bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention and Treatment of Liver Fibrosis Based on Pathogenesis
Authors: Lieber Charles S.
Published: May 2006

Multiple agents have been proposed for the prevention and treatment of fibrosis. S‐adenosylmethionine was reported to oppose CC14,‐induced fibrosis in the rat, to attenuate the consequences of the ethanol‐induced oxidative stress, and to decrease mortality in cirrhotics. Anti‐inflammatory medications and agents that interfere with collagen synthesis, such as inhibitors of prolyl‐Chydroqlase and antioxidants, are also being tested. In nonhuman primates, polyenylphosphatidylcholine (PPC), extracted from soybeans, protected against alcohol‐induced fibrosis and cirrhosis and prevented the associated hepatic phosphatidyl‐cholinc (PC) depletion by increasing 18:2 containing PC species; it also attenuated the transformation of stellate cells into collagen‐producing transitional cells. Furthermore, it increased collagen breakdown, as shown in cultured stellate cells enriched with PPC or pure dilinoleoyl PC, the main PC species present in the extract. Because PPC and dilinoleoyl PC promote the breakdown of collagen, there is reasonable hope that this treatment may be useful for the management of fibrosis of alcoholic, as well as nonalcoholic, etiologies and that it may affect not only the progression of the disease, but may also reverse pre‐existing fibrosis, as demonstrated for CC14,‐induced cirrhosis in the rat and as presently tested in an ongoing clinical trial.
Limited Access Alcohol Drinking in High‐ and Low‐Alcohol Preferring Selected Lines of Mice
Authors: Grahame Nicholas J. , Li Ting‐Kai , Lumeng Lawrence
Published: May 2006

Background:Selection studies and genetic analyses of drinking behavior in rodents often involved unlimited access to alcohol over a period of weeks, with water and food freely available. Most studies investigating the pharmacology of alcohol drinking, on the other hand, use procedures in which access to alcohol is limited to a particular time each day. Reconciliation of findings between these two conditions likely depends on their sharing common genetic mechanisms as indicated, for example, by covariation in response to selection. To this end, high‐ and low‐alcohol preferring (HAP and LAP, respectively) mice, selected for differences in 24‐hr access alcohol drinking over a 4‐week period, were subjected to a limited access alcohol drinking protocol.

Method:During 2‐hr sessions, mice had access to various concentrations of alcohol (7‐15%, v/v) in the home cage for 2 hr a day, with ad libitum access to food and water. Additional sessions were conducted with no food present.

Result:Although both strains consumed alcohol and water during these sessions, HAP mice drank far more alcohol than did LAP mice. HAP but not LAP mice drank alcohol at a high rate early in the session compared with later in the session. Additionally, HAP mice responded to changes in alcohol concentration, whereas LAP mice did not. Removal of food did not influence alcohol drinking, although water drinking decreased following food removal. HAP mice reached appreciable blood alcohol concentrations after limited access.

Conclusions:These findings indicate that in these selectively bred mice, alcohol drinking during limited and unlimited access may be genetically related, and that drinking during limited access sessions in HAP mice is likely for the pharmacological properties of alcohol.
Alcoholics’Deficits in the Decoding of Emotional Facial Expression
Authors: Philippot Pierre , Kornreich Charles , Blairy Sylvie , Baert Iseult , Dulk Anne Den , Bon Olivier Le , Streel Emmanuel , Hess Ursula , Pelc Isy , Verbanck Paul
Published: May 2006

The present study investigated emotional facial expression decoding in alcoholics. Twenty‐five alcoholic patients at the end of the detoxification process were compared with 25 volunteers matched for age, sex, and education. They were presented with facial expressions of neutral, mild, moderate, or strong emotional intensity. Results indicate that alcoholics overestimate the intensity of emotional expressions and make more errors in their decoding with a special bias for anger and contempt. Moreover, this decoding deficit is not perceived by the alcoholic patients. A general model is proposed that links visuospatial deficits, abnormal processing of social information, interpersonal stress, and alcohol abuse.
Impaired Sleep in Alcohol Misusers and Dependent Alcoholics and the Impact Upon Outcome
Authors: Foster John H. , Peters Timothy J.
Published: May 2006

Background: There is very little work that has investigated the self‐reported sleep status of alcohol misusers. This study addressed that imbalance.

Methods: The study consisted of two parts: 1) the outpatient study, a sample of DSM‐IV alcohol‐dependent subjects who were referred to an outpatient clinic and were given a series of questionnaires, including the Pittsburgh Sleep Quality Index (PSQI); and 2) the inpatient study, a group of DSM‐IV alcohol‐dependent subjects whose sleep was assessed by the Nottingham Health Profile (NHP) sleep subscore at the start of the study and again at the 12‐week follow‐up. Both the PSQI and NHP are self‐report indices whereby higher scores indicate a poor sleep quality.

Results: In the outpatient study, the PSQI scores were significantly higher in the alcoholics (n= 31) compared with the controls (n= 49). There were no differences in the PSQI scores among mildly (n= 11), moderately (n= 10), and severely (n= 11) dependent drinkers. The PSQI total scores correlated with the Beck Depression Index but not with severity of dependence or alcohol problem scores. Sleep latency emerged as the most significant predictor of relapse, and sleeping badly was associated with poor outcome at the 12‐week follow‐up in the inpatient study.

