bluuebunny/crossref_metadata_2025 huggingface dataset:
CDT, GGT, and AST As Markers of Alcohol Use: The WHO/ISBRA Collaborative Project
Authors: Conigrave Katherine M. , Degenhardt Louisa J. , Whitfield John B. , Saunders John B. , Helander Anders , Tabakoff Boris ,   on behalf of the WHO/ISBRA Study Group
Published: April 2006

Background: Estimates of the performance of carbohydrate deficient transferrin (CDT) and gamma glutamyltransferase (GGT) as markers of alcohol consumption have varied widely. Studies have differed in design and subject characteristics. The WHO/ISBRA Collaborative Study allows assessment and comparison of CDT, GGT, and aspartate aminotransferase (AST) as markers of drinking in a large, well‐characterized, multicenter sample.

Methods: A total of 1863 subjects were recruited from five countries (Australia, Brazil, Canada, Finland, and Japan). Recruitment was stratified by alcohol use, age, and sex. Demographic characteristics, alcohol consumption, and presence of ICD‐10 dependence were recorded using an interview schedule based on the AUDADIS. CDT was assayed using CDTect™ and GGT and AST by standard methods. Statistical techniques included receiver operating characteristic (ROC) analysis. Multiple regression was used to measure the impact of factors other than alcohol on test performance.

Results: CDT and GGT had comparable performance on ROC analysis, with AST performing slightly less well. CDT was a slightly but significantly better marker of high‐risk consumption in men. All were more effective for detection of high‐risk rather than intermediate‐risk drinking. CDT and GGT levels were influenced by body mass index, sex, age, and smoking status.

Conclusions: CDT was little better than GGT in detecting high‐ or intermediate‐risk alcohol consumption in this large, multicenter, predominantly community‐based sample. As the two tests are relatively independent of each other, their combination is likely to provide better performance than either test alone. Test interpretation should take account sex, age, and body mass index.
Metadoxine in Acute Alcohol Intoxication: A Double‐Blind, Randomized, Placebo‐Controlled Study
Authors: Shpilenya Leonid S. , Muzychenko Alexander P. , Gasbarrini Giovanni , Addolorato Giovanni
Published: April 2006

Background: At present there are only intriguing and preliminary clinical results regarding the efficacy of metadoxine (pyridoxol L‐2‐pyrrolidone‐5‐carboxylate) in acute alcohol intoxication. The present study was planned with the aim of investigating the effectiveness of metadoxine in the management of patients affected by acute ethanol intoxication.

Methods: A double‐blind, randomized, multicenter, placebo‐controlled trial was carried out on 58 patients of both sexes with acute ethanol intoxication. Patients were treated with a single dose of 900‐mg intravenous metadoxine (n= 29) or with placebo (n= 29). Patients were clinically and biochemically evaluated at 0.5, 1, 2, 3, 6, 9, and 12 hr after treatment.

Results: Treatment with metadoxine significantly decreased the half‐life of ethanol in blood (from 6.70 ± 1.84 to 5.41 ± 1.99 hr;p < 0.013) and showed a faster rate of ethanol elimination. The effects on ethanol half‐life in blood were accompanied by a faster onset of recovery from intoxication, defined as the time of the transition of blood ethanol levels to the immediately lower range defined by intoxication categories (in g/liter: 0 to 0.5, absent; 0.51 to 1.0, mild; 1.1 to 2.5, moderate; >2.5, severe). Thus the median time to onset of recovery was 0.95 hr with metadoxine and 2.34 hr with placebo (p= 0.013). The effects of treatment on blood alcohol levels were paralleled by a significant decrease in the rating of the toxic clinical symptomatology. At 2 hr the improvement of toxic symptoms (in percent of maximum possible) was 68 ± 28 vs. 44 ± 27% in controls (p < 0.002).

Conclusions: In patients with acute ethanol intoxication metadoxine accelerated the elimination of ethanol from blood, which led to faster recovery from intoxication, and improved the behavioral toxic symptomatology. Metadoxine could be helpful in the management of acute ethanol intoxication.
Altered Emotion‐Modulated Startle in Young Adults With a Family History of Alcoholism
Authors: Miranda Robert , Meyerson Lori A. , Buchanan Tony W. , Lovallo William R.
Published: April 2006

Background: Alcoholism risk may be accompanied by poor regulation of emotions, signaling altered central nervous system processes. This study used the emotion‐modulated startle paradigm to test the hypothesis that young adults with a positive paternal history of alcoholism (FH+), relative to family‐history‐negative persons (FH−), have altered emotional reactivity to environmental cues.

Methods: We tested 30 FH+ and 30 FH−, 15 males and 15 females in each group. Participants completed self‐report instruments and interviews and had eye blink electromyograms (EMG) measured to acoustic startle probes while viewing color photographs rated as affectively pleasant, neutral, and unpleasant.

Results: FH− had the expected linear increase in startle magnitude, with eye blink EMG gaining in strength (F= 18, p < 0.0002) from pleasant to neutral to unpleasant slides. In contrast, FH+ did not show EMG potentiation to the unpleasant slides and therefore lacked the same linear trend (F < 1, p > 0.4). Notably, FH groups rated the emotional valence and arousal of the photographs in similar ways. Self‐reported negative affect partly accounted for the lack of startle potentiation in FH+, suggesting that startle modulation differences between the groups may be associated with underlying psychological characteristics.

