bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperhyaluronanemia in Alcoholic Hepatitis Is Associated with Increased Levels of Circulating Soluble Intercellular Adhesion Molecule‐1
Authors: Hill Daniell B. , Deaciuc Ion V. , McClain Craig J.
Published: May 2006

The purpose of this study was to evaluate the role of the sinusoidal endothelial cell (SEC) during the clinical course of alcoholic hepatitis. Twenty consenting patients (mean age: 49.4 ± 11.0 years) with moderate or severe hepatitis were studied. The patients were selected and characterized according to their history of drinking and laboratory profile, including serum aminotransferases, bilirubin, total white blood cell and neutrophil count, and prothrombin times. C‐reactive protein and interleukin‐6 were also measured as markers of the hepatic acute phase response. A marker of the SEC functional state, the circulating level of hyaluronan, was measured in parallel with the circulating levels of soluble intercellular adhesion molecule (sICAM)‐1 over a 6‐month observation period. All patients were hospitalized for the first month and encouraged to abstain from drinking for the duration of the study. The initial increased levels of both hyaluronan (542 ± 32 ng ml−1 serum) and sICAM‐1 (488 ± 70 ng ml−1 serum), gradually fell during the 6‐month observation period, eventually reaching values close to those seen in healthy subjects. A positive correlation was obtained between changes in these two markers of SEC function/activation on the one hand, and between these two tests and bilirubin, on the other hand. These data indicate that abnormalities of SEC function/activation, as reflected by serum hyaluronan and sICAM‐1, are prominent in alcoholic hepatitis, and these alterations improve within relatively short periods of time after cessation of alcohol consumption.
Extension of a Typology of Alcohol Dependence Based on Relative Genetic and Environmental Loading
Authors: Johnson Eric O. , van den Bree Marianne B. M. , Gupman Anne E. , Pickens Roy W.
Published: May 2006

Mild, severe, and dyssocial subtypes of alcohol dependence, previously identified among Caucasian men from the Epidemiologic Catchment Area study, were also identified among Caucasian men and women with DSM‐IV alcohol dependence from the National Longitudinal Alcohol Epidemiologic Survey (n= 2,703; 1,746 respectively). These subtypes were not identified among African American and Hispanic American men or women with DSM‐IV alcohol dependence. Among Caucasians with alcohol dependence, the subtypes were characterized by differential loading on three dimensions: genetic, general environmental, and dyssocial environmental symptom scales developed in a prior twin study. The mild subtype (60% of men and 66% of women) was distinguished by low mean scores on all three scales; the dyssocial subtype (24% of men and 20% of women) by low mean genetic and general environmental scores but high mean dyssocial environmental scores; and the severe subtype (16% of men and 14% of women) by high scores on the genetic and general environmental scales. These subtypes also showed the expected distinctions in clinical characteristics. The severe subtype showed greater comorbid drug dependence and major depression, more treatment seeking, and a higher prevalence of parental alcoholism. The severe subtype also showed significantly greater genetic influence adjusted for overall severity of alcohol dependence (genetic ratio). Only the severe subtype showed a pattern of scale scores and clinical characteristics suggestive of substantial genetic influence. The present study indicates a robustness of the typology originally developed among DSM‐III alcohol‐dependent Caucasian men by empirical extension of the subtypes to a different sample of Caucasian men and, separately, Caucasian women. The use of this typology may aid in distinguishing between Caucasian alcohol‐dependent individuals on the basis of relative genetic influence, enabling genetic, behavioral, and epidemiological investigations to reduce genetic or environmental “noise” and better focus on specific aspects of alcohol dependence.
Dopamine Release During Ethanol Drinking in AA Rats
Authors: Nurmi Maria , Sinclair John David , Kiianmaa Kalervo
Published: May 2006

The dopamine overflow in the nucleus accumbens of rats from the high alcohol drinking AA line was measured by microdialysis before, during, and after one‐half hour sessions of cued drinking of ethanol flavored with saccharin and peppermint or, as a control, saccharinpeppermint drinking. The animals had had extensive previous experience with ethanol drinking. Self‐administration of the ethanol solution did not raise the dopamine level substantially: there was a small (17%) but significant increase only during the first 10 min after the onset of drinking. Giving the rats a cue for ethanol, which was part of their daily routine drinking regime, did not raise the dopamine level before ethanol was presented to the rats (i.e., during “anticipation”). The results are consistent with our previous studies showing a lack of a large ethanol‐induced dopamine response in rats with previous experience of drinking ethanol and with the idea that although dopamine may play some role in alcohol drinking, it is not the central substrate producing the reinforcement from ethanol in AA rats.
Chemokine and Cell Adhesion Molecule mRNA Expression and Neutrophil Infiltration in Lipopolysaccharide‐Induced Hepatitis in Ethanol‐Fed Rats
Authors: Pennington Helen L. , Wilce Peter A. , Worrall Simon
Published: May 2006

