bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetic Resonance Relaxometry Reveals Central Pontine Abnormalities in Clinically Asymptomatic Alcoholic Men
Authors: Sullivan Edith V. , Pfefferbaum Adolf
Published: April 2006

Background: Central pontine myelinolysis (CPM) is a rare, debilitating, life‐threatening condition, associated with chronic alcoholism, rapid correction of hyponatremia, and advanced age. It is unknown, however, whether older alcoholic patients who by age and diagnosis are at risk for CPM have objectively determined neuroimaging evidence of preclinical CPM that could be valuable in understanding its development and in initiating appropriate treatment. Accordingly, we examined central pontine magnetic resonance (MR) transverse relaxation time (T2), which reflects myelin and axonal integrity when measured in white matter and is prolonged with pathology that causes increased free water content in tissue.

Methods: The subjects were 46 alcoholic men who were abstinent from alcohol for about 1 month and were asymptomatic for CPM, 9 men and 1 woman with alcoholic Korsakoff's syndrome (KS), and 74 healthy control men. All subjects received coronally acquired dual‐echo MR imaging (MRI), from which T2 times were calculated in central pons. MRI films were read clinically and independently of relaxometry results. Hematological and neuropsychological data were also available for many subjects.

Results: Only the KS group showed prolonged T2 times; however, pontine T2 prolongation increased significantly with older age in the asymptomatic alcoholics but not controls. Clinical radiological readings detected pontine signal hyperintensity in five KS subjects (two without dementia and three with dementia), one control, and no alcoholic patient. Hematologic indexes of macrocytic anemia and nutritional deficiency and neuropsychological measures of verbal and nonverbal fluency correlated with prolonged T2 times in alcoholic men.

Conclusions: This CPM‐like condition, manifest as prolonged T2, may occur with higher incidence than previously thought in clinically asymptomatic alcoholism and may contribute to neuropsychological compromise of initiation and production. Preclinical detection of abnormal pontine signal properties with MR relaxometry may identify patients at high risk for developing CPM.
Association of the ADH2 Genotypes With Skin Responses After Ethanol Exposure in Japanese Male University Students
Authors: Takeshita Tatsuya , Yang Xing , Morimoto Kanehisa
Published: April 2006

Background: A contribution of the alcohol dehydrogenase‐2 (ADH2) polymorphism to alcohol sensitivity and alcohol drinking behavior is still controversial. In this study, we examined the effects of the ADH2 genotypes on skin reactions to ethanol and habitual alcohol intake among Japanese male university students, controlling for the effects of the low Km aldehyde dehydrogenase (ALDH2) genotype, as an extension of our previous study.

Methods: The study subjects were 357 Japanese male students [average age (mean ± SD) was 23.7 ± 3.0 years] in a medical university. The subjects completed a questionnaire regarding self‐reported alcohol‐associated symptoms and alcohol‐drinking behavior. The ADH2 and ALDH2 genotypes were determined through digestion of polymerase chain reaction products by restriction enzymes. All subjects participated in the ethanol patch test. We observed skin responses at 0, 5, 15, and 20 min after removal of the tape.

Results: Among the ALDH2*1/*1 genotypes, only some subjects with ADH2*1/*2 or ADH2*2/*2 exhibited a positive response, which increased with increasing time after the removal. However, none of comparisons between the different ADH2 genotypes reached statistical significance. Among the ALDH2*1/*2 genotypes, those with ADH2*1/*2 or ADH2*2/*2 showed a significant increase in response with increasing time after the removal and revealed a significantly higher positivity rate at 15 min than those with ADH2*1/*1. In those with the ALDH2*1/*2 genotype, the positive rate of facial flushing with one glass of beer was higher in those with ADH2*1/*2 and ADH2*2/*2 than those with ADH2*1/*1, although this was not significant. However, the ADH2 genotype did not seem to influence drinking frequency or amounts of alcohol intake in each ALDH2 genotype.

Conclusions: This study finds further evidence for a contribution of the ADH2 polymorphism to skin reactions after either local or systemic ethanol exposure in Asian people. However, the effects of the ADH2 polymorphism may be mild because this polymorphism does not seem to influence alcohol drinking behavior in these study subjects.
Acamprosate Is Neuroprotective Against Glutamate‐Induced Excitotoxicity When Enhanced by Ethanol Withdrawal in Neocortical Cultures of Fetal Rat Brain
Authors: Al Qatari Mona , Khan Shabeena , Harris Barton , Littleton John
Published: April 2006

Background: Acamprosate reduces relapse, and the drug may interact with glutamate transmission and with glutamate/NMDA receptors. Because these systems are implicated in excess calcium entry leading to alcohol withdrawal–induced neurotoxicity, we evaluated the effects of acamprosate on these parameters in neuronal cultures.

Methods: Primary cultures of neocortical neurons from fetal Sprague‐Dawley rats were maintained either in normal medium or in medium containing 100 mM ethanol for 4 days. After this time, cultures were challenged with glutamate for 10 min and then returned to medium (all in the absence of ethanol). 45Ca2+ uptake was measured during the challenge, and glutamate‐induced toxicity was assessed after 20 hr. The effects of acamprosate present during the glutamate challenge were measured on both parameters.

Results: In controls, acamprosate did not significantly affect glutamate‐induced neurotoxicity but produced a significant inhibition of calcium entry. The NMDA receptor antagonists dizocilpine and d‐amino‐phosphonovalerate (D‐APV) inhibited both glutamate neurotoxicity and calcium entry. In cultures previously exposed to ethanol, glutamate‐induced neurotoxicity and calcium entry were both significantly enhanced. Dizocilpine reduced both these parameters to unstimulated control values, and D‐APV reduced both calcium entry and neurotoxicity with the same relation that we obtained in control cultures. In the ethanol‐withdrawn cultures, acamprosate reduced both the enhanced glutamate‐induced calcium entry and the enhanced neurotoxicity in a concentration‐dependent manner. Acamprosate also significantly reduced calcium entry caused by 80 mM K+ in control and ethanol‐exposed cultures.