Conclusions: These findings implicate altered limbic outputs to the startle pathway in FH+ despite normal conscious evaluation of emotional arousal and pleasantness of the slides. This method may provide a useful paradigm for testing processing of emotionally relevant stimuli in relation to risk for alcohol use disorders.
Comparison of 3190 Alcohol‐Dependent Individuals With and Without Suicide Attempts
Authors: Preuss U. W. , Schuckit M. A. , Smith T. L. , Danko G. P. , Buckman K. , Bierut L. , Bucholz K. K. , Hesselbrock M. N. , Hesselbrock V. M. , Reich T.
Published: April 2006

Introduction: Suicidal behaviors are often seen in alcohol‐dependent individuals. The aim of this study is to identify and confirm risk factors for suicide attempts in a large, family‐based sample of alcoholics.

Methods: Semistructured, detailed interviews were administered to 3190 alcohol‐dependent individuals as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Information about suicidal behavior, socioeconomic characteristics, psychiatric comorbidity, substance use disorders, and characteristics of alcohol dependence were obtained from alcohol‐dependent probands, controls, and their relatives.

Results: As determined by both univariate comparison and multivariate logistic regression analysis, alcohol‐dependent individuals with a history of suicide attempts were found to have a significantly more severe course of alcohol dependence and a higher prevalence of both independent and substance‐induced psychiatric disorders and other substance dependence. First‐degree relatives of subjects with suicide attempts showed a significantly higher rate of suicide attempts even after controlling for additional relevant diagnoses.

Conclusion: These results support the hypothesis that alcohol‐dependent individuals with a history of suicide attempts are more severely impaired. Screening and subsequent treatment of alcohol use disorder, psychiatric comorbidity, and substance use disorders among alcoholics may be crucial in preventing suicide attempts and completions.
Binge Ethanol Exposure in Adult Rats Causes Necrotic Cell Death
Authors: Obernier J. A. , Bouldin T. W. , Crews F. T.
Published: April 2006

Background: Although alcoholics show neurodegeneration after decades of drinking, recent studies with an animal model of binge drinking have found corticolimbic damage after as few as four days. Neurodegeneration can occur through apoptotic or necrotic mechanisms. The goal of this research is to characterize the time course of binge ethanol‐induced neurodegeneration and to identify apoptotic or necrotic characteristics of this neurodegeneration.

Methods: Histologic methods (e.g., amino cupric silver staining, Fluoro‐Jade B, hematoxylin and eosin, transmission electron microscopy) were used to quantify the time course of degeneration and to characterize the ultrastructural changes that occur with binge ethanol‐induced neurodegeneration.

Results: After 2 days of binge ethanol, significant damage was evident in the olfactory bulb. After 4 days of binge ethanol, there was significant damage in the agranular insular cortex, anterior piriform cortex, perirhinal cortex, lateral entorhinal cortex, and the temporal dentate gyrus. Ultrastructural examination revealed shrunken soma, vacuolated cytoplasm, pyknotic nucleus, and irregularly clumped chromatin consistent with dark cell degeneration, a form of necrotic neuronal death.

Conclusions: Binge drinking causes necrotic neurodegeneration after 2 days of exposure and increased damage after 4 days but does not increase during withdrawal. These studies indicate that binge drinking induced neurodegeneration is necrotic and occurs during ethanol intoxication and not as a result of ethanol withdrawal.
Gene and Antisense Delivery in Alcoholism Research
Authors: Israel Y. , Crews F. T. , Thurman R. G. , Tu G.‐ C. , Garver E. , Ponnappa B. , Karahanian E. , Rubin R. , Hoplight B. , Sethna M. , Hanes R. , Wilkie M. B. , Wheeler M. D.
Published: April 2006

This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. Drs. Yedy Israel and Fulton Crews were organizers and co‐chairpersons. The presentations were (1) Introduction to the symposium, by Yedy Israel; (2) Gene delivery to the brain, by Fulton T. Crews; (3) Gene therapy in alcoholic liver injury, by Ronald Thurman; and (4) Antisense oligonucleotides and antisense‐gene delivery, by Yedy Israel.
Forward, Relaxed, and Reverse Selection for Reduced and Enhanced Sensitivity to Ethanol's Locomotor Stimulant Effects in Mice
Authors: Phillips Tamara J. , Shen Elaine H. , McKinnon Carrie S. , Burkhart‐Kasch Sue , Lessov Christina N. , Palmer Abraham A.
Published: April 2006

Background: Rarely have trait markers for alcoholism risk been identified. However, relative sensitivity to the arousing effects of ethanol and sensitivity to ethanol's sedative effects have been distinguished as potentially valuable behavioral risk factors. Both traits are genetically influenced and have been modeled in mice by measuring sensitivity to ethanol‐induced locomotor stimulation and hypnosis. Reverse selection was performed to examine the hypothesis that forward selection for differential sensitivity to ethanol's locomotor stimulant effects resulted in homozygous fixation of selection trait‐relevant alleles and to test the hypothesis that common genes influence ethanol's stimulant and sedative effects.

Methods: Bidirectional selective breeding was completed for enhanced (FAST mice) and reduced (SLOW mice) sensitivity to ethanol's locomotor stimulant effects. Selection was terminated (relaxed), and the lines were tested to detect genetic drift. Reverse selection for enhanced sensitivity to ethanol‐induced stimulation in SLOW mice and reduced sensitivity in FAST mice was performed for 16 generations. Forward and reverse selected lines were tested for sensitivity to ethanol's sedative effects by measuring duration of ethanol‐induced loss of righting reflex.