Conclusion: Self‐reported sleep disturbance can provide clinicians with information to plan better treatment for alcohol misusers.
Behavioral and Psychosocial Profiles of Alcohol‐Exposed Children
Authors: Roebuck Tresa M. , Mattson Sarah N. , Riley Edward P.
Published: May 2006

Background: It is widely known that prenatal alcohol exposure is related to cognitive and behavioral deficits throughout childhood and adolescence. Much research has focused on understanding and quantifying the cognitive profile of children with fetal alcohol syndrome (FAS) with relatively less empirical research on behavioral or psychosocial adjustment. The primary purpose of this study was to examine the behavioral and psychosocial profile of children exposed to heavy amounts of alcohol prenatally.

Method: Two groups of subjects were evaluated: an alcohol‐exposed group (ALC) and a nonexposed control group (NC) each made up of 32 subjects matched for age, gender, and ethnicity. The alcohol‐exposed group consisted of children heavily exposed to alcohol in utero, including 19 children diagnosed with FAS. The Personality Inventory for Children (PIC) was completed by the caretaker of each child. Four validity/screening scales and 12 clinical scales were scored for all subjects.

Result: Analyses revealed significant group differences on four validity/screening scales and 12 substantive scales. Within the ALC group, the profile of children without FAS was similar to that of children with FAS, with the exception that their profiles were consistent with less cognitive impairment.

Conclusions: These findings indicate that in addition to previously reported cognitive impairments, heavy prenatal alcohol exposure is related to significant impairments in psychosocial functioning. Even children without alcohol‐related physical anomalies suffer from impaired psychosocial functioning. Because impairments of this nature can interfere with functioning across multiple domains, effective early intervention programs should be considered for families of alcohol‐exposed children. Furthermore, given the similarities of alcohol‐exposed children with and without FAS, it is imperative to obtain prenatal alcohol exposure histories on all children experiencing cognitive or psychosocial deficits.
Effects of Ethanol Treatment on Proliferation and Differentiation in a Head and Neck Squamous Cell Carcinoma Cell Line
Authors: Kornfehl J. , Temmel A. , Formanek M. , Knerer B.
Published: May 2006

Introduction: Epidemiologic studies have provided evidence that chronic ethanol consumption is an independent risk factor in upper aerodigestive tract cancer, but the underlying mechanisms are largely unknown.

Method: To examine ethanol effects on mucosal keratinocytes in vitro, we used a squamous cell carcinoma of the head and neck (SCCHN) cell line as a model and, to exclude line specific effects, two other cell lines. The influence of ethanol on proliferation (using [3H]thymidine uptake/cell number), cell cycle distribution, cytokeratin pattern, and growth factor receptor expression (using FACS analyses) was investigated.

Result: Ethanol increased in a dose dependent manner (tested range 10‐3M to 10‐10 M) the [3H]thymidine uptake and cell number, with unaltered viability (>95%) in all concentrations. In ail tested cell lines, addition of 10‐3 M ethanol caused: (a) a significant increase of cells in the S‐phase of the cell cycle; (b) a shift of cytokeratin pattern that suggested inhibition of differentiation; and (c) significant upregulation of EGF, IL‐4, and PDGF receptors.

Conclusions: Our results demonstrated an increased proliferation and reduced differentiation induced by ethanol in mucosa derived neoplastic cells, which may enhance further growth of neoplastic cells. These effects may also be involved in the carcinogenesis of upper aerodigestive tract malignancies.
Prenatal Alcohol Use Among Teenagers: Effects on Neonatal Outcomes
Authors: Cornelius Marie D. , Goldshmidt Lidush , Taylor Paul M. , Day Nancy L
Published: May 2006

Background:This longitudinal study examines the effects of alcohol use during pregnancy on the growth and gestational age at birth of 413 offspring of adolescents.

Methods:Data were collected during 1990 to 1994. The adolescents were from a prenatal clinic in Pittsburgh, PA. They were interviewed at mid‐pregnancy and at delivery to obtain information on alcohol and other substance use before and during pregnancy. Infants were examined 24 to 36 hr after birth.

Results:The average maternal age was 16.3 (12‐18) years; 68% were African American. Prenatal exposure to alcohol during the second trimester was significantly related to decreases in head circumference, birthweight, and chest circumference. There was also a significant relationship between alcohol exposure in each trimester and lower Apgar scores. All of the analyses controlled for other prenatal substance use and covariates of drinking during pregnancy.

Conclusion:Prenatal alcohol exposure is associated with decreases in fetal growth and in APGAR scores in the offspring of adolescents.
Effects of Continuous Versus Intermittent Ethanol Exposure on Rat Sympathetic Neurons
Authors: Riikonen Jamo , Jaatinen Pia , Karjala Kirsi , Rintala Jyrki , Pörsti Llkka , Wu Xiumin , Eriksson C.J. Peter , Hervonen Antti
Published: May 2006

Background:Binge ethanol exposure is known to induce degeneration of central nervous system (CNS) neurons. Sympathetic hyperactivity has been related to ethanol withdrawal symptoms, but the effects of repeated withdrawals on peripheral sympathetic neurons have not been studied previously.

Methods:The effects of continuous versus intermittent ethanol consumption on sympathetic neurons of the superior cervical ganglion (SCG) were studied in male Wistar rats. Two‐month‐old rats were divided into three groups: one group with ethanol (10% v/v) as the drinking fluid throughout the 5½‐month experiment (continuous, n=9), one group drinking ethanol on 4 days/week and water on 3 days/week (intermittent, n=9), and a control group (n=9) with water as the only available fluid. All groups had food ad libitum. SCG volume, neuron density, and total number of neurons were measured by using unbiased morphometric methods.

Results:As the mean daily ethanol consumption did not differ between the two ethanol‐exposed groups (continuous5.7 g/kg/day versusintermittent5.8 g/kg/day), the total dose of ethanol consumed was 42% smaller in theintermittentgroup. The total number of SCG neurons decreased by 28%, and neuron density by 23%, in theintermittentgroup compared with the control group, whereas no significant neuron loss was observed in thecontinuousgroup. The volume of the SCG was similar in all study groups. The results suggest that repeated ethanol withdrawals, rather than ethanol exposure per se, are deleterious to sympathetic neurons.

