bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum IgA Antibodies to Human Gut Luminal Aspirates and Human Liver in Alcoholic Liver Disease
Authors: Douds A. C. , Lewis D. J. M. , Lim A. G. , Maxwell J. D. , Poulton T. A.
Published: May 2006

Background: Elevation of serum IgA is a characteristic feature of alcoholic liver disease. It has been proposed that this occurs partly as an antigenic response to gut‐derived proteins or acetaldehyde‐modified liver proteins, but the principal antigens responsible remain unknown. Aims: The goal of this study was to determine if serum IgA antibodies were present against human gut luminal antigens or liver antigens in alcoholic liver disease. Patients and Methods: Twenty‐nine patients with alcoholic liver disease, 10 with primary biliary cirrhosis, 12 with “other” liver diseases, 8 alcoholics, and healthy subjects were studied. Western blotting was used to examine the reactivity of sera from these groups against human small and large bowel aspirates and liver tissue from alcoholic liver disease patients. Results: Serum IgA antibodies to a 140 kDa colonic luminal protein were found in 22 (76%) patients in the alcoholic liver disease group (p < 0.0001), and 7 (24%) patients had serum IgA antibodies to a 40 kDa colonic luminal protein (p= 0.04). These responses were confined to colonic aspirates and not observed in other disease groups, alcoholics or healthy subjects. There was no significant serum IgA response to human liver proteins in alcoholic liver disease. Conclusions: Serum IgA antibodies to a human 140 kDa colonic luminal protein are frequently found in alcoholic liver disease. This novel antigen may contribute to the increased levels of circulating IgA in alcoholic liver disease.
Cognitive Efficiency in Alcoholics and Polysubstance Abusers
Authors: Nixon Sara Jo , Paul Robert , Phillips Mary
Published: May 2006

Previous studies have found alcoholics to be impaired on tests of cognitive efficiency. However, it is unclear to what extent individuals who abuse drugs in addition to alcohol exhibit similar deficits. To answer this question, 63 healthy control subjects were compared with 40 individuals who abused alcohol only, 24 individuals who abused alcohol and stimulants, 16 individuals who abused alcohol and marijuana, and 41 individuals who abused alcohol and depres‐sants/narcotics, or alcohol and two or more other drugs. All subjects were administered tests of Short‐term memory, spatial orientation, visual‐spatial perception, and problem‐solving. Results from the study indicated that control subjects and individuals who abused both alcohol and marijuana performed significantly better than the other groups on most tests. These results were not attributable to differences on measures of affect or chronicity of alcohol consumption.
Differences in NMDA Receptor Antagonist‐Induced Locomotor Activity and [3H]MK‐801 Binding Sites in Short‐Sleep and Long‐Sleep Mice
Authors: Velardo M. Jo , Simpson Vicky J. , Zahniser Nancy R.
Published: May 2006

Short‐Sleep (SS) and Long‐Sleep (LS) mice differ in initial sensitivity to ethanol. Ethanol acts as an antagonist at N‐methyl d‐aspartate receptors (NMDARs). Therefore, we tested whether SS and LS mice also differ in initial sensitivity to NMDAR antagonists. Systemic injection (intraperitoneal) of either the noncompetitive NMDAR antagonist MK‐801 (dizocilpine) or the competitive NMDAR antagonist 2‐carboxypiperazin‐4‐yl‐propyl‐1‐phosphonic acid (CPP) produced similar results. At lower drug doses, SS mice showed greater loco‐motor activation than LS mice; and at higher doses, SS mice continued to be activated whereas LS mice became sedated. Brain levels of [3H]MK‐801 were 40% higher in SS, compared with LS, mice. However, blood levels of [3H]MK‐801 and [3H]CPP and brain levels of [3H]CPP were similar in the two lines. NMDARs were measured using quantitative autoradiographic analysis of in vitro [3H]MK‐801 binding to SS and LS mouse brains. Significantly higher (20 to 30%) receptor densities were observed in the hippocampus and cerebral cortex of SS mice. Our results support the hypothesis that SS and LS mice differ in initial sensitivity to NMDAR antagonists and suggest that the line differences in the dose‐response relationships for MK‐801‐ and CPP‐induced locomotor activity are qualitatively similar to those reported for ethanol. Differences in pharmacokinetics and number of NMDARs may contribute to, but are unlikely to entirely account for, the differential behavioral responsiveness of SS and LS mice to MK‐801 and CPP.
Pharmacokinetics of the Ethanol Bioavailability in the Regenerating Rat Liver Induced by Partial Hepatectomy
Authors: Morales‐González José A. , Gutiérrez‐Salinas Jose , Hernández‐Muñoz Rolando
Published: May 2006