Results: Differential sensitivity to the sedative effects of ethanol emerged with selection for differential ethanol stimulation, indicating a common genetic influence on these traits. SLOW mice developed greater sensitivity to ethanol's sedative effects relative to FAST mice. Reverse selection, never before reported for a pharmacogenetic trait, was effective in eliminating most of the difference in stimulant sensitivity between the FAST and SLOW lines and also eliminated the difference in loss of righting reflex duration.

Conclusions: Residual heterozygosity persisted at trait‐relevant loci even at the selection plateau, possibly due to heterosis, natural selection favoring heterozygosity, or epistatic phenomena involving differences in the sets of genes regulating the high‐ versus low‐sensitivity traits. They also suggest that some common genes influence sensitivity to ethanol's locomotor stimulant and sedative effects.
Acamprosate Has No Effect on NMDA‐Induced Toxicity But Reduces Toxicity Induced by Spermidine or by Changing the Medium in Organotypic Hippocampal Slice Cultures From Rat
Authors: Mayer Sveta , Harris Barton , Gibson D. Alex , Blanchard John , Prendergast Mark A. , Holley Robert C. , Littleton John
Published: April 2006

Background: It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor‐mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA receptor subunits. These effects on NMDA receptors imply that the drug may have neurotoxic or neuroprotective actions under different conditions, and these studies were undertaken to evaluate this possibility in hippocampal neuronal cultures.

Methods: Organotypic hippocampal cultures from 8‐day‐old neonatal rats were maintained in medium for 28 days. The effects of acamprosate (100 μM) alone or on neurotoxic challenges induced by either 50 μM NMDA or 100 μM spermidine were studied. Neurotoxicity was assessed by uptake of propidium iodide 24 hr after challenge. Calcium entry was measured by uptake of 45Ca2+ into the culture during the challenge.

Results: Acamprosate produced no neurotoxicity in these cultures after acute or subchronic exposure. In contrast, the presence of acamprosate significantly reduced “basal” propidium iodide uptake caused by the medium change procedure; similar effects were obtained with dizocilpine (MK‐801; 30 μM) and, to a lesser extent, with ifenprodil (50 μM). Acamprosate did not significantly potentiate or inhibit NMDA‐induced neurotoxicity, but the presence of acamprosate significantly reduced spermidine‐induced neurotoxicity.

Conclusion: No evidence was obtained that the putative agonist or coagonist effects of acamprosate on the NMDA receptor are able to cause neurotoxicity. Similarly, no evidence for inhibitory effects of acamprosate on NMDA‐induced toxicity was observed under any of these conditions. However, acamprosate significantly inhibited the toxicity associated with changing medium and the toxicity induced by spermidine in these hippocampal cultures. The mechanism is unknown but is compatible with previously reported inhibition of polyamine‐mediated effects.
Effects of Ethanol and Basic Fibroblast Growth Factor on the Transforming Growth Factor β1 Regulated Proliferation of Cortical Astrocytes and C6 Astrocytoma Cells
Authors: Miller Michael W. , Luo Jia
Published: April 2006

Background: The effects of ethanol on transforming growth factor β1 (TGFβ1)‐regulated proliferation of primary cultured cortical astrocytes and C6 astrocytoma cells were determined.

Methods: Cultured cells were treated with TGFβ1 (0 or 10 ng/ml) and ethanol (0 or 400 mg/dl) for as many as 4 days. The effects of these treatments on cell growth (the change in cell number) and cell proliferation (incorporation of [3H]thymidine) were determined. In addition, the effects of serum and basic fibroblast growth factor (bFGF) on TGFβ1‐affected cell proliferation were examined.

Results: Both TGFβ1 and ethanol inhibited cell growth and proliferation among the two types of cells; this effect was only evident when the cells were grown in the presence of a mitogen, serum, or bFGF. When added together (either in a serum‐supplemented or serum‐free medium), however, TGFβ1 and the mitogen effectively nullified each other. TGFβ1 blocked the mitogenic effect of bFGF on astrocytes and C6 cells. Ethanol did not affect (i.e., neither added nor nullified) this antagonistic effect.

Conclusions: TGFβ1, like ethanol, is a potent anti‐proliferative agent; either can nullify the mitogenic activity of serum or bFGF. Astrocytes and astrocyte‐like cells react to combined TGFβ1 and ethanol treatment differently than do neurons for which the inhibitory effects of TGFβ1 and ethanol are additive.
Speed and Efficiency but Not Accuracy or Timing Deficits of Limb Movements in Alcoholic Men and Women
Authors: Sullivan Edith V. , Desmond John E. , Lim Kelvin O. , Pfefferbaum Adolf
Published: April 2006

Background: Lesions of the cerebellum, a concomitant of alcoholism, can disrupt quality and regularity of movement. Whether evidence for such dysfunction lingers in patients with uncomplicated alcoholism, which is known to affect cerebellar structural integrity, is controversial.

Methods: We used quantitative measures to examine component processes of five classes of movement associated with regional cerebellar function: limb ataxia (alternated finger tapping and variants of the finger‐to‐nose and heel‐to‐shin tests), paced tapping, eye‐hand coordinated tracing, timed response reflecting preparation and execution time, and postural stability. The subjects examined were 39 abstinent alcoholics (13 men and 26 women) and 21 age‐matched controls (9 men and 12 women). For limb ataxia, the dependent measures were the trajectory deviation from the subject's own average movement path and the speed of travel from beginning points to endpoints.

