bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial Effects of Ethanol Consumption in the Rat With Streptozotocin‐Induced Diabetes
Authors: Giles Thomas D. , Given Michael B. , Greenberg Stan S. , Zhao Xinfang , Kerut Edmund Kenneth , McElwain Elizabeth , Allen Gayle
Published: April 2006

Background Rats with streptozotocin (STZ)‐induced diabetes exhibit alterations in cardiac function, ventricular remodeling, and changes in cell signaling, which includes protein kinase C (PKC) isoforms. Moderate consumption of ethanol has a beneficial effect on cardiovascular outcomes in the general population, an effect that has recently been found to extend to patients with diabetes mellitus. We studied the effect of low‐dose ethanol consumption on cardiac function, geometry, and PKC isoforms in the rat with STZ‐induced diabetes.

Methods Four groups of rats were studied over 8 to 10 weeks: control, STZ‐induced diabetes, 12% (v/v) ethanol consumption, and STZ‐induced diabetes plus 4% (v/v) ethanol consumption. Invasive hemodynamic measurements were performed; myocardial tissue was obtained for analysis for total PKC and cytosolic and membrane protein content of PKC‐α, PKC‐δ, and PKC‐ε, and two‐dimensional and M‐mode echocardiograms were obtained.

Results Compared with rats with diabetes alone, consumption of 4% ethanol prevented the decrease in left ventricular dP/dt seen with diabetes alone, as well as the increase in left ventricular internal dimension. Up‐regulation of PKC‐α, ‐δ, and ‐ε occurring in the diabetic animals was also prevented by ethanol consumption, whereas ethanol alone had no effect on PKC isoform pattern.

Conclusions These data suggest that STZ‐induced cardiac remodeling and dysfunction are associated with increases in PKC activity, particularly PKC‐α, ‐δ, and ‐ε, and that consumption of ethanol can prevent these changes.
Alcohol Consumption Is Associated With Enrichment of High‐Density Lipoprotein Particles in Polyunsaturated Lipids and Increased Cholesterol Esterification Rate
Authors: Perret Bertrand , Ruidavets Jean‐Bernard , Vieu Claude , Jaspard Béatrice , Cambou Jean‐Pierre , Terce François , Collet Xavier
Published: April 2006

Background Alcohol consumption is associated with high levels of high‐density lipoproteins (HDLs). Moreover, changes in the fatty acid patterns of red blood cell phospholipids and plasma lipids have been observed in drinkers. The objectives of this study were to characterize the composition of HDL particles with respect to lipid molecular species in regular wine drinkers and to assess the functional properties of those HDLs as regards key steps of reverse cholesterol transport.

Methods Forty‐six subjects were recruited in the frame of a population study performed in Toulouse, southern France, and a nutritional investigation, including daily alcohol consumption, was performed. Subjects were sorted according to their daily alcohol intake (0, ≤35, and >35 g/day), mostly as red wine. The plasma HDL fraction was isolated, and neutral lipid molecular lipids and phospholipid fatty acids were analyzed by gas liquid chromatography. Efflux of cellular cholesterol and rates of cholesterol esterification and cholesteryl ester transfers between lipoproteins were assayed in a cell‐plasma incubation system.

Results Wine drinking, at 47 g/day, was associated with an increase in HDL cholesterol and apolipoprotein A‐I, but not with triglycerides. Isolated HDL displayed a 27% increase in all cholesteryl ester molecular species. The particles were also enriched in unsaturated phospholipids and, particularly, in those containing arachidonic (+30%) and eicosapentaenoic (+90%) acids. The plasma cholesterol esterification rate, reflecting lecithin cholesterol acyl transferase activity on HDL, was found to be higher (+27%) in drinkers than in nondrinkers, whereas the rate of cellular cholesterol efflux to plasma was identical.

Conclusions Regular wine consumption is associated with high levels of polyunsaturated lipids in HDL and with increases in the cholesterol esterification rate.
The Relationship Between Hippocampal Acetylcholine Release and Cholinergic Convulsant Sensitivity in Withdrawal Seizure–Prone and Withdrawal Seizure–Resistant Selected Mouse Lines
Authors: Mark Gregory P. , Finn Deborah A.
Published: April 2006

Background The septo‐hippocampal cholinergic pathway has been implicated in epileptogenesis, and genetic factors influence the response to cholinergic agents, but limited data are available on cholinergic involvement in alcohol withdrawal severity. Thus, the relationship between cholinergic activity and responsiveness and alcohol withdrawal was investigated in a genetic animal model of ethanol withdrawal severity.

Methods Cholinergic convulsant sensitivity was examined in alcohol‐naïve Withdrawal Seizure—Prone (WSP) and—Resistant (WSR) mice. Animals were administered nicotine, carbachol, or neostigmine via timed tail vein infusion, and the latencies to onset of tremor and clonus were recorded and converted to threshold dose. We also used microdialysis to measure basal and potassium‐stimulated acetylcholine (ACh) release in the CA1 region of the hippocampus. Potassium was applied by reverse dialysis twice, separated by 75 min. Hippocampal ACh also was measured during testing for handling‐induced convulsions.

Results Sensitivity to several convulsion endpoints induced by nicotine, carbachol, and neostigmine were significantly greater in WSR versus WSP mice. In microdialysis experiments, the lines did not differ in basal release of ACh, and 50 mM KCl increased ACh output in both lines of mice. However, the increase in release of ACh produced by the first application of KCl was 2‐fold higher in WSP versus WSR mice. When hippocampal ACh was measured during testing for handling‐induced convulsions, extracellular ACh was significantly elevated (192%) in WSP mice, but was nonsignificantly elevated (59%) in WSR mice.