Neutrophil infiltration is a feature of alcoholic hepatitis (AH), and although the mechanism by which this occurs is unclear, it may involve a chemotactic gradient. We used lipopolysaccharide (LPS) to induce, in ethanol‐fed rats, liver damage similar to that seen in AH. To our knowledge, this study is the first to examine the effect of ethanol on LPS‐stimulated chemokine mRNA expression in this model. Hepatic cytokine‐induced neutrophil chemoattractant (CINC)‐1, CINC‐2, monocyte chemoattractant protein‐1 (MCP‐l), macrophage inflammatory protein (MIP)‐1 β, MIP‐2, and eotaxin mRNA levels were elevated 1 to 3 hr post‐LPS in both groups. Maximal expression of MIP‐2 and MCP‐1 mRNA was higher in ethanol‐fed rats 1 hr post‐LPS, whereas CINC‐2 mRNA expression was elevated above controls at 12 to 24 hr. Hepatic intercellular adhesion molecule‐1 and vascular cell adhesion molecule‐1 mRNA levels were elevated in both groups at 1 hr, whereas L‐selectin expression in ethanol‐fed rats was elevated above controls at 12 to 24 hr. Hepatic neutrophil infiltration was highest during maximal hepatocyte necrosis. These data suggest that cell adhesion molecules, in conjunction with elevated cytokines and the subsequently induced chemokines, may assist in the formation of a chemotactic gradient within the liver, causing the neutrophil infiltration seen both in this model and possibly in AH.
Chronic Ethanol Consumption Induces the Production of Tumor Necrosis Factor‐α and Related Cytokines in Liver and Adipose Tissue
Authors: Lin H. Z. , Yang S. Q. , Zeldin G. , Diehl A. M.
Published: May 2006

Increases in monocyte/macrophage production of the proinflammatory cytokine, tumor necrosis factor‐α (TNF‐α), parallel the evolution of liver injury in rats and humans with alcoholic liver disease. However, the possibility that TNF‐α expression may be induced in other cell populations before serious liver disease develops has not been evaluated. To clarify this issue, mRNAs and/or protein levels of TNF‐α and cytokines [interleukin (IL)‐6, IL‐10, transforming growth factor‐β(TGF)‐β, IL‐12, and interferon‐γ] that regulate its biological activity were measured in sera, liver, and adipose tissues of rats that had developed hepatic steatosis after consuming ethanol‐containing diets for 6 weeks. Cytokine expression in the ethanolfed groups was compared with that of pair‐fed controls rats that had received isocaloric amounts of a similar, ethanol‐free diet for the same time period. Animals were studied both before and after a surgical stress (partial hepatectomy) that is known to provoke cytokine production. Chronic ethanol consumption led to increased serum concentrations of TNF and related cytokines, at least in part, by inducing the overproduction of these factors in the liver and peripheral adipose tissues. Despite the pair‐feeding protocol that ensured similar calorie consumption in both groups, adipose tissues in ethanol‐fed rats also expressed more leptin, a TNF‐α‐inducible mRNA that encodes an appetite‐suppressing hormone. Thus, white adipose tissue can be an important source of cytokines in nonobese animals and may be a target for ethanol's actions. These data implicate TNF‐α as a potential mediator of the nutritional‐metabolic ab‐berratJons that often accompany chronic alcohol intake, even in the absence of advanced liver disease.
Fetal Alcohol Effects in Rats Exposed Pre‐ and Postnatally to a Low Dose of Ethanol
Authors: Vaglenova J. , Petkov V. V.
Published: May 2006

Wistar rats were exposed pre‐ and/or postnatally to a low dose of ethanol (1 g/kg of body weight of dams/day) via maternal peroral intubation. This dose significantly increased the mortality rate (23 to 32% vs. 7% in controls) in offspring exposed to ethanol during pregnancy, with a continued postnatal exposure having no additional effect. However, offspring cross‐fostered to dams that had been exposed to ethanol only during gestation (the offspring themselves never being directly exposed to ethanol) displayed an even greater (59%) mortality. Growth of the offspring was initially delayed, but 9 weeks after birth their body weight reached that of the controls. The two‐way active avoidance test showed an impairment, compared with the controls, of learning and memory in both male and female adolescent (9‐week‐old) rats, as well as in male (but not in female) 5‐month‐old rats born of dams exposed to ethanol during gestation and lactation. In the group of male rats treated prenatally and postnatally with ethanol, 60% were “poor learners,” compared with 33% in the control group. Results suggest that ethanol at a dose of 1 g/kg/day administered to dams during gestation and lactation produced growth and behavioral changes in the offspring.
Proceedings: International Workshop on Consumption Measures and Models for Use in Policy Development and Evaluation
Authors: Dawson Deborah A.
Published: May 2006

The International Workshop on Consumption Measures and Models for Use in Policy Development and Evaluation was held in Bethesda, MD, on May 12–14,1997. Participants included the following: Salme Ahlström, Finland; Timo Alanko, Finland; Loran Archer, USA; Susan Bondy, Canada; Fe Caces, USA; Raul Caetano, USA; Deborah Dawson, USA; Kaye Fillmore, USA; Kathryn Graham, Canada; Thomas Greenfield, USA; Paul Gruenewald, USA; Thomas Harford, USA; Deborah Hasin, USA; Michael Hilton, USA; Harold Holder, USA; Bryan Johnstone, USA; Ronald Knibbe, Netherlands; Eckhart Kühlhorn, Sweden; Paul Lemmens, Netherlands; Klaus Mäkelä, Finland; Maria Elena Medina‐Mora, Mexico; Lorraine Midanik, USA; M. W. Bud Perrine, USA; Jürgen Rehm, Canada; Anders Romelsjö, Sweden; Robin Room, Canada; Marcia Russell, USA; John Searles, USA; Eric Single, Canada; Linda Sobell, USA; Tim Stockwell, Australia; Gerald Williams, USA; Richard Wilsnack, USA.
Towards Guidelines for Low‐Risk Drinking: Quantifying the Short‐ and Long‐Term Costs of Hazardous Alcohol Consumption
Authors: Stockwell Tim
Published: May 2006