Conclusions:Ethanol‐induced degeneration of neurons is not only related to the amount of ethanol consumed, but also to the patterns of drinking.
Neonatal Ethanol Exposure Alters bcl‐2 Family mRNA Levels in the Rat Cerebellar Vermis
Authors: Moore D. Blaine , Walker Don W. , Heaton Marieta Barrow
Published: May 2006

Background: The objective of the present work was to determine whether ethanol‐induced cerebellar cell death during development is related to alterations in the expression of bcl‐2 family genes.

Methods: Rats were exposed to ethanol or control conditions during the neonatal period and transcript levels of bcl‐2 family members relative to cyclophilin were determined. Pups exposed in parallel were taken for cerebellar cell counts.

Results: Ethanol exposure during the first postnatal week significantly reduced Purkinje and granule cell numbers by postnatal day 21 (P21). Acute first postnatal week ethanol exposure up‐regulated mRNA transcripts encoding the cell death‐promoting molecules bax and bcl‐xs as measured on P4. An additional day of exposure on P5 resulted in no further alterations in bcl‐2 family transcripts, likely because Purkinje cell death was detectable as early as P5. To determine whether proapoptotic gene expression changes were specific to first postnatal week ethanol neurotoxicity, we examined bcl‐2 family mRNA levels in rats exposed to ethanol during a developmental period of cerebellar insusceptibility, the second postnatal week. Exposure on P7 to P8 produced no change in cerebellar cell number, but also resulted in increased levels of bax, although only after 2‐day ethanol exposure and not after acute exposure on P7.

Conclusions: These data implicate altered expression of proapoptotic members of the bcl‐2 gene family in acute ethanol‐mediated cerebellar cell death during the first postnatal week. They also suggest that the differential survival of cerebellar neurons after ethanol exposure during more mature developmental stages may be related to more successful suppression of proapoptotic processes.
Selective Effects of Alcohol Drinking on Restraint‐Induced Expression of Immediate Early Genes in Mouse Brain
Authors: Ryabinin Andrey E. , Wang Yuan‐Mei , Freeman Pierre , Risinger Fred O.
Published: May 2006

Background:Analysis of immediate early gene expression in brain is a common contemporary method for mapping changes in neuronal activation with cellular resolution. This method has been applied previously in models of involuntary alcohol exposure. In this study, immunohistochemical expression analysis of immediate early genes c‐fos, fosB, and zif268 was performed in brain of C57BL/6J mice after voluntary alcohol consumption.

Methods:Mice were trained to consume 10% ethanol/10% sucrose, using a 30‐min limited‐access paradigm. Animals consumed approximately 1.5 g/kg of ethanol per session. Control animals consumed 10% sucrose solution. Gene expression was determined in half of the animals 1.5 hr after the drinking session. Gene expression in the remaining animals was determined after 0.5 hr of restraint stress, which is known to elevate expression of immediate early genes in many brain regions. Analysis of the stressed animals was also performed 1.5 hr after the drinking session.

Results:Blood alcohol concentrations were significantly reduced in animals exposed to restraint stress. However, stressed mice showed the greatest alcohol‐induced changes in gene expression. Specifically, animals consuming ethanol/sucrose with subsequent exposure to restraint stress had lower c‐Fos expression in the CA3 region of hippocampus, and higher c‐Fos expression in nucleus accumbens than mice exposed to restraint stress after drinking the sucrose solution. Consumption of the ethanol/sucrose solution also significantly reduced FosB expression in the basolateral amygdala and lateral hypothalamus, and Zif268 expression in the CA1 region of the hippocampus of stressed animals.

Conclusions:These data confirm previous observations showing selective effects of alcohol administration on immediate early gene expression. Furthermore, the effects of voluntary alcohol self‐administration on immediate early gene expression differ from involuntary alcohol exposure and suggest several brain regions as substrates for alcohol consumption.
Psychometric Properties of the Penn Alcohol Craving Scale
Authors: Flannery B. A. , Volpicelli J. R. , Pettinati H. M.
Published: May 2006

Background: This study introduces the Penn Alcohol Craving Scale (PACS), which has been used in several clinical trials at the University of Pennsylvania's Treatment Research Center. The PACS is a five‐item, self‐report measure that includes questions about the frequency, intensity, and duration of craving, the ability to resist drinking, and asks for an overall rating of craving for alcohol for the previous week. Each question is scaled from 0 to 6.

Methods: To examine the questionnaire's psychometric properties, we sampled responses from 147 individuals participating in a 9‐month combined natrexone (100 mg/day)/psychotherapy trial. The psychotherapy consisted of weekly sessions of nurse‐administered medication compliance and supportive treatment.

Results: The PACS proved to have excellent internal consistency. Predictive validity was demonstrated via a logistic regression analysis of craving during the 2nd week of the study on alcohol relapse during weeks 3‐12 of the trial. Construct validity of the PACS was demonstrated via its convergence with two commonly used measures for assessing craving, the Obsessive Compulsive Drinking Scale and the Alcohol Urge Questionnaire. Lack of correlation between PACS scores and several other noncraving, self‐report measures indicates that the PACS also had good discriminant validity. Additional analyses revealed that there were significant differences in craving scores during the initial 3 weeks of the trial among those who did and those who did not relapse during weeks 3‐12.