Conclusions These results suggest that differences in cholinergic activity and postsynaptic sensitivity to cholinergic convulsants may be associated with ethanol withdrawal severity and implicate cholinergic mechanisms in alcohol withdrawal. Specifically, WSP mice may have lower sensitivity to cholinergic convulsants compared with WSR because of postsynaptic receptor desensitization brought on by higher activity of cholinergic neurons.
Diurnal Effects of Acute and Chronic Administration of Ethanol on Sleep in Rats
Authors: Kubota Takeshi , De Alok , Brown Richard A. , Simasko Steven M. , Krueger James M.
Published: April 2006

Background Disturbances in sleep patterns are a complicating factor in recovery from alcoholism. The effects of acute and chronic alcohol treatments on sleep in rats were determined.

Methods Adult male Sprague‐Dawley rats were acclimated to a temperature‐controlled chamber, and electromyograms and electroencephalograms (EEGs) were obtained during 23‐hr recording sessions. Time spent in rapid eye movement sleep (REMS) and non‐REM sleep (NREMS), EEG slow‐wave activity (SWA) during NREMS, a spectral analysis of the EEG by fast Fourier transform, and brain temperatures were determined.

Results Acute exposure to alcohol (2.3 and 3.0 g/kg) by gastric intubation at the beginning of dark onset produced an increase in NREMS and a suppression of SWA. Spectral analysis revealed that during the first 4 hr there was a small increase in very‐low‐frequency bands (0.5–2 Hz), with a suppression of higher‐frequency bands. This was followed by a suppression of low‐frequency bands. A dose of 3.0 g/kg at light onset caused an increase in NREMS and a suppression of SWA. Spectral analysis revealed a suppression of low‐frequency bands throughout the first 12 hr of recording but no change on high‐frequency bands with light‐onset alcohol. Chronic treatment with alcohol (6% alcohol in a liquid diet with pair‐fed isocaloric controls) for 3 weeks produced an increase in NREMS and a decrease in EEG power density in frequency bands above 2 Hz. Chronic alcohol also reduced the circadian variation of REMS, an effect that showed a rebound 1 week after the alcohol treatment was terminated. Two weeks after the alcohol treatment was stopped, NREMS and REMS values returned to baseline.

Conclusions These results demonstrate differences in the effect of acute alcohol on sleep depending on the time of administration and demonstrate that distinct alterations in sleep patterns are induced by chronic treatments in as little as 3 weeks.
Nitrendipine Blocks the Nociceptive Effects of Chronically Administered Ethanol
Authors: Gatch Michael B.
Published: April 2006

Background Calcium channel blockers prevent the development of tolerance to ethanol and prevent seizures and other signs of ethanol withdrawal. Calcium channels may also mediate the development of tolerance to the antinociceptive effects of ethanol.

Methods A radiant‐heat tail‐flick assay was used to assess the effects of nitrendipine, a dihydropyridine L‐type calcium channel blocker, on ethanol‐induced changes in nociception in rats. Chronic effects of ethanol were tested in four groups of rats, which received 10 days of exposure to a liquid diet. The groups received twice‐daily injections of saline or nitrendipine (1, 5, or 10 mg/kg). Tail‐flick latencies were measured on days 0 (baseline), 2, 4, 6, 8, and 10 and at 12 hr after removal of the liquid diet.

Results Chronic exposure to ethanol produced maximal levels of antinociception by day 4 of exposure. The observed level of antinociception gradually decreased to baseline levels by day 8. Marked decreases in tail‐flick latencies below baseline (hyperalgesia) were observed during ethanol withdrawal. Repeated administration of nitrendipine blocked the antinociceptive effects of chronic ethanol and prevented the hyperalgesia produced by ethanol withdrawal. The highest dose of nitrendipine (10 mg/kg, twice daily) reduced consumption of the ethanol diet.

Conclusions L‐type calcium channel blockers block hyperalgesia during ethanol withdrawal and may mediate, at least in part, the antinociceptive effects of chronic ethanol.
Disruption of Maternal Behavior by Alcohol Intoxication in the Lactating Rat: A Behavioral and Metabolic Analysis
Authors: Pepino Marta Yanina , Abate Paula , Spear Norman E. , Molina Juan Carlos
Published: April 2006

Background Preweanling rats exhibit clear behavioral signs of distress after interacting with an alcohol‐intoxicated dam. Interestingly, behavioral reactivity of infants to the experience of alcohol in the nursing context decreases as a function of repeated alcohol administrations to the mother. In this study, maternal activities were examined when dams were exposed to repeated administrations of a subnarcoleptic alcohol dose. Maternal changes in alcohol metabolism were also analyzed as a function of repeated exposures to the drug.

Methods During postpartum days 3, 5, 7, 9, 11, and 13, nursing dams received an intragastric administration of either 2.5 g/kg of alcohol or water. Maternal behaviors were evaluated (experiment 1). Blood alcohol levels (BALs) of the dams were determined on postpartum day 16 after all mothers received either an intragastric (experiment 2) or an intraperitoneal (experiment 3) dose of alcohol. The doses used (2.5 g/kg intragastrically and 1.5 g/kg intraperitoneally) were chosen because they promote similar peak BALs in dams naive to alcohol.

