bluuebunny/crossref_metadata_2025 huggingface dataset:
Herpesvirus Infection of the Respiratory Tract in Patients with Alcoholic Hepatitis
Authors: Pol Stanislas , Durand François , Bernuau Jacques , Colin Jean‐François , Dubois Frédéric , Hautekeete Marc , Rouzioux Christine , Degott Claude , Rueff Bernard , Benharnou Jean‐Pierre
Published: April 2006

Respiratory herpesvirus infections have rarely been described in alcoholics. We report four cases of severe respiratory herpesvirus infections in patients with alcoholic liver disease. Two were related to Herpes Simplex Virus and two to Cytomegalovirus. Both chronic alcoholism and severe liver disease induce immunosuppression, which might account for these unusual herpesvirus infections of the respiratory tract.

These cases suggest that infections with herpesviruses should be considered in patients with alcoholic liver disease and pulmonary or tracheobronchial disease unresponsive to standard antibiotic therapy. Bronchoscopy, viral culture, and serological tests appear warranted, particularly given the existence of specific therapy.
Oral Magnesium Supplementation Improves Metabolic Variables and Muscle Strength in Alcoholics
Authors: Gullestad Lars , Dolva Lars Øystein , Søyland Einar , Manger Arne Thomas , Falch Dagfinn , Kjekshus John
Published: April 2006

Magnesium deficiency is common among chronic alcoholics, but the knowledge of oral magnesium supplementation to this group is limited. We, therefore, randomized 49 chronic alcoholics, moderate to heavy drinkers for at least 10 years to receive oral magnesium or placebo treatment for 6 weeks according to a double‐blind protocol. Effects on metabolic variables and muscle strength were analyzed. Significant reduction of aspartate‐aminotransferase (ASAT), alanine‐aminotransferase (ALAT) and gamma‐glutamyl‐transpeptidase (GGT) were seen after magnesium, whereas no change was observed with placebo. Bilirubin decreased in both groups. Serum Na, Ca, and P increased significantly during magnesium therapy compared with no statistically significant change in the placebo group. Serum K and Mg increased slightly after magnesium supplementation and decreased in the placebo group, resulting in a significant difference between the two groups at the end of the study. Muscle strength increased significantly during magnesium treatment, contrasting to no change with placebo. Blood pressure, heart rate, hematological variables, serum lipids (cholesterol, HDL, TG), glucose tolerance, and creatinine were unchanged in the two groups after treatment. Alcohol consumption was similar before and during the trial and does not explain the differences between the two groups. The results shows that short‐term oral magnesium therapy may improve liver cell function, electrolyte status, and muscle strength in chronic alcoholics.
Subjective Feelings of Alcohol Intoxication in Asians with Genetic Variations of ALDH2 Alleles
Authors: Wall Tamara L. , Thomasson Holly R. , Schuckit Marc A. , Ehlers Cindy L.
Published: April 2006

Asian‐American men who possess ALDH2*2 alleles and who experience a facial flush after consuming alcohol were carefully matched on drinking history and demographic variables with nonflushing Asian males with only ALDH2*1 alleles. Each man was tested following placebo and a challenge dose of 0.75 ml/kg alcohol. Following alcohol, flushers reported experiencing significantly more positive feelings of intoxication than nonflushers, despite equivalent blood alcohol concentrations. These data suggest that Asians who flush after drinking, particularly those with ALDH2*1/2*2 genotype, have a more intense, although not necessarily a more negative, response to alcohol than comparable nonflushing Asians. This alcohol sensitivity reaction that many Asian flushers experience may contribute to their lower tendency to drink excessively, even though their response to alcohol is not predominantly negative.
Effect of Chronic Ethanol on the Septohippocampal System: A Role for Neurotrophic Factors?
Authors: Walker Don W. , Heaton Marieta B. , Lee Nancy , King Michael A. , Hunter Bruce E.
Published: April 2006

The mechanisms by which chronic ethanol exposure produces neuronal damage have not been established. Potentially ethanol may reduce normal neurotrophic influences necessary for neuronal survival, growth, and function. We hypothesized that chronic ethanol exposure might produce a decrease in the synthesis, availability, upregulation, delivery, and/or the biological activity of normally occurring neurotrophic factors, or may alter the capacity of target neurons to respond to these factors. The available evidence leading to this hypothesis and supporting data from our laboratory are discussed.
Excitotoxicity and Alcohol‐Related Brain Damage
Authors: Lovinger David M.
Published: April 2006

Hyperexcitability following chronic alcohol exposure appears to result in enhanced activation of glutamatergic synapses in the brain. This enhanced glutamatergic transmission probably results from a combination of increased NMDA receptor activation, decreased GABAA receptor activation and increased function of voltage‐activated calcium channels. Prolonged or repetitive bouts of enhanced excitatory transmission during withdrawal may destroy central neurons via “excitotoxic” mechanisms. Increased NMDA receptor activation might initiate toxicity by increasing intracellular calcium. Summation of these effects with increased intracellular calcium from voltage‐activated channels might promote disinhibition and enhance cellular damage. Recent studies suggest that NMDA receptor‐initiated excitotoxicity may result from thiamine deficiency. Alterations in neurotransmitter levels and receptor function during alcohol‐related thiamine deficiency may contribute to this neuropathology. Thus, excitotoxic damage due to neural compensation for sustained alcohol levels and nutritional deficits may underlie aspects of alcohol‐related brain damage.
Molecular Mechanism of Ethanol Metabolism by Human Brain to Fatty Acid Ethyl Esters
Authors: Bora Puran S. , Lange Louis G.
Published: April 2006