This paper is based on the session entitled “Moderate Drinking Guidelines” that was held on May 13,1997 at the International Workshop on Consumption Measures and Models for Use in Policy Development and Evaluation, Bethesda, MD. The session chair was Tim Stockwell; presenters were Loran Archer, Tim Stockwell, Tom Greenfield, Susan Bondy, Eric Single, and Maria Elena Medina‐Mora; and discussants were Paul Gruenewald and Harold Holder.
Glutamate Receptors in the Cingulate Cortex, Hippocampus, and Cerebellar Vermis of Alcoholics
Authors: Freund Gerhard , Anderson Kevin J.
Published: May 2006

This study tests the hypothesis that glutamate receptors are altered in the brains of alcoholics as a result of chronic alcohol neurotoxicity. Excessive release of the excitatory neurotransmitter glutamate may damage postsynaptic neurons by increasing calcium flux through N‐methyl‐D‐aspartate (NMDA) receptor‐gated ion channels. Alcohol has opposite effects on the NMDA receptor, depending on the duration of exposure. Acute exposure to alcohol inhibits ion flow through NMDA receptors, whereas chronic exposure upregulates the number of these receptors and thereby increases ion flow. Acute withdrawal from alcohol results in hyperexcitability and seizures in the presence of upregulated NMDA receptors, making postsynaptic neurons vulnerable to excitotoxic damage. For this study, 13 grossly and histologically normal brains from alcoholics and 13 brains from nonalcoholic controls were selected from our brain bank. The two groups were matched for age, postmortem interval, and storage time. Maximal binding and affinities of NMDA receptors were determined by quantitative autoradiography in the cingulate cortex, the cornu Ammonis of the hippocampus, and in the cerebellar vermis. Binding was determined with an agonist, L‐[3H]glutamate, with a competitive antagonist, [3H]CGP‐39653, and with an antagonist binding in the channel interior, [3H]MK‐801. No significant differences were found in receptor densities or affinities between alcoholics and controls. Real differences were not likely to be obscured by nonalcohol‐related variables because the groups were closely matched for age, autopsy delay, time in storage, and central nervous system medications. Various diseases causing acute and chronic hypoxia did not significantly affect receptor density or affinity. Liver diseases and thiamine deficiency were excluded. A long‐lasting up‐regulation of the number or affinity of NMDA receptors is not a key feature of chronic alcoholics.
Age at First Drink and Risk for Alcoholism: A Noncausal Association
Authors: Prescott Carol A. , Kendler Kenneth S.
Published: May 2006

Prior research indicates risk for alcoholism is increased among individuals who begin to drink at an early age. We replicate and extend these findings, addressing causal and noncausal explanations for this association. Structured psychiatric interviews, including assessment of lifetime DSM‐IV alcohol abuse and alcohol dependence (AD), were conducted with 8746 adult twins ascertained through a population‐based twin registry. We found strong evidence for an association between early drinking onset and risk for AD, but less evidence for an association with alcohol abuse. The results of twin‐pair analyses suggest that all of the association between early drinking and later AD is due to familial sources, which probably reflect both shared environmental and genetic factors. These results suggest the association between drinking onset and diagnosis is noncausal, and attempts to prevent the development of AD by delaying drinking onset are unlikely to be successful.
Clinical Characteristics of Alcoholism in Alcohol‐Dependent Subjects With and Without a History of Alcohol Treatment
Authors: Raimo Eric B. , Daeppen Jean‐Bernard , Smith Tom L. , Danko George P. , Schuckit Marc A.
Published: May 2006

Background: Most clinical alcohol research is carried out on alcoholics who are in treatment, usually inpatients. However, most alcohol‐dependent men and women never enter treatment, and even fewer ever receive inpatient care. Thus, some generally accepted data on the clinical course of alcoholism, derived from treatment samples, might not generalize to the entire population of alcohol‐dependent individuals. This article characterizes the clinical characteristics of alcohol dependence in three groups of alcoholics, based on their histories of treatment for alcohol problems: those without prior rehabilitation; those with only outpatient approaches or Alcoholics Anonymous (AA); and subjects with an inpatient experience.

Methods: Semistructured interviews were administered to 3572 DSM‐III‐R‐defined alcohol‐dependent subjects from the Collaborative Study on the Genetics of Alcoholism. The clinical patterns were compared across the three groups of alcoholics: Group 1, never‐treated (n= 1582; 44%); Group 2, histories of outpatient or AA only (n= 399; 11%); and Group 3, at least one inpatient experience (n= 1591; 45%).

Results: A progression was shown from Groups 1 to 3 for more general life problems (e.g., unemployment, marital instability); higher rates of additional drug dependencies and psychiatric disorders; and more alcohol‐related adverse events. Logistic regression analyses revealed that those with no prior treatment were more likely to be women, Caucasian, and employed, and to report a lower rate of divorce/separation, lower levels of alcohol intake, and fewer alcohol problems. Among those who received help, inpatient care was predicted by an opposite profile.

