bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol‐Induced Leukocyte Adherence and Albumin Leakage in Rat Mesenteric Venules: Role of CD18/Intercellular Adhesion Molecule‐1
Authors: Takaishi Masaaki , Kurose Iwao , Higuchi Hajime , Watanabe Naoyuki , Nakamura Tetsuya , Zeki Shigeyuki , Nishida Jiro , Kato Shinzo , Miura Soichiro , Mizuno Yoshio , Kvietys Peter R. , Granger D. Neil , Ishii Hiromasa
Published: April 2006

The adherence and emigration of leukocytes have been implicated as a rate‐limiting step in the microvascular disturbance in a variety of pathogenic events. The objective of the present study was to investigate leukocyte‐endothelial cell adhesion and endothelial barrier function in rat mesenteric microvessels exposed to ethanol, which is known to cause inflammation and injury in various organs. Mesentery of male Wistar rats was used for intravital microscopic observations. Leukocyte adherence and albumin leakage were monitored in single postcapillary venules using the intravital fluorescence microscope. Supervision of 50 mM ethanol elicited the leukocyte adherence and albumin leakage within 60 min. Pretreatment with a monoclonal antibody directed against either CD18 or intercellular adhesion molecule‐1 (ICAM‐1) significantly prevented the ethanol‐induced increase in leukocyte adherence and decrease in barrier function of endothelium. These results suggest that ethanol‐induced leukocyte adherence is mediated by CD18 on leukocytes and ICAM‐1 on endothelial cells. The present study further supports that CD18/ ICAM‐1‐dependent leukocyte‐endothelial adhesive interactions lead to macromolecular leakage in the postcapillary venules exposed to ethanol.
Effect of Alcohol Intake on the Efficacy of Interferon Therapy in Patients with Chronic Hepatitis C as Evaluated by Multivariate Logistic Regression Analysis
Authors: Mochida Satoshi , Ohnishi Kunihiko , Matsuo Shuichi , Kakihara Kohji , Fujiwara Kenji
Published: April 2006

The effect of alcohol intake on the efficacy of interferon (IFN) therapy was evaluated retrospectively in patients with chronic hepatitis C diagnosed by liver histology and positive serum hepatitis C virus (HCV)‐RNA. Patients included 119 given IFN therapy and 11 no IFN therapy. Serum HCV‐RNA was measured 6 months after discontinuation of IFN therapy in 92 treated patients, 27.2% of whom showed disappearance of serum HCV‐RNA. Multivariate logistic regression analysis revealed that this disappearance was affected by alcohol intake, the presence of its history (p < 0.05) or cumulative alcohol consumption (kg) (p < 0.01), and serum HCV‐RNA levels (p < 0.001). The odds ratio associated with serum HCV‐RNA still positive at 6 months was 7.016 (95% confidence interval: 1.444‐34.082) and 1.004 (1.001‐1.007) for the presence of alcohol intake history and the cumulative alcohol consumption, respectively. Other predictor variables–such as sex and age of patients, history of blood transfusion, HCV genotype, histological findings of the liver, and types of IFN– had no influence on the efficacy of the therapy. Cumulative alcohol consumption showed a negative correlation with serum HCV‐RNA levels pretreatment, when the outcome variable was divided into two categories based on serum HCV‐RNA levels: 106 copy/ml or less and 107 copy/ml or more. Alcohol intake was positively correlated with histological extent of alcoholic fibrosis, but affected neither grading nor staging of chronic viral hepatitis. We conclude that alcohol intake was a risk factor on the efficacy of IFN therapy in chronic hepatitis C patients. This effect was independent of serum HCV‐RNA levels and histological findings specific for viral hepatitis in the liver.
Prognostic Factors for Short‐Term Survival in Alcoholic Hepatitis in Japan: Analysis by Logistic Regression
Authors: Kumashiro Ryukichi , Sata Michio , Ishii Kunihide , Koga Yuriko , Furudera Shigeki , Seo Jun , Kusaba Nobuhide , Sakai Megumi , Ikejiri Naoki , Tanikawa Kyuichi
Published: April 2006