Ethanol metabolism in the human brain has been documented to occur with the formation of fatty acid ethyl esters. These neutral lipids can disorder membranes and interrupt mitochondrial function. Their formation is under the control of three synthases, localized to grey matter and purified to homogeneity. cDNA cloning demonstrates two of these enzymes to be GSH S‐transferases and has enabled initiation of genetic studies of alcohol‐induced CNS injury.
Ethanol Inhibits NMDA Receptor‐Mediated Excitotoxicity in Rat Primary Neuronal Cultures
Authors: Chandler L. Judson , Sumners Colin , Crews Fulton T.
Published: April 2006

Excessive or prolonged stimulation of, N‐methyl‐D‐aspartate (NMDA) receptors appears to play an important role in many neurodegenerative processes in brain through a process known as excitotoxicity. This study examined the effects of ethanol on NMDA receptormediated excitotoxicity in primary neuronal cultures obtained from embryonic rat whole brain. Neurotoxicity was quantitated by measuring the amount of lactate dehydrogenase released into the media during a 20‐hr time period following NMDA washout. Exposure of 12‐to 14‐day‐old cultures to NMDA in Mg2+‐free HEPES buffer (pH 7.4) for a 25‐min period resulted in a concentration‐dependent toxicity (EC50= 54 μM). Time‐course experiments showed that exposure to NMDA for as little as 5 min was excitotoxic and reached a plateau after a 20‐min exposure period. Preincubation of the cultures with ethanol (25 to 200 mm) resulted in a concentration‐dependent inhibition of NMDA‐mediated toxicity with approximately 38% inhibition produced by 25 mm ethanol and essentially complete inhibition at 200 mm ethanol (IC50= 60 mm). Increasing the glycine concentration to 100 μM did not potentiate NMDA neurotoxicity or antagonize the neuroprotective effect of ethanol. NMDA‐Mediated excitotoxicity was reduced by approximately 50% by the glycine antagonist 7‐chlorokynurenate (50 μM). Ethanol (50 mm) reduced NMDA neurotoxicity similar to 7‐chlorokynurenate, and the two together produced greater inhibition than either alone. These results show that intoxicating concentrations of ethanol can potently inhibit NMDA receptor‐mediated excitotoxicity and may have important implications in terms of ethanols interactions with brain trauma, ischemia, and other neuropathologies associated with NMDA receptor‐mediated neurotoxicity.
Reaction of Acetaldehyde with Proteins: Formation of Stable Fluorescent Adducts
Authors: Hoffmann Tomas , Meyer Richard J. , Sorrell Michael F. , Tuma Dean J.
Published: April 2006

The properties of stable acetaldehyde‐protein adducts, using bovine serum albumin as a model protein, were investigated. Upon prolonged incubation at 37°C and pH 7.4, the reaction of acetaldehyde and albumin yielded stable adducts that exhibited fluorescent properties. Reaction mixtures of acetaldehyde with polylysine or ethylamine also formed fluorescent products with similar fluorescent spectral properties like acetaldehyde‐albumin adducts, indicating that the amino groups of protein alone can generate fluorescent products on reaction with acetaldehyde. When reactions of acetaldehyde with albumin or polylysine were conducted at 22°C, stable binding reached a maximum after 24 hr of incubation and essentially remained at this level during the remaining 216 hr of incubation, and minimal‐to‐no fluorescence was associated with this binding. At 37°C, stable binding was greater and increased continuously over the entire 216 hr of incubation. After an initial lag period of 24 to 48 hr, increases in fluorescence intensity paralleled the increases in stable binding. The presence of sodium cyanoborohydride, which reduces Schiff bases, in the reaction mixtures prevented fluorescence, indicating that Schiff bases are intermediates in the formation of fluorescent products. Both stable binding and fluorescence intensities were minimally affected by exhaustive dialysis (up to 144 hr), indicating that the fluorescent products were quite stable. These results suggest that an initial reaction of a Schiff base with another acetaldehyde molecule via an aldol condensation reaction gives rise to the formation of a crotonaldehyde Schiff base derivative. This reactive intermediate could then undergo further condensation reactions and form advanced conjugated products, some of which could be fluorescent.
Chronic Ethanol Intoxication Induces Differential Effects on GABAA and NMDA Receptor Function in the Rat Brain
Authors: Sanna Enrico , Serra Mariangela , Cossu Anna , Colombo Giancarlo , Follesa Paolo , Cuccheddu Tonino , Concas Alessandra , Biggio Giovanni
Published: April 2006

