bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attenuation of Alcohol‐Induced Apoptosis of Hepatocytes in Rat Livers by Polyenylphosphatidylcholine (PPC)
Authors: Mi Li‐Jun , Mak Ki M. , Lieber Charles S. 
Published: May 2006

Background:Alcohol consumption increases apoptosis of hepatocytes. This effect appears to be mediated by the induction of hepatic cytochrome P‐4502E1(CYP2E1) and its generation of free radicals, which results in an enhanced lipid peroxidation that initiates apoptosis. Because polyenylphosphatidylcholine (PPC), a soybean extract rich in polyunsaturated phosphatidylcholines, decreases the induction of ethanol‐specific CYP2E1 and opposes oxidative stress, we hypothesized that PPC supplementation may attenuate hepatocyte apoptosis caused by ethanol ingestion.Methods:Twenty‐eight male Sprague Dawley® rats were pair‐fed Lieber‐DeCarli liquid diets containing 36% of energy as alcohol or an isocaloric amount of carbohydrate for 28 days. Half of the rats were given PPC (3 g/liter), whereas the other half received the same amount of linoleate (as safflower oil) and of choline as the bitartrate. An additional dose of alcohol (3 g/kg) was given intragastrically 90 min before the livers were removed. We assessed apoptosis in formalin‐fixed, paraffin‐embedded liver sections by using the TUNEL (terminal transferase dUTP nick end labeling) assay. Apoptotic hepatocytes were identified by positive TUNEL staining in conjunction with condensation of nucleoplasm or margination of chromatin. In each rat, 20,000 to 60,000 hepatocytes were counted by light microscopy by using Image‐Pro Plus computer software, and the incidence of apoptosis was expressed as the percentage of total hepatocytes.Results:Alcohol feeding resulted in a 4.5‐fold increase in apoptosis of hepatocytes compared to pair‐fed control rats; PPC supplementation decreased the alcohol‐induced apoptosis to less than half. No difference in the incidence of apoptosis between the control and PPC‐supplemented rats was found in the absence of alcohol. Apoptosis was distributed randomly in the liver lobules of the rats fed the control diet, whereas the alcohol‐induced apoptosis was significantly increased in the perivenular area. PPC supplementation strikingly reduced this effect.Conclusions:PPC attenuates alcohol‐induced apoptosis of hepatocytes; this effect may provide a mechanism for PPC's protection against liver injury, possibly in association with its antioxidative action via the down‐regulation of ethanol‐mediated CYP2E1 induction.
Acute Effects of Ethanol on Kainate Receptors in Cultured Hippocampal Neurons
Authors: Costa Edmar T. , Soto Eli E. , Cardoso Rita A. , Olivera Dorian S. , Valenzuela C. Fernando 
Published: May 2006

Background:Kainate receptors are a subclass of ionotropic glutamate receptors that regulate excitability and mediate synaptic transmission and plasticity in the hippocampus. The acute effects of ethanol on these receptors are not completely understood.Methods:The acute effects of ethanol on pharmacologically isolated kainate receptor‐mediated currents were studied in cultured hippocampal neurons obtained from neonatal rats. Whole‐cell patch‐clamp electrophysiological techniques were used for these studies. LY303070 (GYKI‐53784), a potent AMPA (α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid) receptor‐selective noncompetitive antagonist, was used to isolate kainate currents.Results:Kainate receptor‐mediated currents corresponded to 7% of the total non‐N‐methyl‐d‐aspartate (non‐NMDA) currents in these neurons and were reduced to 24% of control values in the presence of 15 μM lanthanum. These kainate receptor‐mediated currents were significantly inhibited by ethanol concentrations of 50 mM or more. Under our recording conditions, ethanol inhibited non‐NMDA receptor‐ and NMDA receptor‐mediated currents to a similar extent as kainate receptor‐mediated currents. Western blot analysis indicated that glutamate receptor‐5 and ‐6/7 subunits, and kainic acid‐2 subunits are expressed in these cultured hippocampal neurons.Conclusions:The present results suggest that kainate receptors are important targets for the actions of ethanol in the central nervous system.
Pronounced Hepatic Free Radical Formation Precedes Pathological Liver Injury in Ethanol‐Fed Rats
Authors: Reinke Lester A. , Moore Danny R. , Nanji Amin A. 
Published: May 2006