Results Maternal behaviors were strongly affected by the state of intoxication. Nevertheless, these disruptions clearly subsided with progression of alcohol‐related experiences (experiment 1). Chromatographic analysis of alcohol metabolism indicated the development of tolerance in dams that had prior experience with alcohol (experiment 2). Changes in BALs as a function of prior experience with alcohol seemed related to first‐pass alcohol metabolism rather than hepatic oxidative processes of the drug (experiments 2 and 3).

Conclusions When the dam first experiences a moderate state of alcohol intoxication, maternal behaviors are uniformly disrupted. Subsequent exposures to alcohol lead to maternal metabolic tolerance. In conjunction with previous studies, these data indicate that infantile reactivity to alcohol is dependent on how the members of the dam/pup dyad express or perceive ethanol's postabsorptive effects.
Carbohydrate‐Deficient Transferrin and γ‐Glutamyltransferase for the Detection and Monitoring of Alcohol Use: Results From a Multisite Study
Authors: Anton Raymond F. , Lieber Charles , Tabakoff Boris
Published: April 2006

Background The purpose of this article is to evaluate the biological marker of heavy alcohol use, carbohydrate‐deficient transferrin (CDT), in contrast to the older and more widely used γ‐glutamyltransferase (GGT) for the detection and monitoring of heavy alcohol use.

Methods In this report, CDT and GGT sensitivity and specificity for heavy alcohol intake are examined in a large multisite study in which 444 recently admitted inpatient alcoholics were compared with 204 matched social drinker controls. In addition, changes in these biomarkers were evaluated during an initial abstinence period and biweekly over 14 weeks of monitoring to compare changes in CDT and GGT during continued abstinence or relapse.

Results CDT and GGT were comparable in identifying heavy alcohol consumption in men, but GGT appeared to be better for women. For both genders, when these markers were combined, there was better sensitivity than when used alone. CDT and GGT both decreased during 4 weeks of abstinence. When we used a 30% increase from baseline abstinent levels as an indicator, CDT appeared marginally better than GGT at indicating relapse in men but not in women. For men in particular, relapse over the course of the study was best identified by evaluating changes (30% increase) in both markers simultaneously.

Conclusions These results support the utility of CDT, especially when used in conjunction with GGT, as an aid in detecting and monitoring heavy alcohol consumption.
Glutathione Replacement Preserves the Functional Surfactant Phospholipid Pool Size and Decreases Sepsis‐Mediated Lung Dysfunction in Ethanol‐Fed Rats
Authors: Velasquez Alvaro , Bechara Rabih I. , Lewis James F. , Malloy Jaret , McCaig Lynda , Brown Lou Ann S. , Guidot David M.
Published: April 2006

Background Alcohol abuse increases the incidence of acute respiratory distress syndrome (ARDS). Previous evidence from our laboratory links ethanol‐mediated glutathione depletion to impaired surfactant production by alveolar epithelial cells in vitro and to endotoxin‐mediated edematous injury in isolated lungs ex vivo. ARDS patients have an imbalance between the inactive small aggregate (SA) and the bioactive large aggregate (LA) forms of surfactant phospholipid (as reflected by increased SA/LA ratios). Therefore, we hypothesized that ethanol ingestion, via glutathione depletion, could alter surfactant phospholipid distribution between LA and SA forms and thereby exacerbate sepsis‐mediated lung dysfunction in vivo.

Methods Rats fed an isocaloric diet with or without ethanol (36% total calories) for 6 weeks were made septic via cecal ligation and perforation. Some ethanol‐fed rats had their diets supplemented with the glutathione precursor procysteine (l‐2‐oxothiaxolidine‐4‐carboxylate). Sepsis physiology was assessed by determining respiratory rates, arterial blood pressures, and plasma lactate levels, and lung dysfunction was assessed by determining lung lavage fluid protein levels (index of alveolar endothelial/epithelial barrier disruption), arterial hypoxemia (index of impaired gas exchange) and surfactant phospholipid SA and LA fractions (index of the alveolar epithelium's ability to maintain a functional surfactant pool during sepsis).

Results Ethanol ingestion decreased (p < 0.05) lung lavage fluid glutathione levels, and this defect was prevented by procysteine. Although ethanol ingestion had no effect (p < 0.05) on any of the indices of sepsis, it increased (p < 0.05) lung lavage fluid protein levels, worsened hypoxemia, and decreased the functional (LA) surfactant phospholipid pool after sepsis, all of which was prevented by procysteine.

Conclusions Ethanol ingestion, via glutathione depletion, increased sepsis‐mediated lung dysfunction, and these effects could contribute to the increased risk of ARDS seen in alcoholic patients.
The effects of chronic alcohol consumption and exercise on the skeleton of adult male rats
Authors: Reed Adam H. , McCarty Heidi L. , Evans Glenda L. , Turner Russell T. , Westerlind Kim C.
Published: April 2006

Background Lifestyle factors are known to affect skeletal development and integrity. Specifically, running has been reported to increase risk of fatigue fractures, whereas chronic alcohol consumption has been shown to reduce bone formation and bone mass. The combined effect of exercise and alcohol on the skeleton has yet to be explored, although alcohol consumption is common among certain physically active populations (e.g., military recruits, college athletes). It was hypothesized that chronic alcohol consumption would accentuate the inherent risk associated with endurance running exercise.