It is well known that a single ethanol administration is capable of inhibiting the two‐thirds partial hepatectomy (PH)‐induced liver regeneration (LR); nonetheless, it has not been elucidated how ethanol metabolism by the remnant liver is exerting the deleterious ethanol actions on LR. Indeed, pharmacokinetics analysis of ethanol elimination is lacking in rats subjected to PH, which might extend our understanding in the mechanisms that account for the ethanol‐induced inhibition on LR after PH in the rat. Therefore, the present study is a pharmacokinetics analysis comparing intragastric and in‐traperitoneal administrations of ethanol to rats under PH, at several times after surgery (0 to 96 hr postsurgery). Our results show that PH rats had a much lower blood ethanol peak than sham‐operated, when intragastrically administered during the first 4 hr after surgery that was transient and normalized at 6 hr post‐PH. The area under the curve for blood ethanol was higher in PH animals, starting after 6 hr postsurgery and extended to the all replicative period, and returned within the control values thereafter. The quantity of ethanol absorbed after its intraperitoneal injection was essentially the same as the administered dose for all of the groups tested. Hence, ethanol bioavailability diminished due to an enhanced rate of the first‐pass metabolism for ethanol in PH rats at the very early times post‐PH. At later times of PH, ethanol bioavailability was practically normalized, and these effects were accompanied by a drastic increase in the liver capacity to metabolize ethanol, mainly at 48 to 96 hr after surgery, as calculated as ethanol elimination per gram of liver, as well as by total body weight. The very early changes in ethanol bioavailability in PH rats were not accounted for gastric ethanol retention in these animals. In conclusion, first‐pass metabolism importantly participates in the modified ethanol bioavailability at very early times after PH, an event presumably attained to gastric catabolism of ethanol. However, the very enhanced metabolism of ethanol showed by the regenerating liver, particularly after the first 24 hr postsurgery, seems to be the main factor affecting ethanol pharmacokinetics in rats subjected to PH. The underlying mechanisms in this liver enhancement of ethanol oxidation by PH rats remains to be elucidated.
ADH4‐lacZ Transgenic Mouse Reveals Alcohol Dehydrogenase Localization in Embryonic Midbrain/ Hindbrain, Otic Vesicles, and Mesencephalic, Trigeminal, Facial, and Olfactory Neural Crest
Authors: Haselbeck Robert J. , Duester Gregg
Published: May 2006

Pursuit of endogenous functions for various members of the alcohol dehydrogenase (ADH) enzyme family has led to exploration of gene expression patterns. Herein, we have used transgenic mice to examine the mouse gene encoding class IV ADH (ADH4), an enzyme that is weakly effective as an ethanol dehydrogenase, but highly effective as a retinol dehydrogenase in vitro. ADH4 promoter and upstream regulatory sequences were fused to lacZ and stably introduced into mice so that embryonic expression of ADH4 could be easily monitored by examination of β‐galactosidase activity in situ. Several independent founder mice carrying ADH4‐lacZ transgenes with either 2.7 or 9.0 kb of upstream regulatory sequences produced embryos in which expression was highly localized in the brain and craniofacial region at stages E8.5 to 9.5 during neurulation. Expression in the brain was limited to the ventral midbrain and its boundary with the hindbrain. At stage E8.5, ADH4‐lacZ expression was noticed in several dispersed regions throughout the head, and by stage E9.5 it was evident that these regions corresponded to the otic vesicles and migrating neural crest cells, particularly the mesencephalic, trigem‐inal, facial, and olfactory neural crest. ADH4‐lacZ expression in the trigeminal neural crest appeared as long fibers emanating from the midbrain/hindbrain boundary and extending to the first branchial arch following the tract of the trigeminal nerve. These findings support the hypothesis that ADH4 may normally function in retinoic acid synthesis needed for brain and neural crest development and that it participates in the mechanism of ethanol‐induced brain and craniofacial birth defects.
Characteristics and Consequences of Free‐Feeding Ethanol Ingestion During the First Two Postnatal Weeks of the Rat
Authors: Lee Jieun Sasha , Crawford Julie , Spear Norman E.
Published: May 2006

The present experiment used a free‐feeding technique devised by Hall to compare ingestion of ethanol and water during postnatal days 3 to 12. More intake of ethanol than water was observed, subject to reasonably consistent individual differences in ethanol intake unrelated to body weight or general fluid intake. Relative to Low ethanol consumers, pups that ingested higher quantities of ethanol showed less “place” aversion for stimuli associated with ethanol ingestion. High ethanol consumers did not, however, show an absolute conditioned place preference relative to water‐only controls, and they exhibited a conditioned aversion to the odor of ethanol. These results indicate that ethanol intake during the first two postnatal weeks is modulated by the early occurrence of individual differences and a disposition to drink more ethanol than water, but the reinforcement effects of ethanol at this age are unclear.
Effect of Alcohol on Bacterial Translocation in Rats
Authors: Mason Carol M. , Dobard Elizabeth , Kolls Jay , Nelson Steve
Published: May 2006

Bacterial translocation has been proposed to be important in the pathophysiology of sepsis, as well as to be a consequence of sepsis. To study the effect of alcohol on bacterial translocation from the gut, normal Sprague‐Dawley rats were administered alcohol by gavage by two regimens: Acute (3.7 g/kg, one dose) or Subacute (1 of 2 doses, 2.4 or 3.7 g/kg/day once daily for 14 days). Mesenteric lymph node cultures were performed, and portal venous blood was assayed for endotoxin. Ileal and cecal permeability studies were performed in the Acute and Subacute groups using fluorescein isothiocyanate‐labeled dextrans of either 4,000 or 70,000 kDa size. As an index of the effect of systemic endotoxin, tissues from mesenteric lymph nodes, liver, and intestinal Peyer's patches were assayed for the presence of mRNA for tumor necrosis factor. Additionally, because extrapulmonary sepsis has been shown to suppress pulmonary antibacterial defenses, animals in the Subacute group were challenged by aerosol inoculation with Pseudomonas aenrginosa to determine bacterial clearance and alveolar cellular responses. The results show that neither of the alcohol regimens resulted in bacterial growth from mesenteric lymph nodes or portal blood. Animals in the Subacute group had more endotoxin present in portal blood than did the Control group (92.9 pg/ml vs. 40.2 pg/ml; p < 0.02). None of the animals had demonstrable mRNA for tumor necrosis factor in any of the tissues assayed. There were no demonstrable increases in ileal or cecal permeability for either the small or large molecular weight dextran in either alcohol group. Furthermore, there was no delay in the clearance of P. aeruginosa from the lung in the Subacute group, but these animals recruited fewer neutrophils into the airspaces in response to this challenge than did the Control animals. Thus, alcohol intoxication does not result in bacterial translocation from the gut in this model. Despite higher levels of portal venous endotoxin in the animals in the Subacute alcohol group, no adverse systemic consequences of this phenomenon could be demonstrated.
Effect of Alcohol Consumption on Adult and Aged Bone: Composition, Morphology, and Hormone Levels of a Rat Animal Model
Authors: Sampson H. Wayne , Hebert Valerie A. , Booe Holli L. , Champney Thomas H.
Published: May 2006