Conclusion: The PACS is a reliable and valid measure of alcohol craving and can predict which individuals are at risk for subsequent relapse.
Chronic Alcoholism Is Associated With an Imbalanced Production of Th‐1/Th‐2 Cytokines by Peripheral Blood T Cells
Authors: Laso Francisco Javier , Iglesias‐Osma Carmen , Ciudad Juana , Lopez Antonio , Pastor Isabel , Orfao Alberto
Published: May 2006

Background: In the present study, we analyzed, at the intracellular level, the pattern of cytokine secretion by the major CD4+ and CD8strong+ peripheral blood (PB) T‐cell subsets in patients with chronic alcoholism, and we correlated it both with the ethanol (EtOH) intake status and with the presence or not of alcoholic liver disease.

Methods: For that purpose, a total of 30 chronic alcoholic patients, 10 without liver disease (AWLD group) and 20 diagnosed with alcoholic liver cirrhosis (ALC) were studied. In all cases, flow cytometric measurement of intracellular expression of interferon–γ (IFN‐γ), interleukin (IL)‐2, and IL‐4 was performed on PB CD4+ and CD8strone+ T lymphocytes.

Results: After studying AWLD patients, we found increased numbers of both CD4+ and CD85trong+ PB T cells with detectable cytoplasmic levels of the IL‐2 and IFN‐γ T helper (Th)‐1‐associated cytokines, the greater increase being observed for this latter cytokine (p < 0.001 for CD4+ and p < 0.01 for CD8strong+ T cells). Regarding ALC patients, the pattern of expression of intracellular cytokines by PB T cells was different depending on the status of EtOH intake at the moment of entering this study. Accordingly, as in AWLD patients, ALC individuals who were actively drinking also displayed increased numbers of both CD4+ and CD8strong+ T cells expressing Th‐1‐associated cytokines. However, in these patients, expression of IFN‐γ although being significantly greater than that observed in control individuals (p < 0.05), was significantly lower than that in AWLD patients (p < 0.01 and p < 0.05, for CD4+ and CD8strong+ T cells, respectively). After a withdrawal period of ≥ 1 yr, ALC patients did not show significant changes in the cytoplasmic expression of Th‐1‐associated cytokines compared with the control group; in contrast, these patients showed a marked increase on the proportion of CD4+ and CD8strong+ T cells expressing IL‐4, a Th‐2‐associated cytokine (p < 0.01). After considering the ratio between the number of T cells expressing Th‐1 (IFN‐γ)‐and Th‐2 (IL‐4)‐associated cytokines in each individual, we found that there was a significant imbalance in this ratio, with a predominance of IFN‐γ‐producing T cells over IL‐4+ T lymphocytes during EtOH intake.

Conclusions: Our results showed that in patients with chronic alcoholism, active EtOH intake is associated with a Th‐1 pattern of cytokine production by PB T cells.
CSF Monoamine Metabolite and Beta Endorphin Levels in Recently Detoxified Alcoholics and Healthy Controls: Prediction of Alcohol Cue‐Induced Craving?
Authors: Petrakis Ismene L. , Trevisan Louis , D'Souza Cyril , Gil Roberto , Krasnicki Susan , Webb Elizabeth , Heninger George , Cooney Ned , Krystal John H.
Published: May 2006

Background: Abnormalities in central neurotransmitter systems have been described in alcohol‐dependent individuals and may contribute to alcohol craving. This study compared cerebrospinal fluid (CSF) levels of monoamine metabolites and beta endorphin levels in samples from early‐onset alcohol‐dependent patients (n= 20), late‐onset alcohol‐dependent patients (n= 14), and healthy controls (n= 23). It also evaluated whether these CSF measures levels predicted the degree of craving experienced in response to an alcohol cue.

Methods: Individuals meeting DSM‐III and ‐IV R‐criteria for alcohol dependence, 1 to 3 months postdetoxification, and healthy controls underwent a lumbar puncture. Patients also completed a cue exposure test day between 3 and 15 days later.

Results: Alcohol‐dependent patients had lower CSF levels of the norepinephrine metabolite MHPG compared with the healthy subjects, but this difference disappeared when differences in age between the groups were accounted for. No other group comparisons between patients and healthy subjects reached significance. CSF levels of the dopamine metabolite HVA were significantly higher in the early‐onset patients compared with the late‐onset patients and controls. The CSF measures did not predict the precue levels of craving, or the increase in craving after alcohol cue exposure.

Conclusions: These results are inconclusive about the role of monoaminergic dysregulation in recovering alcoholics. They also question the utility of these CSF measures to predict alcohol cue reactivity in patients who have been sober at least 1 month.
Clozapine's Effects on Ethanol's Motivational Properties
Authors: Thrasher Michael J. , Freeman Pierre A. , Risinger Fred O.
Published: May 2006

Background: Although dopamine D1 and D2 receptors have been implicated in ethanol's motivational effects, little is known about the contribution of dopamine D4 receptors. The present experiments examined the effects of clozapine, a dopamine D4 receptor antagonist, on ethanol's aversive, rewarding, stimulant, and reinforcing properties.

Methods: For taste conditioning, adult male Swiss‐Webster mice received five conditioning trials consisting of 1‐hr access to 0.2 M NaCl. After NaCl access on trials 1‐4, subjects received clozapine (0,1, or 2 mg/kg) followed 30 min later by 0,2, or 4 g/kg ethanol. For place conditioning, Swiss‐Webster mice received six pairings of a tactile stimulus with ethanol (2 g/kg, intraperitoneally), clozapine (1 mg/kg, intraperitoneally) + ethanol, or clozapine alone. Locomotor activity in a 30‐min test was determined in Swiss‐Webster mice receiving 0,0.5, or 1.0 mg/kg clozapine and 0,1, or 2 g/kg ethanol. In a drinking study, separate groups of adult male C57BL/6J mice were allowed 30‐min access to either 10% v/v ethanol mixed in 10% w/v sucrose or 10% sucrose without ethanol. During testing, both groups were given 0 or 1 mg/kg clozapine 30 min before fluid access.