Background: The role of free radicals in alcoholic liver injury remains uncertain. These experiments were conducted to measure radical formation in rats that were fed alcohol along with either fish oil or saturated fats, which cause different types of liver pathology.Methods: Liquid diets containing alcohol or isocaloric dextrose were administered to rats by intragastric infusion for 2 weeks. Radical intermediates detected by spin trapping were measured in bile.Results: In rats that were fed alcohol plus fish oil, biliary concentrations of trapped radicals, which most likely originated from lipids, were 6‐fold higher than in controls that were fed fish oil plus dextrose. High rates of radical formation persisted 24 hr after alcohol withdrawal, when all alcohol had been metabolized. In contrast, diets containing alcohol and medium chain triglycerides did not stimulate lipid radical formation.Conclusions: High rates of lipid radical formation were observed only in rats that were fed alcohol in combination with a fish oil diet, and a persistent flux of radical formation continued after alcohol with‐ drawal. These radical phenomena precede serious liver pathology, which develops after longer periods of fish oil plus alcohol diets.
Association Study Between Genetic Polymorphisms in the 14–3‐3 η Chain and Dopamine D4 Receptor Genes and Alcoholism
Authors: Ishiguro H. , Saito T. , Shibuya H. , Arinami T. 
Published: May 2006

Background:The dopaminergic system may be involved in the development of alcoholism. As part of our ongoing studies on the association between alcoholism and dopaminergic genes, we report herein a mutation analysis of the 14–3‐3 η chain gene (YWHAH) and an association study between alcoholism and theYWHAHand dopamine D4 receptor gene (DRD4) polymorphisms.Methods:Nucleotide mutations were investigated using single‐strand conformation polymorphism methods. Associations were analyzed using a case‐control design involving 185 Japanese alcoholics and 286 Japanese controls.Results:Five polymorphisms, ‐147G>A, ‐134(GCCTGCA)2–4, IVS1+31(G)7–8. IVS1+73–74ins(G), and 753A>G, were detected on theYWHAH, and three of them were novel. No significant associations were found between alcoholism and these polymorphisms or two additional polymorphisms onDRD4exon III andDRD4‐521C/T.Conclusions:YWHAHandDRD4do not appear to play a major role in the development of alcoholism.
Ethanol Improves Decreased Filterability of Human Red Blood Cells Through Modulation of Intracellular Signaling Pathways
Authors: Oonishi Tadahiro , Sakashita Kanako 
Published: May 2006

Background: Deformability of red blood cells (RBCs) is one of the most important factors in maintaining the microcirculation system. In vitro studies have revealed that ethanol seriously impairs the deformability of RBCs at concentrations far higher than those easily achievable in the blood after alcohol consumption. We examined the effect of ethanol on deformability at the physiologically achievable concentrations.Methods: To impair deformability quantitatively, washed RBCs from healthy young male volunteers were mechanically stressed by being injected rapidly through a fine needle. The deformability of RBCs was evaluated by measuring the filterability through a nickel mesh filter. The activities of protein kinase A and protein kinase C in RBCs were measured by the ELISA method using an antibody for the phosphorylated substrate of the kinases.Results: Ethanol exhibited a biphasic effect on the mechanically impaired filterability of human RBCs, that is, an improvement at concentrations from 0.02% to 0.2% (v/v) and a marked deterioration at 0.5% and higher. Without mechanical stress, ethanol decreased filterability at concentrations of 0.5% and higher. Ethanol increased the protein kinase A and protein kinase C activities of the mechanically stressed RBCs at concentrations of 0.02% and higher and those of the RBCs without mechanical stress at concentrations of 0.05% and higher.Conclusions: The present results suggest a beneficial effect of ethanol on blood rheology at concentrations that are physiologically achievable in the blood and indicate the importance of intracellular signaling pathways in regulating the deformability of RBCs.
Prospective Study on Alcohol Intake and Risk of Subarachnoid Hemorrhage Among Japanese Men and Women
Authors: Sankai Tomoko , Iso Hiroyasu , Shimamoto Takashi , Kitamura Akihiko , Naito Yoshihiko , Sato Shinichi , Okamura Tomonori , Imano Hironori , Lida Minoru , Komachi Yoshio 
Published: May 2006