The effect of long‐term treatment with ethanol was investigated on the function of γ‐aminobutyric acid A (GABAA) and N‐methyl‐d‐as‐partic acid (NMDA) receptors. Rats were rendered ethanol‐dependent by repeated forced administration of a 20% ethanol solution (12 to 18 g/kg/day po) for 6 days and tested while still intoxicated or at different time intervals after withdrawal. t‐[36S]Butylbicyclophosphorothionate (35S‐TBPS) binding was increased by 30% in cortical homogenates of rats killed 1 to 3 hr after last ethanol administration, when compared with saline‐treated animals. However, GABA‐stimulated 36Cl‐uptake and its enhancement by flunitrazepam was decreased in the ethanol‐treated animals. 35S‐TBPS binding and 36Cl‐influx measured 9 to 24 hr following the last ethanol injection, when withdrawal signs were present, were unmodified with respect to saline‐treated rats. Moreover, the effects of both isoniazid and FG 7142 on 36S‐TBPS binding were unchanged in ethanol‐dependent rats tested at 1 to 3 and 9 to 24 hr, compared with controls. In contrast, ethanol‐withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc). The same animals were also more susceptible to the convulsant action of NMDA (0.5 to 5 μg/5 μl/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of 3H‐MK 801 recognition sites in the hippocampus. The increased pharmacological response to both isoniazid and excitatory amino acids was no longer detectable as early as 3 to 6 days of ethanol withdrawal, when most of the withdrawal signs disappeared. Moreover, 6 days after withdrawal we observed a significant reduction of 3H‐MK 801 binding in the hippocampl of ethanol‐dependent rats compared with controls. These results indicate that, in contrast to acute administration, chronic ethanol intoxication may lead to a reduction of GABAA receptor function, an effect no longer detectable during withdrawal. On the contrary, we found a good correlation between development of withdrawal symptoms and the increase in 3H‐MK 801 binding sites. The latter finding strongly suggests that a functional activation of glutamatergic synapses, rather than a decrease in GABAA receptor function, is a crucial event during ethanol withdrawal.
GABA Antagonist and Benzodiazepine Partial Inverse Agonist Reduce Motivated Responding for Ethanol
Authors: Rassnick Stefanie , D'Amico Elizabeth , Riley Edward , Koob George F.
Published: April 2006

Brain γ‐aminobutyric acid (GABA) systems have long been associated with the behavioral actions of ethanol. This study investigated the effects of GABAergic agents on ethanol reinforcement. Rats were trained to orally self‐administer ethanol in a 30‐min, free‐choice operant task. Responses at one of two levers produced contingent access to ethanol (10% w/v) or water. Pretreatment with RO 154513, a benzodlazepine inverse agonist (0.375 to 3.0 mg/kg ip), selectively reduced responses for ethanol, and a higher dose of RO 15‐4513 (6.0 mg/kg) reduced both ethanol and water responses. Self‐administration of saccharin in a free‐choice task with access to saccharin (0.05%) and water was unaffected by RO 15‐4513, suggesting that the effects of RO 15‐4513 on ethanol reinforcement may not necessarily generalize to other reinforcers. Isopropylbicyclophosphate (IPPO), a picrotoxin ligand (5 and 10 μg/kg ip), selectively reduced responses for ethanol in alcohol‐preferring, nonpreferring and Wistar rats. However, the highest dose of IPPO (20 μg/kg) reduced both ethanol and water responses. Chlordiazepoxide, a benzodiazepine, did not reduce responses for ethanol in the selectively bred animals, suggesting that this drug does not substitute for the reinforcing properties associated with acute ethanol intake. Together, these results suggest that compounds that act at the benzodiazepine inverse agonist and picrotoxin sites of the GABA/benzodiazepine receptor complex may decrease motivated responding for ethanol.
Screening for Disulfiram‐Induced Liver Test Dysfunction in an Inpatient Alcoholism Program
Authors: Wright Curtis , Moore Richard D. , Grodin Douglas M. , Spyker Daniel A. , Gill Edward V.
Published: April 2006

The objective of this study was to report the frequency of disulfiramrelated elevations of four commonly used hepatic screening chemistries using a retrospective record review design. An inpatient alcoholism program was selected for the setting. Patients who had initial laboratory values within the normal range started daily supervised doses of disulfiram, then underwent follow‐up testing after 2 and 4 weeks on the drug. The study population consisted of 108 patients receiving disulfiram and 27 patients who did not receive disulfiram (controls). The four screening serum chemistries performed were aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT), alkaline phosphatase, and γ‐glutamyl transferase. Twenty‐seven (25%) of the 108 patients who were taking 250 mg of disulfiram a day for 2 to 4 weeks had disulfiram‐related elevations in alanine aminotransferase above the upper limit of normal, as opposed to one elevation in 27 patients (4%) for whom disulfiram was not prescribed. In the 108 patients (with initially normal serum chemistries) who were prescribed disulfiram, 32 were discontinued from the drug at 2 weeks and an additional 11 were discontinued from the drug at 4 weeks because of one or more abnormal serum chemistries. Alanine aminotransferase was the most specific and sensitive indicator of the four screening chemistries performed.
Neuropsychological Deficits Are Correlated with Frontal Hypometabolism in Positron Emission Tomography Studies of Older Alcoholic Patients
Authors: Adams Kenneth M. , Gilman Sid , Koeppe Robert A , Kluin Karen J. , Brunberg James A. , Dede Duane , Berent Stanley , Kroll Phillip D.
Published: April 2006

In an extension of previous work, we studied the behavioral correlates of medial frontal lobe glucose hypometabolism in chronically alcohol‐dependent patients. Thirty‐one male patients who were detoxified, medically stable, and free of other central nervous system risk factors for neuropsychological impairment were examined with (1) anatomic imaging (CT or MR), (2) functional imaging with [18F] fluorodeoxyglucose (18F‐FDG) and positron emission tomography (PET), and (3) a battery of neuropsychological tests, including two measures of abstraction known to be generally sensitive to frontal lobe disease or dysfunction [the Wisconsin Card Sorting Test (WCST) and the Halstead Category Test (HCT)]. 18F‐FDG PET data from 18 age‐ and sex‐matched normal control subjects were used for comparison. All patients met criteria for severe alcohol dependence and for at least a mild degree of alcoholic‐induced cognitive impairment. Although the mean IQ level of the alcoholic patients was in the average range, the concepts attained and the error scores on the WCST and HCT were significantly impaired in comparison with established norms. Local cerebral metabolic rate for glucose (LCMRglc) was significantly decreased in a sagittal strip of the medial frontal cortex in the alcoholic patients as compared with the normal controls. Comparison of data from PET scans and anatomic images indicated that the reduced LCMRglc could not be attributed to reduced amounts of tissue alone. A statistically significant relationship was found between LCMRglc in the medial frontal region of the cerebral cortex and performance on the WCST, but not the HCT. These findings suggest that chronic alcohol intake results in impaired function of cerebral tissue in the medial frontal region. The impairment pertains both to tissue metabolic rates and the behavioral correlates of these rates.
Measurement of Acute Tolerance to Alcohol in Human Subjects
Authors: Martin Christopher S. , Moss Howard B.
Published: April 2006