Results: Ethanol flavor pairings during taste conditioning reduced subsequent flavor intakes, indicating the development of conditioned taste aversion. Clozapine reduced the magnitude of 4 g/kg ethanol‐conditioned aversion only on trial 4 at the 2 mg/kg dose. Conditioned place preference for the ethanol‐paired stimulus was not altered by clozapine. Clozapine alone did not produce either conditioned preference or aversion. Ethanol‐stimulated activity was reduced by clozapine treatment. However, clozapine alone did not alter locomotor activity levels. Clozapine reduced sucrose consumption but did not alter ethanol/sucrose intake.

Conclusions: These data suggest that clozapine influences a limited range of ethanol‐motivated behaviors. Specifically, dopamine D4 receptors appear important for ethanol's stimulant effect and possibly ethanol aversion, but not ethanol reward and reinforcement.
Treating Neonatal Rats With 6‐Hydroxydopamine Induced an Increase in Voluntary Alcohol Consumption
Authors: Yoshimoto K. , Kaneda S. , Kawai Y. , Ueda S. , Takeuchi Y. , Matsushita H. , Yuri K. , Yasuhara M.
Published: May 2006

Brain dopamine (DA) and serotonin (5‐HT) neurotransmission have been implicated in the mediation of alcohol‐seeking behavior. We examined the effects of treatment of neonatal rats (3 days after birth) with the neurotoxin 6‐hydroxydopamine (6‐OHDA; 100 μg/10 μl, intracerebroventricularly) on the relationship between the levels of neurotransmitters and alcohol drinking behavior at the age of 14 weeks. 6‐OHDA treatment reduced the levels of DA and its metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (ACC), frontal cortex, striatum (STR), tegmentum/substantia nigra, and dorsal raphe nucleus. 5‐HT levels in the ACC and STR were increased in the 6‐OHDA‐treated rats. 6‐OHDA‐treated rats showed increased alcohol consumption. There was a significant change in the ratio of [5‐hydroxyindoleacetic acid]/[5‐HT] in the ACC and STR of the treated rats, but no difference in the ratio of [DOPAC]/[DA] between the sham‐operated controls and treated rats. 6‐OHDA‐treated rats had dopaminergic dysfunction in the five brain regions related to the reward system, in part, and a decrease in 5‐HT turnover, including the accumulation of 5‐HT in the ACC and STR. Furthermore, basal extracellular releases of DA and 5‐HT of the ACC were significantly lower in the 6‐OHDA‐treated rats, compared with the controls. It was suggested that alcohol seeking behavior is associated with the alterations of dopaminergic neurons and the release of 5‐HT in the mesocorticolimbic system.
Mutations in the Exons and Exon‐Intron Junction Regions of Human Cytochrome P‐4502E1 Gene and Alcoholism
Authors: Itoga Sakae , Nomura Fumio , Harada Shoji , Tsutsumi Mikihiro , Takase Shujiro , Nakai Toshiaki
Published: May 2006

Cytochrome P‐4502E1 (CYP2E1) is a major component of the microsomal ethanol‐oxidizing system (MEOS) and is also involved in the metabolism of a variety of foreign compounds, including carcinogens. It has been shown that there are interindividual variations in the expression of human CYP2E1. Gene‐environmental interactions have been suggested to account for the difference. In this study, we screened nine exons and exonintron junctions of the human CYP2E1 gene for detecting allelic variants in genomic DNA samples obtained from 115 Japanese controls, 96 alcoholics, and 44 patients with alcoholic liver diseases. A novel missense mutation in exon 2 (V72L) was found in Japanese controls, but the frequency was low (2.6%). In addition, two novel silent mutations (T303T and F420F), together with one mutation in intron 2, were found. However, no association of these mutations with alcoholism and alcoholic liver diseases was found. Our data indicate that nucleotide replacement in the open reading frame of CYP2E1 gene is not a major factor for interindividual differences in expression of CYP2E1 and susceptibility to alcohol‐related disorders.
Relationship Between Serum Levels of Anti‐Low‐Density Lipoprotein‐Acetaldehyde‐Adduct Antibody and Aldehyde Dehydrogenase 2 Heterozygotes in Patients With Alcoholic Liver Injury
Authors: Nagata Naruhiko , Watanabe Norihito , Tsuda Michio , Tsukamoto Hideo , Matsuzaki Shohei
Published: May 2006

We prepared low‐density lipoprotein (LDL)‐acetaldehyde‐adduct (hereafter abbreviated as LDL‐adduct) and anti‐LDL‐adduct antibody by using Watanabe hyperlipidemic rabbits, and determined values of serum anti‐LDL‐adduct antibody levels by the ELISA method in healthy adults and patients with alcoholic liver injury. In the nondrinking group in healthy adults, values of anti‐LDL‐adduct antibody levels were 25 ± 13 μg/ml, and there was no significant difference between moderate drinkers without diseases and the nondrinking group in healthy adults. Values of anti‐LDL‐adduct antibody in alcoholic disease groups, 17 ± 9 μg/ml for the patients with the fatty liver group, 21 ± 14 μg/ml for the hepatic fibrosis group, 70 ± 21 μg/ml for the alcoholic hepatitis group, 41 ± 50 μg/ml for the alcoholic cirrhosis group, and 19 ± 18 μg/ml for the alcoholic pancreatitis group. Examinations of aldehyde dehydrogenase 2 (ALDH2) genetic variations by the polymerase chain reaction‐single‐strand conformation polymorphism (PCR‐SSCP) method in the healthy group and the liver injury group revealed a tendency for patients with ALDH21/22 in the liver injury group to have relatively mild liver lesions. When comparing anti‐LDL‐adduct antibody levels between ALDH2 genetic variations, those for the patients with ALDH21/21 (36 ± 40 μg/ml) were significantly higher than those for patients with ALDH1/22 (11 ± 5 μg/ml). Results of the present study suggest that genetic variation may influence the progression of liver injury.
Clinicopathological Study of Chronic Hepatitis Induced by Alcohol With or Without Hepatitis G Virus
Authors: Shimanaka Koshi , Tsutsumi Mikihiro , Sawada Makoto , Tsuchishima Mutsumi , Urashima Sachio , Ueshima Yasuhiro , Kawahara Hiromu , Takase Shujiro
Published: May 2006