Methods Six‐month‐old male Sprague Dawley® rats were assigned to one of five groups: baseline, exercise‐alcohol diet, exercise‐normal diet, sham‐alcohol diet, and sham‐normal diet. Alcohol‐fed rats (35% caloric intake) received a liquid diet ad libitum. Normal animals were pair‐fed the identical diet with a maltose dextrin caloric substitute. Exercise was conducted on a motorized treadmill 5 days/wk for 16 weeks. Sham rats were placed on a stationary treadmill for matching time periods. Fluorochrome labels were administered 3 days before baseline and at 10 and 2 days before animals were killed. Heart, soleus, and rectus femoris muscles were wet weighed to assess the effects of training. Tibiae were collected for static and dynamic histomorphometric measurements on cancellous and cortical bone.

Results Muscle weights were larger in the exercised rats versus the sham rats. Alcohol had no significant effect on skeletal muscle weight but did result in larger heart weights in both alcohol‐treated groups. Cancellous and periosteal bone formation rates were significantly decreased in the alcohol‐fed rats versus rats on the normal diet and were associated with a significant reduction in trabecular thickness in the tibial metaphysis. Cortical and cross‐sectional areas were also significantly lower in the alcohol‐fed groups compared with the non‐alcohol‐fed groups. Exercise had no significant effect on cancellous or cortical bone measurements.

Conclusions Chronic alcohol consumption significantly reduced bone formation. Exercise had no effect on the bone and did not attenuate any of the negative effects of alcohol. The results suggest that alcohol consumption weakens the skeleton and increases the incidence of endurance‐exercise‐related bone injuries. Thus, individuals who are participating in endurance exercise and consuming alcohol may be at greater risk for exercise‐related skeletal injuries. Further investigation of the potential for alcohol to induce detrimental effects on the hearts of individuals participating in endurance exercise is indicated.
Ethanol Induces Morphological and Dynamic Changes on In Vivo and In Vitro Neural Crest Cells
Authors: Rovasio Roberto A. , Battiato Natalia L.
Published: April 2006

Background Fetal alcohol syndrome (FAS) is an embryopathology related to maternal alcohol drinking. The information concerning the factors involved in the prenatal mechanisms of ethanol action at the cellular and molecular levels is scarce. Because several abnormal changes in FAS involve regions colonized by cell lineages derived from neural crest cells (NCCs), it is reasonable to propose that epigenetic alteration of this cell population can represent an important component of the etiopathogeny. The aim of this work was to evaluate the direct effect of ethanol on a chick embryo model, as well as on in vitro NCC morphology and dynamic behavior.

Methods After ethanol treatment, in ovo or cultured chick embryos were used to determine the anatomical development of and to quantify the migratory parameters and apoptosis of NCCs. Scanning electron microscopy was performed on ethanol‐perfused (and control) cultures of cephalic and trunk NCCs; the actin cytoskeleton was evaluated, and morphometric and dynamic parameters were determined after time‐lapse videorecording. Recovery capacity after ethanol treatment was also determined.

Results Chick embryos submitted to conditions sufficient to induce FAS in mammals displayed developmental disruptions frequently accompanied by cephalic/facial anomalies. In vitro studies also indicated that cephalic and trunk NCCs exposed to ethanol exhibited significant and permanent changes regarding cell shape, surface morphology, apoptotic cell death, cytoskeleton, and distance and velocity traveled, as well as an abnormal pattern of migration.

Conclusions Taking into account that even a limited period of abnormal behavior may imply serious consequences in the final cues of an embryonic cell population, our results indicate that the biological effects of ethanol on early development—even during a short time—could induce permanent ontogenetic perturbations of NCCs, with potentially dramatic effects on embryonic morphogenesis. These results support an important participation of NCCs in the etiopathogeny of FAS.
Reduced Adrenal Activation in a Rat Line Selected for High Alcohol Sensitivity
Authors: Raatesalmi Kristina , Virtanen Antti , Sarviharju Maija , Pelto‐Huikko Markku , Korpi Esa R.
Published: April 2006

Background A rat line developed by selective breeding for high alcohol sensitivity has blunted corticosterone responses to alcohol and stress. In the present study, we determined possible differences in adrenal activation after alcohol and motor performance testing between the alcohol‐sensitive alcohol‐nontolerant and alcohol‐insensitive alcohol‐tolerant rats.

Methods The animals received ethanol (2 g/kg, intraperitoneally), and 30 min later they were subjected to a motor function test (i.e., normal selection test used in the breeding of the lines); the control animals for both rat lines received no treatment and minimal handling. Blood corticosterone and ACTH levels at the single time point were determined by radioimmunoassay, and adrenal activation was determined by in situ hybridization of the immediate early gene c‐fos, nor1, nurr1, and NGFI‐B mRNA expression.

Results The alcohol nontolerant rats had lower corticosterone but normal ACTH levels after ethanol and motor testing. Adrenal early gene expression of all of the genes studied was strongly induced by the treatment in both rat lines, but the inductions of c‐fos, nor1, and nurr1 were significantly lower in the alcohol‐sensitive animals. Acute treatment with a high dose of ACTH also induced less adrenal gene expression in the alcohol‐sensitive animals.

Conclusions The results suggest that the reduced adrenal activation is associated with high alcohol sensitivity in a genetic animal model, which is in agreement with the human findings of alcohol insensitivity during glucocorticoid treatment.
Substance Use–Related Outpatient Consultations in Specialized Health Care: An Underestimated Entity
Authors: Sillanaukee Päivi , Kääriäinen Janne , Sillanaukee Pekka , Poutanen Pauli , Seppä Kaija
Published: April 2006

Background To study the occurrence and documentation of substance use related outpatient visits in specialized health care.

