bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced Alloreactive T‐Cell Activation After Alcohol Intake is Due to Impaired Monocyte Accessory Cell Function and Correlates With Elevated IL‐10, IL‐13, and Decreased IFNγ Levels
Authors: Szabo Gyongyi , Mandrekar Pranoti , Dolganiuc Angela , Catalano Donna , Kodys Karen 
Published: April 2006

Background: Immunosuppression associated with chronic alcohol use is characterized by reduced antigen‐specific T‐cell response and impaired delayed type hypersensitivity. Increasing evidence suggests in chronic alcohol consumption models that reduced antigen‐specific T‐cell proliferation is due to insufficient accessory cell function. Accessory cell function, a critical step in recognition of viral antigens, is reduced in chronic hepatitis C. The severity of hepatitis C is increased by alcohol consumption. Thus, we investigated the effects of alcohol consumption on accessory cell activity of monocytes in supporting alloreactive T‐cell proliferation.Methods: Alloreactive T‐cell proliferation was evaluated in a one‐way mixed lymphocyte reaction (MLR). Mononuclear cells were isolated by Ficoll density gradient and monocytes by adherence. Alcohol (0.8 g/kg body weight, an equivalent of approximately three drinks) was given to nonalcohol‐consuming individuals and blood samples were collected before, 4 hr, or 18 hr after alcohol consumption. Alcohol in vitro was administered at concentrations of 25–100 mM.Results: T‐cell proliferation in MLR was significantly reduced in the presence of physiologically relevant concentrations of alcohol in vitro (25–100 mM ethanol) (p < 0.05). In vivo alcohol consumption also depressed proliferation in the MLR when stimulator cells were obtained 4 hr after alcohol consumption. MLR was not decreased, however, in the presence of alcohol‐exposed responder cells and normal stimulator cells, suggesting that the accessory cell population and not T cells are affected by alcohol. Decreased accessory cell function was further evidenced by reduced superantigen‐induced (SEB) but not mitogen‐induced (PHA) T‐cell proliferation in samples obtained 18 hr after alcohol intake (35% reduction). Reduced accessory cell function was not due to changes in surface expression of monocyte costimulatory molecules (HLA class I, HLA‐DR, CD80, CD86, CD40). We found reduced IFNγ, elevated IL‐10, and unchanged IL‐4 levels during T‐cell proliferation in samples obtained 18 hr after alcohol consumption. Acute alcohol treatment resulted in increased IL‐13 in the MLR.Conclusion: These data suggest that even on one occasion moderate alcohol intake can reduce allostimulatory T‐cell activation via decreasing accessory cell function. Increased IL‐10 and IL‐13 plus the reduced IFNγ production after acute alcohol use are likely to contribute to both the reduced T‐cell proliferation and monocyte accessory cell function. These accessory cell mediated defects in T‐cell activation may result in impaired antiviral and antitumor immunity after moderate acute alcohol use.
Association of the ADH2*3 Allele With A Negative Family History Of Alcoholism in African American Young Adults
Authors: Ehlers Cindy L. , Gilder David A. , Harris Lilach , Carr Lucinda 
Published: April 2006

Background: Two of the class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode for multiple isozymes that differ in their kinetic properties. Polymorphisms at both of these gene loci have been linked to alcoholism and/or alcohol‐induced disabilities in some populations. At the ADH2 locus, three polymorphisms are present (ADH2*1, ADH2*2, ADH2*3). ADH2*3 allele codes for a high Km and Vmax variant that has been reported to occur exclusively in African Americans and some tribes of Native Americans. In African Americans, the presence of the ADH2*3 allele is associated with protection from alcohol‐related birth defects. However, its relationship to risk for alcoholism in African Americans remains relatively unexplored.Methods: The participants were 97 African American young adults (18–25 years old). A structured interview was used to gather information on demographics, psychiatric diagnoses, personal drinking and drug use history, and familial history of alcohol use disorders. A blood sample was obtained from each participant and leukocyte DNA extracted and genotyped for the presence of ADH2*3 alleles. The specific aim of the study was to investigate the associations between the presence of the ADH2* 3 allele and personal and family history of alcohol use/abuse.Results: Thirty participants (31%) had at least one ADH2*3 allele and two were homozygous for the allele. A significant association between the presence of an ADH2*3 allele and a negative family history of alcoholism was uncovered (p < 0.04). No significant associations of an ADH2*3 allele with personal history of alcohol use disorders or with current drinking were found ; however, power to detect associations was limited in this population because half the population did not drink regularly.Conclusions: Because family history of alcoholism is one of the best predictors of the development of alcohol use disorders, this pilot study suggests that, in this sample of African American young adults, the ADH2*3 allele may be associated with a lowered risk for the development of alcoholism.
Polyphenolics Increase t‐PA and u‐PA Gene Transcription in Cultured Human Endothelial Cells
Authors: Abou‐Agag Laila H. , Aikens Michael L. , Tabengwa Edlue M. , Benza Raymond L. , Shows Stephen R. , Grenett Hernan E. , Booyse Francois M. 
Published: April 2006