Background: Few prospective data are available to evaluate potential risk factors of subarachnoid hemorrhage among the Japanese, although several prospective studies conducted in the United States and in Europe have shown a positive relationship between alcohol intake and the risk of subarachnoid hemorrhage.Methods: A 9.4 year follow‐up study was conducted on 12,372 men and women age 40 to 69 years who had no history of stroke, in six communities in Japan. The incident cases of subarachnoid hemorrhage were confirmed with computed tomography findings and/or clinical findings. Alcohol intake and other cerebro‐vascular risk factors were measured at the baseline examination. A Cox proportional hazard analysis was used to estimate the relative risks and 95% confidence intervals of the incidence of subarachnoid hemorrhage.Results: During the follow‐up assessment, 71 cases of subarachnoid hemorrhages occurred. For men, heavy drinking appeared to be an independent risk factor for subarachnoid hemorrhage; multivariate‐adjusted relative risk was 4.3 (95% confidence interval [CI]: 1.1–16.8; p= 0.04). Among women, no excess risk was found for heavy drinking, probably due to the small number of heavy drinkers (n= 15). The combination of heavy drinking with smoking or hypertension increased the risk of subarachnoid hemorrhage substantially for men; the multivariate‐adjusted relative risk was 6.0 (95% CI: 1.8–20.1; p= 0.004) for heavy drinking smokers and 13.0 (95% CI: 3.9–43.9; p < 0.001) for heavy drinking hypertensives.Conclusions: A reduction in alcohol intake, smoking cessation, and control of hypertension are important in preventing subarachnoid hemorrhage among Japanese men.
Alcoholism Susceptibility Loci: Confirmation Studies in a Replicate Sample and Further Mapping
Authors: Foroud Tatiana , Edenberg Howard J. , Goate Alison , Rice John , Flury Leah , Koller Daniel L. , Bierut Laura J. , Conneally P. Michael , Nurnberger John I. , Bucholz Kathleen K. , Li Ting‐Kai , Hesselbrock Victor , Crowe Raymond , Schuckit Marc , Porjesz Bernice , Begleiter Henri , Reich Theodore 
Published: May 2006

Background: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members.Methods: Additional, genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM‐III‐R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD‐10 criteria for alcoholism were considered affected under a more severe definition of disease.Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4).Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.
Contribution of Gastric Oxidation to Ethanol First Pass Metabolism in Baboons
Authors: Baraona Enrique , Abittan Chaim S. , Lieber Charles S. 
Published: May 2006

Background: A portion of ingested alcohol does not reach the systemic blood, undergoing a first‐pass metabolism (FPM) during gastric and hepatic circulation.Methods: To determine whether the stomach can metabolize sufficient ethanol to account for the FPM, and to what extent gastric alcohol dehydrogenase (ADH) activity is responsible, the hepatic vein, the portal vein, and the aorta were cannulated nonocclusively in baboons to measure the conversion of ethanol to acetate in vivo. 14C‐ethanol (300 mg/kg as a 15% solution) was given intragastrically (IG) whereas 3Hacetate was continuously infused intravenously (IV).14C‐acetate was measured after exhaustive evaporation of ethanol. Simultaneous sampling of hepaticvenous, portal and arterial blood was carried out for 3 hr, at the end of which the same alcohol dose was given IV to calculate the Michaelis‐Menten parameters of elimination.Results: Analysis of the IV and IG ethanol curves revealed a FPM of 94 ± 11 mg/kg (31% of dose). The portal‐arterial differences were negative for 3H‐acetate (indicating net extraction) and positive for 14Cethanol and 14C‐acetate (indicating net output). Portal acetate production (extraction plus net output multiplied by the portal plasma flow) increased with time and accounted, over the first 3 hr (82 ± 13 mg/kg), for 87% of the FPM. Alcohol oxidation by gastric ADH activity (28.7 ± 7.2 mg/kg) accounted for only 31% of the FPM.Conclusions: The in vivo oxidation of ethanol to acetate in the upper digestive tract accounts for the FPM of ethanol and is mediated, at least in part, by ADH activity.
Ethanol Uses cAMP‐Independent Signal Transduction Mechanisms to Activate Proenkephalin Promoter Activity in Rat C6 Glioma Cells
Authors: Yang Xiaoju , Wand Gary 
Published: May 2006