Acute tolerance can be defined as a decrease in response to alcohol within a single exposure to the drug, which occurs independently of changes in blood alcohol concentrations (BACs). BACs change over time in most human alcohol administration studies, and computational techniques that account for these changes must be used to measure the rate of acute tolerance development. The most widely used acute tolerance measure in human research is often called the Mellanby effect, and involves the comparison of responses at the same BAC on the ascending and descending limbs of the blood alcohol curve. We compared the Mellanby measure with two other measures of acute tolerance: a conceptually similar area under the curve measure, and a slope function approach that used data only from the descending limb of the blood alcohol curve. The measures were intercorrelated and discussed with regard to empirical and conceptual issues. Exploratory comparisons of those with and with‐out a family history of alcoholism are reported. Methodological recommendations for the computation of acute tolerance are made. The results suggest new methods for measuring the rate of acquisition of acute tolerance, and suggest areas for future research on tolerance‐proneness and risk for alcoholism.
Comparative Evaluation of the Clinical Utility of Three Markers of Ethanol Intake: The Effect of Gender
Authors: Halvorson Michael R. , Campbell Jan L. , Sprague Gwen , Slater Karen , Noffsinger Jimmie K. , Peterson Charles M.
Published: April 2006

We evaluated three markers of ethanol intake [whole blood associated acetaldehyde (WBAA), serum β‐hexosaminidase, and γ‐glutamyl transpeptidase (GGT)] in four groups of subjects: teetotalers (n= 104), random insurance applicants or “normals”(n= 1,010), subjects enrolling in an alcohol treatment program or “alcoholics”(n= 31), and subjects attending outpatient drug/alcohol treatment follow‐up clinics (n= 128). Significant differences (p < 0.004 for each assay and each comparison) were found in the mean values between teetotalers and normals and normals and alcoholics. Male teetotalers and normals had significantly (p < 0.002) higher levels of WBAA than females of the same group. Male normals had significantly higher levels of GGT than females (p < 0.001). GGT increased with age in the normal population into the fifth decade and decreased thereafter. WBAA was the most sensitive assay with 97% of alcoholics having values above the 99th percentile for the teetotaler population (vs. 66% for serum β‐hexosaminidase and 70% for GGT). None of the alcoholic subjects had values for all three assays below the 99th percentile for teetotalers compared with 21% of those in follow‐up and 72% of normals. We conclude that WBAA appears to be the best of the three markers studied and that measurement of multiple markers for ethanol use appears clinically useful and incremental.
Alcoholic Beverage Licensing Practices in California: A Study of a Regulatory Agency
Authors: Rabow Jerome , Watts Ronald K. , Hernandez Anthony C. R.
Published: April 2006

A mail survey sent to all 25 State of California Alcoholic Beverage Control (ABC) offices and distributed to all 167 investigators assessed investigators' decisions to recommend issuance or denial of alcoholic beverage license applications. Investigators responded to three hypothetical vignettes that involved applications for liquor licenses. Findings show that although ABC investigators are influenced by public protests, illegal applications, and an applicant's moral character, they consistently favor licensing the applicant. The two formal rules that were designed specifically to respond to the community's welfare do not present serious barriers to obtaining an alcohol license. As a state regulatory organization, ABC is influenced greatly by the industry that it is supposed to regulate.
Alcohol‐Related Mortality in Spain
Authors: Yañez Jose Luis , Rio M. Carmen Del , Alvarez F. Javier
Published: April 2006

Alcohol‐related mortality and years of potential life lost in Spain in 1986 have been studied according to the official statistics with regard to the population mortality in our country. 6.1% of the deaths in Spain in 1986 were related to alcohol consumption, mainly caused by malignant neoplasm (26.0%), digestive diseases (23.6%), and unintentional injuries (21.1%). Mean potential years of life lost for alcohol‐related deaths until 65 was 7.3. Unintentional injuries were responsible for the greater part (61.2%) of alcohol‐related years of potential life lost. The present study shows the high mortality rate associated with alcohol consumption in our country, as well as its importance in premature death.
Immune Function in Alcoholism: A Controlled Study
Authors: Kronfol Ziad , Nair Madhavan , Hill Elizabeth , Kroll Philip , Brower Kirk , Greden John
Published: April 2006