To determine the effect of life‐long alcohol consumption on the adult and aged rat model, 4‐week‐old, female Sprague‐Dawley rats were divided into three diet groups. Alcohol‐treated animals were fed a modified Lieber‐DeCarli diet ad libitum containing 35% ethanol‐derived calories, whereas the pair‐fed animals (weight‐matched to ethanol rats) received an isocaloric liquid diet in which maltose‐dextrin substituted calories supplied by ethanol. Chow animals were fed a standard rat chow ad libitum. Proximal tibiae (primarily cancellous bone) and femora (primarily cortical bone) were removed for analysis after 3, 6, 9, 12, or 18 months on the diets. Serum was collected for analysis of calcium levels, the calcium regulating hormones; parathyroid hormone, 25‐hydroxyvitamin D, calcitonin, cor‐ticosterone, estradiol, testosterone, and IGF‐1. Creatinine, SGOT/ AST, and SGPT/ALT levels were measured to determine kidney and liver integrity. Previous studies, with young animals, showed that chronic alcohol consumption during the age of bone development reduced bone density and bone mass in both cortical and cancellous bone. The present study demonstrates that these reductions last throughout life, whereas morphological values, such as length and diameter, attain control levels. Calcium regulating hormones and sex hormones are essentially normal and do not appear to be the primary causative agent for adult alcohol‐induced osteopenia, but it appears to be due to a more direct effect of alcohol on bone cells.
Interaction of Ethanol and Nitric Oxide in the Hypothalamic‐Pituitary‐Gonadal Axis in the Male Rat
Authors: Shi Qin , Hales Dale B. , Emanuele Nicholas V. , Emanuele Mary Ann
Published: May 2006

Ethanol (EtOH) exerts deleterious actions on reproductive function at all three levels: the hypothalamus, pituitary, and gonad (HPG). Nitric oxide (NO), a newly identified messenger molecular in a variety of biological systems, has been suggested as playing a role in HPG hormone regulation. NO stimulates luteinizing hormone releasing hormone secretion from the hypothalamus and has variable effects on luteinizing hormone release from the pituitary. NO is inhibitory to testosterone production, and it may also directly inhibit some steroidogenic enzymes. Related studies in the accompanying paper have demonstrated that inhibiting NO synthase (NOS) using various NOS inhibitors can prevent the EtOH‐induced suppression of testosterone on the male HPG axis, and this action is mainly, although not entirely, due to a direct gonadal effect. To further investigate the role of NO in the HPG axis, we assessed the HPG NO‐NOS system by determining NOS mRNA levels, protein levels, and enzyme activity in the presence and absence of EtOH. At the testicular level, EtOH's action did not appear to be mediated by increasing NO content. However, EtOH was able to potentiate NO'S suppressive effect on the testicular synthesis system. One locus where EtOH and NO interacted was at the steroidogenic enzyme level. NQ‐nitro‐l‐arginine methyl ester, a NOS inhibitor, was found to antagonize the EtOH‐induced fall on P‐450 17α‐hydroxylase/C17‐20 lyase mRNA levels when administered along with EtOH. EtOH had no apparent effect on the pituitary NO‐NOS system and its effects on the hypothalamic NO‐NOS system do not explain its ability to reduce luteinizing hormone releasing hormone secretion.
Neuropeptide Y Levels in Ethanol‐Naive Alcohol‐Preferring and Nonpreferring Rats and in Wistar Rats after Ethanol Exposure
Authors: Ehlers Cindy L. , Li Ting‐Kai , Lurneng Lawrence , Hwang Bang H. , Somes Christine , Jimenez Patricia , Mathé Aleksander A.
Published: May 2006

Neuropeptide Y (NPY) is a hexatriacontapeptide amide that is now well characterized as a neuromodulator in the central nervous system (CNS). When infused into the CNS, NPY produces both anxiolytic and orexigenic effects. NPY's anxiolytic effects appear to be mediated through receptors in the central amygdala, whereas its orexigenic effects are localized in discrete hypothalamic nuclei. Both food restriction and food deprivation produce increased levels of the pep‐tide in the hypothalamus that are ameliorated by refeeding. However, the effects of alcohol consumption/deprivation on NPY levels remain unknown. The present study sought to determine if brain NPY levels were affected by either alcohol exposure and/or correlated with genetic differences in preference for drinking alcohol. In the first experiment, NPY‐like immunoreactivity (NPY‐LI) was compared in alcohol‐naive, alcohol‐preferring (P), and nonpreferring (NP) rats. After tissue extraction, NPY‐LI was measured by radioimmunoassay: amygdala, hippocampus, frontal cortex, hypothalamus, and caudate. P rats were found to have significantly lower NPY‐LI in amygdala (F= 4.69, p 0.04), hippocampus (F= 7.03, p < 0.01), and frontal cortex (F= 4.7, p < 0.04), compared with NP rats. In the second experiment, heterozygous Wistar rats were exposed to alcohol for 14 hr/day for 7 weeks in alcohol vapor chambers (mean blood alcohol concentrations =180 mg%) or control chambers. At 7 weeks of alcohol exposure, no significant changes in NPY‐LI in were found. At 1 month after ethanol withdrawal, however, the ethanol‐exposed animals had significantly higher NPY‐LI in the hypothalamus (F= 4.78, p < 0.04) when compared with the nonexposed controls. Taken together, these studies suggest that exposure to chronic ethanol may affect NPY‐LI at the level of the hypothalamus in a fashion similar to food restriction, because 4 weeks after alcohol withdrawal, significantly higher NPY levels are found. In addition, differences in NPY‐LI in limbic areas and frontal cortex between alcohol‐naive P and NP rats suggest that NPY may also play a role in risk for the development of alcohol preference either by modulating the “tension‐reduction” properties of alcohol or by influencing consummatory behaviors.
Five‐Shot Questionnaire on Heavy Drinking
Authors: Seppä Kaija , Lepistö Jaana , Sillanaukee Pekka
Published: May 2006