Conclusions: These results indicate that studies using data from inpatient populations may give a skewed picture of the clinical characteristics of alcohol dependence.
Alcohol and Aldehyde Dehydrogenase Gene Polymorphisms Influence Susceptibility to Esophageal Cancer in Japanese Alcoholics
Authors: Yokoyama Akira , Muramatsu Taro , Omori Tai , Matsushita Sachio , Yoshimizu Haruko , Higuchi Susumu , Yokoyama Tetsuji , Maruyama Katsuya , Ishii Hiromasa
Published: May 2006

Background

Studies have consistently demonstrated that inactive aldehyde dehydrogenase‐2 (ALDH2), encoded byALDH2*1/2*2, is closely associated with alcohol‐related carcinogenesis. Recently, the contributions of alcohol dehydrogenase‐2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the flushing response have also been described.

Methods

To determine the effects of ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with and 577 without esophageal cancer) were genotyped and the results were expressed as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal cancer to determine whether cancer susceptibility is associated with patients’ responses to simple questions about current or former flushing after drinking a glass of beer.

Results

: The frequencies ofADH2*1/2*1andALDH2*1/2*2were significantly higher in alcoholics with, than in those without, esophageal cancer (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with eitherADH2*1/2*1(OR = 2.03) orALDH2*1/2*2(OR = 12.76). For those havingADH2*1/2*1combined withALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing questions showed that only 47.8% of theALDH2*1/2*2heterozygotes withADH2*1/2*1, compared with 92.3% of those withALDH2*1/2*2and theADH2*2allele, reported current or former flushing. Genotyping showed that for alcoholics who reported ever flushing, the questionnaire was 71.4% correct in identifyingALDH2*1/2*2and 87.9% correct in identifyingALDH2*1/2*1.

Conclusion

: Japanese alcoholics can be divided into cancer susceptibility groups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high riskALDH2*1/2*2fairly accurately in persons withADH2*2allele, but a reliable screening procedure for the highest risk gene combination (ADH2*1/2*1andALDH2*1/2*2) will require further investigation.
Osteopenia Due to Chronic Alcohol Consumption by Young Actively Growing Rats Is Not Completely Reversible
Authors: Sampson H. Wayne , Spears Heather
Published: May 2006

Our project was conducted to determine if the deleterious effects of chronic alcohol consumption on growing bone are reversible if the adolescent stops drinking. Four‐week old, female, Sprague‐Dawley rats were housed and maintained in an AAALAC‐accredited facility. Six animals each were placed on alcohol‐fed (35% ethanol‐derived calories), pair‐fed or chow‐fed diets for 2 or 4 weeks. A recovery group of six animals was alcohol‐fed for 2 weeks followed by an additional 2 weeks of chow feeding. This group was pair‐fed to an additional group of six animals that received liquid diet, pair fed to the recovery group for 2 weeks followed by 2 weeks on a pair‐fed chow diet. Blood alcohol concentrations averaged 309 ± 9 mg/dl. Morphological parameters of the femur, such as length, diameter, and volume were smaller in alcohol treated animals at both 2 and 4 weeks of feeding. Femur length and volume of recovery alcohol‐fed animals were more than either 2‐ or 4‐week alcohol‐fed animals, but they were not as great as the same‐age 4‐week pair‐fed or chow‐fed animals. Diameter was similar to the 4‐week alcohol‐fed, but less than the chow‐fed. Femur density was reduced at all time periods in the alcohol‐fed animals. The recovery alcohol‐fed animals had greater density than the 2‐week alcohol, but not the 4‐week alcohol‐fed animals. They did not, however, reach 4‐week chow‐ or pair‐fed levels. Tibia BV/TV was reduced in the 2‐ and 4‐week alcohol‐ and pair‐fed animals. BV/TV was greater in the recovery animals than either 2‐ or 4‐week alcohols, but not as great as the chow‐fed animals. At 2 weeks, calorie deprivation caused a reduction in insulin‐like growth factor‐1 (IGF‐1) that was reduced even more by alcohol. By 4 weeks, the calorie deprivation was no longer seen, but alcohol continued to reduce the values. Two weeks of alcohol followed by 2 weeks of chow diet returned the IGF‐1 values to almost normal, but significantly different levels. The apparent improvement was probably due to continued growth of the young bones and not a regaining of bone lost during alcohol consumption.
A Physiologically‐Based Pharmacokinetic (PBPK) Model for Alcohol Facilitates Rapid BrAC Clamping
Authors: Ramchandani Vijay A. , Bolane Jesse , Li Ting‐Kai , O'Connor Sean
Published: May 2006

Alcohol clamping is a technique that maintains a constant breath alcohol concentration (BrAC) for prolonged intervals, thereby reducing experimental variance in the time course of organ exposure to alcohol, when compared with oral alcohol administration paradigms. The technique employs an intravenous (iv) infusion of an ethanol solution at a rate that is intermittently adjusted based on real‐time BrAC measurements. In earlier studies, when the clamped state was induced with an oral ethanol loading dose, the vagaries of gastric emptying and absorption were associated with a 45 min delay (RST: reliable start time) before collection of dependent measurements could be planned with confidence. The objective of the present study was to develop an induction method that provides an earlier RST, and to compare the performance of the two methods. The “quick‐clamping” method replaced the oral loading dose with a preprogrammed infusion rate profile. A three‐compartment physiologically‐based pharmacokinetic (PBPK) model for ethanol was constructed, then tailored to each subject using individualized estimates of model parameters. The model was used to compute the infusion‐rate profile that would produce the desired time course of BrAC when infused in the corresponding subject. The two clamping methods were compared in a two‐session crossover study in 20 healthy young subjects (10 males, 10 females). Compared with the oral/iv method, quick clamping produced a comparable precision in the control of BrACs during the clamped interval, and provided a much earlier RST (mean ± SE for quick‐clamp: 17 ± 4 min; for oral/iv clamp: 45 ± 7 min). The quick‐clamping method enables, for the first time, the examination of the early‐phase neuroadaptive responses to alcohol in human subjects.
Leukocytes as Modulators of Stellate Cell Activation
Authors: Maher Jacquelyn J.
Published: May 2006