Several studies have shown an increased risk for infection and cancer in alcoholic patients. The mechanisms for such observations remain largely unknown. In an effort to investigate the possibility of immunological dysfunction in alcoholism, we studied three immune parameters in 47 hospitalized chronic alcoholic patients and 47 age‐and sex‐matched normal controls. The immune measures were: (1) lymphocyte phenotyping, with estimates of percentages of T cells, B cells, T helpers, T suppressors, natural killer (NK) cells, and cells carrying the activation markers IL2R1 and l2; (2) NK cell activity; and (3) lymphokine‐activated killer cell activity. Results indicate a significant increase in the IL2R and l2 lymphocyte markers in alcoholic patients compared with matched controls. We also found a nonsignificant trend for a decrease in the percentage of suppressor T cells in the alcoholic group, as well as a trend for a negative correlation between the percentage of T suppressor cells and age. There were no significant differences in either NK or lymphokine‐activated killer cell activities between the two groups. Furthermore, there were no significant associations between duration and intensity of alcohol consumption and any of the immune measures. These results suggest subtle alterations in immune regulation in alcoholic patients that cannot be explained solely on the basis of duration and/or amount of alcohol consumed.
Secondary Immune Response to Hepatitis B Virus Vaccine in Alcoholics
Authors: Nalpas Bertrand , Thepot Véronique , Driss Francoise , Pol Stanislas , Courouce Anne Marie , Saliou Pierre , Berthelot Pierre
Published: April 2006

The efficacy of full vaccination against hepatitis B virus (i.e., including the 1‐year booster injection) was evaluated in 28 alcoholic patients with minimal liver disease. Although such patients are reportedly poor responders, the proportion of those protected (anti‐HBs titer > = 10 mlU/ml) rose from 42.8% after primary immunization to 82% after the booster. The mean anti‐HBs titer, which remained low in the overall group, was significantly lower In the subjects who resumed drinking during the follow‐up period than in those who did not. This suggests a direct influence of alcohol itself on the response, because none of our patients had cirrhosis and none were clearly malnourished. Among the 17 patients for whom the 2‐year post‐booster anti‐HBs titer could be determined, all those with a 1‐month postbooster titer above 1000 mlU/ml still had a high anti‐HBs level (>100), whereas 80% of those with a 1‐month postbooster titer < 1000 had 2 years later only a low (< 100) or even an unprotective anti‐HBs level; this means that only the latter should be considered for a new booster injection. Our data indicate that protection against hepatitis B virus can be achieved in a good proportion of alcoholics with a full vaccination protocol. We suggest that efficacy should be evaluated 1 month after the booster, and that patients with low postbooster anti‐HBs titers should be tested at regular intervals, because they can also be protected provided an adapted schedule of further injections is conducted.
Migration of Cortical Neurons Is Altered by Gestational Exposure to Ethanol
Authors: Miller Michael W.
Published: April 2006

Rats prenatally exposed to ethanol exhibit a variety of structural anomalies in the central nervous system. One of the key features of experimental fetal alcohol syndrome is microencephaly. Cerebral cortex is particularly susceptible to the effects of prenatal exposure to ethanol. Its total mass is reduced, it is thinner, and it contains fewer neurons and glia. Various studies in rats and humans suggest that chronic early exposure to ethanol leads to a massive reorganization of cortex characterized by heterotopic clusters of neurons. A pulse and chase study with [3H]thymldine autoradiography was used to determine if gestational exposure to ethanol leads to defects in neuronal migration. Rats were fed an ethanol‐containing diet between gestational day (G) 6 and G21, pair‐fed a liquid control diet, or fed chow. Ethanol delayed the migration of early‐generated neurons (those born on G13) to deep cortex by 2 days. Moreover, the migration of late‐generated neurons (those born on G21) was delayed 4 to 6 days by ethanol, and often these neurons terminated their migration in ectopic locations. Ethanol significantly decreased the rate of migration and the time postmitotic cells remained in the proliferative zones. On the other hand, ethanol did not have a significant effect on the rate of cortical expansion and the fraction of cells that left the proliferating population in order to migrate to cortex. Thus, the migration of young neurons was profoundly altered by prenatal exposure to ethanol. Such delays may lead to a desynchronization of cortical development that makes it impossible for cortical neurons to establish a normal circuitry.
Enhanced Expression of the Inhibitory Protein Gi2α and Decreased Activity of Adenylyl Cyclase in Lymphocytes of Abstinent Alcoholics
Authors: Waltman Claire , Levine Michael A. , McCaul M. E. , Svikis D. S. , Wand Gary S.
Published: April 2006

Ethanol exposure alters signal transduction through the adenylyl cyclase (AC) system. To elucidate the basis for this effect, we investigated the AC system in peripheral lymphocytes from abstinent alcoholic men (n= 22), actively drinking alcoholic men (n= 41), and nonalcoholic control men (n= 16). Immunoblot analysis of lymphocyte membranes from abstinent alcoholics demonstrated a 3.0‐fold increase in the level of Gi2α protein (p < 0.05) compared with controls. However, levels of Gi2α protein were similar in both groups. Abstinent alcoholics had a 2.9‐fold increase in Gi2α mRNA (p < 0.001) and a 2.7‐fold increase in G2α mRNA (p < 0.03) compared with lymphocytes from control subjects. Actively drinking alcoholics, in contrast, had unaltered G2α protein, Gi2α protein, and Gi2α mRNA levels compared with control subjects, but did have a 1.8‐fold increase (p < 0.01) in Gi2α mRNA. Consistent with enhanced Gi2α expression, lymphocyte membranes from abstinent alcoholics had decreased basal, prostaglandin E1‐, guanosine 5′‐0‐(3‐thiotriphosphate)‐γS‐, and forskolin‐stimulated AC activity compared with both controls and actively drinking alcoholics (p < 0.05). We conclude that lymphocyte AC is reduced during abstinence from alcohol and enhanced expression of the inhibitory G‐protein, Gi2α, may account for this change.
Electrophysiological Interactions of Ethanol with GABAergic Mechanisms in the Rat Cerebellum in Vivo
Authors: Freund Ronald K. , van Home Craig G. , Harian Timothy , Palmer Michael R.
Published: April 2006