To develop an effective, but short, questionnaire to detect heavy drinking, we combined two questions from AUDIT and three from CAGE. We have tested earlier this new Five‐Shot questionnaire among male alcoholics who all had a total score of at least 4/7. The purpose of the present study was to find out the effectiveness of the Five‐Shot questionnaire among middle‐aged men. In the present study, the Five‐Shot questionnaire was distributed to all (n= 853) 40‐year‐old men attending health screening in a Finnish town. The participation percentage in the screening was 70.3%. Self‐reported alcohol consumption was used as a gold standard; 557 of these men gave a self‐report that they consumed less absolute alcohol than 140 g/week (moderate drinkers), and 70 reported consuming ≥280 g/week (heavy drinkers). None of the individual Five‐Shot questions was superior to any other in detecting heavy drinkers. The cut‐off point ≥3 for Five‐Shot gave a 77% sensitivity in detecting heavy drinkers, with a specificity of 83% and an overall accuracy of 83%. The corresponding figures with ≥2.5 cut‐off were 96%, 76%, and 78%. The commonly used cut‐off for CAGE, ≥2, gave a result of 47%, 87%, and 83%, respectively. The area under the receiver operating characteristic curve for the CAGE was clearly worse, compared with that of the Five‐Shot. The new Five‐Shot questionnaire seems to be efficient in differentiating between moderate and heavy drinkers. It is also easy and fast for physicians to use in different health‐care settings. Thus, it can serve as a good aid in early detection of heavy drinking.
The AUDIT Alcohol Consumption Questions: Reliability, Validity, and Responsiveness to Change in Older Male Primary Care Patients
Authors: Bradley Katharine A. , McDonell Mary B. , Bush Kristen , Kivlahan Daniel R. , Diehr Paula , Fihn Stephan D.
Published: May 2006

Objectives: To determine the reliability, validity, and responsiveness to change of AUDIT (Alcohol Use Disorders Identification Test) questions 1 to 3 about alcohol consumption in a primary care setting. Patients: Randomly selected, male general medical patients (n= 441) from three VA Medical Centers, who had 5 or more drinks containing alcohol in the past year and were willing to be interviewed about their health habits. Measures: Three self‐administered AUDIT consumption questions were compared with a telephone‐administered version of the trilevel World Health Organization interview about alcohol consumption. Results: Of 393 eligible patients, 264 (67%) completed interviews. Test‐retest reliability—Correlations between baseline and repeat measures 3 months later for four dimensions of consumption according to the AUDIT, ranged from 0.65 to 0.85, among patients who indicated they had not changed their drinking (Kendall's Tau‐b). Criterion validity—Correlations between AUDIT and interview for four dimensions of alcohol consumption ranged from 0.47 to 0.66 (Kendall's Tau‐b). Discriminative validity—The AUDIT questions were specific (90 to 93%), but only moderately sensitive (54 to 79%), for corresponding criteria for heavy drinking. Responsiveness to change—The AUDIT consumption questions had a Guyatt responsiveness statistic of 1.04 for detecting a change of 7 drinks/week, suggesting excellent responsiveness to change. Conclusions: AUDIT questions 1 to 3 demonstrate moderate to good validity, but excellent reliability and responsiveness to change. Although they often underestimate heavy alcohol consumption according to interview, they performed adequately to be used as a proxy measure of consumption in a clinical trial of heavy drinkers in this population.
Mechanism of HIV Pathogenesis: Role of Superantigens in Disease
Authors: Torres Barbara A. , Tanabe Taishi , Subramaniam Prem S. , Yamamoto Janet K. , Johnson Howard M.
Published: May 2006

Initial infection with human immunodeficiency virus (HIV) results in a burst of viremia and an ensuing spread of virus to secondary lymphoid organs, after which a “latency” period occurs with little or no virus detectable in the circulation. The term latent period has been shown to be a misnomer, because substantial viral replication occurs during this time in lymph nodes, although clinically there appears to be few symptoms of disease. However, a telling indicator of active infection during this period is the initiation of decline in CD4+ T‐cell numbers. A number of hypotheses have been postulated for the mechanism(s), as of yet not fully elucidated, by which T cells are depleted. Although quiescent cells can be infected, it has been shown that replication of HIV in CD4+ T cells requires cellular activation. The levels of viremia early in infection indicate that a large number of cells are actively infected, further suggesting that a mechanism must exist by which HIV activates a large pool of cells and ultimately causes their depletion. One possible mechanism for activation would be the presence of an HIV‐encoded superantigen. Superantigens are proteins that are polyclonal stimulators of CD4+ T lymphocytes. This occurs as a result of their ability to form a trimo‐lecular complex with MHC class II molecules on antigen‐presenting cells and the Vβ‐specific region on the T‐cell receptor. Thus, superantigen activation of T cells is antigen‐nonspecific. The prototype superantigens are the staphylococcal enterotoxins. Putative viral superantigens include a protein from mouse mammary tumor virus and related retroviruses, rabies nucleocapsid, and the Nef protein of HIV. Nef is required for optimal HIV pathogenesis, and this may be due to its superantigen properties, where CD4 cells are transformed to the activated state for virus replication.
Tumor Necrosis Factor and Alcoholic Liver Disease
Authors: McClain Craig J. , Barve Shirish , Barve Swati , Deaciuc Ion , Hill Daniell B.
Published: May 2006