Background: Moderate red wine consumption has been associated with a reduced risk for coronary heart disease, and this cardioprotection may be mediated, in part, by promoting fibrinolysis. This protection may be attributed to the combined or perhaps synergistic effects of alcohol and other red wine components (i.e., polyphenolics). These studies were carried out to determine whether individual phenolics (i.e., catechin, epicatechin, quercetin, and resveratrol) affect fibrinolytic protein (tissue‐type plasminogen activator [t‐PA] and urokinase‐type PA [u‐PA]) e‐pression and surface‐localized fibrinolytic activity in cultured human umbilical vein endothelial cells (HUVECs).Methods: Cultured HUVECs were preincubated (1 hr, 37°C) in the absence or presence of varying concentrations of catechin, epicatechin, quercetin, and resveratrol (0.001–10 μM) and then were washed and incubated for various times in the absence of phenolics. Secreted t‐PA/u‐PA antigen (24 hr, enzyme‐linked immunoadsorbent assay) and mRNA [0–16 hr, reverse transcription‐polymerase chain reaction(RT‐PCR)] levels and fibrinolytic activity (direct activation of HUVEC‐bound 125I‐labeled glutamyl‐plasminogen, quantitation of 125I‐labeled M r 20 kDa plasmin light‐chain) were measured. Transient transfections of cultured HUVECs were carried out with the pt‐PA222/luc and pu‐PA236/luc promoter constructs, by using lipofectamine.Results: Each of the phenolics similarly increased t‐PA and u‐PA antigen (2‐ to 3‐fold) and mRNA (3‐ to 4‐fold) levels, concomitant with an increase (2‐ to 3‐fold) in sustained (24 hr), surface‐localized fibrinolytic activity. Transcription inhibitor actinomycin D abolished the induction of t‐PA and u‐PA mRNA e‐pression by these phenolics. Transfections with the pt‐PA222/luc and pu‐PA236/luc promoter constructs showed 2‐ to 3‐fold and 2‐ to 4‐fold increases in luciferase activity for t‐PA and u‐PA, respectively.Conclusions: These results demonstrate that each of these phenolics up‐regulates both t‐PA and u‐PA gene transcription, which results in the sustained increased e‐pression of surface‐localized fibrinolytic activity in cultured HUVECs. Wine phenolics increase fibrinolytic activity, independent of ethanol, and it is likely that the overall cardioprotective benefits associated with moderate red wine consumption are attributable to the combined, additive, or perhaps synergistic effects of alcohol and other wine components.
fMRI Measurement of Brain Dysfunction in Alcohol‐Dependent Young Women
Authors: Tapert Susan F. , Brown Gregory G. , Kindermann Sandra S. , Cheung Erick H. , Frank Lawrence R. , Brown Sandra A. 
Published: April 2006