Prognostic factors for the outcome of patients with alcoholic hepatitis were identified by logistic regression analysis. To predict the outcome immediately after admission, clinical data from 97 patients with alcoholic hepatitis on admission were introduced to multivariate analysis. Independent prognostic factors for favorable outcome were hepaplastin time, peripheral white blood cell count, age (40 to 60 years), and serum creatinine level (below 1.4 mg/dl). Sensitivity, specificity, positive predictive value, negative predictive value, and predictive accuracy were 0.78, 0.89, 0.78, 0.89, and 0.86, respectively. The resultant equation for the death rate was applied to another set of patients with alcoholic hepatitis as a validation study. Predictive accuracy estimated 0.95 in validation. The prognostic index derived was simple, accurate, and useful in the prediction of the outcome in patients with alcoholic hepatitis. Furthermore, it provides the clinician with an indication of the necessity for the intensive care of patients in a critical condition.
Chronic Alcohol Feeding in Liquid Diet or in Drinking Water Has Similar Effects on Electron Microscopic Appearance of the Hepatic Sinusoid in the Rat
Authors: Sarphie Theodore G. , D'Souza Nympha B. , Spitzer John J. , Deaciuc Ion V.
Published: April 2006

Electron microscopic appearance of the liver sinusoid was examined in rats fed alcohol chronically in a complete liquid diet or in sucrose‐containing drinking water. The animals were kept on liquid diet (±alcohol) for 14 weeks or on sucrose‐containing drinking water (±alcohol) for 12.5 weeks and sacrificed thereafter. To rule out possible artifact induced by fixation procedure, livers were fixed by immersion (no perfusion), immersion preceded by perfusion, and by perfusion with glutaraldehyde and examined with both scanning and transmission electron microscopy. Regardless of the mode of its administration, and of the fixation procedure used, alcohol induced similar changes in liver sinusoid ultrastructure. Such changes included disruption of the sieve‐plate pattern of the sinusoidal endothelial cell fenestrations with the appearance of large gaps and resulting in a meshwork lining, wherein large areas of the sinusoid communicated freely with the underlying hepatocytes. Transmission electron microscopy complemented these findings. The results reported in this study demonstrate that alcohol‐induced structural changes of the liver sinusoid in the rat are similar whether alcohol is fed via a liquid diet or in drinking water. Therefore, alcohol administration in drinking water may provide a simple, inexpensive, and convenient method of inducing structural changes in the rat liver sinusoid.
Oxidative Susceptibility of Low‐Density Lipoproteins—Influence of Regular Alcohol Use
Authors: Croft Kevin D. , Puddey Ian B. , Rakic Valentina , Abu‐Amsha Rima , Dimmitt Simon B. , Beilin Lawrence J.
Published: April 2006

In population studies, a low‐to‐moderate intake of alcohol has been consistently linked to a lower risk of coronary artery disease. The recent suggestion that alcoholic beverages may be conferring this decrease in risk because they contain antioxidant phenolic compounds that reduce the oxidizability of low‐density lipoprotein (LDL) has to be reconciled with the possible counteracting influence of a pro‐oxidant effect of alcohol. In a controlled crossover study, we have now measured the oxidizability of LDL in 27 regular beer drinkers during consecutive 4‐week periods, wherein they consumed a high versus low alcohol beer (4.9 vs. 0.9% alcohol v/v, respectively), with the two beers being similar in phenolic content. This resulted in a decrease in alcohol consumption by ˜80% (408 ± 25 ml/week vs. 75 ± 11 ml/week). During the low alcohol period, there was no change in LDL vitamin E or its cholesterol or protein content. Analysis of LDL oxidation kinetics revealed an increase in oxidizability during the high alcohol phase. This was despite a decrease in arachidonic acid content of LDL and a corresponding increase in palmitic acid during high alcohol intake—a change in fatty acid composition that has the potential to favor a decrease in oxidizability. Our results suggest that alcohol ingestion increases LDL oxidation, despite reducing the polyunsaturated fatty acid composition. The overall effect of alcoholic beverages on LDL oxidation may be a balance between the pro‐oxidant and antioxidant activity of its various constituents. The predominant pro‐oxidant effect demonstrated in these beer drinkers, although not relevant to any potential decrease in coronary artery disease, may be important in the pathogenesis of alcohol‐related disease in other organ systems.
Effects of Cholinergic Agents on Locomotor Activity of P and NP Rats
Authors: Katner S. N. , McBride W. J. , Lumeng L. , Li T.‐K. , Murphy J. M.
Published: April 2006