Biochemical studies indicate that ethanol (EtOH) will facilitate the activation of the GABAA/CI– channel, and behavioral studies demonstrate that EtOH‐induced sedative and incoordinating effects can be potentiated by GABA mimetics and blocked by GABA antagonists. It has been difficult, however, to demonstrate an EtOH‐induced potentiation of the depressant electrophysiological effects of locally applied GABA in mammalian brain in vivo. Similarly, in this study, local EtOH applications only infrequently caused potentiations of the depressant effects of microiontophoretically applied GABA on cerebellar Purkinje neurons, and this interaction was modest when present. The predominant interaction of locally applied EtOH was an antagonism of GABA‐induced depressions of neuronal activity. However, the GABAA receptor antagonist bicuculline reversibly and apparently competitively blocked the depressant effects of locally applied EtOH on single cerebellar Purkinje neurons. Our data suggest that EtOH potentiation of GABA responses alone is insufficient to account for EtOH‐induced depressions of cerebellar Purkinje neurons. However, these data clearly imply that activation of a GABAA receptor is required for the expression of EtOH‐induced depressions of neuronal activity in this brain area. It is less clear how lower, nondepressant doses of EtOH interact with GABA mechanisms. We hypothesize that either the GABAA receptor mechanism must be sensitized to the potentiative effects of EtOH through the influences of neuromodulatory and/or hormonal regulation, or that EtOH interacts directly with these regulatory processes.
Role of Gangliosides in Behavioral and Biochemical Actions of Alcohol: Cell Membrane Structure and Function
Authors: Hungund Basalingappa L. , Mahadik Sahebarao P.
Published: April 2006

Alcohol exerts its pharmacological effects in adult brain by altering the physicochemical properties of cellular plasma membranes. Although alcohol does induce changes in membrane lipid composition, studies to relate these alterations to the development of behavioral tolerance to alcohol and the withdrawal effects have been unsuccessful. Actions of alcohol on developing brain are even more complex. Some of the reported effects include inhibition of embryogenesis, cell migration, and differentiation, including synaptogenesis. Gangliosides have neuroprotective action against a variety of neural insults (e.g., mechanical injury, drug toxicity, or hypoxic insult). This review addresses the role and significance of gangliosides in the CNS pathophysiology of alcohol exposure, as well as the effect of changes in endogenous gangliosides on membrane structure and function. We also describe the role of exogenous gangliosides in prevention of alcohol (acute and/or chronic)‐induced CNS (prenatal and postnatal) neurotoxicity through their action on cellular plasma membranes. We propose that ganglioside's neuroprotective effects against alcohol neurotoxicity involve protection and restoration of plasma membrane structure (proteins and lipids) and thereby its function (ionic homeostasis, neurotransmitter receptor‐mediated signal transduction). Thus gangliosides may have potential therapeutic use in treatment of alcohol‐related problems.
Selective Inhibition of Luteinizing Hormone Action by Ethanol in Cultured Human Granulosa Cells
Authors: Wimalasena Jay , Meehan Daniel , Dostal Robert , de Silva Mahendra
Published: April 2006

To extend further our previous observations on the inhibition of luteinizing hormone (LH)‐induced increases in steroid secretion by ethanol (EtOH) (Alcohol. Clin. Exp. Res. 14:522–527, 1990), cultured human granulosa cells were pretreated with several EtOH concentrations (0– 100 mm), and cells were stimulated with human LH (25 ng/ml) or human follicle stimulating hormone (FSH) (100 ng/ml) and the secretion of 17‐β‐estradiol (E2) and progesterone (P) was measured. EtOH significantly increased basal E2 secretion in a dose‐related manner (0–20 mm); however, in the same concentration range EtOH did not produce consistent changes in FSH‐stimulated E2 secretion. In contrast, EtOH decreased LH‐stimulated E2 secretion between 0–20 mm such that at 20 mm EtOH, the positive effect of LH was abolished. EtOH increased P secretion by 40% at 20 mm and at 100 mm, there was a 100% increase. The FSH‐stimulated P secretion was not consistently changed by EtOH, whereas LH‐stimulated P secretion was decreased in a dose‐dependent manner. LH/human chorionic gonadotropin (hCG) receptors in cells exposed to EtOH showed a 15% (p < 0.01) and a 47% decrease at 20 mm and 50 mm EtOH, respectively. At 50 mm EtOH, there was a decrease in LH/hCG receptor number from 2900/cell to 1670/cell, without a change in receptor affinity for hCG and 50 mm EtOH decreased LH/hCG receptors in intact granulosa cells in a time‐dependent manner. These results indicate that the selective effects of EtOH on LH action in human granulosa cells may be mediated in part by an action on LH/hCG receptors.
Cholesterol Exchange and Lateral Cholesterol Pools in Synaptosomal Membranes of Pair‐Fed Control and Chronic Ethanol‐Treated Mice
Authors: Wood W. Gibson , Rao A. Muralikrishna , Igbavboa Urule , Semotuk Michael
Published: April 2006