Conclusions: Acamprosate had protective effects against glutamate‐induced neurotoxicity only in ethanol‐withdrawn cultures. The neuroprotective effects of the drug did not correlate with its effects on calcium entry, making it unlikely that acamprosate directly affects NMDA receptors via the glutamate binding site or the receptor‐operated calcium channel. The results are, however, compatible with other inhibitory effects on NMDA receptor function.
Alcohol‐Naïve Alcohol‐Preferring (P) Rats Exhibit Higher Local Cerebral Glucose Utilization Than Alcohol‐Nonpreferring (NP) and Wistar Rats
Authors: Smith D.G. , Learn J.E. , McBride W.J. , Lumeng L. , Li T.‐K. , Murphy J.M.
Published: April 2006

Background: The present study determined local cerebral glucose utilization (LCGU) rates in alcohol‐naïve alcohol‐preferring (P), alcohol nonpreferring (NP), and outbred Wistar rats to test the hypothesis that innate differences in functional neuronal activity are present in limbic regions as a result of selective breeding for high‐alcohol drinking behavior.

Methods: All procedures were conducted during the dark cycle. 2‐[14C]deoxyglucose ([14C]2‐DG; 125 μCi/kg) was injected intravenously and timed arterial blood samples were collected during the following 45 min and assayed for glucose and [14C]2‐DG content. Rats were then decapitated, the brains removed and frozen to −70°C, and 20 μm coronal sections were prepared for quantitative autoradiographic analysis.

Results: Rates of LCGU were determined in 55 regions and subregions, including limbic, cortical, and subcortical structures. LCGU rates were significantly (p < 0.01) higher in several limbic (e.g., ventral tegmental area, nucleus accumbens shell, olfactory tubercle, medial prefrontal cortex, and lateral hypothalamus), cortical (e.g., parietal, temporal, occipital, cingulate, piriform, and entorhinal), and subcortical (e.g., thalamus, habenula, preoptic area, and striatum) regions in P rats, compared with NP and Wistar rats, whereas rates in Wistar rats were higher in a few regions (e.g., CA1 and CA3 regions of the posterior hippocampus) than NP rats.

Conclusions: The data suggest that selective breeding for high‐alcohol drinking produces intrinsically higher functional neuronal activity in the central nervous system regions of the high‐alcohol consuming P line compared with low‐alcohol drinking NP or Wistar rats, although these differences may not generalize to other rat lines selectively bred for divergent alcohol drinking.
Effects of CB1 Cannabinoid Receptor Blockade on Ethanol Preference After Chronic Ethanol Administration
Authors: Lallemand F. , Soubrié P. H. , de Witte P. H.
Published: April 2006

Background: Chronic ethanol administration results in neurobiological alterations similar to those observed after chronic cannabinoid exposure. The purpose of this study was to investigate alcohol drinking and the withdrawal responses after pulmonary chronic alcoholization with intraperitoneal or oral administration of a cannabinoid CB1 receptor antagonist.

Methods: The cannabinoid receptor antagonist SR141716A, 1, 3 or 10 mg/kg/day intraperitoneally or orally, was administered to Wistar rats either during a 30‐day chronic ethanol exposure or at the cessation of this procedure. Motility was recorded during 18 hr after the cessation of chronic alcoholization just before the beginning of the free‐choice paradigm (water versus alcohol 10% v/v).

Results: A significant increase in ethanol preference was observed during the free‐choice paradigm after chronic alcoholization with concurrent SR141716A administration (3 or 10 mg/kg/day). A significant decrease in withdrawal motility after administration of SR141716A was observed with only the highest dose (10 mg/kg/day). The administration of SR141716A, 3 or 10 mg/kg/day, after chronic pulmonary alcoholization significantly decreased the preference for alcohol. Finally, a significant decrease in ethanol preference was seen during the free‐choice paradigm of nonalcoholized rats treated with SR141716A, 3 or 10 mg/kg/day, during 30 days before the free‐choice paradigm.

Conclusions: The concurrent administration of the CB1 antagonist together with the chronic alcoholization increases the preference for ethanol. Also, the administration of the CB1 antagonist after the chronic alcoholization or at the time of withdrawal drastically diminishes the ethanol preference.
Efficacy of Naltrexone and Acamprosate for Alcoholism Treatment: A Meta‐Analysis
Authors: Kranzler Henry R. , Van Kirk Jeffrey
Published: April 2006

Background: Renewed interest in medications to prevent relapse in alcoholics (i.e., antidipsotropics) resulted in approval by the Food and Drug Administration of naltrexone to treat alcohol dependence. Acamprosate, although not approved in the United States, is used in alcoholism treatment in many other parts of the world. In the absence of studies that compare the effects of these medications, we used a meta‐analytic approach to the literature to compare their efficacy in alcoholism treatment.

Methods: All published placebo‐controlled trials of naltrexone or acamprosate for alcohol dependence were examined, and, when suitable, data were extracted for calculation of a mean effect size. A sample of studies of selective serotonin reuptake inhibitors for treatment of major depression conducted over the last two decades served as a comparator for the antidipsotropics.