Methods The diagnosis recorded in retrospective discharge data in Tampere University Hospital for 6 years was compared with the prospective data gathered from separately completed forms added during an 8‐week period to every outpatient's discharge data. In this form, the relation of substance use and the actual reason for the consultation were specifically elicited.

Results On the basis of diagnoses, retrospectively, 0.4% (6,666 of 1,555,898) of outpatient visits were caused by substance use. In the prospective part of the study, 5.6% of visits (1,401/25,014) were related to substance use. Retrospective study demonstrated 2% prevalence of substance use, whereas prospective study showed 36% substance use–related visits at the emergency room. According to the retrospective discharge data, alcohol‐related organ damages were the major reason for substance use–related outpatient visits. In the prospective study, the proportion of acute traumas was most prevalent.

Conclusions Our study indicates that substance use–related visits often remain undetected in specialized health care. Substance use–related visits were underdocumented/undetected in the emergency room. Using a simple separate form could dramatically increase the detection of substance use–related visits.
Serum Sialic Acid Levels Are Increased During Relapse to Alcohol Drinking: A Pilot Study
Authors: Pönniö Maritta , Sillanaukee Pekka , Franck Johan
Published: April 2006

Background Sialic acid has been suggested to be a potential marker for alcohol abuse. A previous study showed that sialic acid levels were significantly higher in serum among alcoholics as compared with social drinkers. In addition, serum sialic acid concentrations decreased after a treatment program aiming at abstinence. In this study, sialic acid was investigated as a possible marker for relapse to alcohol drinking.

Methods Serum from alcohol‐dependent patients in outpatient treatment (n= 8) was analyzed for sialic acid by a colorimetric assay. A baseline sample was taken when the subject had been abstinent for longer than 4 weeks. A second sample was taken after relapse within 3 days after cessation of drinking. A relapse was defined as two or more days with daily drinking of more than 60 g of pure alcohol.

Results The sialic acid levels were significantly increased by 21% (median; range, 6–33%;p < 0.01;n= 8) after a relapse as compared with the level after 4 weeks or longer of abstinence.

Conclusions This study suggests that serum sialic acid levels are significantly increased even after a short period of heavy drinking and may be a potential marker for relapse.
A Double‐Blind, Placebo‐Controlled Study of Naltrexone in the Treatment of Alcohol‐Dependence Disorder: Results from a Multicenter Clinical Trial
Authors: Guardia José , Caso Carlos , Arias Francisco , Gual Antoni , Sanahuja Jordi , Ramírez Marisa , Mengual Ildefonso , Gonzalvo Begoña , Segura Lidia , Trujols Joan , Casas Miguel
Published: April 2006

Background A 12‐week, multicenter, double‐blind, randomized, parallel‐group clinical trial to compare naltrexone and placebo was carried out to determine the efficacy, safety, and tolerability of naltrexone together with a psychosocial intervention in the treatment of alcoholism.

Methods A total of 202 alcohol‐dependent patients were assigned to 12 weeks’ treatment with either naltrexone or placebo. The relapse rate was evaluated by means of intention‐to‐treat analyses. Alcohol consumption, craving, adverse events, and changes in the biochemical markers of heavy drinking and possible toxicity were evaluated in the 192 patients who were considered to be assessable.

Results The survival function for patients who were treated with naltrexone was significantly better than that of the patients who were treated with placebo (Kaplan‐Meier log rank = 4, df = 1, p < 0.05). In addition, 7.9% of patients who were treated with naltrexone relapsed as compared with 18.8% of those who received placebo [χ2= 5.89, df = 2, p= 0.050]. In comparing naltrexone with placebo‐treated patients, the most common adverse events were abdominal pain [8.6% vs. 1%; (χ2= 6.1, df = 1, p < 0.05)] and headache [7.5% vs. 1% (χ2= 5.1, df = 1, p < 0.05)].

Conclusions Naltrexone was well‐tolerated, as the rate of adverse events was low, and safe, as it did not interfere with the normalization of biochemical markers of heavy drinking or alter liver function markers. Naltrexone seemed to reduce relapse rate to heavy drinking, but we found no differences in other alcohol consumption variables between naltrexone‐ and placebo‐treated groups. Although the naltrexone group showed a tendency to consume fewer drinks per drinking day and had a longer time to first drink, differences were not statistically significant.
Fractionated Simple and Choice Reaction Time in Children with Prenatal Exposure to Alcohol
Authors: Simmons Roger W. , Wass Tara , Thomas Jennifer D. , Riley Edward P.
Published: April 2006

Background The present study investigated central and peripheral processing speed using simple reaction time (SRT) and choice reaction time (CRT) tasks in children who were exposed to alcohol in utero compared with control subjects. Each RT interval was fractionated into premotor and motor components to assess the central processing of stimulus information and peripheral motor unit recruitment, respectively.

Methods Eleven children with confirmed prenatal alcohol exposure (ALC) and 13 control subjects (NC), aged 5 to 10 years, completed 20 trials of both SRT and CRT tasks. Muscle activity was recorded from the biceps brachii muscle of each arm using electromyography to facilitate the fractionating of RT into premotor and motor components.

Results ALC children exhibited significantly slower premotor RTs during the CRT task. Motor RTs were also slower for the ALC group during both SRT and CRT tasks. ALC children exhibited greater response variability compared with control subjects; however, the magnitude of this variability was not greater than would be predicted, given their lengthened RTs. In contrast, response variability was greater for young children of both groups even after accounting for mean RT. Significant age‐related differences in premotor and motor RTs were also observed.