Background: Studies of brain functioning in alcohol‐dependent adults have produced varied results but generally suggest that alcohol affects brain functioning and that relatively short durations of heavy drinking may adversely affect women. It remains unclear when in the course of alcohol dependency and at which developmental stage these brain changes emerge. Our neuropsychological studies have indicated that drinking‐related neurocognitive effects occur as early as adolescence (Brown et al., 2000; Tapert & Brown, 1999). This study seeks to characterize brain regions that subserve the affected neurocognitive functions.Methods: Alcohol‐dependent young women (n= 10) were recruited from a longitudinal study of alcohol‐ and drug‐abusing youth, all of whom met criteria for alcohol dependence. Control participants (n= 10) had no history of alcohol or drug problems and were comparable with alcohol‐dependent participants on age (18–25 years), family history of alcohol use disorders, and education. After a minimum of 72 hr of abstinence, functional magnetic resonance imaging, neuropsychological, alcohol/drug involvement, and mood data were collected. Participants performed spatial working memory and vigilance tasks during functional magnetic resonance imaging acquisition to probe brain response.Results: Alcohol‐dependent women demonstrated significantly less blood oxygen level‐dependent response than controls during the spatial working memory task in the right superior and inferior parietal, right middle frontal, right postcentral, and left superior frontal cortex, after controlling for the baseline vigilance response.Conclusions: Working memory produces a larger neuronal response in some cortical regions than vigilance. Alcohol‐dependent women showed less differential response to working memory than controls in frontal and parietal regions, especially in the right hemisphere. Heavy, chronic drinking appears to produce adverse neural effects that are detectable by functional magnetic resonance imaging.
Azide Inhibits Human Cytochrome P‐4502E1, 1A2, and 3A4
Authors: Salmela Katja S. , Tsyrlov Ilya B. , Lieber Charles S. 
Published: April 2006

Background: Recently, we showed that, in addition to cytochrome P‐4502E1 (CYP2E1), CYP1A2 and CYP3A4 also contribute to the microsomal ethanol o‐idizing system (MEOS). When MEOS activity is measured, sodium azide commonly is used to block the contaminating catalase. However, although CYP2E1 is considered insensitive to azide, its effect on the other P‐450s is unknown. Therefore, the aim of the present study was to determine the effect of azide on human recombinant and hepatic CYP2E1, CYP1A2, and CYP3A4.Methods and Results : Concentrations of sodium azide as low as 0.1 mM markedly inhibited the specific ethanol o‐idation (mean ± SEM) by recombinant CYP1A2 and CYP3A4 e‐pressed in HepG2 cells (to 16 ± 1% and 22 ± 2% of control without azide, respectively;p < 0.01). By contrast, the specific activity of CYP2E1 was only slightly (and not significantly) inhibited at this azide concentration (to 79 ± 12% of control). Similarly, in human liver microsomes (n= 6), 0.1 mM azide strongly inhibited CYP1A2‐dependent (to 25 ± 2%) and CYP3A4‐dependent (to 15 ± 2%) ethanol oxidation, whereas CYP2E1 was inhibited only at 10 mM azide (to 60 ± 10%). Azide also strongly affected the apparent kinetic values of all three isoenzymes. Furthermore, azide inhibited the specific monooxygenase activities, both by recombinant and microsomal P‐450s. CYP2E1‐specific p‐nitrophenol hydroxylation was the most sensitive to azide, whereas CYP1A2‐dependent 7‐methoxyresorufin O‐ dealkylation was only slightly inhibited. Judging from its effect on p‐nitrophenol hydroxylation by human liver microsomes, the inhibition of azide was competitive (K i 0.09 mM).Conclusions: Sodium azide at a concentration as low as 0.1 mM inhibited ethanol o‐idation by CYP1A2 and CYP3A4. With CYP2E1, although o‐idation of 50 mM ethanol was not inhibited by 0.1 mM azide, higher azide concentrations were inhibitory and 0.1 mM azide seemed to affect the kinetics of ethanol o‐idation by CYP2E1. Therefore, azide should be avoided when measuring the MEOS activity because it may lead to underestimation, especially of CYP1A2‐ and CYP3A4‐dependent ethanol o‐idation.
Endotoxin, Endotoxin‐Neutralizing‐Capacity, sCD14, sICAM‐1, and Cytokines in Patients With Various Degrees of Alcoholic Liver Disease
Authors: Urbaschek Renate , McCuskey Robert S. , Rudi Volker , Becker Klaus‐Peter , Stickel Felix , Urbaschek Bernhard , Seitz Helmut K. 
Published: April 2006