Increased levels of hepatic and serum tumor necrosis factor (TNF) have been documented in animal models of alcoholic liver disease and in human alcoholic liver disease. This dysregulated TNF metabolism has been postulated to play a role in many of the metabolic complications and the liver injury of alcoholic liver disease. One potential therapy for alcoholic liver disease may be agents that down‐regulate TNF production or block TNF activity. Indeed, agents such as prostaglandins and glucocorticoids (both inhibit TNF production) have been used in both human liver disease and experimental models of liver injury, and anti‐TNF antibody has recently been shown to attenuate the hepatotoxicity in an animal model of alcoholic‐related liver disease. In this study, we demonstrate that a simple ex vivo system can be used to initially assess potential efficacy of anticytokine agents when administered to humans. Both prednisone and a prostaglandin analog were effective in downregulating TNF and interleukin‐8 production. The liver is normally resistant to TNF cytotoxicity. Sensitivity to TNF cytotoxicity is thought to occur when there is inadequate production of hepatic protective factors. In this study, we showed that, when patients with acute alcoholic hepatitis were matched with trauma patients for serum levels of interleukin‐6, they had similar depressions in the negative acute phase protein, albumin, but markedly different increases in the major acute phase protein, C reactive protein. Patients with alcoholic hepatitis had a very blunted response. We also showed that inhibiting activation of the redox sensitive transcription factor NFKB sensitizes to TNF‐induced hepatocyte death in vitro. This transcription factor is important for the production of both cytokines and many acute phase protective factors. Several hepatic protective factors are induced by TNF. One possible mechanism for liver injury in alcoholic hepatitis may be inadequate generation of hepatic protective factors. Our future understanding of mechanisms of alcoholic liver disease will involve understanding the balance between noxious and protective factors in the liver, and this should lead to rational therapy for this disease process.
Alveolar Macrophage Release of Tumor Necrosis Factor‐α in Chronic Alcoholics without Liver Disease
Authors: Omidvari Karan , Casey Richard , Nelson Steve , Olariu Ruxandra , Shellito Judd E.
Published: May 2006

Alcohol is an immunosuppressive drug, and chronic abuse has been associated with increased susceptibility to a variety of infections, including bacterial pneumonia and tuberculosis. Alveolar macrophages are the resident phagocytes of the lung and play a central role in lung host defenses against infection ranging from direct antibacterial activity to the release of proinflammatory cytokines such as tumor necrosis factor‐α (TNFα). TNFα, in particular, plays a key role in the development of the early inflammatory response. In this study, we investigated the effects of chronic alcohol consumption on alveolar macrophage release of TNFα in vitro. We prospectively studied lipopolysaccharide (LPS)‐stimulated release of TNFα from alveolar macrophages obtained from bronchoalveolar lavage fluid (BALF) in 22 alcoholic (18 smokers, 4 nonsmokers) and 7 nondrinking healthy volunteers (3 smokers, 4 nonsmokers). The total number of cells recovered by bronchoalveolar lavage (BAL) and their differential distribution were not significantly different in alcoholics versus controls (43 ± 8 × 106 and 39 ± 13 × 106, respectively). However, the total number of cells recovered from BALF was significantly higher in smokers (51 ± 8 × 106) than in nonsmokers (19 ± 5 × 108). Spontaneous (basal) release of TNFα by alveolar macrophages was the same in alcoholics and controls. In contrast, LPS‐stimulated release of TNFα was significantly suppressed in alcoholics compared with that of controls (1343 ± 271 vs. 3806 ± 926 U TNF/ml/106 cells, respectively, p < 0.015). When controlled for smoking, LPS‐stimulated TNFα production was suppressed in alcoholic nonsmokers (563 ± 413 U TNF/ml/106) compared with control nonsmokers (5113 ± 1264 U TNF/ml/106). LPS‐stimulated TNFα production was also less in control smokers (2063 ± 386 U TNF/ml/106 cells) than in control nonsmokers (5113 ± 1264 U TNF/ml/106 cells). There was no difference in TNFα production between smoking alcoholics and smoking control subjects. We conclude that chronic alcohol consumption significantly suppresses LPS‐stimulated alveolar macrophage production of TNFα. This effect is obscured if the subject also smokes. Because TNFα production is an important element in host defense, this may explain, in part, the susceptibility of chronic alcohol abusers to a variety of infections.
Preference for Higher Sugar Concentrations and Tridimensional Personality Questionnaire Scores in Alcoholic and Nonalcoholic Men
Authors: Kampov‐Polevoy Alexey B. , Garbutt James C. , Davis C. E. , Janowsky David S.
Published: May 2006

Animal studies have shown a positive association between the consumption of high concentrations of sweet solutions and subsequent alcohol intake. In a previous clinical study, it was shown that a preference for a high (0.83 M) concentration of sucrose (sweet liking) is characteristic of alcoholics, compared with controls. The present study was designed to determine whether personality variables, reported to be associated with subtypes of alcoholism, differentiate sweet liking alcoholics from sweet liking controls. Fifty‐two male controls and 26 alcoholic patients were tested for sweet preference and administered the Tridimensional Personality Questionnaire. Sweet liking alcoholics scored significantly higher on the Tridimensional Personality Questionnaire Novelty Seeking and Harm Avoidance scales and related subscales when compared with sweet liking controls. Further analysis showed that preferred sucrose concentration, Harm Avoidance score, and Novelty Seeking predicted alcoholic versus nonalcoholic group status at 65% sensitivity and 94% specificity, with a correct classification in 85% subjects. We hypothesize that sweet liking may identify a specific alcoholism subtype also characterized by high novelty seeking and high harm avoidance. These findings may have theoretical biological significance and practical clinical implications.
Usefulness of Carbohydrate‐Deficient Transferrin in Alcoholic Patients with Normal γ‐Glutamyltranspeptidase
Authors: Reynaud Michel , Hourcade Florence , Planche François , Albuisson Eliane , Meunier Marie‐Nadia , Planche Roger
Published: May 2006