Results: Both antidipsotropics exerted significant, but modest, effects on treatment retention and/or drinking outcomes. There was significant variability among the studies for the measure on which the largest effect was exerted by each of these medications. Based on limited comparisons of the two medications, there appears to be no statistical difference in their efficacy in the treatment of alcohol dependence. In contrast, there was a consistent effect of selective serotonin reuptake inhibitors on depressive symptoms in major depression, which was significantly greater than the effects observed for the antidipsotropics.

Conclusions: Both naltrexone and acamprosate are efficacious in reducing alcohol consumption in alcoholics. However, their specific role in alcoholism treatment remains to be more clearly defined. New approaches to the use of these medications and development of new medications are needed if pharmacotherapy is to play a substantial role in the treatment of alcoholism.
Screening for High‐ and Moderate‐Risk Drinking During Pregnancy: A Comparison of Several TWEAK‐Based Screeners
Authors: Dawson Deborah A. , Das Abhik , Faden Vivian B. , Bhaskar Brinda , Krulewitch Cara J. , Wesley Barbara
Published: April 2006

Purpose: This study investigated the use of the TWEAK and nine alternative screeners for predicting high‐risk and moderate‐risk drinking during pregnancy.

Method: The analysis was based on self‐reports from 404 lifetime drinkers who presented for an initial visit at nine prenatal clinics in Washington, DC. Data were collected anonymously by having women directly enter their responses onto an audio, computer‐assisted interview that was programmed onto a laptop computer. Pregnancy risk drinking status was based on both average daily volume of intake and frequency of drinking 3+ drinks in a day. Each of the alternative screeners was constructed by adding one additional risk indicator to the TWEAK, and three different scoring options were explored.

Results: Using thresholds of 2 points for high‐risk drinking and 1 point for moderate‐risk drinking, the TWEAK demonstrated a sensitivity and specificity of 70.6% and 73.2% for high‐risk drinking and a sensitivity and specificity of 65.6% and 63.7% for any (high‐ or moderate‐) risk drinking during pregnancy. None of the alternative screeners resulted in significant improvement, but the addition of current smoking status showed enough promise to warrant further testing in larger samples.

Conclusions: Despite some loss in sensitivity and specificity, the TWEAK, in its original or a modified form, can be extended to measures of high‐risk drinking that incorporate infrequent heavy intake and can be used to test for moderate‐ as well as high‐risk drinking. Because identification of moderate‐risk drinkers substantially increases the pool of women targeted for intervention, cost implications must be considered in designing appropriate interventions.
Effect of β‐Carotene on Hepatic Cytochrome P‐450 in Ethanol‐Fed Rats
Authors: Kessova Irina G. , Leo Maria A. , Lieber Charles S.
Published: April 2006

Background: Hepatotoxicity of ethanol is increased by β‐carotene in both rodents and nonhuman primates. Furthermore, in smokers who are also drinkers, β‐carotene increases the incidence of pulmonary cancer. The hepatotoxicity was associated with proliferation of the membranes of the smooth endoplasmic reticulum, suggesting the involvement of cytochromes P‐450. Therefore, the aim of the present study was to assess the effect of β‐carotene and ethanol treatment on rodent hepatic cytochromes P‐450.

Methods and Results: Weanling male Sprague‐Dawley rats were pair‐fed β‐carotene (56.5 mg/l of diet) for 8 weeks, with and without ethanol (Lieber‐DeCarli, 1994 liquid diet). As expected, ethanol increased CYP2E1 (measured by Western blots) from 67 ± 8 to 317 ± 27 densitometric units (p < 0.001). Furthermore, β‐carotene potentiated the ethanol induction to 442 ± 38 densitometric units (p < 0.01) with a significant interaction (p= 0.012). The rise was confirmed by a corresponding increase in the hydroxylation of p‐nitrophenol, a specific substrate for CYP2E1, and by the inhibition with diethyl dithiocarbamate (50 μM). β‐Carotene alone also significantly induced CYP4A1 protein (328 ± 49 vs. 158 ± 17 densitometric units, p < 0.05). The corresponding CYP4A1 mRNA (measured by Northern blots) was also increased (p < 0.05) and there was a significant interaction of the two treatments (p= 0.015). The combination of ethanol and β‐carotene had no significant effect on either total cytochrome P‐450 or CYP1A1/2, CYP2B, CYP3A, and CYP4A2/3 contents.

Conclusions: β‐Carotene potentiates the CYP2E1 induction by ethanol in rat liver and also increases CYP4A1, which may, at least in part, explain the associated hepatotoxicity.
Finding Paradigms for the Future of Alcoholism Research: An Interdisciplinary Perspective
Authors: Meyer Roger E.
Published: April 2006