Results: Repeated‐measures analysis of variance comparing movement speed of finger to nose and heel to shin yielded significant interactions in all conditions (p < 0.007); this indicated that the alcoholics were relatively slower in the upper‐ than lower‐limb tasks. Movements by the alcoholic men were significantly slower but less deviant from an ideal trajectory in all upper‐limb conditions than those of the control men (p < 0.002). Although measures of lower‐limb movement trajectory did not distinguish the groups, tests of ataxia of stance and gait did. The groups did not differ, however, on tests of timed tapping or sinusoid tracing.

Conclusions: Alcohol‐related postural instability in abstinent alcoholics is functional evidence supporting the postulated damage to the anterior superior vermis. Altered speed or accuracy trade‐offs, with alcoholics moving slower to attain equivalent or even smaller trajectory deviations, are symptomatic of cerebellar hemisphere dysfunction that is characterized by deliberation of otherwise automatic movements.
The Corticotropin‐Releasing Factor/Urocortin System and Alcohol
Authors: Ryabinin Andrey E. , Bachtell Ryan K. , Heinrichs Stephen C. , Lee Soon , Rivier Catherine , Olive M. Foster , Mehmert Kristin K. , Camarini Rosana , Kim Joseph A. , Koenig Heather N. , Nannini Michelle A. , Hodge Clyde W. , Roberts Amanda J. , Koob George F.
Published: April 2006

This article represents the proceedings of a symposium at the RSA meeting in Montreal, Canada. The organizer was Andrey E. Ryabinin, and the chair was George F. Koob. The presentations were (1) Introduction, by Stephen C. Heinrichs; (2) Role of CRF and its receptors in the hypothalamic‐pituitary‐adrenal response to alcohol, by Soon Lee and Catherine Rivier; (3) A role for CRF in the allostasis of alcohol dependence, by George F. Koob and Amanda J. Roberts; (4) CRF and alcohol: Lessons from knockouts, microinjections, and microdialysis, by M. Foster Olive, Kristin K. Mehmert, R. Camarini, Joseph A. Kim, Heather N. Koenig, Michelle A. Nannini, and Clyde W. Hodge; and (5) Selective sensitivity of urocortin‐containing neurons to alcohol self‐administration, by Andrey E. Ryabinin and Ryan K. Bachtell.
Pathogenesis of Alcoholic Liver Disease–Recent Advances
Authors: Nanji Amin A. , Su Grace L. , Laposata Michael , French Samuel W.
Published: April 2006

The article summarizes the proceedings of a symposium on recent advances in research on the pathogenesis of alcoholic liver disease at the 2001 RSA meeting in Montreal, Canada. The chairs were Amin A. Nanji and Samuel W. French. The presentations were (1) Role of inflammatory mediators in alcoholic liver injury by Amin A. Nanji, (2) Role of endotoxin, lipopolysaccharide binding protein, CD14 and Toll receptors in alcoholic liver injury by Grace Su, (3) Fatty acid ethyl esters: toxicity, metabolism and markers of ethanol intake by Michael Laposata, and (4) Cyclic changes in gene expression when rats are fed alcohol at a constant rate by Samuel W. French.
Discriminative Stimulus Effects of Ethanol in C57BL/6J and DBA/2J Inbred Mice
Authors: Shelton Keith L. , Grant Kathleen A.
Published: April 2006

Background: Two of the most widely used mouse strains for studying the behavioral effects of ethanol are C57BL/6J (B6) and DBA/2J (D2) mice. These strains exhibit marked differences in behavioral and physiological responses to ethanol. The subjective discriminative stimulus effects of ethanol may play a role in ethanol abuse, but the discriminative stimulus profile of ethanol has not been compared in B6 and D2 mice. Examination of the discriminative stimulus effects of ethanol in B6 and D2 mouse strains may enhance our understanding of the relationship between the subjective effects of ethanol and other ethanol‐induced behavioral effects.

Methods: Twelve adult male C57BL/6J mice and 12 male DBA/2J mice were trained to discriminate 1.5 g/kg ethanol from saline in daily 15 min, milk‐reinforced operant sessions. After training, ethanol substitution and response‐rate suppression dose response curves were determined for ethanol, midazolam, diazepam, pentobarbital, pregnanolone, 4,5,6,7‐Tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP), dizocilpine, and morphine.

Results: D2 mice learned the ethanol discrimination significantly more quickly than did B6 mice. Ethanol, midazolam, pregnanolone, and dizocilpine fully substituted for ethanol in both strains. Pentobarbital was more potent in producing ethanol‐like discriminative stimulus effects in D2 than B6 mice. Midazolam and diazepam were significantly more potent in suppressing response rates in D2 than B6 mice. Morphine failed to substitute for ethanol in either strain, but the ED50 for morphine suppression of responding was significantly lower in B6 than D2 mice.