Conclusions Alcohol‐related increases in CRT were attributable to longer premotor and motor components, reflecting both reduced speed of information processing and peripheral delays in responding. These alterations likely are associated with alcohol‐related changes in the central and peripheral nervous systems that could impede or slow neuronal transmission.
Differential Effects of T‐Cell Activation on Gastric and Small Bowel Permeability in Alcohol‐Consuming Mice
Authors: Alnadjim Ziad , Kayali Zeid , Haddad Wael , Holmes Earl W. , Keshavarzian Ali , Mittal Navdha , Ivancic David , Koehler Ronald , Goldsmith David , Waltenbaugh Carl , Barrett Terrence A.
Published: April 2006

Background A number of variables influence the effect(s) of alcohol on distinct segments of the intestine. In these studies, we examined the effect of T‐cell activation on gastric and small bowel permeability in alcohol‐fed mice.

Methods Gastric permeability was assessed using sucrose absorption, whereas small bowel permeability was followed using the ratio of lactulose to mannitol absorption and inulin absorption. T cells were activated by injecting antigen OVA323–339 into DO11.10 T‐cell receptor transgenic mice.

Results T‐cell activation increased gastric and small bowel permeability through a pathway mediated by interferon‐γ and tumor necrosis factor. In mice that were fed a liquid diet that contained 30% ethanol‐derived calories for 2 weeks, T‐cell activation increased gastric permeability to levels greater than that observed in solid diet or pair‐fed, liquid control diet. By comparison, changes in small bowel permeability induced by T‐cell activation were abrogated in alcohol‐fed mice. Analysis of intestinal cytokine mRNA levels (interferon‐γ and tumor necrosis factor) indicated that relevant mucosal T‐cell function was preserved in alcohol‐fed mice

Conclusions Overall, these data suggest that alcohol potentiates the effects of T‐cell activation on gastric permeability, at the same time blunting effects on small bowel permeability
Investigation of Quantitative Trait Loci in the CCKAR Gene With Susceptibility to Alcoholism
Authors: Okubo Takehito , Harada Shoji , Higuchi Susumu , Matsushita Sachio
Published: April 2006

Background Cholecystokinin (CCK) plays an important role in the function of the central nervous system by interacting with dopamine and other neurotransmitters. We previously reported genetic variations in the promoter and coding regions of the CCKA receptor (CCKAR), CCKBR, and CCK genes and a possible association between polymorphisms of the CCKAR gene and alcoholism. In this study, association analyses were re‐examined between the polymorphisms of the promoter region of the CCKAR gene and patients with alcohol withdrawal symptoms, in addition to patients with alcoholic liver injury.

Methods A total of 131 Japanese male patients with alcohol withdrawal symptoms, 70 Japanese patients with alcoholic liver injury, and 98 age‐matched Japanese male controls (nonhabitual drinkers) were examined using polymerase chain reaction‐based single strand conformational polymorphism and sequencing analyses.

Results Significant differences between patients with hallucination and controls were found in the allele frequencies at the −388 and −85 loci of the CCKAR gene (p= 0.0095, p= 0.0087, respectively), but these differences were not significant after Bonferroni correction for multiple testing. In contrast, the frequency of the homozygous genotype −85 CC was significantly higher in hallucination‐positive patients than in controls (p= 0.0031) and in patients with hallucination accompanying delirium tremens than in controls (p= 0.0022), and these differences were significant after Bonferroni correction.

Conclusions The data from the case control suggest that polymorphisms of the promoter region of the CCKAR gene do not play a major role in the pathogenesis of alcohol withdrawal symptoms or alcoholic liver injury. However, a significant association was found between polymorphism at the −85 locus of the CCKAR gene and patients with hallucination, and especially patients with hallucination accompanying delirium tremens.
Assessment of a Difference in ALDH2 Heterozygotes and Alcoholic Liver Injury
Authors: Nagata Naruhiko , Hiyoshi Mineyoshi , Shiozawa Hirokazu , Shiraishi Koichi , Watanabe Norihito , Tsuda Michio , Matsuzaki Shohei
Published: April 2006

We have speculated that the degree of liver dysfunction in alcoholic liver disease with ALDH2*1/2*2 may be less pronounced than that with ALDH2*1/2*1. In the present study, outpatients with alcoholic liver injury were examined for ALDH2 genotype and biochemical data. The number of patients was 29 cases of nonspecific changes, 16 cases of fatty liver, 5 cases of liver fibrosis, and 44 cases of liver cirrhosis. Biochemical data were evaluated with ALDH2 heterozygotes data obtained by PCR‐SSCP. The ALDH2*1/2*1 and ALDH2*1/2*2 genotypes accounted for 90% and 10%, respectively. As for ALDH2*1/2*2, there were three patients with nonspecific changes, three with fatty liver, one with liver fibrosis, and two with liver cirrhosis. In alcoholic liver disease patients, when the ALDH2*1/2*2 genotype was compared with the ALDH2*1/2*1 genotype with biochemical data, the γ‐GTP value in patients with ALDH2*1/2*2 was significantly higher than with ALDH2*1/2*1 (p < 0.005). When the frequency of ALDH2 genotype was determined in patients with alcoholic liver injury, ALDH2 heterozygotes accounted for 15% for the non‐cirrhosis group, and 5% for the cirrhotic group. When a relationship between the amount of ethanol intake and biochemical data were determined in patients with alcoholic liver injury who have ALDH2 heterozygotes, the glutamic oxaloacetic transaminase (GOT) and γ‐GTP values were significantly higher at an ethanol intake amount of ethanol more than 100 g per day than intake less than 100 g per day (p < 0.05). The alcoholic patients with ALDH2*1/2*2 drink a slight amount of ethanol, the liver injury is found to be stronger than those with ALDH2*1/2*1 when they drink more than 100 g ethanol per day.
Tandem Repeat Polymorphism of the CYP2E1 Gene: An Association Study With Esophageal Cancer and Lung Cancer
Authors: Itoga Sakae , Nomura Fumio , Makino Yasuhiko , Tomonaga Takeshi , Shimada Hideaki , Ochiai Takenori , Iizasa Toshihiko , Baba Masayuki , Fujisawa Takehiko , Harada Shoji
Published: April 2006