This is a review article and critique of current research strategies in the alcohol field. Although the alcohol field is proud of its multidisciplinary tradition and scientific findings within specific disciplines, there are very few models of cross‐disciplinary research and communication. Currently, the favored model of risk is genetic; the favored model of pathophysiology is molecular neuroscience; and the favored model of clinical investigation is narrowly categorical. If there is a hierarchy within science that is based on explanatory power, then models of alcoholism emerging from neuroscience, molecular biology, and genetics should be able to accommodate (if not account for) the findings on clinical aspects of alcohol dependence, as well as data on differential risk, course, and recovery that come from the behavioral and social sciences. The first section of this article reviews the most popular models of alcohol dependence over the past 40 years. I argue that the currently fashionable categorical approach to diagnosis in DSM‐IV (and ICD‐10) has failed to serve as a framework for interdisciplinary research and has failed to meet the needs of human geneticists, population‐based researchers, psychosocial researchers, basic scientists working in animal models, and patient‐oriented researchers. I argue for a return to the dimensional approach to diagnosis in the alcohol dependence syndrome construct. In the second section of the article, I lay out an agenda for revitalized patient‐oriented research in the alcohol field, as a bridge between basic biological research and innovations in clinical practice, as well as the key to a valid diagnostic system that can inform research strategies in genetics and population‐based research. In the third section of the article, I highlight the interface between genetic and psychosocial models of risk and propose a possible structure for future collaboration. I conclude with a plea to funding agencies and investigators to translate discipline‐based scientific findings into a science relevant to alcoholism by addressing the challenges and opportunities of an interdisciplinary research agenda on the pathophysiology of alcohol dependence and the multidimensional sources of risk.
The Protein Kinase C Family and Lipid Mediators for Transmembrane Signaling and Cell Regulation
Authors: Nishizuka Yasutomi
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan.
Alcoholic Liver Disease and Apoptosis
Authors: Casey Carol A. , Nanji Amin , Cederbaum Arthur I. , Adachi M. , Takahashi T.
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Carol A. Casey and Amin Nanji. The presentations were (1) Mechanisms of apoptosis in alcoholic liver disease, by Amin A. Nanji; (2) Impaired receptor‐mediated endocytosis: Its role in alcoholic apoptosis, by Carol A. Casey; (3) Toxicity of ethanol in HepG2 cells that express CYP2E1, by Arthur I. Cederbaum; (4) Mitochondrial regulation of ethanol‐induced hepatocyte apoptosis, by M. Adachi; and (5) Apoptosis in alcoholic hepatitis, by T. Takahashi.
WHO/ISBRA Study on State and Trait Markers in Alcoholism
Authors: Tabakoff Boris , Helander Anders , Conigrave Kate M. , Martinez Larry , Hoffman Paula L. , Whitfield J. , Degenhardt L. , Saunders J. , Barón A. , Glanz J. ,   Members of the WHO/ISBRA Study Group
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Boris Tabakoff. The presentations were (1) Overview of the WHO/ISBRA study on state and trait markers in alcoholism, by Boris Tabakoff; (2) Biochemical markers of acute and chronic drinking: Results of the WHO/ISBRA study, by Anders Helander; (3) The impact of country of recruitment and body mass index on biological marker dose‐response curves in the WHO/ISBRA Study, by Kate M. Conigrave; (4) Relationship of body water to carbohydrate‐deficient transferrin measures, by Larry Martinez; and (5) Platelet adenylyl cyclase activity as a trait marker of alcohol dependence, by Paula L. Hoffman.
Pharmacological Relapse Prevention in Alcohol Dependence: From Animal Models to Clinical Trials
Authors: Boening Jobst August‐Ludwig , Lesch Otto Michel , Spanagel Rainer , Wolffgramm Jochen , Narita Minoru , Sinclair David , Mason Barbara J. , Wiesbeck Gerhard A.
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Jobst August‐Ludwig Boening and Otto Michel Lesch. The presentations were (1) Pharmacological validation of a new animal model of alcoholism, by Rainer Spanagel; (2) Persisting loss of control as main criterion for alcohol addiction in rats and mice, by Jochen Wolffgramm; (3) Role of NMDA receptor subunits associated with protein kinase C in the prevention of alcohol dependence, by Minoru Narita; (4) Long‐term follow up of continued naltrexone treatment, by David Sinclair; (5) Pharmacological treatment trials with dopaminergic and serotonergic substances: Myths or facts? by Gerhard A. Wiesbeck; and (6) Methodology and behavioral therapy of the U.S. acamprosate study, by Barbara J. Mason.
Role of Polyamines and NMDA Receptors in Ethanol Dependence and Withdrawal
Authors: Littleton John M. , Lovinger David , Liljequist Sture , Ticku Raj , Matsumoto Izuru , Barron Susan
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was John M. Littleton. The presentations were (1) Examination of ethanol spermine and acamprosate actions on native and recombinant NMDA receptors, by David Lovinger; (2) Ethanol inhibition of NMDA neurotoxicity on the polyamine site in cerebellar granule cells, by Sture Liljequist; (3) Alterations in expression of NMDA receptor subunits during ethanol exposure and withdrawal, by Raj Ticku; (4) Alterations in polyamine synthesis and release as a potential mechanism for ethanol dependence and withdrawal, by Izuru Matsumoto; (5) The role of polyamines in neurotoxicity induced by alcohol withdrawal in vitro, by John Littleton; and (6) Agmatine reduces some of the effects of “third trimester” alcohol exposure using a rodent model, by Susan Barron.
Alcohol and Cancer
Authors: Seitz Helmut K. , Matsuzaki Shohei , Yokoyama Akira , Homann Nils , Väkeväinen Satu , Wang Xian Dong
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Helmut K. Seitz and Shohei Matsuzaki. The presentations were (1) Alcohol dehydrogenase‐2 and aldehyde dehydrogenase‐2 genotype and cancer risk for upper aerodigestive tract in Japanese alcoholics, by Akira Yokoyama; (2) The role of acetaldehyde in alcohol‐associated carcinogenesis, by Nils Homann; (3) High salivary acetaldehyde levels after a moderate dose of alcohol in ALDH2‐deficient subjects, by Satu Väkeväinen; (4) Alcohol and vitamin A interactions, by Xian Dong Wang; and (5) Alcohol and colorectal cancer, by Helmut K. Seitz.
Mechanisms of Alcohol‐Nicotine Interactions: Alcoholics Versus Smokers
Authors: Narahashi Toshio , Söderpalm Bo , Ericson M. , Olausson P. , Engel J. A. , Zhang X. , Nordberg A. , Marszalec William , Aistrup Gary L. , Schmidt L. G. , Kalouti U. , Smolka M. , Hedlund L.
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Bo Söderpalm. The presentations were (1) Nicotinic mechanisms and ethanol reinforcement: Behavioral and neurochemical studies, by Bo Söderpalm, M. Ericson, P. Olausson, and J. A. Engel; (2) Chronic nicotine and ethanol: Differential regulation in gene expression of nicotinic acetylcholine receptor subunits, by X. Zhang and A. Nordberg; (3) Nicotine‐ethanol interactions at neuronal nicotinic acetylcholine receptors, by Toshio Narahashi, William Marszalec, and Gary L. Aistrup; (4) Relapse prevention in alcoholics by cigarette smoking? Treatment outcome in an observational study with acamprosate, by L.G. Schmidt, U. Kalouti, M. Smolka, and M. Soyka; and (5) Effect of nicotine on voluntary ethanol intake and development of alcohol dependence in male rats, by L. Hedlund and G. Wahlström.
Fetal Alcohol Syndrome: An International Perspective
Authors: Warren Kenneth R. , Calhoun Faye J. , May Philip A. , Viljoen Denis L. , Li Ting‐Kai , Tanaka Harumi , Marinicheva Galina S. , Robinson Luther K. , Mundle Goetz
Published: April 2006