Most studies on effects of ethanol on membrane cholesterol have reported on changes in the total or bulk amount of cholesterol. Membrane cholesterol, however, can be described in terms of its kinetics and domains. The kinetics and size of lateral cholesterol exchangeable and nonexchangeable pools were examined in synaptosomes of pair‐fed controls and chronic ethanol‐treated mice. Effects of sphingomyelin, an exofacial leaflet phospholipid, that has been shown to affect cholesterol pools, were also examined. Radiolabeled small unilamellar vesicles were used to exchange cholesterol with synaptosomes. The total amounts of membrane cholesterol, phospholipid phosphorus, and the ratio of cholesterol to phospholipid did not differ between the pair‐fed control and ethanol groups. In control mice, the rate constant (hr‐1) and the t1/2 (hr) of cholesterol exchange were 0.065 ± 0.001 and 10.7 ± 0.25 (hr), respectively. The rate constant was significantly slower (0.053 ± 0.001, p < 0.05) and the t1/2 significantly longer (13.33 ± 0.58, p < 0.05) in synaptosomes of the ethanol group compared with the control group. The size of the exchangeable pool of cholesterol did not differ significantly between the two groups. Sphingomyelinase‐induced hydrolysis of sphingomyelin significantly slowed cholesterol exchange with the largest effect in synaptosomes of the control group as compared with the ethanol group (p < 0.05). Hydrolysis of sphingomyelin had significantly (p < 0.05) less of an effect on cholesterol exchange in synaptosomes of the ethanol group. Membrane cholesterol can be described in terms of total content, transbilayer distribution, kinetics, and size of lateral pools. This study supports the general hypothesis, that not all properties or domains of membrane cholesterol are equally affected by ethanol.
Effect of Chronic Alcohol Feeding on Hepatic Iron Status and Ferritin Uptake by Rat Hepatocytes
Authors: Zhang H. , Loney L. A. , Potter B. J.
Published: April 2006

Alcohol abuse is known to cause disturbances to iron homeostasis in man and is associated with elevated serum ferritin levels. We have previously shown that ethanol metabolism in the rat hepatocyte is associated with an immediate reduction in ferritin uptake by this cell. In this study we have examined the effect of pair‐feeding the Lieber‐DeCarli liquid alcohol diet on ferritin uptake by rat hepatocytes.

Rat liver ferritin was radiolabeled with 59Fe in vivo and isolated by conventional techniques. Rats were pair‐fed the Lieber‐DeCarli liquid alcoholic diet for 4–6 weeks. Hepatocytes, isolated from their livers by collagenase perfusion, were incubated with [59Fe]ferritin in L‐15 medium at 37°C and 4° to measure ferritin uptake and binding. The in vitro effect of ethanol on these hepatocytes was also studied. Ferritin and iron parameters were measured in the sera and hepatocytes of these animals and a comparable group of normal chowfed rats.

The rate of ferritin uptake by hepatocytes from alcohol‐fed rats was significantly faster than that of their pair‐fed controls (0.743 ± 0.061 vs. 0.540 ± 0.042 ng/min/106 cells, p < 0.05). However, the rats on Lieber‐DeCarli control diet exhibited a lower hepatocyte ferritin uptake rate than chow‐fed animals (79.3 ± 8.1% of the control values, p < 0.01). In vitro incubation of cells in 100 mm ethanol resulted in less inhibition of ferritin uptake by hepatocytes from alcoholic rats than from their pair‐fed controls (11 ± 7.1% inhibition vs. 43.6 ± 10.7% for controls, p < 0.05). Receptor‐mediated binding of ferritin to hepatocytes showed a 61% increase in saturable binding capacity for alcoholic rats (15,820 ± 4950 molecules/cell vs. 9798 ± 3622, p= 0.05). The presence of ethanol in the medium did not affect ferritin binding significantly.

Although there was no significant difference in the serum iron values between all three groups, transferrin concentrations were markedly elevated in the alcohol‐fed rats, resulting in a much lower transferrin iron saturation than for the control animals. Because the corresponding serum values for the diet controls were intermediate between those for the alcohol‐fed rats and the chow‐fed animals, these findings may reflect dietary restriction by the liquid diet, which is exacerbated by the addition of alcohol.

These findings suggest that there is increased iron uptake by the hepatocyte following chronic alcohol administration, which may be due to the increased ferritin receptors. This is supported by the observation that this alcohol treatment also causes a depletion of serum ferritin. However, the decreased iron content in the alcohol‐fed rats indicate that this may be due to a response to changes in iron homeostasis by the hepatocyte and/or redistribution in the body.
Effects of Acute Ethanol Administration on Polyphosphoinositide Turnover and Levels of Inositol 1,4,5‐Trisphosphate in Mouse Cerebrum and Cerebellum
Authors: Lin Tai‐An , Navidi Meena , James William , Lin Teng‐Nan , Sun Grace Y.
Published: April 2006