Conclusions: The initial stimulus effects of 1.5 g/kg ethanol may be more salient in D2 than B6 mice. This does not appear to result from differences in the neurotransmitter systems that mediate ethanol's discriminative stimulus effects. In both strains, γ‐aminobutyric acid‐positive modulators and a noncompetitive NMDA antagonist substituted for ethanol. However, strain differences did exist in the potency of γ‐aminobutyric acid‐positive modulators and morphine for suppressing operant responding.
Detection and Localization of Protein‐Acetaldehyde Adducts in Rat Brain After Chronic Ethanol Treatment
Authors: Upadhya Sudarshan C. , Ravindranath Vijayalakshmi
Published: April 2006

Background: Ethanol is metabolized to acetaldehyde in the cell, which is potentially deleterious because it can react with cellular proteins and form protein‐acetaldehyde adducts, which can interfere with normal cellular function. Because the primary site of ethanol action is the brain, the present study was carried out to determine whether protein‐acetaldehyde adducts are formed in rat brain after chronic ethanol administration.

Methods: Rats were treated with ethanol for 1 year, and the formation of protein‐acetaldehyde adducts was examined by immunoblot analysis and localized in brain by immunohistochemical analysis by using affinity purified antibody to acetaldehyde‐hemocyanin adduct.

Results: In the brain of rats administered ethanol for up to 1 year, protein‐acetaldehyde adducts were detectable by immunoblot analysis. In brain, mitochondria was the primary site of adduct formation, unlike the liver, where the major protein‐acetaldehyde adduct has been detected in the cytosol. Immunohistochemical localization of protein‐acetaldehyde adducts in chronic ethanol‐treated rat brain demonstrated the selective presence of adducts in cortical neurons, granule cell layer of dentate gyrus, neurons in the midbrain, and granular cell layers of cerebellum.

Conclusions: These results demonstrate the significant formation of protein‐acetaldehyde adducts in rat brain after ethanol ingestion. The modification of mitochondrial proteins in brain by protein‐acetaldehyde adduct formation is significant because mitochondrial dysfunction has been implicated in neurodegeneration.
Epidermal Growth Factor Protects the Liver Against Alcohol‐Induced Injury and Sensitization to Bacterial Lipopolysaccharide
Authors: Deaciuc Ion V. , D'Souza Nympha B. , Burikhanov Ravshan , Lee Eun Y. , Tarba Corneliu N. , McClain Craig J. , de Villiers Willem J. S.
Published: April 2006

Background: Whereas the role of proinflammatory cytokines in the pathogenesis of alcoholic liver disease has been at the forefront of investigation, a possible role for anti‐inflammatory cytokines in this disease has received little attention. This study investigated (1) the hepatic protective effect of an anti‐inflammatory cytokine, epidermal growth factor (EGF), against deleterious effects of alcohol and sensitization to bacterial lipopolysaccharide (LPS), and (2) the possible mechanisms that underlie such protection.

Methods: Male C57BL/6 mice were fed a Lieber‐DeCarli liquid diet that contained alcohol or an isocaloric replacement for 6 weeks. The animals then were treated daily with human EGF for 7 days (5 μg/mouse), after which they were injected with either LPS (1 mg/kg of body weight) or vehicle and killed 8 hr later. Blood and liver were analyzed for plasma aminotransferase activity, liver histology, liver apoptotic nuclei, mRNA of several cytokines (tumor necrosis factor [TNF]‐α, interleukin [IL]‐1β, IL‐6, and IL‐10), apoptotic ligands (TRAIL), cytokine receptors (TNFRp55), pro‐ and antiapoptotic regulators/adaptors (Fas receptor, FasL, FADD, TRADD, RIP, Bak, Bax, Bcl‐X, Bcl‐2 and Bcl‐w), and caspase‐8.

Results: Alcohol increased plasma aminotransferase activity and sensitized the liver to the effects of LPS, such as polymorphonuclear infiltration, occurrence of necrotic foci and microabscesses, and increased apoptosis. These changes were associated with elevated mRNA expression of proapoptotic regulators/adaptors. EGF either counteracted or markedly blunted most of these effects. EGF did not affect liver mRNA expression of TNF‐α, IL‐1β, IL‐6, and IL‐10, which suggested that these cytokines were not involved in EGF protective effect. EGF protection was mediated by down‐regulation of apoptosis through suppression of proapoptotic gene expression.

Conclusions: EGF protects the liver against both alcohol‐induced liver damage and liver sensitization to bacterial LPS through down‐regulation of apoptosis.
Acquisition and Retention of Verbal and Nonverbal Information in Children With Heavy Prenatal Alcohol Exposure
Authors: Mattson Sarah N. , Roebuck Tresa M.
Published: April 2006

Background: Memory deficits are reported commonly in children with fetal alcohol syndrome. However, little is known about nonverbal memory performance in this population.

Methods: The current study examined learning and memory abilities in alcohol‐exposed children and nonexposed controls. Multiple verbal and nonverbal measures were used that incorporated repeated learning trials and delayed recall trials. The alcohol‐exposed group included children with heavy prenatal alcohol exposure with and without fetal alcohol syndrome. Children ranged in age from 8 to 16 years, and groups were matched on age, sex, ethnicity, and socioeconomic status.

Results: Children with heavy prenatal alcohol exposure displayed deficits in learning and recall of verbal and nonverbal information across all measures. On learning trials, they recalled fewer words and displayed a lower rate of acquisition. However, when we analyzed delayed verbal recall data after controlling for initial verbal learning, group differences were not apparent. The same pattern did not occur for nonverbal information; children with prenatal alcohol exposure recalled less on delayed recall even when we accounted for initial learning.