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Kenneth R. Warren and Faye J. Calhoun. The presentations were (1) Epidemiological research on fetal alcohol syndrome (FAS) in the United States, by Philip A. May; (2) An overview of fetal alcohol syndrome in the Western Cape Province of South Africa, by Denis L. Viljoen and Ting‐Kai Li; (3) Diagnostic perspectives of fetal alcohol and tobacco syndromes, by Harumi Tanaka; (4) FAS among pupils of special boarding schools and orphanages in Moscow, Russia, by Galina S. Marinicheva and Luther K. Robinson; and (5) Research on FAS and FAE in Germany: Update and perspectives, by Goetz Mundle.
Alcohol and Retinoids
Authors: Crabb David W. , Pinairs J. , Hasanadka R. , Fang M. , Leo M. A. , Lieber Charles S. , Tsukamoto Hidekazu , Motomura K. , Miyahara T. , Ohata M. , Bosron William , Sanghani S. , Kedishvili N. , Shiraishi Haruko , Yokoyama Hirokazu , Miyagi Michiko , Ishii Hiromasa , Bergheim Ina , Menzl Ina , Parlesak Alexandr , Bode Christiane
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Hirokazu Yokoyama and David Crabb. The presentations were (1) Roles of vitamin A, retinoic acid, and retinoid receptors in the expression of liver ALDH2, by J. Pinaire, R. Hasanadka, M. Fang, and David W. Crabb; (2) Alcohol, vitamin A, and β‐carotene: Adverse interactions, by M. A. Leo and Charles S. Lieber; (3) Retinoic acid, hepatic stellate cells, and Kupffer cells, by Hidekazu Tsukamoto, K. Motomura, T. Miyahara, and M. Ohata; (4) Retinoid storage and metabolism in liver, by William Bosron, S. Sanghani, and N. Kedishvili; (5) Characterization of oxidation pathway from retinol to retinoic acid in esophageal mucosa, by Haruko Shiraishi, Hirokazu Yokoyama, Michiko Miyagi, and Hiromasa Ishii; and (6) Ethanol in an inhibitor of the cytosolic oxidation of retinol in the liver and the large intestine of rats as well as in the human colon mucosa, by Ina Bergheim, Ina Menzl, Alexandr Parlesak, and Christiane Bode.
The Chemistry and Biological Effects of Malondialdehyde‐Acetaldehyde Adducts
Authors: Thiele Geoffrey M. , Worrall Simon , Tuma Dean J. , Klassen Lynell W. , Wyatt Todd A. , Nagata Naruhiko
Published: April 2006

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Geoffrey M. Thiele and Simon Worrall. The presentations were (1) The chemistry of malondialdehyde‐acetaldehyde (MAA) adducts, by Dean J. Tuma; (2) The formation and clearance of MAA adducts in ethanol‐fed rats, by Simon Worrall; (3) Immune responses to MAA adducts may play a role in the development of alcoholic liver disease, by Lynell W. Klassen; (4) Unique biological responses to MAA‐modified proteins that may play a role in the development and/or progression of alcoholic liver disease, by Geoffrey M. Thiele; (5) MAA‐adducted bovine serum albumin activates protein kinase C and stimulates interleukin‐8 release in bovine bronchial epithelial cells, by Todd A. Wyatt; and (6) An enzyme immune assay for serum antiacetaldehyde adduct antibody using low‐density lipoprotein‐adduct and its significance in alcoholic liver injury and ALDH2 heterozygotes, by Naruhiko Nagata.
Role of Estrogen in Alcohol Promotion of Breast Cancer and Prolactinomas
Authors: Sarkar Dipak K. , Liehr Joachim G. , Singletary Keith W.
Published: April 2006

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Dipak K. Sarkar. The presentations were (1) Dual role of estrogen as hormone and carcinogen in mammary carcinogenesis, by Joachim G. Liehr; (2) Alcohol and breast cancer: Studies using animals, by Keith W. Singletary; and (3) Evaluation of the role of estrogen in mediation of ethanol effect on prolactinoma: Studies using animals, by Dipak K. Sarkar.
Study of Cytochrome P4502E1 mRNA Level of Mononuclear Cells in Patients With Alcoholic Liver Disease
Authors: Yano Hirokazu , Tsutsumi Mikihiro , Fukura Masayuki , Chen Wun‐Bil , Shimanaka Koshi , Tsuchishima Mutsumi , Takase Shujiro , Imaoka Susumu , Funae Yoshihiko
Published: April 2006

Background: Cytochrome P‐4502E1 (CYP2E1) is an important enzyme because of its unique ability to convert many substrates to cytotoxins. The increased production of reactive intermediates by elevated enzyme concentrations leads to various pathological conditions. Therefore, it is important to detect induced CYP2E1 levels in alcoholic individuals to avoid xenobiotic‐promoted liver injury. In the present investigation, we detected CYP2E1 mRNA levels of mononuclear cells obtained from 10 ml of blood by using competitive polymerase chain reaction (PCR) method.