Although ethanol is known for its central depressant action, its effect on the polyphosphoinositide (poly‐Pl) signal transduction activity in brain has not been examined in detail. In this study, C57BI/6J mice were injected intracerebrally with [3H]inositol, and poly‐PI turnover in brain was assessed by determining the levels of labeled inositol monophosphates (IP1) accumulated after intraperitoneal injection of LiCl (6 meq/kg body weight) 4 hr before killing. Using this experimental protocol, acute ethanol administration (by gavage) resulted in time‐ and dose‐dependent decreases in the levels of labeled IP1 in both cerebrum and cerebellum as compared with controls. The ethanol‐induced decrease in labeled IP1 correlated well with the decrease in levels of inositol 1,4,5‐triphosphate (as measured by the radioreceptor assay) and the increase in blood ethanol concentration. Despite a 4‐fold higher accumulation of labeled IP1 in the cerebrum compared with the cerebellum, there were no major differences in the steady‐state levels of inositol 1,4,5‐triphosphate (based on tissue weight) in either brain region. Intraperitoneal injection of atropine (50 mg/kg) (a muscarinic cholinergic receptor antagonist) to the lithium‐treated mice resulted in a 34% decrease in labeled IP1 as compared with controls. This result suggests that a substantial proportion of the signals transduced were due to activation of the muscarinic cholinergic receptor. Administration of ethanol (5 g/kg) to the atropine‐treated mice resulted in a further decrease in labeled IP1 and longer sleep time as compared with those given ethanol alone. Taken together, these results indicate a relationship between the acute effect of ethanol and the poly‐PI signaling activity in brain and modulation of the ethanol effect by compounds affecting the poly‐PI signaling pathway.
Bestatin, an Aminopeptidase B Inhibitor, Selectively Reduces Alcohol Intake in Rats
Authors: Szczepanska R. , Grupp Larry A.
Published: April 2006

Extensive research has shown that manipulations that augment activity in the renin‐angiotensin system can reduce alcohol intake. Inhibition of aminopeptidase B and M can prolong the action of angiotensin (ANG) II and ANG III by preventing their degradation. This study assesred the ability of bestatin, an aminopeptidase B and M inhibitor, to decrease alcohol intake. Bestatin produced a dose‐dependent reduction in alcohol intake without altering water intake. The angiotensin antagonist Sar‘Thr3‐ANG II, however, did not attenuate the effect of bestatin, suggesting that the reduction in alcohol intake was mediated by a system other than the reninangiotensin system. Bestatin (Ubenimex®) is used extensively in Japan as an anticancer agent. It has a low toxicity and is readily absorbed after oral administration. Although further research is needed to uncover the mechanism of its effect, the potential of this drug as an adjunct for the treatment of alcohol abuse should be evaluated.
Effects of Maternal Alcohol Consumption on Milk and Blood Lymphocytes and IgG Antibody Levels from Trichinella spiralis‐Infected Rats
Authors: Na Hyung R. , Chervenak Robert , Seelig Leonard L.
Published: April 2006

Immunity to the intestinal parasite Trichinella spiralis can be transferred from the mother to the neonate during lactation. Previous studies in our laboratory showed that the passage of immunity to pups from ethanol‐treated dams was depressed. This study examined the effect of ethanol consumption during pregnancy and lactation on the T. spiralis‐associated immune components in milk and blood. Groups of female rats were fed either ethanol‐containing or isocaloric liquid diets for 30 days before T. spiralis infection, mated and maintained on corresponding diets through pregnancy and lactation. Two‐color flow cytometric analysis was performed for lymphocyte populations, enzyme‐linked immunoabsorbent assay for specific IgG, and radial immunodiffusion assay for total IgG. The percentage of total T cells and their subsets, T helper cells and T cytotoxic/suppressor cells in milk and those in blood were similar between pair‐fed and ethanol‐treated animals. However, the percentage of natural killer cells in milk from ethanol animals was significantly reduced compared with the pair‐fed group (33% vs. 54%). The percentage of activated or memory type T helper cell subset (OX22−W3/25+) was significantly increased in the blood of the ethanol‐treated group. Pair‐fed animals showed higher T. spiralis‐specific IgG antibody levels both in milk and blood compared with ethanol‐treated animals. In ethanol‐treated animals, specific IgG levels and total IgG concentration in milk were significantly lower than those in blood, whereas in pair‐fed animals, only total IgG concentration in milk was lower than that in blood. This study indicates that ethanol consumption during pregnancy and lactation alters the maternal immune system. Decreased milk natural killer cells and depressed specific antibody levels in milk of ethanol‐treated animals are possible contributing factors to the previously observed depressed lactational immune transfer to the pups.
Dietary Betaine Promotes Generation of Hepatic S‐Adenosylmethionine and Protects the Liver from Ethanol‐Induced Fatty Infiltration
Authors: Barak Anthony J. , Beckenhauer Harriet C. , Junnila Matti , Tuma Dean J.
Published: April 2006

Previous studies have shown that ethanol feeding to rats alters methionine metabolism by decreasing the activity of methionine synthetase. This is the enzyme that converts homocysteine in the presence of vitamin B12 and N5‐methyltetrahydrofolate to methionine. The action of the ethanol results in an increase in the hepatic level of the substrate N5‐methyltetrahydrofolate but as an adaptive mechanism, betaine homocysteine methyltransferase, is induced in order to maintain hepatic S‐adenosylmethionine at normal levels. Continued ethanol feeding, beyond 2 months, however, produces depressed levels of hepatic S‐adenosylmethionine. Because betaine homocysteine methyltransferase is induced in the livers of ethanolfed rats, this study was conducted to determine what effect the feeding of betaine, a substrate of betaine homocysteine methyltransferase, has on methionine metabolism in control and ethanol‐fed animals. Control and ethanol‐fed rats were given both betainelacking and betaine‐containing liquid diets for 4 weeks, and parameters of methionine metabolism were measured. These measurements demonstrated that betaine administration doubled the hepatic levels of S‐adenosylmethionine in control animals and increased by 4‐fold the levels of hepatic S‐adenosylmethionine in the ethanol‐fed rats. The ethanol‐induced infiltration of triglycerides in the liver was also reduced by the feeding of betaine to the ethanol‐fed animals. These results indicate that betaine administration has the capacity to elevate hepatic S‐adenosylmethionine and to prevent the ethanol‐induced fatty liver.