Background: Chronic alcohol ingestion leads to endoto‐emia which is believed to play an important role in the pathogenesis of alcoholic liver disease (ALD). The purpose of this study was to determine if chronic ethanol consumption, in addition to affecting plasma endoto‐in and cytokines, also affects the endoto‐in‐neutralizing capacity (ENC), sCD14, and sICAM‐1, in patients with ALD. A second aim was to identify correlations between these latter parameters, endoto‐in, and cytokines, especially IL‐10.Methods: Hospitalized patients with various degrees of ALD (n= 59), and 20 healthy volunteers were studied. Plasma endotoxin and ENC were determined using our kinetic Limulus amebocyte lysate test. Cytokines, sCD14, and sICAM‐1 were measured by enzyme‐linked immunosorbent assay.Results: Patients with ALD e‐hibited a mild endoto‐emia (p < 0.01) and a marked decrease in ENC (p < 0.0002). TNF‐α (p < 0.05), IL‐6 (p < 0.0001), sICAM (p < 0.005), and sCD14 (p < 0.0005) were significantly elevated in all patients with ALD, and IL‐10 (p < 0.05) in patients with cirrhotic ALD. With the exception of IL‐10, the cytokines correlated with each other and with sICAM‐1. No correlations occurred between endotoxin, ENC, and sCD14, and between these and the cytokines and sICAM‐1. Elevated levels of endotoxin correlate with acute excessive alcohol ingestion. No gender differences were observed.Conclusions: Acute alcohol into‐ication rather than severe ALD results in significant endoto‐emia. The limited capacity of plasma to neutralize endoto‐in in liver injury seems to be an important factor in ALD which may be responsible for the release of endoto‐in‐induced mediators, such as cytokines, as well as s‐ICAM‐1, that are relevant in the pathogenesis of ALD.
Effects of SR141716A on Ethanol and Sucrose Self‐Administration
Authors: Freedland C.S. , Sharpe A.L. , Samson H.H. , Porrino L.J. 
Published: April 2006

Background: Previous studies have demonstrated that administration of central cannabinoid receptor (CB1) ligands can produce marked effects on ingestive behaviors. However, the possible relationship to ethanol self‐administration has not been fully examined. The present series of experiments was designed to characterize further the role of CB1 receptors in appetitive and consummatory behaviors related to sucrose and ethanol.Methods: To determine the relative contribution of CB1 receptors to ethanol seeking and consumption, a series of experiments was designed using the sipper‐tube model. In this paradigm, the appetitive and consummatory phases of ethanol and sucrose self‐administration are separated. In the appetitive phase, animals are required to complete a response requirement (16 lever presses) within 20 min. If the requirement is successfully completed, access to a sipper tube containing either sucrose or ethanol (consummatory phase) is made available for 20 min.Results: In the ethanol condition, the CB1 receptor antagonist SR141716A (0.3–3.0 mg/kg, ip) produced dose‐related decreases in the probability of response requirement completion without significantly affecting latency to first lever press or overall lever press rate. In the sucrose condition, SR141716A (0.3–3.0 mg/kg, ip) increased first lever press latency without affecting lever press rate. In the consummatory phase, SR141716A (0.3–3.0 mg/kg, ip) administration markedly decreased total intake and the total number of licks for both ethanol and sucrose.Conclusions: These data indicate that CB1 receptors are involved in mediating both appetitive and consummatory aspects of ingestive behaviors related to sucrose and ethanol.
Acute Effects of Ethanol on Behavior of Adolescent Rats: Role of Social Context
Authors: Varlinskaya Elena I. , Spear Linda P. , Spear Norman E. 
Published: April 2006

Background: First experiences with alcohol in humans occur predominantly in adolescence, and to a large extent the attractiveness of alcohol at this age is based on its ability to facilitate certain forms of social behavior (social facilitation). Adolescence is strongly marked by a focus on peer relationships, and the social nature of the situation plays an important role in responsiveness to alcohol. Peer‐directed social activity of adolescent rats may be a valuable experimental model for the study of ethanol‐induced changes in social behavior and assessment of the role of the social context in responsiveness to ethanol.Method: In the present study we used a modified dyad social interaction test to characterize acute effects of ethanol on different forms of social behavior (social investigation, contact behavior, and play) and social motivation (preference/avoidance of a peer) in adolescent rats. Ethanol effects on behavior directed toward a peer were compared with those induced by exposure to an inanimate novel object.Results: In the social context, the effects of ethanol were dose‐dependent and biphasic. Low doses of ethanol (0.25–0.75 g/kg) produced apparent social facilitation (increased social activity and enhanced social preference), whereas higher doses (3 and 4 g/kg) caused social inhibition (decreased social activity and avoidance of a peer). This pattern was not observed for a nonsocial stimulus: Although overall activity in the nonsocial context was suppressed by 2 and 3 g/kg of ethanol, 0.5 g/kg of ethanol did not activate overall activity directed to the inanimate object.Conclusions: These findings demonstrate that the social nature of the testing situation plays an important role in responsiveness to alcohol in adolescence, especially to its activating effects. The results suggest also that the study of ethanol effects on social behavior of adolescent rats may be an effective tool for the study of adolescent alcohol use and abuse.
Effect of Neuropeptide Y (NPY) on Oral Ethanol Intake in Wistar, Alcohol‐Preferring (P), and ‐Nonpreferring (NP) Rats
Authors: Badia‐Elder N.E. , Stewart R.B. , Powrozek T.A. , Roy K.F. , Murphy J.M. , Li T.‐K. 
Published: April 2006