Background: Previous in vivo studies show that acute ethanol exposure sequentially increases protein kinase A (PKA) activity, the phosphorylation of the adenosine 3′:5′‐cyclic monophosphate (cAMP) dependent transcription factor, CREB, and finally proenkephalin gene expression. The present study was conducted to determine if ethanol could activate directly the adenylyl cyclase pathway and thus enhance proenkephalin promoter activity.Methods: Cultured rat C6 glioma cells stably transfected with a segment of the five prime flanking region of rat proenkephalin promoter (nucleotide ‐2700 + 53) ligated to the chloramphenicol acetyltransferase (CAT) reporter gene were employed to study the effects of ethanol on proenkephalin promoter activity. This region of proenkephalin promoter contains two cAMP response elements (CRE‐1 and CRE‐2) and one AP2 site located in the region upstream of the TATA box. Cultures were exposed to ethanol, isoproterenol, and phorbol‐12, myristate 13‐acetate (PMA) alone and in combination, in the presence and absence of PKA and protein kinase C (PKC) inhibitors.Results: Ethanol and isoproterenol increased proenkephalin promoter activity in a dose‐dependent manner. Ethanol had an additive effect on maximal isoproterenol‐stimulated proenkephalin promoter activity, which suggested that ethanol used a cAMP‐independent signai transduction pathway to increase proenkephalin promoter activation. In contrast with isoproterenol, ethanol exposure did not increase cAMP accumulation, PKA activity, or the phosphorylated form of CREB. However, ethanol exposure modestly increased PKC activity. The PKA‐specific inhibitor, Rp‐cAMP, dampened isoproterenol‐induced activation of CAT activity but did not alter ethanol's ability to increase CAT activity. However, the PKC inhibitors, chelerthyrine and G07874, abrogated ethanol's effect of CAT activity but did not alter isoproterenol's effects.Conclusions: Ethanol enhanced proenkephalin promoter activity and potentiated isoproterenol stimulated promoter activity through a cAMP‐independent pathway.
Cigarette Smoking Decreases the Prolactin Response to Serotonergic Stimulation in Subgroups of Alcoholics and Controls
Authors: Anthenelli Robert M. , Maxwell Rose A. 
Published: May 2006

Background: The prolactin response to serotonergic stimulation has been used as an index of central nervous system serotonin function. We evaluated the prolactin response to d,l‐fenfluramine to determine whether subtypes of alcoholics differed in prolactin responsivity compared with nonalcoholics and whether cigarette smoking affected prolactin response.Methods: One hundred ten healthy, abstinent men across four groups (controls [23% smokers]; alcoholics [72% smokers]; alcoholics with antisocial personality disorder [94% smokers]; nonalcoholic antisocials [88% smokers]) received d,l‐fenfluramine (100 mg orally) in a randomized, double‐blind, placebo‐controlled study. Plasma prolactin levels were obtained at baseline and at half‐hour intervals for 5 hr after fenfluramine/placebo administration. Plasma fenfluramine and norfenfluramine levels were obtained hourly.Results: Smokers had a blunted prolactin response to fenfluramine compared with nonsmokers without any alcoholism or antisocial personality effects. Using a cutoff point of Δ peak prolactin < 10 ng/ml, more smokers (41/76, 54%) had a dampened response to fenfluramine than did nonsmokers (7/34, 21%) [X2(1)=10.6, p < 0.003]. The percentage of low responders was greatest among smokers regardless of whether they were healthy controls, alcoholics, or antisocial. Multiple regression revealed that three variables—(1) number of pack‐years of smoking, (2) actual dosage of fenfluramine received, and (3) plasma norfenfluramine level obtained—explained 43% of the variance (R2= 0.43) in Δ prolactin area under the curve. Variables that included alcoholism diagnostic status, antisocial personality diagnostic status, and impulsive aggressive personality, depressive, and suicidal traits failed to explain any additional unique variance.Conclusions: Cigarette smoking blunted the prolactin response to a pharmacological challenge with d,l‐fenfluramine. Pharmacodynamic and pharmacokinetic factors related to smoking both appear to influence fenfluramine‐induced prolactin secretion. Phenotypes of alcoholics did not differ in their prolactin response to this serotonergic probe.
Intellectual, Cognitive, and Academic Performance Among Sons of Alcoholics During the Early School Years: Differences Related to Subtypes of Familial Alcoholism
Authors: Poon Edwin , Ellis Deborah A. , Fitzgerald Hiram E. , Zucker Robert A. 
Published: May 2006