Experiments were undertaken to compare the selectively bred, alcohol‐preferring (P) and alcohol‐nonpreferring (NP) rat lines for differences in the locomotor activity (LMA) response to intracerebroventricular infusions of muscarinic‐ and nicotinic‐cholinergic agents. Scopolamine, a nonselective muscarinic antagonist (40 to 120 μg/0.5 μl), dose‐dependently increased LMA in both P and NP rats (up to 90 to 100% above baseline; p < 0.05). On the other hand, pirenzepine, a selective M1 muscarinic antagonist (10 to 80 μg/0.5 μl), decreased LMA in P and NP rats (as much as 35 to 40% below control values; p < 0.05). Mecamylamine, a nicotinic antagonist (20 to 120 μg/0.5 μl), also decreased LMA in P and NP rats (as much as 30 to 40% below baseline; p < 0.05). The agonist nicotine (20 to 80 μg/0.5 μl) dose‐dependently decreased LMA in both P and NP rats (to a maximum of ˜60 to 65% below control values; p < 0.05). Based on standardized z‐scores, NP rats were more sensitive (p < 0.05) to the locomotor depressant effects of nicotine than P rats, whereas no differences were observed for standardized z‐scores between the P and NP lines on the effects of scopolamine, pirenzepine, or mecamylamine on LMA. The results suggest that subtypes of muscarinic and nicotinic receptors are involved in regulating LMA in a complex manner, with the M1 subtype possibly mediating behavioral activation, and that P and NP rats may possess innate differences in CNS nicotinic receptors regulating LMA.
Chronic Ethanol Feeding Impairs Glucose Tolerance But Does Not Produce Skeletal Muscle Insulin Resistance in Rat Epitrochlearis Muscle
Authors: Wilkes Jason J. , Nagy Laura E.
Published: April 2006

Herein, we have investigated whether male Wistar rats develop impaired glucose tolerance after ethanol feeding. Rats were fed a liquid diet providing 35% calories from ethanol (EF) or a control diet that isocalorically replaced ethanol with maltose‐dextrins for 4 weeks. Intravenous glucose tolerance was impaired in EF rats compared with pair‐fed (PF), but not ad libitum (AL) controls. Areas under the intravenous glucose tolerance test curve were 5476 ± 516 mm2, 3056 ± 421 mm2, and 4199 ± 613 mm2 (p < 0.05) for AL, PF, and EF rats, respectively. Initial plasma insulin concentrations in EF rats were comparable with PF rats; however, 15 min after a dextrose challenge, plasma insulin levels in EF rats were 39% lower than PF rats. Because skeletal muscle is the primary sink for insulin‐mediated glucose disposal, the development of skeletal muscle insulin resistance after ethanol feeding could contribute to impaired glucose tolerance. Total GLUT1 was not affected by diet in either red or white muscle. No difference in the total quantity of insulin‐responsive glucose transporter, GLUT4, was observed in red muscle. In contrast, GLUT4 was 20% lower in white muscle from EF rats, compared with PF and AL rats. However, insulin‐stimulated glucose transport into the epitrochlearis, a white muscle group, was not impaired with ethanol feeding. These data demonstrate that chronic ethanol feeding impairs glucose tolerance; impaired glucose tolerance was associated with an inability to maintain plasma insulin levels, rather than the development of skeletal muscle insulin resistance.
Expression Patterns of Class I and Class IV Alcohol Dehydrogenase Genes in Developing Epithelia Suggest a Role for Alcohol Dehydrogenase in Local Retinoic Acid Synthesis
Authors: Ang Hwee Luan , Deltour Louise , Žgombić‐Knight Mirna , Wagner Michael A. , Duester Gregg
Published: April 2006