Conclusions: These data are consistent with previous studies that indicate immediate memory deficits but suggest that, at least for verbal information, delayed recall deficits in this population are better accounted for by deficits in initial learning. Importantly, a different pattern of results was demonstrated for verbal versus nonverbal information, which suggests the need for additional research in this area.
Ethanol Consumption Increases Nitric Oxide Production in Rats, and Its Peroxynitrite‐Mediated Toxicity Is Attenuated by Polyenylphosphatidylcholine
Authors: Baraona Enrique , Zeballos Guillermo A. , Shoichet Lilia , Mak Ki M. , Lieber Charles S.
Published: April 2006

Background: Nitric oxide generally mediates beneficial responses but becomes deleterious when coexistence with enhanced superoxide formation leads to the synthesis of peroxynitrite, a potent oxidant and nitrating agent.

Methods: To study the effects of ethanol and polyenylphosphatidylcholine on nitric oxide metabolism and toxicity, 36 rats were pair‐fed liquid diets with 36% of energy either as ethanol or as additional carbohydrate for 24 days and were killed 90 min after intragastric feeding. Half received polyenylphosphatidylcholine in the diet (3 g/liter), and the other half equivalent amounts of essential fatty acids and choline. Nitric oxide was measured by chemiluminescence in arterial blood and liver cytosol and as a product of the inducible nitric oxide synthase activity. Peroxynitrite formation was assessed by the increase in nitrotyrosine protein residues, measured immunochemically.

Results: In blood, administration of ethanol with or without polyenylphosphatidylcholine doubled nitric oxide levels. In the liver, ethanol increased nitric oxide by 52% (p < 0.01), and polyenylphosphatidylcholine attenuated this effect. Ethanol consumption increased the cytosolic activity of the inducible nitric oxide synthase and induced microsomal cytochromes P‐450 capable of producing both nitric oxide and superoxide. This was associated with an 18% (p < 0.01) increase in nitrotyrosine protein residues, products of peroxynitrite toxicity, which occurred predominantly in steatotic hepatocytes. Polyenylphosphatidylcholine attenuated these changes by decreasing the ethanol effect on both the cytosolic and the microsomal activities, in addition to acting as a powerful antioxidant. Acute administration of the same ethanol dose increased nitric oxide levels, but did not affect nitrotyrosine protein residues.

Conclusions: Chronic, but not acute, ethanol administration increases peroxynitrite hepatotoxicity by enhancing concomitant production of nitric oxide and superoxide, both of which are prevented by polyenylphosphatidylcholine.
Advancing the Expectancy Concept via the Interplay Between Theory and Research
Authors: Del Boca Frances K. , Darkes Jack , Goldman Mark S. , Smith Gregory T.
Published: April 2006

Four papers from a 2001 Research Society on Alcoholism symposium on expectancy theory and research are summarized. The symposium contributors describe recent advances in expectancy theory and discuss their implications for assessment and for understanding the processes of development and change in the behavioral domain of alcohol use. First, findings are integrated across the diverse domains in which the expectancy concept has been applied. Second, the implications of expectancy theory for the measurement of expectancy structure and process are examined. Third, research and theory regarding alcohol expectancy development and change are presented, with an emphasis on the role of expectancies as mediators of known antecedents of drinking. Finally, an experimental procedure for investigating the causal role of expectancies is described, together with its implications for theory testing and prevention or intervention programming. Collectively, the symposium contributions demonstrate the utility of an integrated expectancy theory for the generation of innovative research operations and new insights regarding behavior development and change. Consistent with the notion of consilience, expectancy theory has demonstrated a convergence of findings across different levels of analysis, as well as across different operations, methods, and research designs.
Promoting Self‐Change With Alcohol Abusers: A Community‐Level Mail Intervention Based on Natural Recovery Studies
Authors: Sobell Linda Carter , Sobell Mark B. , Leo Gloria I. , Agrawal Sangeeta , Johnson‐Young Lisa , Cunningham John A.
Published: April 2006

Background: By using a public health approach to the treatment of alcohol problems, this study analyzed the efficacy and cost analysis of two versions of a community‐level mail intervention to promote self‐change among alcohol abusers who had never sought help or treatment.

Methods: A total of 825 participants who responded to media solicitations were randomly assigned to one of two interventions: (a) for bibliotherapy/drinking guidelines (n= 411), they were given two pamphlets with information about the effects of alcohol and guidelines for low‐risk drinking and self‐monitoring, and (b) for motivational enhancement/personalized feedback (n= 414), personalized advice/feedback was provided on the basis of the participants’ assessment of their drinking and related behaviors.

Results: Although both groups exhibited significant reductions in drinking from 1 year before to 1 year after intervention, there were no significant differences between the two interventions for any variable. This suggests that the materials, irrespective of whether they were personalized, facilitated the reduction of drinking. Cost analysis revealed that a brief mail intervention could reduce drinking at a very low cost per participant (US$46 to US$97).

Conclusions: A brief community‐level mail intervention for problem drinkers who had never sought treatment resulted in sizable reductions in alcohol use over the year after the intervention compared with the year before. Furthermore, many of those with poorer outcomes engaged in a natural stepped‐care process by seeking help. These results, coupled with the low cost to deliver the intervention, suggest that public health campaigns could have a substantial effect on reducing alcohol problems and associated costs as well as getting some individuals into treatment. Such an approach would represent a shift from the alcohol field's long‐standing clinical focus to a broader public health perspective.
Chronic‐Intermittent Ethanol Exposure During Adolescence Prevents Normal Developmental Changes in Sensitivity to Ethanol‐Induced Motor Impairments
Authors: White Aaron M. , Bae Jon G. , Truesdale Melanie C. , Ahmad Sukaina , Wilson Wilkie A. , Swartzwelder H. Scott
Published: April 2006

Background Recent evidence indicates that adolescent and adult rats are differentially sensitive to many of the acute effects of ethanol. Little is known about the neurobehavioral consequences of repeated ethanol exposure during adolescence relative to adulthood. In the present study we examined the impact of repeated ethanol exposure during adolescence and adulthood on subsequent sensitivity to ethanol‐induced motor impairments.