Activation of stellate cells is central to the process of hepatic fibrogenesis. Stellate cell activation can be influenced by many factors, including cytokines, oxidants, and alterations in the perisinusoidal extracellular matrix. These factors can be produced by resident liver cells (hepatocytes, Kupffer cells, or stellate cells themselves); however, infiltrating leukocytes may also play an important role. Because liver fibrosis often follows a prolonged period of hepatic inflammation, investigators have begun to study leukocytes as modulators of stellate cell activation. The following data summarize recent investigations in this area that focus on neutrophils as well as mononuclear cells.
Acetaldehyde‐Mediated Collagen Regulation in Hepatic Stellate Cells
Authors: Greenwel Patricia
Published: May 2006

Alcohol‐induced liver cirrhosis is one of the major causes of death worldwide. Strong evidence has established that ethanol's first metabolite, acetaldehyde, is highly fibrogenic and enhances the deposition of many extracellular matrix components by hepatic stellate cells. This article reviews our current knowledge of the molecular mechanisms whereby acetaldehyde induces these activities, with particular emphasis on those related to the upregulation of type I collagen.
Ethanol Consumption by Fawn‐Hooded Rats Following Abstinence Effect of Naltrexone and Changes in μ‐Opioid Receptor Density
Authors: Cowen Michael S. , Rezvani Amir H. , Jarrott Bevyn , Lawrence Andrew J.
Published: May 2006

Background: Relapse after abstinence can be modelled in rats using an alcohol deprivation effect (ADE) of enhanced ethanol consumption after a period of enforced abstinence from ethanol; however, not all rat strains display such an effect. We wanted to examine the effect of naltrexone on ethanol consumption by ethanol‐preferring Fawn‐Hooded (FH) rats using such a model.

Method: FH rats were given continual free‐choice access to a 5% ethanol solution or water (4 weeks) followed by 2 weeks of water alone. At the end of this abstinence period, osmotic minipumps were implanted subcutaneously to deliver saline (n= 4) or naltrexone (n= 4; 8.4 mgkgiday for 4 weeks). After recovery from surgery, the rats were again given access to 5% ethanol under the same free‐choice conditions (4 weeks). A third group of age‐matched controls drank only water during the behavioral trial. At the end of the behavioral trial, the rats were decapitated and an autoradiographic examination was made of μ‐opioid receptor density through the forebrain using the ligand [125I]FK‐33824.

Result: First, a period of enforced abstinence from ethanol consumption caused a significant (p < 0.05) and prolonged increase in ethanol preference (+18%) and decrease in water consumption (‐53%), although the volume of ethanol consumed (ml/day) did not vary, indicating an atypical ADE in this rat strain. Second, naltrexone significantly (p < 0.05) decreased ethanol consumption by the FH rats in terms of absolute amount of ethanol consumed and preference for ethanol solution, but this effect of naltrexone diminished over time, concurrent with a robust and significant elevation in μ‐opioid receptor density in all brain regions examined (p < 0.05). Finally, ethanol consumption alone also upregulated μ‐opioid receptor density relative to nondrinking controls in a number of brain regions, which included the nucleus accumbens (+29%) and caudate‐putamen (+ 15%,p < 0.05), but decreased μ‐opioid receptor density in other regions including the substantia nigra pars reticulata, which was suggestive of an indirect effect on μ‐opioid receptors.

Conclusions: The data suggest that continual long‐term naltrexone treatment may not be effective in the treatment of alcoholism, possibly because of the induced increase in μ‐opioid receptor density.
Sialic Acid: New Potential Marker of Alcohol Abuse
Authors: Sillanaukee Pekka , Pönniö Maritta , Seppä Kaija
Published: May 2006

Background: A number of laboratory markers are suggested for the detection and monitoring of alcohol abuse. However, there is still a need to find better indicators of alcohol abuse. Sialic acid (SA) is the name for a series of acyl‐derivatives of neuraminic acids that occur as nonreducing terminal residues of glycoproteins or glycolipids in biological fluids and cell membranes. In this study, we investigated the diagnostic value of SA as a marker of alcohol abuse.

Method: Sera from social drinkers (n= 38) and alcoholics (n= 77) were analyzed for sialic acid by a colorimetric assay and for carbohydrate‐deficient transferrin (CDT) by a radioimmunoassay method. Mean corpuscular volume (MCV), ‐γ‐glutamyltransferase (GGT), aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT) were determined by using routine methods.