The biological diagnosis of alcoholism is conducted routinely by assay of γ‐glutamyltranspeptidase (GGT) and mean corpuscular volume (MCV). However, their low specificity and sensitivity have prompted research to find other more reliable parameters. Stibler showed an increase in desialylated transferrin [carbohydrate‐deficient transferrin (CDT)] in alcoholic patients. The normal value of the serum CDT concentration is under 60 mg/liter; a value between 60 and 100 mg/liter indicates probable alcoholism, and a value >100 mg/liter indicates a very high probability of alcoholism (specificity: 99%). Its sensitivity ranges from 60 to 91%, and its specificity ranges from 92 to 100%. Its half‐life is 17 ± 4 days. CDT is thus a useful laboratory marker, but its assay is costlier and more complex than that of GGT. This study concerns 31 alcohol‐dependent patients as defined by DSM‐IV, with GGT levels in the normal range. It evaluates CDT at day 0 and its time course after 15 days withdrawal. GGT and MCV were assayed concomitantly. Remarkably, the results show a sensitivity of 83.9 (26 positives of 31) in this particular population and a specificity of 92.2. The fall in CDT after 15 days withdrawal was 36%. CDT is thus a particularly useful marker for the diagnosis and follow‐up of alcoholics with normal GGT levels.
Carbachol‐Stimulated Ca2+ Increase in Single Neuroblastoma SH‐SY5Y Cells: Effects of Ethanol
Authors: Larsson Christer , Thomas Andrew P. , Hoek Jan B.
Published: May 2006

The effect of ethanol on the characteristics of carbachol‐stimulated release of Ca2+ from intracellular Ca2+ stores was studied in single SH‐SY5Y cells. Stimulation with carbachol, in the absence of extracellular Ca2+, elicited a rapid Ca2+ increase in SH‐SY5Y cells peaking within seconds after addition of maximal agonist concentration. The Ca2+ response pattern in single cells resembled the population response, and there was no evidence of oscillatory changes in cytosolic [Ca2+] ([Ca2+]i). However, cell‐to‐cell variability could be detected in the magnitude and the latency time of the response, and in the rate of [Ca2+]i increase. In a carbachol dose‐response analysis, the EC50 for the number of responsive cells and for the peak [Ca2+]i response was lower than that for carbachol‐induced inositol 1,4,5‐trisphosphate formation by a factor of 5 to 50. Ethanol (100 mM) caused a significant suppression of the number of responsive cells, but only when cells were stimulated with nonsaturating carbachol concentrations (1 and 10 μM). The suppression by ethanol was evident primarily in those cells that gave a Ca2+ response after several seconds of stimulation, whereas cells that responded within the initial seconds of receptor stimulation remained relatively unaffected. In responding cells stimulated with 10 μM carbachol, ethanol exposure also suppressed the maximal Ca2+ increase primarily in those cells that responded late. We suggest that ethanol suppression of muscarinic receptor‐mediated signal transduction through the phospholipase C pathway may depend on the potentiation of feedback inhibition that requires receptor stimulation.
Prenatal Ethanol Exposure Differentially Alters Behavior in Males and Females on the Elevated Plus Maze
Authors: Osborn J. A. , Kim C. K. , Steiger J. , Weinberg J.
Published: May 2006

Rodents prenatally exposed to ethanol demonstrate hypothalamic‐pituitary‐adrenal and behavioral hyperactivity to a variety of stressful situations. The present study examined both behavioral and corticosterone (CORT) responses to the elevated plus maze (+‐maze), an anxiety‐ or fear‐provoking task. Sprague‐Dawley male and female offspring from fetal ethanol‐exposed (E), pair‐fed (PF), and ad libitum‐fed control (C) groups were tested at 60 to 90 days of age. In experiment 1, behavior was measured in animals exposed to the +‐maze for 5 min on two consecutive days; 2 weeks later, both behavioral and CORT responses were measured in animals confined to the open and closed arms of the maze for 20 min. In experiment 2, animals were placed in an open field (OF) for 5 min before a single 5‐min exposure to the +‐maze. Factor analysis of the scored behaviors from the two experiments indicated two main factors, designated “exploration” and “fear.” E males and females both exhibited higher levels of exploratory behaviors when placed directly on the +‐maze from their homecages without prior exposure to the OF, compared with C males and females. In addition, when confined to the closed arms of the +‐maze, E males and females demonstrated higher levels of activity, compared with C males and females. After OF exposure, however, both E males and females demonstrated lower levels of exploratory behaviors than C males and females, and E females also had increased CORT levels, compared with PF and C females. Interestingly, E females, but not E males, showed an increase in fear‐related behaviors on the +‐maze, compared with controls, regardless of prior OF exposure. These data demonstrate that prenatal ethanol exposure may differentially affect both behavioral and hormonal responses of males and females in an aversive behavioral task and suggest that there may be a sex difference in the sensitivity of the mechanism(s) underlying these responses.
Altered T‐Lymphocyte Responsiveness to Polyclonal Cell Activators Is Responsible for Liver Cell Necrosis in Alcohol‐fed Rats
Authors: Cao Q. , Batey R. , Pang G. , Clancy R.
Published: May 2006

