinking, smoking, and dietary habits. Esophageal SCC was detected at a high rate by endoscopic mass-screening in high HRA score persons. A total of 5.0% of 4,879 alcoholics had a history of (4.0%) or newly diagnosed (1.0%) gastric cancer. Their high frequency of a history of gastric cancer is partly explained by gastrectomy being a risk factor for alcoholism because of altered ethanol metabolism, e.g., by blood ethanol level overshooting. The combination of H. pylori-associated atrophic gastritis and ALDH2*1/*2 showed the greatest risk of gastric cancer in alcoholics. High detection rates of advanced colorectal adenoma/carcinoma were found in alcoholics, 15.7% of 744 immunochemical fecal occult blood test (IFOBT)-negative alcoholics and 31.5% of the 393 IFOBT-positive alcoholics. Macrocytosis with an MCV≥106 fl increased the risk of neoplasia in the entire aerodigestive tract of alcoholics, suggesting that poor nutrition as well as ethanol/acetaldehyde exposure plays an important role in neoplasia.

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) modulate exposure levels to ethanol/acetaldehyde. Endoscopic screening of 6,014 Japanese alcoholics yielded high detection rates of esophageal squamous cell carcinoma (SCC; 4.1 %) and head and neck SCC (1.0 %). The risks of upper aerodigestive tract SCC/dysplasia, especially of multiple SCC/dysplasia, were increased in a multiplicative fashion by the presence of a combination of slow-metabolizing ADH1B*1/*1 and inactive heterozygous ALDH2*1/*2 because of prolonged exposure to higher concentrations of ethanol/acetaldehyde. A questionnaire asking about current and past facial flushing after drinking a glass (≈ 180 mL) of beer is a reliable tool for detecting the presence of inactive ALDH2. We invented a health-risk appraisal (HRA) model including the flushing questionnaire and drinking, smoking, and dietary habits. Esophageal SCC was detected at a high rate by endoscopic mass-screening in high HRA score persons. A total of 5.0 % of 4,879 alcoholics had a history of (4.0 %) or newly diagnosed (1.0 %) gastric cancer. Their high frequency of a history of gastric cancer is partly explained by gastrectomy being a risk factor for alcoholism because of altered ethanol metabolism, e.g., by blood ethanol level overshooting. The combination of H. pylori-associated atrophic gastritis and ALDH2*1/*2 showed the greatest risk of gastric cancer in alcoholics. High detection rates of advanced colorectal adenoma/carcinoma were found in alcoholics, 15.7 % of 744 immunochemical fecal occult blood test (IFOBT)-negative alcoholics and 31.5 % of the 393 IFOBT-positive alcoholics. Macrocytosis with an MCV ≥ 106 fl increased the risk of neoplasia in the entire aerodigestive tract of alcoholics, suggesting that poor nutrition as well as ethanol/acetaldehyde exposure plays an important role in neoplasia.

Background: We examined the effects of glutathione depletion on the level of superoxide anion released into hepatic sinusoids after lipopolysaccharide challenge. Methods: Rats were given 1 mg/kg of maleic acid diethyl ester to deplete glutathione in vivo and then 0.5 mg/kg body weight of lipopolysaccharide. Results: This treatment significantly depleted serum reduced glutathione (32.7 ± 1.7 vs. 23.0 ± 3.2 mM, p = 0.002). However, it did not affect the serum oxidized glutathione concentration (2.88 ± 0.56 vs. 3.10 ± 0.78 mM, not significant). The lipopolysaccharide challenge caused significant superoxide anion formation as compared with controls (0.12 ± 0.04 vs. 0.22 ± 0.05 o.d.,p

Background/Aims: The aim of this study was to determine whether the spleen contributes to superoxide anion release into the hepatic sinusoids and subsequent damage to endothelial cells of the hepatic sinusoids after lipopolysaccharide challenge. Methods: Rats were given 2 mg/kg body weight lipopolysaccharide. Three hours after the treatment, superoxide anion release into the hepatic sinusoids was examined in a liver perfusion model using the cytochrome C method. Damage to endothelial cells of the hepatic sinusoids was assessed from the purine nucleoside phosphorylase/glutamic-pyruvic transaminase ratio in the liver perfusate. To further characterize the mechanisms behind these changes, these studies were done in rats given superoxide dismutase or an anti-TNFα antibody. To study whether the spleen plays a role in the mechanisms, experiments with splenectomized rats were performed. Results: Lipopolysaccharide challenge resulted in superoxide anion release into the hepatic sinusoids and damage to endothelial cells of the hepatic sinusoids. These changes were significantly attenuated by the treatments with superoxide dismutase or an antibody against TNFα, as well as by splenectomy. The hepatic macrophage and Kupffer cell populations after lipopolysaccharide challenge were significantly smaller in the rats given splenectomy than in those given a sham operation. There were no significant differences in the neutrophil populations between the two groups. Levels of TNFα were significantly lower in the former than the latter, whereas there were no significant differences in levels of Interleukin-8 between the two groups. Conclusions: Splenectomy reduced the superoxide anion release into the hepatic sinusoids caused by the lipopolysaccharide challenge and subsequent damage to endothelial cells of the hepatic sinusoids. This supports the view that splenectomy has a protective effect in lipopolysaccharide-induced liver injury.