Result: The sialic acid levels of both female and male subjects were significantly (p < 0.001) increased among alcoholic subjects when compared with social drinkers. SA levels were decreased after 3 weeks of treatment. The sensitivity and specificity for SA, respectively, were 57.7 and 95.5 for women and 47.8 and 81.3 for men. The respective values for CDT were 57.7 and 95.5 for women and 78.3 and 100.0 for men; for GGT, 60.0 and 95.5 for women and 60.9 and 87.5 for men; for MCV, 52.4 and 95.5 for women and 47.8 and 100.0 for men; for ASAT, 53.8 and 95.5 for women and 43.5 and 100.0 for men; and for ALAT, 38.5 and 90.9 for women and 39.1 and 87.5 for men. Among women, SA and GGT, and among men CDT, showed the largest area under receiver operation curve.

Conclusion:

This study indicated that sialic acid levels were elevated by high alcohol consumption and reduced during abstinence, especially among women. Thus, sialic acid seems to be an interesting marker that needs further evaluation as a diagnostic tool for alcohol abuse.
Multiple Previous Alcohol Detoxifications Are Associated With Decreased Medial Temporal and Paralimbic Function in the Postwithdrawal Period
Authors: George Mark S. , Tenebäck Charlotte C. , Malcolm Robert J. , Moore Juliann , Stallings Laurie E. , Spicer K.M. , Anton Raymond F. , Ballenger James C.
Published: May 2006

Background: Functional neuroimaging studies after alcohol cessation have demonstrated that chronic alcohol use globally reduces neuronal activity for several weeks. Less is known about the effects of previous alcohol use patterns on regional brain activity. Multiple previous alcohol detoxifications are associated with a worse clinical course and increased risk of seizures, perhaps due to sensitization of key brain structures. We performed the following imaging study in alcoholics in the postwithdrawal period to determine if blood flow in medial temporal structures would differ as a function of previous alcohol use (i.e., whether regions were kindled or sensitized due to multiple detoxifications).

Method: Fourteen adults meeting DSM‐IV criteria for alcohol dependence (mean age 35, 8 SD; 10 men) and participating in a double‐blind detoxification medication study underwent a brain perfusion Tc99 m‐ECD (Neurolite) single photon emission computed tomography scan on days 7 through 9 (mean 7.6, .5 SD) after their last drink and 2 to 3 days since their last detoxification medication. Seven nonpsychiatrically ill, nonalcohol‐dependent healthy adults were scanned as control subjects.

Result: Alcoholics compared with controls had widely reduced relative activity in cortical secondary association areas and relatively increased activity in the medial temporal lobes (p < 0.01). Five alcoholic patients with ≥2 previous detoxifications were compared with five patients in their first detoxification (age and detoxification medication matched). Multiple detoxification patients had significantly lower relative activity in bilateral anterior temporal poles and medial temporal lobes and in visual cortex (p < 0.01) compared with first episode patients.

Conclusions: These studies are consistent with other studies comparing alcoholics and controls. They also suggest that on day 7 of detoxification, alcoholic subjects with multiple previous detoxifications have decreased visual cortex, medial temporal lobes, and anterior paralimbic blood flow, compared with those in their first detoxification. Further studies seem warranted to confirm these initial exploratory results.
Endothelial Cell Fibrinolysis: Transcriptional Regulation of Fibrinolytic Protein Gene Expression (t‐PA, u‐PA, and PAI‐1) by Low Alcohol
Authors: Booyse Francois M. , Aikens Michael L. , Grenett Hernan E.
Published: May 2006

Epidemiological studies have associated moderate alcohol consumption with a reduced risk for coronary artery disease (CAD) and myocardial infarction (MI). This cardioprotection may be attributed to alcohol‐induced changes in a variety of cellular functions, including increased fibrinolysis. Fibrinolysis is important in regulating normal hemostasis. Endothelial cells (ECs) synthesize fibrinolytic proteins, t‐PA, u‐PA, and PAs inhibitor, PAI‐1. Systemic factors, i.e., alcohol, that affect one or more of these components, resulting in increased EC fibrinolysis, will reduce the risk for thrombosis, CAD, and MI and afford cardioprotection. These studies will identify/define the effects of low ethanol (< 0.1%, v/v) on the expression of PAs, PAI‐1, and surface‐localized fibrinolytic activity in cultured ECs. Low ethanol exerted a short‐term time‐ and dose‐dependent increase (∼ 5‐ to 8‐fold) in activity at ∼ 20 min and 0.05% ethanol, which was sustained for ∼ 1 hr. On the other hand, a single brief exposure to low ethanol (< 0.1%, < 120 min), followed by 4‐24 hr incubation in the absence of ethanol, showed a time‐ and dose‐dependent increase (∼ 2‐ to 3‐fold) in PAs antigen/mRNA and a concomitant ∼ 2‐ to 3‐fold sustained increase (∼ 24 hr) in fibrinolytic activity. Further nuclear transcription run‐on assays and transient transfection experiments, using pPAs/luc and pPAI‐1/luc promoter constructs, demonstrated that low ethanol transcriptionally upregulates t‐PA and u‐PA gene expression and downregulates PAI‐1 gene expression. These combined studies have described a feasible molecular mechanism by which low ethanol can induce and sustain increased surface‐localized EC fibrinolysis that may underlie and contribute, in part, to the cardioprotective benefit associated with moderate alcohol consumption.
Sex Differences in the Sources of Genetic Liability to Alcohol Abuse and Dependence in a Population‐Based Sample of U.S. Twins
Authors: Prescott Carol A. , Aggen Steven H. , Kendler Kenneth S.
Published: May 2006

Background: There are substantial sex differences in all levels of alcohol involvement among U.S. adults. The goal of this study was to test whether the magnitude and sources of genetic and environmental influences on liability for alcohol abuse and dependence differ for men and women.