The concept of chronic hepatitis induced by alcohol (AL‐CH) has not been widely accepted, because AL‐CH may be due to non‐A‐E hepatitis virus in heavy drinkers. Recently, hepatitis G virus (HGV) was identified as a positive‐strand RNA virus related to members of the Flaviviridae family. In this study, we determined serum HGV in patients with AL‐CH and analyzed the clinicopathological changes after abstinence to evaluate whether AL‐CH is caused by alcohol or not. Serum samples were obtained from 16 patients with AL‐CH who had neither hepatitis B nor C virus. The diagnosis was confirmed histologically. In eight patients, liver biopsy was performed twice, within 3 days and 4 to 8 weeks after abstinence. The NS3 region of the HGV genome was detected using an reverse transcriptase‐polymerase chain reaction method. Serum levels of AST, ALT and ‐γ‐glutamyltranspeptidase were measured once a week sequentially after admission. Serum HGV‐RNA was detected in only one patient with AL‐CH (6.3%). In all patients, including one patient with HGV, serum levels of AST, ALT and γ‐glutamyltranspeptidase clearly decreased to normal levels after abstinence. Inflammatory activity in the periportal area of patients with actively drinking decreased or disappeared after abstinence for 4 to 8 weeks. These results suggest that HGV may not play an important role for development of AL‐CH, and that AL‐CH may be caused by alcohol itself, although a more larger number of patients with AL‐CH are needed to obtain definitive conclusions.
Intralobular Distribution of Class I Alcohol Dehydrogenase and Aldehyde Dehydrogenase 2 Activities in the Hamster Liver
Authors: Watabiki Toshimitsu , Tokiyasu Takuma , Yoshida Manabu , Okii Yutaka , Yoshimura Sumitaka , Akane Atsushi
Published: May 2006

The hepatic lobular localization of class I alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) 2 activities was examined histochemically using livers of hamsters with high ethanol preferences. The activity of class I ADH detected by the nitro blue tetrazolium method using 5 mM ethanol as a substrate was extremely high and was almost homogeneously distributed throughout the lobule. The ALDH 2 activity (substrate, 8 μM acetaldehyde) was localized to the centrilobular zone, whereas low Km ALDH (ALDH 1 + ALDH 2) activity (substrate, 50 μM acetaldehyde) showed a gradient distribution in the lobule with high centrilobular to moderate periportal activity, suggesting that the ALDH 1 activity was distributed throughout the lobule.
Histochemical Study of Hyaluronate in Alcoholic Liver Disease
Authors: Urashima Sachio , Tsutsumi Mikihiro , Shimanaka Koshi , Ueshima Yasuhiro , Tsuchishima Mutsumi , Itoh Tohoru , Kawahara Hiromu , Takase Shujiro
Published: May 2006

Recently, it has been reported that serum hyaluronate (hyaluronic acid; HA) concentrations increase in various liver diseases, especially in alcoholic liver disease (ALD), and serum HA concentration has been used as a marker for hepatic fibrosis. However, it is unknown whether hepatic HA contents in ALD increase by alcohol or not. In this study, we histochemically stained HA in liver biopsy specimens obtained from ALD patients while actively drinking and after abstinence to clarify the effects of alcohol on hepatic HA contents. Liver biopsy specimens were obtained from 13 patients with ALD and 10 patients with non‐ALD. In ALD patients, liver biopsy was performed twice within 3 days, and 4 to 8 weeks after abstinence when serum levels of AST and ALT normalized. HA in biopsy specimens was stained histochemically with biotinylated HA binding protein. Staining intensity of HA in liver tissue was also determined by computer‐assisted imaging analyzer. HA staining was clearly observed in sinusoidal wall and fibrous regions around the portal tract and central vein in liver diseases. HA staining intensities in patients actively drinking with ALD increased markedly, compared with those in patients with non‐ALD, and these intensities decreased with abstinence. These results clearly suggest that hepatic HA contents in ALD may be increased by alcohol in addition to hepatic fibrosis, and, therefore, increased HA deposition in the liver may be reversible by abstinence of alcohol.
Increase of Serum Des‐gamma‐Carboxy Prothrombin in Alcoholic Liver Disease Without Hepatocellular Carcinoma
Authors: Ohhira M. , Ohtake T. , Saito H. , Ikuta K. , Tanaka K. , Tanabe H. , Kawashima T. , Fujimoto Y. , Naraki T. , Ono M. , Kohgo Y.
Published: May 2006