Methods: Mononuclear cells were obtained from healthy individuals who did and did not drink habitually and patients with alcoholic liver disease (ALD). Complementary DNA synthesis was performed with RNA obtained from mononuclear cells by reverse transcription‐PCR. Competitive PCR of CYP2E1 was performed with the sense (5′‐CTGCAACGTCATA‐GCCGACA‐3′) and antisense (5′‐TCCATTTCCACGAGCAGGCA‐3′) primer and competitor DNA. Competitive PCR of β‐actin also was performed. Electrophoresis was scanned, and each band was digitized. The concentration of CYP2E1 and β‐actin mRNA was calculated from the ratio of competitor DNA.

Results: In healthy individuals who did and did not drink habitually, CYP2E1 mRNA levels were 103.3 copies/μl RNA and 101.7 copies/μl RNA, respectively. In actively drinking patients with ALD, CYP2E1 mRNA levels were 103.5 copies/μl RNA, but those levels decreased to 101.7 copies/μl RNA after 4 days of abstinence. No significant difference was observed in CYP2E1 mRNA levels between alcoholic fibrosis and cirrhosis. As control, we measured β‐actin mRNA levels in mononuclear cells in all samples. The mean value of β‐actin mRNA was 104.3 copies/μl RNA in all cases, which included patients with ALD.

Conclusions: The results demonstrated that it is possible to measure the CYP2E1 mRNA levels of mononuclear cells in a 10 ml blood sample. The CYP2E1 mRNA level in mononuclear cells increases during drinking and decreases in abstinence for a short period of 3 to 4 days. It is concluded that CYP2E1 mRNA level may be used as an effective marker for alcoholic intake.
Polymorphism of Tumor Necrosis Factor‐β and Alcohol Dehydrogenase Genes and Alcoholic Brain Atrophy in Japanese Patients
Authors: Yamauchi Masayoshi , Takamatsu Masashi , Maezawa Yoshihiko , Takagi Masaru , Araki Takashi , Satoh Shunnya , Toda Gotaro , Saito Saburo
Published: April 2006

Background: Alcohol abuse can induce brain atrophy, but it only occurs in some alcoholics. Many inflammatory cytokines such as tumor necrosis factor (TNF) are produced rapidly in the brain by experimental or clinical injury.

Method: To investigate whether genetic polymorphism of TNF was related to alcoholic brain atrophy, we determined restriction fragment‐length polymorphisms of the TNF‐β genes in 72 male alcoholics. Computed tomography was used to determine the severity of brain atrophy.

Results: Digestion with Nco I and Msp I after polymerase chain reaction amplification showed that the TNFB1 allele frequency was significantly higher in patients with brain atrophy than in those without brain atrophy (χ2= 10.20, p= 0.0034). A multivariate analysis that included age, total alcohol intake, ADH2 genotype, and TNF‐β genotype showed that the ADH21/21 genotype and TNFB1/B1 genotype are independently associated with alcoholic brain atrophy. These findings suggest that the TNFB1 allele may be associated with alcoholic brain atrophy.
Nicotinamide Adenine Dinucleotide‐Dependent Retinoic Acid Formation From Retinol in the Human Gastric Mucosa: Inhibition by Ethanol, Acetaldehyde, and H2 Blockers
Authors: Yokoyama Hirokazu , Matsumoto Michinaga , Shiraishi Haruko , Miyagi Michiko , Kato Shinzo , Ishii Hiromasa
Published: April 2006

All‐trans retinoic acid formation from all‐trans retinol (vitamin A) in the human gastric mucosa was studied. When all‐trans retinol and the human gastric mucosa were incubated together, all‐trans retinoic acid was formed in the presence of nicotinamide adenine dinucleotide (NAD). When the NAD was not added, hardly any formation was observed. The formation of all‐trans retinoic acid tended to be attenuated by 10 mM ethanol. Moreover, it was significantly attenuated in a concentration‐dependent manner by ethanol at concentrations of 100 mM and above. Acetaldehyde at concentrations of 50 μM and above also significantly attenuated its formation in a concentration‐dependent manner. Some H2 blockers, which include ranitidine hydrochloride and cimetidine, significantly attenuated the formation of all‐trans retinoic acid, whereas famotidine failed to suppress it. There is an NAD‐dependent pathway by which all‐trans retinoic acid is produced from all‐trans retinol in the human gastric mucosa. Inhibitors of alcohol dehydrogenase, which include ethanol and some H2 blockers, and of aldehyde dehydrogenase, which include acetaldehyde, inhibit its production.
Alcohol Dehydrogenase Activities in the Human Gastric Mucosa: Effects of Helicobacter pylori Infection, Sex, Age, and the Part of the Stomach
Authors: Matsumoto Michinaga , Yokoyama Hirokazu , Shiraishi Haruko , Suzuki Hidekazu , Kato Shinzo , Miura Souichiro , Ishii Hiromasa
Published: April 2006

Background: Human gastric mucosa contains three alcohol dehydrogenase (ADH) isozymes (classes I, III, and IV). Various factors such as Helicobacter pylori infection, sex, age, and the part of the stomach involved have been suggested to affect alcohol dehydrogenase activities, although these views are controversial. In this study, these unsettled issues were reexamined.