Background: Neuropeptide Y (NPY) deficient mice consume more ethanol than controls, whereas NPY over‐expressing mice consume less ethanol than controls. Thus, ethanol drinking may be inversely associated with NPY activity. To determine whether exogenously administered NPY would alter ethanol intake, two experiments were conducted.Methods: A within‐subject design was used with intracerebroventricular (ICV) administration of NPY or artificial cerebral spinal fluid (aCSF) into the lateral ventricles. Infusions were separated by 2 to 7 days. In experiment 1, male Wistar rats (n= 10) were tested for the effects of NPY on an intake of 5% sucrose or 8% (w/v) ethanol during daily 2‐hr testing periods with food and water available at all other times. In experiment 2, male alcohol‐preferring (P) and alcohol‐nonpreferring (NP) rats (n= 8/line) were tested for the effects of NPY on 8% (w/v) ethanol intake.Results: In experiment 1, NPY (5, 10, 20 μg) significantly increased sucrose intake relative to aCSF baseline in Wistar rats, a finding consistent with previous observations of the orexigenic effects of the peptide. However, NPY (10 μg) did not alter ethanol intake in Wistar rats. In experiment 2, NPY (5 and 10 μg) significantly decreased ethanol intake in P rats, but not in NP rats.Conclusion: The reduction in ethanol intake seen with the P rats is consistent with the postulated negative relationship between NPY activity and ethanol intake. The lack of effect of NPY on ethanol intake in Wistar and NP rats may be related to the lower baseline levels of ethanol intake in these rats or to differential central nervous system basal NPY activity or sensitivity to the peptide.
Ethanol as a Reinforcer in the Newborn's First Suckling Experience
Authors: Cheslock Sarah J. , Varlinskaya Elena I. , Petrov Evgeniy S. , Silveri Marisa M. , Spear Linda P. , Spear Norman E. 
Published: April 2006

Background: Recent evidence suggests that human infants prefer alcohol‐flavored milk when fed through a bottle. Animal models also indicate a surprising predisposition for neonatal and infant rats to voluntarily and willingly ingest ethanol. These findings suggest high susceptibility to the reinforcing properties of ethanol early in ontogeny.Methods: A surrogate nipple technique—a highly effective tool for investigation of the reinforcing properties of different fluids—was applied in the present study. Tests of ethanol reinforcement were accomplished in terms of two basic paradigms of Pavlovian conditioning. In one paradigm, the conditioned stimulus (CS) was the surrogate nipple, and in the other, the CS was a novel odor.Results: Newborn rats showed sustained attachment to the nipple providing 5% ethanol, and later reproduced this behavioral pattern toward the empty nipple (CS alone). Ingestion of ethanol yielding appetitive reinforcement was accompanied by detectable blood alcohol concentrations, with most in the range of 20–30 mg/dl. The reinforcing efficacy of ethanol was also confirmed in the classical olfactory conditioning paradigm: following pairing with intraoral ethanol infusions, the odor (CS) alone elicited sustained attachment to an empty nipple. Females showed better olfactory conditioning with low concentrations of ethanol, whereas males were effectively more conditioned to high concentrations. Although there were no reinforcing consequences of intraperitoneally injected ethanol [as an unconditioned stimulus (US)] when a neutral odor was the CS, when paired with ingestion of water from a nipple, the injection of ethanol had a reinforcing effect.Conclusions: The present series of experiments revealed ethanol reinforcement in the newborn rat. Two varieties of Pavlovian conditioning established that ethanol can serve as an effective US, and hence reinforcer, in such a way as to increase the approach and responsiveness toward stimuli paired with that US, indicating appetitive reinforcement.