Methods The tilting plane test was used to assess the impact of acute ethanol (3.0 g/kg) on motor coordination before (test 1), 2 days after (test 2), and 16 days after (test 3) a 20 day period of chronic‐intermittent ethanol (CIE; 5.0 g/kg intraperitoneally every 48 hrs for 20 days) or isovolumetric chronic‐intermittent saline (CIS) treatment in adolescent (postnatal (PD) 30) and adult (PD 70) rats.

Results Adolescent subjects were less sensitive than adults to the effects of ethanol on motor coordination during test 1. Adolescent CIS‐treated subjects exhibited an increase in sensitivity to ethanol‐induced motor impairments that reached adult levels by test 2 (PD 51) and remained stable between test 2 and test 3 (PD 65). Adolescent CIE‐treated subjects did not exhibit this age‐related increase in sensitivity. In this group, the effects of acute ethanol remained unchanged across the three testing days. Adult CIE‐treated subjects exhibited a small degree of tolerance between test 1 and test 2 (PD 91) that was no longer evident during test 3 (PD 105). In adult CIS‐treated subjects, the effects of acute ethanol remained stable across the three testing days. Blood ethanol concentrations assessed during testing suggest that age‐related changes in sensitivity to ethanol‐induced motor impairments are not related to changes in ethanol metabolism.

Conclusions The data suggest that CIE exposure during adolescence has a lasting impact on sensitivity to ethanol‐induced motor impairments. This effect might stem from a disruption of normal developmental processes.
Chronic Continuous Nicotine Exposure During Periadolescence Does Not Increase Ethanol Intake During Adulthood in Rats
Authors: Smith Andrew M. , Kelly Ryan B. , Chen Wei‐Jung A.
Published: April 2006

Background Nicotine has been considered as the gateway drug, because many teenagers experience cigarette smoking before seeking out other drugs. By using an animal model system, we assessed the effects of chronic continuous nicotine exposure during periadolescence on ethanol intake during young adulthood.

Methods Periadolescent Sprague‐Dawley rats (35 days old) were used at the beginning of this study. These animals received subcutaneous implantation of nicotine pellets (15 or 25 mg in 21‐day time‐release pellets) or placebo pellets (0 mg of nicotine) on postnatal day 35. Beginning on postnatal day 53, the animals received various concentrations of ethanol solution during their active period (5:00 PM to 9:00 AM) starting with 2% (v/v, 4 days), then 5% (5 days), 8% (6 days), and 10% (6 days). Between 9:00 AM and 5:00 PM of the same day, the ethanol solution was replaced by regular tap water. The amounts of ethanol solution and regular water were measured daily.

Results The analyses showed that ethanol intake (grams per kilogram of body weight) in the nicotine 15 and 25 mg groups did not differ from that in the nicotine 0 mg group, and no sex difference was found in ethanol intake. However, ethanol intake was increased as a function of the treatment days.

Conclusions The results showed that chronic continuous nicotine exposure during adolescence did not increase ethanol intake in rats during young adulthood.
Alcohol Intake and Future Incidence of Hypertension in a General Japanese Population: The Hisayama Study
Authors: Ohmori Susumu , Kiyohara Yutaka , Kato Isao , Kubo Michiaki , Tanizaki Yumihiro , Iwamoto Hiromitsu , Nakayama Keizo , Abe Isao , Fujishima Masatoshi
Published: April 2006

Background The question remains as to whether light to moderate alcohol intake is associated with an increased risk of hypertension.

Methods In 1978, a total of 1101 residents (433 men and 668 women) in a subrural community, Hisayama, in Japan, aged 40 years or more, with normal blood pressure, who were free from cardiovascular disease, were enrolled in a 10‐year follow‐up study. Inquiries regarding regular drinking were made in an interview based on a self‐administered questionnaire.

Results During the follow‐up, 101 men and 166 women developed hypertension (blood pressure ≥140/90 mm Hg or use of antihypertensive drugs). The age‐adjusted incidence of hypertension among current male drinkers increased significantly even with a light intake of alcohol (<23 g of ethanol per day). In women, the incidence was also significantly higher in drinkers than in nondrinkers. In multivariate analysis, alcohol intake, in addition to age and body mass index, remained a significant independent risk factor for hypertension in men, but not in women. In men, all three categories of current drinking were found to be significant risk factors for the development of hypertension after adjustment for age and body mass index [relative risk (RR), 2.00; 95% confidence interval (CI), 1.07–3.76 for light drinking compared with nondrinking; RR, 2.60; 95% CI, 1.50–4.49 for moderate drinking (23–45 g per day); and RR, 2.24; 95% CI, 1.26–3.99 for heavy drinking (≥46 g/day)].