Methods: Activities of class I and IV ADHs were evaluated in the cytosolic fraction of human gastric mucosa samples by reduction of their preferred substrates, namely acetaldehyde and m‐nitrobenzaldehyde, and activities of class III were evaluated by oxidation of its preferred substrate, formaldehyde. Then, effects of Helicobacter pylori infection, sex, age, and the part of the stomach involved were examined.

Results: Class I, III, and IV ADH activities were 17.5 ± 8.4, 4.2 ± 2.5, and 8.9 ± 3.9 nmol of nicotinamide adenine dinucleotide oxidation per minute per milligram of protein, respectively, for the entire population. Helicobacter pylori infection significantly reduced class I and IV ADH activities but did not affect activity of class III. In the samples without Helicobacter pylori infection and severe gastritis, sex did not affect class I, III, or IV ADH activities. In the same series, class IV ADH activity significantly decreased with age (p= 0.006), whereas no correlation was found between age and ADH activity of class I and III ADHs. The level of class IV ADH activity was significantly higher in the upper body than in the lower regions, whereas no such heterogeneity was observed in class I and III ADH.

Conclusions: Various factors affect human gastric ADH activities, such that careful interpretation of their significance is necessary.
Alteration of Annexin IV Expression in Alcoholics
Authors: Sohma Hitoshi , Ohkawa Hiroko , Hashimoto Eri , Toki Sadamu , Ozawa Hiroki , Kuroki Yoshio , Saito Toshikazu
Published: April 2006

Western blot analysis was performed by using a specific antibody to measure annexin IV in human postmortem brain samples from alcoholic subjects. The analysis showed a significantly augmented expression in the hippocampus compared with controls, whereas the expression in the frontal cortex was equivalent in both groups. Annexin IV expression in the occipital cortex tended to increase in alcoholics. It was shown further that autoantibodies to annexin IV were increased significantly in alcoholic patients compared with controls. Thus, annexin IV may become a novel biological marker for alcoholics.
Electroacupuncture Stimulation Suppresses the Increase in Alcohol‐Drinking Behavior in Restricted Rats
Authors: Yoshimoto K. , Kato B. , Sakai K. , Shibata M. , Yano T. , Yasuhara M.
Published: April 2006

Background: Although a number of studies on traditional eastern or Chinese medicine, such as acupuncture, moxibustion, and herbal drugs, have been reported, few reports describe electroacupuncture (EAC) effects on drug‐ and alcohol‐seeking behaviors in animal models. The purpose of the present study was to investigate the effect of EAC on changes in alcohol‐drinking behavior in rats challenged with restriction and immobilization stress.

Material and Methods : Male Sprague Dawley® rats (260–280 g) were tightly hung and immobilized in restriction models for 10 min. These immobilization stresses were performed twice a week for 1 week and for 3 consecutive weeks for the short‐ and long‐restricted stress groups, respectively. EAC was applied for 10 min to the hindlimb point, Tsu‐San‐Li (ST 36), and the lumbar point, Shen‐Shu (BL 23). These points are used to treat mental and psychosomatic disorders and are known clinically to produce a sedation effect. Time‐access alcohol‐drinking behavior was determined at 24 hr after the termination of EAC. Finally, brain dopamine (DA) levels were assayed in the two groups. A sham‐control group underwent only restricted stress without EAC.

Results: Time‐access alcohol‐drinking behavior increased significantly in the long‐restricted group compared with the short‐restricted group and controls. EAC applied to the ST 36 (Tsu‐San‐Li) point suppressed the increased alcohol‐drinking behavior in restricted rats. However, EAC applied to the Shen‐Shu (BL 23) point was not effective, because alcohol‐drinking behavior was significantly increased in long‐restricted rats compared with short‐restricted rats. Striatal DA levels of restricted rats with EAC stimulated at Tsu‐San‐Li were increased significantly compared with the rats with EAC applied to the Shen‐Shu point.

Conclusion: These findings suggest that EAC applied at ST 36 (Tsu‐San‐Li) was more effective for reducing the increased alcohol‐drinking behavior in restricted rats, and they showed that a point specific in EAC procedure was associated with an increase of striatal DA levels. These findings provide new information for understanding alcohol‐drinking behavior and for treating human alcoholics.
A Clinicopathological Study of Acute Hepatitis in Heavy Drinkers, Unrelated to Hepatitis A, B, or C Viruses
Authors: Miyano Shintaro , Maeyama Shiro , Iwaba Akiko , Ogata Seiichirou , Koike Junki , Kishi Masaya , Uchikoshi Toshiyuki
Published: April 2006

Background: There are six histological classifications of alcoholic liver disease (ALD) in Japan. However, it is unclear whether all cases of the disease conform to these criteria. This study investigated the clinicopathological features of eight histologically unusual cases of ALD.

Methods: The characteristic features of alcohol drinking behavior, subjective and objective symptoms, laboratory data on admission, and progress after admission were analyzed for eight patients with acute‐onset hepatitis.

Result: The eight patients showed histologically acute hepatitis, with much spotty necrosis that contained granular ceroid pigment by Kupffer cells, which indicated acute parenchymal damage of the liver, but with no Mallory bodies and unremarkable intrasinusoidal neutrophilic infiltration. The only etiological factor for all the cases was habitual alcohol consumption, with increased consumption just before the onset of symptoms. In five cases that were tested, the patients were negative for hepatic viral markers, which included hepatitis G virus RNA and TT virus DNA.