The role of T‐cell activation in alcoholic liver disease was investigated in rats fed alcohol and subsequently exposed to concanavalin A (Con A). Following Con A injection (20 mg/kg body weight), greater increases in liver‐to‐body weight ratio and ALT levels were observed at 12 and 24 hr in rats fed ethanol, compared with control rats fed sucrose. Furthermore, increases in serum interleukin‐6 and tumor necrosis factor‐α levels were noted in ethanol‐fed rats, with maximal levels detected at 4 hr declining thereafter, but remaining above control levels at 24 hr. Analysis of T‐cell subpopulations showed an increased percentage of CD4+, CD5+, and CD8+ T cells in blood from all groups, but not in liver perfusate. In contrast, a significant increase in the percentage of activated CD25+ T cells was detected in both blood and liver perfusate from rats fed ethanol even 24 hr after Con A injection. When CD4+ and CD8+ T cells from liver perfusate were cultured in the absence or presence of Con A, an increase in interleukin‐6 and tumor necrosis factor‐α production in supernatants was observed in ethanol‐fed rats. In cultures stimulated with Con A, a 2‐ to 8‐fold increase in cytokine production was detected, with intrahepatic CD4+ T cells being the major source. Immunohistological analysis revealed infiltration of CD4+ T cells around portal vein and central vein areas associated with fatty liver and severe hepatic necrosis. The results suggest that alcohol consumption induced a dysregulated T‐cell population that mediated hepatic necrosis following polyclonal activation with Con A.
Modeling the Distribution and Consequences of Alcohol Consumption
Authors: Gruenewald Paul J.
Published: May 2006

This paper is based on the session “Modeling the Distribution and Consequences of Alcohol Consumption” that was held on May 12‐14, 1997 at the International Workshop on Consumption Measures and Models for Use in Policy Development and Evaluation, Bethesda, MD. The session chair was Paul J. Gruenewald; presenters were Timo Alanko, Bryan Johnstone, Paul J. Gruenewald, Susan Bondy, Thomas Harford, Raul Caetano, and Maria Elena Medina‐Mora; and the discussants were Jiirgen Rehm and Bryan Johnstone.
Moderate Alcohol Consumption and Cardiovascular Disease: Is There Evidence for a Preventive Effect?
Authors: Svärdsudd Kurt
Published: May 2006

It is well‐known that the intake of large quantities of alcohol is hazardous to the health. During the last few decades, moderate alcohol consumption has been claimed to have a protective effect in the cardiovascular system. For this study, literature search and review on moderate alcohol consumption and cardiovascular disease was performed. Data from ecological studies indicate that the consumption of wine, but not hard liquor or beer, are associated with a reduced mortality from cardiovascular diseases. Data from case‐referent studies indicate no beneficial effect at all, whereas data from prospective cohort studies indicate a beneficial effect from all types of alcohol. There are several interpretational problems involved in this issue. No results from interventional studies are available. In the absence of such data, less valid conclusions are drawn from other types of studies. The soundness of conclusions based on comparisons of moderate drinkers and abstainers in case‐referent and cohort studies has been questioned, because abstainers may have a higher than normal incidence of cardiovascular disease due to self‐selection. Several possible modes of action have been proposed. However, provided that there is a protective effect of moderate alcohol consumption, there is no hard evidence that any of the proposed modes of action would be the sole one. Probably more than one mechanism is involved.
Alcohol and J‐Shaped Curves
Authors: Andréasson Sven
Published: May 2006

Many studies report J‐ or U‐shaped curves in describing the association between level of alcohol consumption and mortality. J‐shaped curves may, however, be the result of complex associations between psychosocial and other confounding factors and health, rather than a simple causal association derived from the biological effects of alcohol. In this review, nine methodological issues are discussed: age and sex, causes of death, characteristics of abstainers, drinking pattern, smoking, diet, physical activity, social support and personality, and psychopathology.
Mutation of Putative Phosphorylation Sites in the 5‐Hydroxytryptarnine3Receptor Does Not Eliminate Its Modulation by Ethanol
Authors: Machu Tina K. , Coultrap Steven J. , Waugh M. Denae' , Hamilton Margaret E.
Published: May 2006

The function of the 5‐hydroxytryptamine3(5‐HT3) receptor is enhanced by ethanol, but the amino acid residue(s) that confers sensitivity to ethanol remains to be identified. Phosphorylation of the related GABAAreceptor has been implicated in conferring its sensitivity to ethanol. In common with the GABAAreceptor, the 5‐HT3receptor contains multiple consensus sites for protein kinases. To evaluate the possibility that phosphotylation of the 5‐HT3receptor underlies its ethanol sensitivity, we examined the ability of ethanol to enhance 5‐HT‐mediated currents in a mutant 5‐HT3receptor containing no intracellular serines, threonines, or tyrosines. Mutation of these 13 residues in the intracellular loops produced a modest leftward shift in the 5‐HT concentration response curve, with the EC50's for 5‐HT decreasing from 0.839 ± 0.03 μM in the wild‐type receptor to 0.713 ± 0.03 μM in the mutant receptor. Cooperativity of the 5‐HT binding sites was enhanced by the mutations, with Hill coefficients of 2.92 for the wild‐type receptor and 3.74 for the mutant receptor, respectively. In oocytes expressing mutant receptors, ethanol (50 to 200 mM) enhanced the currents produced by low concentrations of 5‐HT by ∼5 to 45%, which was not statistically different from the potentiation produced by ethanol in wild‐type receptors. These results suggest that ethanol enhancement of the 5‐HT3receptor function does not require receptor phosphorylation.
Effects of Prenatal Exposure to Alcohol on the Release of Adenocorticotropic Hormone, Corticosterone, and Proinflammatory Cytokines
Authors: Kim C. Kwon , Turnbull Andrew V. , Lee Soon Y. , Rivier Catherine L.
Published: May 2006