Methods: Structured personal interviews were used to assess DSM‐III‐R‐ and DSM‐IV‐defined alcohol abuse and dependence among 5091 male and 4168 female twins (including 1546 identical, 1128 same‐sex fraternal, and 1423 opposite‐sex pairs) born in Virginia between 1934 and 1974. Twin correlations were analyzed using structural equation modeling.

Results: The magnitude of twin‐pair resemblance was similar across several definitions of alcoholism and was substantially higher among identical than fraternal pairs. The proportion of population variation in liability attributed to genetic factors was substantial among both women (55‐66%) and men (51‐56%), and we found little evidence of a role of environmental factors shared by family members. In all definitions studied, we could reject a model that the genetic sources of liability in the two sexes overlap completely.

Conclusion: In this first population‐based study of alcoholism among male and female twins from the U.S., we found that genetic factors play a major role in the development of alcoholism in both sexes, that the magnitudes of genetic influence were equally high for men and women, and that the genetic sources of vulnerability are partially, but not completely, overlapping in men and women.
Effect of Dietary Fat on Chronic Ethanol‐Induced Oxidative Stress in Hepatocytes
Authors: Bailey Shannon M. , Cunningham Carol C.
Published: May 2006

Background: Although oxidative stress and deficits in hepatic energy metabolism have been implicated as important factors in the initiation of alcoholic liver disease, their relative contribution to ethanol‐induced cell death is not known. The purpose of this study was to examine the effects of chronic ethanol administration on hepatocyte reactive oxygen species (ROS) generation, energy state, and viability, as well as the effect of dietary fat on these parameters.

Methods: Male Sprague‐Dawley rats were fed liquid diets that provided 36% total calories as ethanol, with fat as either 12% (low fat) or 35% (high fat) of total calories. Pair‐fed controls received liquid diets in which maltose‐dextrin was substituted for ethanol calories. The fluorescent probe 2′,7′‐dichlorofluorescin diacetate was used to detect ROS, lactate dehydrogenase leakage was used to assess viability, and ATP levels were used as a measure of the energy state. The effect of chronic ethanol feeding on these parameters was determined by incubating hepatocytes under a 5% oxygen‐containing atmosphere or an atmosphere ≤ 1% oxygen for 60 min.

Results: In general, chronic ethanol feeding stimulated ROS production and decreased ATP concentrations, which were associated with decreased viability in hepatocytes isolated from rats fed either high‐ or low‐fat, ethanol‐containing diets, compared to the corresponding controls. Incubation under an atmosphere ≤ 1% oxygen and/or ethanol (10 mM) augmented these effects in both high‐ and low‐fat control and ethanol‐fed hepatocytes. The addition of antimycin to the incubations increased ROS production, decreased ATP concentrations, and accelerated loss of hepatocyte viability. Viability loss under all conditions used in this study was correlated with decreases in cellular ATP.

Conclusions: Comparisons of incubations performed under the two oxygenation conditions revealed that viability loss was inversely associated with ROS production, which indicates that ATP loss and not ROS production was a better predictor of loss in cell integrity. This study also demonstrates that the level of dietary fat has only minor effects on generation of ROS and the cellular energy state. In contrast, ethanol consumption had significant effects on generation of ROS, energy state, and hepatocyte viability.
Effect of Chronic Ethanol Treatment on Ca2+‐Inhibited Adenylyl Cyclase in Mouse Striatum
Authors: Ikeda Hiroshi , Hatta Shinichi , Ozawa Hiroki , Ohshika Hideyo , Saito Toshikazu
Published: May 2006

In the present study, to investigate the possibility that chronic ethanol treatment might alter Ca2+‐inhibited type 5 adenylyl cyclase (AC) activity, we examined the effect of chronic ethanol treatment on striatal dopaminergic signal transduction, especially the AC system, in mice. We fed male C57BL/6 mice for 7 days with a 5% ethanol‐containing or control liquid diet. Basal and forskolin‐stimulated AC activities were reduced in striatal membranes of ethanol‐treated mice. 5′‐guanylylimidodiphosphate‐stimulated AC activity was also decreased in ethanol‐treated mice. But no significant differences were observed in the levels of the guanine nucleotide binding protein subunits Gsα and Gi1&2α determined by immunoblotting, between ethanol‐treated and control mice. These results indicated that the function of the catalytic subunit of AC was decreased in the straitum of chronically ethanol‐treated mice. We further examined the inhibitory regulation of AC activity in the context of a change of type 5 AC. Inhibition of forskolin‐stimulated AC activity by 10 μM free Ca2+ was smaller in ethanol‐treated mice than in control mice. However, the protein level of type 5 AC in the striatum, determined by immunoblotting, was not significantly different between ethanol‐treated and control mice. These findings suggest that Ca2+‐inhibited, presumably type 5, AC activity is reduced in mouse striatum by chronic ethanol treatment, and that this reduction is not due to a decrease in type 5 AC expression.
Hepatic Veno‐Occlusive Lesions in Severe Alcoholic Hepatitis and Alcoholic Liver Cirrhosis: A Comparative Histopathological Study in Autopsy Cases
Authors: Kishi Masaya , Maeyama Shiro , Ogata Seiichiro , Koike Junki , Uchikoshi Toshiyuki
Published: May 2006