Conclusion: Some cases of ALD may not conform to the current histological classifications in either Japan or Western countries. It seems natural to consider that these cases are developed by other, unknown causes that overlap with ALD rather than as a result of damage from alcoholic overload.
Inverse Genetic Association Between Alcohol Preference and Severity of Alcohol Withdrawal in Two Sets of Rat Lines Selected for the Same Phenotype
Authors: Chester J. A. , Price C. S. , Froehlich J. C.
Published: April 2006

Background: The purpose of the present study was to determine whether alcohol‐naïve rats selectively bred for alcohol preference or nonpreference differ in alcohol withdrawal severity using two sets of rat lines selectively bred for the same phenotype.

Methods: Alcohol‐naïve male rats from the high alcohol drinking (HAD1) and low alcohol drinking (LAD1) rat lines and from the alcohol preferring (P) and nonpreferring (NP) rat lines received an intragastric infusion of alcohol (4.0 g/20.3 ml/kg; 25% v/v) or an equal volume of water once a day for 10 consecutive days. Alcohol withdrawal severity was assessed at using a behavioral rating scale and a radiant heat assay measured analgesia at 10, 12, 14, 16, 18, and 24 hrs following infusion of alcohol or water on days 1, 5, and 10 of treatment.

Results: Data were analyzed using body weight as a co‐factor to correct for differences in body weight between the HAD1/LAD1 and P/NP lines. Acute (1 day) but not repeated alcohol treatment (5 or 10 days) produced mild behavioral signs of withdrawal in LAD1 but not in HAD1 rats. HAD1 and LAD1 rats showed alcohol‐induced analgesia after 1 and 5 days of alcohol treatment that disappeared by day 10 in both lines. Repeated alcohol treatment (5 days) produced mild behavioral signs of withdrawal in NP but not in P rats. Neither P nor NP rats showed alcohol‐induced analgesia after 1, 5, or 10 days of alcohol treatment.

Conclusions: An inverse genetic association was found between alcohol preference and severity of alcohol withdrawal in two sets of rat lines selected for the same phenotype. The pattern of alcohol withdrawal that emerged over the course of the 10 days of alcohol treatment differed between the two lines selected for low alcohol drinking (LAD1 and NP), suggesting that unique sets of genes may influence alcohol withdrawal severity in the two lines.
The Alcohol Use Disorders Identification Test and Carbohydrate‐Deficient Transferrin in Alcohol‐Related Sickness Absence
Authors: Hermansson Ulric , Helander Anders , Brandt Lena , Huss Anders , Rönnberg Sten
Published: April 2006

Background: Previous studies have shown that elevated, risky levels of alcohol consumption may lead to higher rates of sickness absence. However, no studies have examined the Alcohol Use Disorders Identification Test (AUDIT) or serum carbohydrate‐deficient transferrin (CDT) in relation to sickness absence in the workplace. The purpose of this study was to examine the relationship between sick‐days, 12 months before screening, and the AUDIT and CDT (CDTect kit). Serum γ‐glutamyltransferase also was used for comparison.

Method: The study was carried out over 36 months in a large workplace and formed part of an ongoing controlled study. In conjunction with a routine health examination, employees were offered the opportunity to undergo an alcohol screening. Absence data were obtained from the company payroll system, and sickness absence was analyzed by using a three‐ordinal level cumulative logistic model on the number of sick‐days. Odds ratios (OR) and 95% confidence intervals (CI) are reported.

Results: Of the 989 subjects who participated in the study, 193 (19.5%) screened positive in relation to either the AUDIT (≥8 points) or CDT (<20 units/liter for men, and <27 units/liter for women), or both. Employees who screened positive with the AUDIT had a significantly higher proportion of sick‐days (p= 0.047) compared with those who screened negative (OR = 1.4, CI 1.0–1.9). Neither long, continuous periods of sickness absence nor absence on Mondays or Fridays gave a clear indication of individuals who screened positive on the AUDIT or CDT test.

Conclusion: Our data indicate that individuals with moderately elevated or risky levels of alcohol consumption show an increase in sick‐days. Accordingly, workplaces have a good reason for using a more systematic approach to alcohol screening in routine workplace health examinations.
Fetal and Maternal Thyroid Hormone Responses to Ethanol Exposure During the Third Trimester Equivalent of Gestation in Sheep
Authors: Cudd Timothy A. , Chen Wei‐Jung A. , West James R.
Published: April 2006

Background: Abnormal thyroid hormone system function in the mother or fetus during pregnancy can result in brain defects, some of which resemble those found in children with fetal alcohol syndrome. It has been hypothesized that ethanol may act to mediate alcohol‐related birth defects in part by altering thyroid hormone system function. We investigated whether a binge pattern of maternal ethanol consumption over the last trimester equivalent of gestation in sheep results in an alteration in fetal or maternal thyroid function.

Methods: Pregnant ewes received saline or ethanol beginning on day 109 of gestation (term, 145 days) for three consecutive days per week followed by 4 days without exposure. The fetuses were surgically instrumented on day 113, and experiments were performed on days 118 or 132. Fetal and maternal blood samples were collected, and plasma tri‐iodothyronine (T3), thyroxine (T4), and free T4 concentrations were measured.

Results: Fetal T3 and T4 on day 118, fetal T3 on day 132, and maternal T3 on day 132 were lower in response to ethanol. Fetal and maternal free T4 and maternal T4 did not change in response to ethanol. Fetal thymus and adrenal weights were reduced in response to ethanol.

Conclusions: We conclude that, in sheep, maternal ethanol exposure during the third trimester equivalent resulting in blood ethanol concentrations that are commonly achieved by ethanol abusers decreases circulating thyroid hormone concentrations in the mother and fetus and fetal thyroid and thymus mass.