Background Cytochrome P‐450 (CYP) enzymes have been shown to play important roles in chemical carcinogenesis. Reports have indicated that polymorphism in CYP1A1, CYP1A2, CYP2A6, CYP2E1, and CYP2D6 are associated with an altered risk of developing cancers of the lung, bladder, liver, and colon. CYP2E1 plays an important role in alcohol metabolism and participates in the metabolic activation of various carcinogens, such as N‐nitrosodimethylamine. Recently, we found repeated sequences that consist of four alleles (A1, A2, A3, and A4) and six genotypes (A1/A2, A2/A2, A2/A3, A2/A4, A3/A4, and A4/A4) of the CYP2E1 gene. In the present study, we investigated whether these polymorphisms are associated with lung cancer and esophageal cancer.

Methods DNA was isolated from blood samples of 192 healthy control subjects, 85 patients with lung cancer, and 82 patients with esophageal cancer in Japanese males. DNA samples were amplified by polymerase chain reaction in the 5′‐flanking region of the CYP2E1 gene and in exon 12 in the ALDH2 gene. The tandem repeat polymorphisms were examined using DNA fragment analysis. Missense mutations in exon 12 of the ALDH2 gene were examined using fluorescence‐based single strand conformational change polymorphism analysis. Written informed consent was obtained from all the subjects.

Results In the CYP2E1 gene 5′‐flanking region polymorphism, patients with esophageal cancer showed significantly higher frequency of the A4/A4 genotype compared with the control subjects (p= 0.02), but no difference was found in patients with lung cancer. The frequencies of the mutant ALDH2*2 allele were significantly higher in patients with esophageal cancer (27.7%) than in healthy control subjects (7.3%;p < 0.0001; habitual alcohol drinkers).

Conclusions The distribution of genotypes and allele frequencies of the tandem repeats of the 5′‐flanking region of the CYP2E1 gene was significantly different in patients with esophageal cancer.
Influence of Moderate Drinking on Purine and Carbohydrate Metabolism
Authors: Nishioka Kusuki , Sumida Takayuki , Iwatani Masako , Kusumoto Aki , Ishikura Yoshiyuki , Hatanaka Haruyo , Yomo Hideko , Kohda Hirofumi , Ashikari Toshihiko , Shibano Yuji , Suwa Yoshihide
Published: April 2006

Background We examined the influences of a moderate intake level of three types of alcoholic beverages—beer, whisky, and Shochu (Japanese distilled liquor)—on purine and carbohydrate metabolism and excretion in healthy male volunteers, concerning (1) the extent of contribution of purine bodies contained in beer to uric acid metabolism and (2) a comparison between two types of distilled spirits with (whisky) and without (Shochu) aging in oak wood barrel storage.

Methods Three sets of studies were conducted in which 10 to 13 healthy adult men were instructed to drink three types of alcoholic beverages at a slightly higher level (0.8 ml of ethanol equivalent/kg body weight) than moderate drinking (approximately 30.4 ml or less for men). A low purine beer was test‐manufactured by treating nucleosides that were contained in wort and remained in beer with purine nucleoside phosphorylase derived from Ochrobacterium anthropi, thereby converting them into corresponding purine bases that were easily assimilated by beer yeast.

Results Although beer intake enhanced the level of serum uric acid by 13.6%, blood glucose by 26.7%, and insulin level by 5.1‐fold, drinking a moderate level of distilled liquor (whisky, Shochu) did not increase the serum uric acid level or the other two parameters. The serum uric acid level observed after drinking beer with a purine body concentration reduced by 28% (68% in nucleosides and purine bases) was almost identical to the level observed after drinking regular beer. Whisky has been found to have a property that decreases the serum uric acid level. Excretion of uric acid from blood is increased by 27% after drinking whisky.

Conclusions Moderate drinking of distilled liquors did not enhance serum uric acid level, blood glucose, or insulin level in healthy male subjects. Increased serum uric acid after beer intake could not be explained mostly with their purine body congeners. Whisky showed the eliminative property in serum uric acid through excretion of it from blood to urine. At a moderate drinking level, beer and whisky have different effects on purine metabolism or excretion.
Up‐regulation of Transferrin Receptor Expression in Hepatocytes by Habitual Alcohol Drinking Is Implicated in Hepatic Iron Overload in Alcoholic Liver Disease
Authors: Suzuki Yasuaki , Saito Hiroyuki , Suzuki Masako , Hosoki Yayoi , Sakurai Shinobu , Fujimoto Yoshinori , Kohgo Yutaka
Published: April 2006

Background Hepatic iron overload is often seen in alcoholic liver disease (ALD). We previously reported that the expression of 4‐hydroxy‐2‐nonenal‐protein adducts, which is a lipid peroxidative product and can be used as a marker of radical‐mediated cellular damage, was increased in iron‐overloaded hepatocytes with ALD. However, the mechanism of hepatic iron overload in ALD has not been clarified. In this study, to elucidate the mechanism of hepatic iron overload in ALD, we immunohistochemically investigated the expression of transferrin receptor (TfR), which mainly acts for cellular iron uptake.