Clinicopathological features of veno‐occlusive lesions in hepatic veins were studied in autopsy cases of severe alcoholic hepatitis (15 cases) and alcoholic liver cirrhosis (15 cases). All the cases were heavy drinkers and died of liver failure or variceal rupture. The frequency and degree of veno‐occlusive lesions, and the diameter and number of hepatic veins were studied from stained sections of liver blocks from each case. The hepatic veins observed ranged from 60 to 3000 μm in diameter. The veno‐occlusive lesions were found in hepatic veins mainly 60 to 1200 μm in diameter. These findings were recognized in the majority of severe alcoholic hepatitis cases and alcoholic liver cirrhosis cases. Furthermore, more severe veno‐occlusive lesions were noted in severe alcoholic hepatitis, compared with alcoholic liver cirrhosis. In the cases with obstruction in hepatic veins of <400 μm, a decrease in the number of hepatic veins and zonal necrosis were noted. In addition, some of the veno‐occlusive lesions were recognized focally in the same cases. Clinical findings also indicated that ascites increased with the progression of the veno‐occlusive lesions. We conclude that investigation of veno‐occlusive lesions in severe alcoholic liver disease has clinicopathological significance.
Accumulation of Hemoglobin‐Associated Acetaldehyde With Habitual Alcohol Drinking in the Atypical ALDH Genotype
Authors: Takeshita Tatsuya , Morimoto Kanehisa
Published: May 2006

Background:

Those with the atypical genotypes of low Km aldehyde dehydrogenase (ALDH2) have high blood concentrations of free acetaldehyde, an active metabolite of ethanol, after drinking alcohol. In the present study, we measured acetaldehyde reversibly bound to hemoglobin (HbAA) in Japanese male workers.

Methods:

One hundred and sixty Japanese male workers in one plant participated with informed consent. The subjects were genotyped for the ALDH2 polymorphism by polymerase chain reaction method. HbAA levels were measured using a high performance liquid chromatography system with a fluorescence detector. For the study in which we examined accumulation of HbAA, eight Asian male volunteers participated with informed consent.

Results:

Although HbAA levels were significantly correlated with recent alcohol consumption in both typical (ALDH2*1/*1) and atypical (ALDH2*1/*2)genotypes, the slope in ALDH2*1/*2 was significantly steeper than that in ALDH2*1/*1. Multiple regression analysis on relevant factors for HbAA revealed that not only recent but also daily alcohol consumption increased HbAA levels in those with the ALDH2*1/*2 genotype, which suggests that HbAA accumulates with habitual drinking. We measured HbAA levels before, during, and after alcohol consumption—one drink (0.4 ml/kg) per day—for 7 consecutive days in male volunteers. During the drinking period, HbAA lincarly increased in ALDH2*1/*2 (n= 4) but not in ALDH2*1/*1 (n= 4). After reaching peak levels (+76.1 nmol/g hemoglobin) following the seventh drink, HbAA levels gradually decreased but were significantly higher for 3 days after drinking was discontinued.

Conclusions:

We demonstrated that HbAA levels accumulate with habitual alcohol drinking in the atypical ALDH2 genotype. HbAA was shown to be a good biomarker for increased internal exposure levels to acetaldehyde.
Parental History of Alcoholism and Problem Behaviors in Native‐American Children and Adolescents
Authors: Wall Tamara L. , Garcia‐Andrade Consuelo , Wong Vincent , Lau Philip , Ehlers Cindy L.
Published: May 2006

Background:

A positive family history of alcoholism is one of the most consistent and powerful predictors of a person's risk for developing this disorder. This finding has stimulated much research on etiological vulnerability factors and mechanisms by which children of alcoholic parents are at high risk for developing alcohol‐related problems. In primarily Euro‐American samples, parental alcoholism has been associated with a variety of negative outcomes for children and adolescents, including problematic behavior. Native‐American Indians, in addition to high rates of alcoholism and alcohol‐related mortality, have the highest prevalence of a positive family history for alcoholism of all ethnic groups in the United States.

Methods:

This study used the Achenbach Child Behavior Checklist (CBCL) to evaluate behavioral problems in 96 Mission Indian children and adolescents based on the presence or absence of parental alcohol dependence and sex of the offspring.

Results:

Consistent with previous research, results indicated a high prevalence of a positive family history of alcoholism in these Native‐American youths. Seventy‐four percent of the offspring had either one or both parents with alcohol dependence (children of alcoholics). Only 7% had no first‐ or second‐degree alcoholic relatives. Results indicated that sons of alcoholics scored significantly higher on the Total Behavior Problem scale, as well as the Internalizing and Externalizing scales, of the CBCL than sons of nonalcoholies, whereas there were no significant differences in CBCL scores between daughters of alcoholics and daughters of nonalcoholics. It is noteworthy that scores on the CBCL for Mission Indian children of alcoholics were comparable to scores in the published literature of children of alcoholics of other ethnicities. In addition, a relatively low percentage of youths were identified with significant levels of behavioral problems.

Conclusions:

These findings suggest that sons of alcoholics of Mission Indian heritage experience more problems than sons of nonalcoholics, but also suggest that Mission Indian children of alcoholics are not more vulnerable to behavioral problems than children of alcoholic parents of other ethnic backgrounds.