The purpose of this study is to determine serum des‐gamma‐carboxy prothrombin (DCP) levels in benign liver diseases by a new sensitive method, and to demonstrate the elevation of serum DCP in alcoholic liver disease (ALD) without hepatocellular carcinoma (HCC). Median values of serum DCP were 16.2 mAU/ml (range: 3.2 to 1570 mAU/ml) in ALD and 16.7 mAU/ml (1.2 to 75.4 mAU/ml) in viral liver disease (VLD). Using the cut‐off value of 40 mAU/ml as a tumor marker for HCC, 21% (11/52) was positive in ALD and 2% (1/57) was positive in VLD (p= 0.0014, Fisher's exact probability test), and 27% (9/33) was positive in alcoholic liver cirrhosis and 3% (1/39) was positive in viral liver cirrhosis (p = 0.0042, Fisher's exact probability test). The positive rate of DCP was significantly (p< 0.001, Spearman's rank correlation test) correlated with the severity of liver disease in ALD. Serum vitamin K level was not decreased in cases with ALD. In a demonstrable case, serum DCP was decreased after abstinence and was increased again after the beginning of ethanol intake, suggesting the involvement of ethanol to the elevation of serum DCP in ALD. In conclusion, serum DCP was significantly elevated in ALD, compared with VLD, although the mechanism of the elevation of DCP was not clarified. Ethanol intake may act, in part, on the increase of serum DCP in ALD.
Serum Ubiquitin Levels in Patients With Alcoholic Liver Disease
Authors: Takagi Masaru , Yamauchi Masayoshi , Toda Gotaro , Takada Koji , Hirakawa Tae , Ohkawa Kiyoshi
Published: May 2006

Serum concentrations of free ubiquitin and multiubiquitin chain as determined by immunoassays were compared between 10 healthy subjects, and 11 patients with alcoholic hepatic fibrosis, 10 with alcoholic cirrhosis, and 6 with viral liver cirrhosis. All measurements of multiubiquitin chains were expressed in terms of a standard multiubiquitin chain reference preparation 1. Serum concentrations (mean ± SD) of free ubiquitin and multiubiquitin chains were significantly higher in patients with alcoholic cirrhosis (63.5 ± 33.7 ng/ml and 7.5 ± 4.6 ng/ml) than in the normal subjects (29.6 ± 6.6 ng/ml, p < 0.05 and 4.1 ±1.7 ng/ml, p < 0.05), and those with alcoholic hepatic fibrosis (34.8 ± 16.3 ng/ml, p < 0.05 and 3.0 ± 0.7 ng/ml, p < 0.05) and viral liver cirrhosis (28.8 ± 7.5 ng/ml, p < 0.05 and 4.2 ± 1.3 ng/ml, p < 0.05). Serum levels of both forms of ubiquitin in six patients with alcoholic cirrhosis showed a tendency to decline after 3 months of abstinence. In a total of 14 patients with alcoholic liver damage, 11 with brain atrophy had significantly higher serum levels of both ubiquitin forms than did three patients without brain atrophy (p < 0.05). No correlation was seen between serum concentrations of either form of ubiquitin and liver function test results in the patients with alcoholic liver damage. However, serum levels of both forms of ubiquitin levels correlated significantly with cumulative alcohol intake (p < 0.05). A significant correlation (p < 0.05) also was observed between serum levels of multiubiquitin chains and mean corpuscular volume, a marker of alcohol consumption. These results suggest that the serum concentrations of ubiquitin, especially multiubiquitin chain is a good marker for the diagnosis of alcoholic cirrhosis.
Alcohol Deprivation Effect Is Prolonged in the Alcohol Preferring (P) Rat After Repeated Deprivations
Authors: Rodd‐Henricks Zachary A. , McKinzie David L. , Shaikh Saame R. , Murphy James M. , McBride William J. , Lumeng Lawrence , Li Ting‐Kai
Published: May 2006

Background:

The alcohol deprivation effect (ADE) is a temporary increase in the ratio of ethanol/total fluid intake and the voluntary intake of ethanol solutions over baseline drinking conditions when ethanol access is reinstated after a period of alcohol deprivation. The ADE has been posited to be an animal model for alcohol craving. The current study examined the effects of initial deprivation length and number of deprivation exposures on the ADE in alcohol‐preferring (P) rats.

Methods:

Adult female P rats received 24‐hr free‐choice access to 10% (v/v) ethanol and water for 6 weeks. Rats were then randomly assigned to five groups deprived of ethanol for O (control), 2, 4, 6, or 8 weeks (W). All deprived groups were then given 24‐hr access to ethanol for 2 weeks before bbeing deprived of ethanol for another 2 weeks.

Results:

After the initial ethanol deprivation period, the deprived groups displayed a similar 2‐fold ADE (e.g., 4‐W group; 4.6 ± 0.5 for baseline vs. 10.5 ± 0.3 g/kg/day for the 1st reinstatement day) during the initial 24‐hr period. Ethanol consumption began to return to control levels 48 (7.1 ± 0.4 g/kg/day) and 72 (6.4 ± 0.4 g/kg/day) hrs later. In addition, each deprived group showed increases in the ratio of ethanol/total fluid intake upon reinstatement, and there was a tendency for sustained higher ethanol intake ratlos during the first 3 postexposure days for the 4‐, 6‐, and 8‐W grups, but only during the first 2 reinstatement days for the 2‐W group. The second deprivation did not increase the magnitude of the ADE over that observed in the first deprivation during the initial 24‐hr period of re‐exposure, but it did prolong the duration of the ADE into the 2nd and 3rd reinstatement day for the 2‐, 4‐, and 6‐W groups and into the 5th reinstatement day for the 8‐W group.