Background: Research on intellectual and cognitive functioning of children of alcoholics has been marked by inconsistency, with some studies unable to document deficits. This discrepancy may reflect the substantial heterogeneity found in the alcoholic population and among families of alcoholics. The current study sought to examine the effects of familial alcoholism subtypes on intellectual, cognitive, and academic performance in early school‐aged sons of alcoholics.Methods: Subjects for the present study were 198 elementary‐age boys who were participants in the larger MSU‐UM Longitudinal Study. Familial alcoholism subtypes were determined based on fathers' alcoholism and antisocial personality disorder diagnoses. Intellectual functioning was measured with the Wechsler Intelligence Scale for Children‐Revised (WISC‐R); academic achievement was measured with the Wide Range Achievement Test–Revised. In addition, Mazes and Freedom from Distractability factor scores of the WISC‐R were used to assess abstract planning and attention abilities.Results: Children of antisocial alcoholics (AALs) displayed the worst IQ and academic achievement compared with children of nonantisocial alcoholics (NAALs) and controls. In addition, children of AALs displayed relatively poorer abstract planning and attention abilities compared with children from control families. Regression analyses revealed that familial alcoholism subtype continued to account for variance in child intellectual ability even when other factors were excluded.Conclusions: Findings indicate that children from AAL families are most susceptible to relative intellectual, cognitive, and academic deficits. The study further supports the proposition that familial risk characteristics (i.e., paternal alcoholism and antisociality) may serve as effective indicators of family risk for poor intellectual outcome among offspring as early as the elementary school years.
The Influence of Traits of Disinhibition on the Association Between Alcohol Use and Risky Sexual Behavior
Authors: Justus Alicia N. , Finn Peter R. , Steinmetz Joseph E. 
Published: May 2006

Background: Past research has demonstrated a link between alcohol use and risky sexual behavior; the processes that may underlie this association remain largely unexplored, however. Recent studies suggest that personality traits such as excitement seeking, impulsivity, and social deviance proneness may play an important role in both behaviors.Methods: A structural model of the association between disinhibited personality traits, alcohol use, and risky sexual behavior (sex with stranges/one‐night stands) was tested. We recruited a sample of 410 college students that reported a wide range of scores on self‐reported measures of disinhibition. We hypothesized that disinhibited personality characteristics would be primarily responsible for the association between risky sexual behavior and alcohol problems. A third‐variable model was proposed to demonstrate this association.Results: The results suggested that the relationship between alcohol use and risky sexual behavior is best explained by their common association with excitement seeking. There was a significant correlation between alcohol use and risky sexual behavior when considered alone. However, when controlling for the effects of personality, the correlation was nonsignificant. In a final model, both excitement seeking and social deviance proneness were found to be significantly associated with alcohol use, and excitement seeking was significantly related to risky sexual behavior.Conclusions: Results suggest the relationship between alcohol use and risky sexual behavior is best characterized by a common association with excitement seeking.