Conclusions Our results suggest that alcohol intake, even light drinking, is a predictor of future hypertension among Japanese men.
Stress Response Caused by Chronic Alcohol Intake in Aged Rat Brain
Authors: Unno Keiko , Asakura Hiromi , Shibuya Yuka , Kaihou Masako , Fukatsu Hideto , Okada Shoji , Oku Naoto
Published: April 2006

Background Chronic alcohol consumption may act as a cellular stressor for brain cells, as has been found for aging. In this study we examined one component of the cellular stress response (heat shock proteins) as a function of age and alcohol exposure. We have found that the level of constitutively expressed heat shock protein 70 (heat shock cognate 70, or Hsc70) increases in the aged rat brain. Among many heat shock proteins and molecular chaperones, Hsc70 might be important not only for the normal protein folding pathway but also for refolding of denatured proteins produced by mild and chronic stress.

Methods Male Wistar rats that were 5.5 to 28.5 months old were fed a liquid diet that contained 5% (w/v) alcohol or a control diet for 6 weeks. The effects of alcohol consumption and aging on the expression of Hsc70 in the brain were investigated. The cytosol proteins in the 12,000 ×g supernatant fraction were heat‐treated at 42°C for 1 hr. After the heat treatment, proteins that transferred from the soluble to insoluble aggregated fraction were estimated as heat‐unstable proteins.

Results In the 24‐ and 30‐month‐old rat brain, chronic consumption of alcohol increased levels of Hsc70 and heat‐unstable proteins. On the other hand, those changes were not detected in the younger rat brain.

Conclusion Chronic alcohol intake causes a stress response in the aged rat brain. It is thought that the increased level of Hsc70 is brought about by an increase of denatured proteins.
Alcoholism and AIDS: Magnetic Resonance Imaging Approaches for Detecting Interactive Neuropathology
Authors: Pfefferbaum Adolf , Rosenbloom Margaret , Sullivan Edith V.
Published: April 2006

Both alcohol abuse and human immunodeficiency virus (HIV) infection have deleterious effects on brain structure, metabolism and function. In individuals with both afflictions these effects are doubtless additive and may interact to produce synergistic adverse effects. Further, the normal processes of aging produce brain degeneration that leaves older people especially vulnerable to the untoward effects of alcohol abuse and HIV infection. Advances in in vivo brain imaging now make practical the clinical study of the interaction of alcoholism and HIV infection and the potential of increased vulnerability produced by advancing age. In addition to structural magnetic resonance imaging (MRI), which provides quantitative assessments of brain macrostructure, are diffusion tensor imaging (DTI), which assesses microstructural integrity, magnetic resonance spectroscopy (MRS), which provides assessment of brain chemical moieties related to neuronal viability, and functional magnetic resonance imaging (fMRI), which provides assessment of localized blood oxygenation state association with performance of specific cognitive or motor tasks. Here, we first review postmortem observations on patients with HIV infection and with alcoholism to identify the cell types and brain regions most affected by the end stage of the disease. We then review in vivo neuroimaging studies of brain changes associated with HIV infection, chronic alcohol use, their interaction, and the potentiating effects of age. While there are many studies of people with either HIV infection or chronic alcohol use alone currently little has been published on the interactive effects of these variables, despite the high prevalence of overlap. We conclude with a consideration of the methodological issues such studies must address.
Evidence in an International Sample of Alcohol‐Dependent Subjects of Subgroups With Specific Symptom Patterns of Antisocial Personality Disorder
Authors: Kovac Ilija , Mérette Chantal , Legault Lucie , Dongier Maurice , Palmour Roberta M.
Published: April 2006

Background An earlier latent class analysis (LCA) of the symptoms of antisocial personality disorder in alcohol‐dependent subjects enrolled in the Montreal sample of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence suggested a three‐class qualitative solution. The present analysis of a larger, international WHO/ISBRA sample provides evidence of a four‐class solution with expanded symptomatic differentiation.

Methods An unrestricted LCA of 15 antisocial behaviors expressed after 15 years of age was performed in 465 males with DSM‐IV diagnosis of alcohol dependence, from the Montreal center (n= 120, overlapping the previous LCA), Helsinki (n= 80), São Paolo (n= 145), Sapporo (n= 22), and Sydney (n= 98); subjects were of various races, were ascertained from various sources, and showed a wide range of social adjustment.

Results Four latent classes that appeared to differ qualitatively were identified. For descriptive purposes, the classes are termed socially adjusted adults (SAA, n= 197), antisocial work‐adjusted adults (AWAA, n= 126), antisocial work‐maladjusted adults (AWMA, n= 120), and antisocial aggressive adults (AAA, n= 23). The AAA class had the earliest age of onset for alcohol dependence, which decreased across classes. Proportion of alcohol‐dependent first‐degree relatives was low in the SAA class (13.6%), moderate in the AWAA and the AWMA classes (20.8% and 18.7% respectively), and high in the AAA class (33.3%).

Conclusions It is unknown if and to what extent racial, cultural, and ascertainment heterogeneity between collaborating centers might have influenced these analyses. The results presented here show qualitative differences among antisocial alcohol‐dependent individuals in job adjustment and aggressive behavior, but only the latter distinction was relevant to familial alcohol dependence. Moreover, both the aggressive class and socially adjusted class differed in familial loading for alcohol dependence from the remaining two antisocial classes. These data provide improved empirical support for qualitative differentiation of aggressive from nonaggressive antisocial alcohol‐dependent individuals and might also have nosological implications for antisocial personality disorder.