Conclusions:

Equivalent robust ADEs can be seen in P rats with deprivation periods of 2–8 W, which suggests that the ADE has a rapid onset and is not affected by the durations of deprivation that were tested. The duration of the ADE was prolonged in P rats exposed to a second deprivation period, suggesting that factors associated with the ADE phenomenon could be strengthened by repated deprivations.
Heritability of the Blood Pressure Response to Acute Ethanol Exposure in Five Inbred Strains of Mice
Authors: Hatton Daniel C. , Qi Yue , Belknap J. K.
Published: May 2006

Background:

Chronic alcohol consumption is a major risk factor for hypertension. There is evidence in humans that the susceptibility to alcohol‐related hypertension may vary based on genotype. As a first step in investigating the genetic basis for alcohol‐related hypertension, the current study was designed to assess the heritability of the blood pressure response to acute ethanol exposure by using AKR/J (AK), C57BL/6J (B6), DBA/2J (D2), Balb/cJ (Balb), and A/J (A) mice.

Methods:

Mean arterial pressure (MAP) was recorded continuously for 24 hr in freely moving mice from an indwelling femoral catheter before we tested the effects of saline or ethanol (2 g/kg ip) on blood pressure.

Results:

Relative to saline, ethanol caused a pressor response that peaked within 10 min, followed by a decline in MAP. Strain A mice had a significantly greater pressor response to ethanol than other strains and did not show a decline in MAP below baseline. All other strains showed a progressive fall in blood pressure below baseline across the 60 min measurement interval. Heritability was estimated to be 0.62 for the pressor response and 0.64 for the maximal depressor response. Repeated doses of ethanol at 1 hr intervals in A and B6 mice (0,2,1.5,1.5,1.5 g/kg ip) resulted in a dose‐dependent increase in MAP in A mice for the first three doses and a dose‐dependent decrease in MAP in B6 mice that was independent of blood ethanol concentrations.

Conclusion:

The results indicate that there is a significant genetic component to the acute blood pressure response to ethanol.
Effects of MDL 72222, a Serotonin3 Antagonist, on Operant Responding for Ethanol by Alcohol‐Preferring P Rats
Authors: McKinzie D. L. , McBride W. J. , Murphy J. M. , Lumeng L. , Li T.‐K.
Published: May 2006

Background:

Previous studies indicated that, under continuous access conditions, the 5‐HT3 antagonist MDL 72222 (MDL) effectively reduced ethanol drinking of alcohol‐preferring P rats. However, MDL was without effect when similar doses were tested under scheduled access conditions, unless the ethanol access period was randomly presented. This study examined the effects of MDL on operant responding for ethanol and water by adult male alcohol‐preferring P rats.

Methods:

During the dark cycle, subjects in the first experiment were trained to respond concurrently for 15% ethanol and water on a fixed‐ratio 5 (FR‐5) and FR‐1 schedule of reinforcement, respectively. Approximately 30 min before the 4‐hr operant session, rats were injected subcutaneously (sc) with saline or MDL (1,3, or 5 mg/kg). A second experiment tested the effects of 1 mg/kg MDL on operant responding for 15% ethanol in 1‐hr sessions when operant access was given at a fixed time each day (fixed scheduled access, FSA group) or at variable time periods throughout the dark cycle (variable scheduled access, VSA group).

Results:

In the first experiment, only the 5 mg/kg dose of MDL decreased responding for ethanol (approximately 20%) during the first 30 min of the 4‐hr session. This dose also reduced total 4‐hr responding for ethanol and water. In the second experiment, the 1 mg/kg dose of MDL had no effect on operant responding by the FSA group, but significantly reduced ethanol responding by the VSA group.

Conclusions:

These results suggest that 5‐HT3 receptors may be involved in mediating the reinforcing effects of ethanol, and that temporal‐environmental cues associated with the presentation of ethanol may be one factor involved in reducing the effectiveness of 5‐HT3 antagonists to attenuate ethanol intake.
Treatment of Problem Alcohol Use in Women of Childbearing Age: Results of a Brief Intervention Trial
Authors: Manwell Linda Baier , Fleming Michael F. , Mundt Marlon P. , Stauffacher Ellyn A. , Barry Kristen Lawton
Published: May 2006

Background:

Studies suggest that 14% of women age 18 to 40 drink alcohol above recommended limits. Of special concern is the increasing use of alcohol by women during pregnancy. This article reports 48 month follow‐up data from a subanalysis of a trial for early alcohol treatment (Project TrEAT) focused on women of childbearing age.

Methods:

Project TrEAT was conducted in the offices of 64 primary care, community‐based physicians from 10 Wisconsin counties. Of 5979 female patients ages 18 to 40 who were screened for problem drinking, 205 were randomized into an experimental group (n= 103) or control group (n= 102). The intervention consisted of two 15 min, physician‐delivered counseling visits that included advice, education, and contracting by using a scripted workbook. A total of 174 subjects (85%) completed the 48 month follow‐up procedures.

Results:

No significant differences were found between the experimental and control groups at baseline for alcohol use, age, socioeconomic status, smoking, depression or anxiety, conduct disorder, lifetime drug use, or health care utilization. The trial found a significant treatment effect in reducing both 7 day alcohol use (p= 0.0039) and binge drinking episodes (p= 0.0021) over the 48 month follow‐up period. Women in the experimental group who became pregnant during the follow‐up period had the most dramatic decreases in alcohol use. A logistic regression model based on a 20% or greater reduction in drinking found an odds ratio of 1.93 (confidence interval 1.07–3.46) in the sample exposed to physician intervention. Age, smoking, depression, conduct disorder, antisocial personality disorder, and illicit drug use did not reduce drinking significantly. No significant differences were found in health care utilization and health status between groups.

Conclusions:

This trial provides the first direct evidence that brief intervention is associated with sustained reductions in alcohol consumption by women of childbearing age. The results have enormous implications for the U.S. health care system.