Methods Hepatic tissues were obtained from 31 patients with ALD and 5 normal livers by percutaneous needle biopsy under laparoscopy or ultrasound guidance. Chemical detection of hepatic iron accumulation was performed by Perls’ Prussian blue stain. Immunohistochemical detection of TfR expression was done using human monoclonal anti‐TfR antibody (TR104) according to the avidin‐biotin complex method with alkaline phosphatase.

Results Excess iron accumulation was found in 22 hepatic tissues with ALD but not in any normal hepatic tissues. TfR expression was increased in hepatocytes of 18 hepatic tissues with ALD but was not detected in any normal hepatic tissues. The mean duration of abstinence of patients who demonstrated positive TfR expression in hepatocytes was significantly shorter than that of patients who demonstrated negative TfR expression (positive: 14 days; negative: 30 days). However, total ethanol consumption, daily ethanol intake, and serum aspartate aminotransferase and γ‐glutamyl transpeptidase values on admission were not significantly correlated with TfR expression in hepatocytes.

Conclusions The up‐regulation of TfR expression in hepatocytes is implicated in hepatic iron overload in ALD, and habitual alcohol drinking is an important factor for the induction of TfR expression.
Ethanol‐Induced Cas Tyrosine Phosphorylation and Fyn Kinase Activation in Rat Brain
Authors: Nishio Hajime , Suzuki Koichi
Published: April 2006

Background Tyrosine phosphorylation signaling has been reported to be involved in regulatory mechanisms of ethanol‐induced modulation of the central nervous system.

Methods We investigated the effect of ethanol administration on tyrosine phosphorylation signaling in rat brain and also examined the possible involvement of Fyn kinase in the process.

Results Immunoprecipitation experiments showed that Crk‐associated src substrate (Cas) was tyrosine‐phosphorylated in response to ethanol administration. Fyn kinase was shown to be activated by ethanol administration and to phosphorylate Cas on tyrosine residue in vitro. Furthermore, Fyn kinase was co‐localized with Cas in rat cerebellum and cerebral cortex.

Conclusions Cas was tyrosine‐phosphorylated in rat brain by ethanol administration, and Fyn kinase was most likely involved in the process.
Michaelis‐Menten Elimination Kinetics of Acetaldehyde During Ethanol Oxidation
Authors: Fujimiya Tatsuya , Yamaoka Kiyoshi , Ohbora Yumiko , Aki Toshihiko , Shinagawa Hiromi
Published: April 2006

Background Acetaldehyde (AcH) is a toxic metabolite of ethanol (EtOH). The pharmacokinetics of blood AcH during EtOH oxidation was studied with or without the administration of aldehyde dehydrogenase 2 inhibitor (cyanamide) in rabbits.

Methods An bolus of EtOH saline solution (0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) was injected intravenously. Cyanamide was administered intraperitoneally (25 mg/kg body weight) to the cyanamide‐treated group. Blood EtOH and AcH concentrations were measured by using head‐space gas chromatography.

Results In the control group, the first peak of the blood AcH appeared immediately and the second elevation appeared 1 to 4 hr after administration at a high EtOH dose. The blood AcH levels other than the second elevation part were significantly correlated to the blood EtOH levels. In the cyanamide‐treated group, a peak and a plateau formed at the time corresponding to the second peak in the control group. The peak and plateau concentration of AcH increased markedly. We attempted simultaneous curve fitting, using the five blood EtOH and AcH concentration‐time curves, to determine the pharmacokinetic model. Consequently, the AcH elimination was best described by a Michaelis‐Menten kinetic model in both groups.

Conclusions The blood AcH profile was suggested to consist of the first and second components that are related to the blood EtOH concentration itself and the metabolic formation of AcH, respectively. With higher EtOH doses or aldehyde dehydrogenase 2 inhibition, the second component becomes prominent as a result of the capacity‐limited property of the metabolism of AcH, which is described by Michaelis‐Menten elimination kinetics.
Estriol Enhances Lipopolysaccharide‐Induced Increases in Nitric Oxide Production by Kupffer Cells via Mechanisms Dependent on Endotoxin
Authors: Enomoto Nobuyuki , Takei Yoshiyuki , Kitamura Tsuneo , Hirose Miyoko , Ikejima Kenichi , Sato Nobuhiro
Published: April 2006

Background Estriol causes sensitization of Kupffer cells to lipopolysaccharide (LPS) via mechanisms dependent on gut‐derived LPS. Accordingly, this study examines the effect of estriol treatment on nitric oxide (NO) production from Kupffer cells.

Methods Rats were given estriol (20 mg/kg body weight) intraperitoneally, and Kupffer cells were isolated 24 hr later. Some rats were treated for 4 days with 150 mg/kg/day of polymyxin B and 450 mg/kg/day of neomycin to prevent growth of intestinal bacteria, the primary source of endotoxin in the gastrointestinal tract. After addition of LPS, NO production by Kupffer cell was detected using a fluorescence indicator, DAF‐2.

Results Twenty‐four hours after estriol administration, LPS‐induced NO production by Kupffer cells was enhanced as compared with control Kupffer cells. Sterilization of the gut with antibiotics blocked this enhancement.

Conclusions Estriol treatment in vivo enhances LPS‐induced NO production in Kupffer cells.