Prenatal alcohol exposure has been shown to produce hyperresponsiveness of the hypothalamic‐pituitary‐adrenal (HPA) axis to immune challenges. Because cytokines, which are released in response to immune challenges, are known to activate the HPA axis, this study determined whether altered release of cytokines contribute to the HPA hyperresponsiveness to immune challenges observed after prenatal alcohol exposure. Pregnant dams were exposed to alcohol vapors (6‐7 hr daily) between days 7 and 18 of gestation. At postnatal days 45 and 60, control (C) and prenatal alcohol‐exposed (E) offspring were subjected to three different types of immune challenges: injections of interleukin‐1β or endotoxin (lipopolysaccharide), or turpentine‐induced tissue injury. We observed the expected higher plasma adrenocorticotropic hormone and corticosterone levels in E compared with C rats, and this HPA hyperresponsiveness was greater in E females compared with E males. Plasma tumor necrosis factor‐α or interleukin‐6 responses were comparable in the C and E groups. Females exhibited significantly higher corticosterone, tumor necrosis factor‐α, and interleukin‐6 responses than males. These results indicate that (1) prenatal alcohol exposure produces HPA hyperresponsiveness to immune challenges; (2) prenatal alcohol treatment does not influence the release of cytokines to immune challenges; and (3) there are gender differences in the secretory pattern of corticosterone and cytokines to immune challenges. Therefore, these data do not support the hypothesis that cytokines play a role in the hyperresponsiveness of the HPA axis to immune challenges observed after prenatal alcohol exposure.
Ethanol‐Induced Apoptosis to Stable HepG2 Cell Lines Expressing Human Cytochrome P‐4502E1
Authors: Wu Defeng , Cederbaum Arthur I.
Published: May 2006

In a previous study (Wu and Cederbaum, J. Biol. Chem. 271:23914‐23919, 1996), ethanol was shown to be cytotoxic to HepG2 cells, which were transduced to express human cytochrome P‐4502E1 (CYPPE1) but not to control HepG2 cells. The goal of the current study was to evaluate whether this toxicity was apoptotic in nature. Incubation of CYP2E1‐expressing HepG2 cells with 100 mM ethanol for 2 days produced morphological changes and DNA fragmentation (in situ labeling, flow cytometry, and DNA ladder formation) indicative of apoptosis. No changes were observed in the control HepG2 cells that do not express CYPPE1. Ethanol‐induced apoptosis was also observed in HepG2 cells transiently transfected to express CYPPE1. The ethanol‐induced apoptosis was prevented by 4‐methylpyrazole, an inhibitor of ethanol oxidation by CYPPE1, and by trolox, an anti‐oxidant that prevents lipid peroxidation. Ethanol treatment of the cells expressing CYP2E1 resulted in increased activities of caspases 1 and 3. An inhibitor of these caspases prevented the ethanol‐induced apoptosis in the stable cell lines and the transiently transfected cell lines. Ethanol did not cause apoptosis in a HepG2 cell line overexpressing bcl‐2 plus CYPPE1, but did cause apoptosis in cell lines expressing CYPPE1 in the absence of bcl‐2. These experiments demonstrate that ethanol can produce apoptosis in HepG2 cells that express CYPPE1. Increased production of reactive oxygen species and lipid peroxidation can be associated with apoptotic cell death. The prevention of the ethanol‐induced apoptosis by 4‐methylpyrazole and by trolox suggests that production of a prooxidative state as a consequence of ethanol oxidation by CYP2E1 results in eventual activation of caspases such as caspases 1 and 3, which can trigger the apoptotic process.
Role of Protein Kinase C in Ethanol‐Induced Activation of Adenylyl Cyclase
Authors: Rabbani Mohammed , Nelson Eric J. , Hoffman Paula L. , Tabakoff Boris
Published: May 2006

Ethanol is known to enhance the activity of adenylyl cyclase (AC) in a number of cells and tissues. Recent work has suggested that the various isoforms of AC show differential sensitivity to ethanol, with Type VII AC being most sensitive. However, the mechanism of action of ethanol is unclear. In the present work, we investigated the effect of ethanol on AC activity in the human erythroleukemia (HEL) cell line, platelets, and AC VII‐transfected HEK 293 cells. The HEL cells contain abundant amounts of mRNA for Type VII AC. We found that both ethanol and phorbol dibutyrate (PDBu) treatment enhanced agonist (prostaglandin E1; PGE1)‐stimulated AC activity in HEL cells, as well as in platelets and HEK 293 cells transfected with AC VII. Inhibitors of protein kinase C (PKC) blocked the stimulatory effects of both ethanol and PDBu. However, the effects of ethanol and PDBu on AC activity were additive, suggesting that the mechanisms of action of ethanol and PDBu were not identical. Furthermore, a 30‐min exposure of HEL cells to ethanol attenuated (desensitized) the ability of ethanol, but not PDBu, to enhance agonist‐activated AC activity. On the other hand, a 30‐min pretreatment with PDBu attenuated the AC response to the phorbol ester, but not to ethanol; but, after a 20 hr preincubation with phorbol ester, the ability of both PDBu and ethanol to enhance prostaglandin E1‐stimulated AC activity was completely eliminated. Finally, pretreatment of HEL cells with pertussis toxin blocked the effect of PDBu, but not ethanol, on AC activity. The results support the involvement of phorbol ester‐sensitive PKC(s) in ethanol's enhancement of agonist‐activated activity of AC in HEL cells, but suggest that the mechanism of ethanol's action is different from that of PDBu. The findings with pertussis toxin suggest that PDBu activation of PKC(s) may affect AC activity through phosphorylation of a G1 protein, whereas ethanol may act by promoting phosphorylation of a different substrate (e.g., AC VII).