Vitamin A (retinol) regulates embryonic development and adult epithelial function via metabolism to retinoic acid, a pleiotrophic regulator of gene expression. Retinoic acid is synthesized locally and functions in an autocrine or paracrine fashion, but the enzymes involved remain obscure. Alcohol dehydrogenase (ADH) isozymes capable of metabolizing retinol include class I and class IV ADHs, with class III ADH unable to perform this function. ADHs also metabolize ethanol, and high levels of ethanol inhibit retinol metabolism, suggesting a possible mode of action for some of the medical complications of alcoholism. To explore whether any ADH isozymes are linked to retinoic acid synthesis, herein we have examined the expression patterns of all known classes of ADH in mouse embryonic and adult tissues, and also measured retinoic acid levels. Using in situ hybridization, class I ADH mRNA was localized in the embryo to the epithelia of the genitourinary tract, intestinal tract, adrenal gland, liver, conjunctival sac, epidermis, nasal epithelium, and lung, plus in the adult to epithelia within the testis, epididymis, uterus, kidney, intestine, adrenal cortex, and liver. Class IV ADH mRNA was localized in the embryo to the adrenal gland and nasal epithelium, plus in the adult to the epithelia of the esophagus, stomach, testis, epididymis, epidermis, and adrenal cortex. Class III ADH mRNA, in contrast, was present at low levels and not highly localized in the embryonic and adult tissues examined. We detected significant retinoic acid levels in the fetal kidney, fetal/adult intestine and adrenal gland, as well as the adult liver, lung, testis, epididymis, and uterus—all sites of class I and/or class IV ADH gene expression. These findings indicate that the expression patterns of class I ADH and class IV ADH, but not class III ADH, are consistent with a function in local retinoic acid synthesis needed for the development and maintenance of many specialized epithelial tissues.
No Sex and Age Influence on the Expression Pattern and Activities of Human Gastric Alcohol and Aldehyde Dehydrogenases
Authors: Lai Ching‐Long , Chao You‐Chen , Chen Yi‐Chyan , Liao Chin‐Shya , Chen Mei‐Chun , Liu Yee‐Chun , Yin Shih‐Jiun
Published: April 2006

Background: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for ethanol metabolism in humans. The stomach is involved in the metabolism of alcohol during absorption. Conflicting reports exist with regard to the influence of sex and age on the activity of ADH in the human gastric mucosa. The purpose of the present study was to determine the effects of age and sex on the expression pattern and activities of stomach ADH and ALDH.

Methods: A total of 115 endoscopic gastric biopsy specimens were investigated from Han Chinese men (n= 70) and women (n= 45) aged 20–79 years with approximately even distribution among 10‐year age intervals. The expression patterns of ADH and ALDH were identified by isoelectric focusing, and the activities were assayed spectrophotometrically.

Results: The expression patterns of gastric ADH and ALDH remained unchanged with respect to sex and age. At 33 mM or 500 mM ethanol, pH 7.5, the ADH activities did not differ significantly among the various age groups or between men and women. At 200 μM or 20 mM acetaldehyde, the ALDH activities did not differ significantly in relation to sex and age. No correlations were found between the ADH or ALDH activities at both the high and low substrate concentrations and the ages in men and women.

Conclusions: The results indicate that there is no significant effect of either sex or age on the expression pattern and activity of ADH and ALDH in the human gastric mucosa. The stomach ADH seems unlikely to account for possible variations in the first‐pass metabolism of alcohol with regard to sex and age.
Effects of Alcohol on the Response to Hyperventilation of Participants High and Low in Anxiety Sensitivity
Authors: MacDonald Alan B. , Baker Jan M. , Stewart Sherry H. , Skinner Michelle
Published: April 2006

Background: Previous research suggests that high levels of anxiety sensitivity (AS; fear of anxiety symptoms) may constitute a risk factor for alcohol abuse. The present study evaluated the hypothesis that high AS levels may increase risk for alcohol abuse by promoting a heightened sober reactivity to theoretically relevant stressors and heightened sensitivity to alcohol's emotional reactivity dampening effects, which would negatively reinforce drinking in this population.

Methods: One hundred and two undergraduate participants (51 high AS, 51 low AS) with no history of panic disorder were assigned to either a placebo, low‐dose alcohol, or high‐dose alcohol beverage condition (17 high AS, 17 low AS per beverage condition). After beverage consumption and absorption, participants underwent a 3 min voluntary hyperventilation challenge.

Results and Conclusions: High‐AS/placebo participants displayed greater affective and cognitive reactivity to the challenge than low‐AS/placebo participants, which indicated increased fear and negative thoughts (e.g., “losing control”) during hyperventilation among sober high AS individuals. Dose‐dependent alcohol dampening of affective and cognitive reactivity to hyperventilation was observed only among high‐AS participants, which suggested that high‐AS individuals may be particularly sensitive to alcohol‐induced reductions in their degree of fear and negative thinking in response to the experience of physical arousal sensations. In contrast, dose‐dependent alcohol dampening of self‐reported somatic reactivity was observed among both high‐ and low‐AS participants. We discuss implications of these results for understanding risk for alcohol abuse in high‐AS individuals, as well as directions for future research.
Effects of Moderate and High Doses of Alcohol on Attention, Impulsivity, Discriminability, and Response Bias in Immediate and Delayed Memory Task Performance
Authors: Dougherty Donald M. , Marsh Dawn M. , Moeller F. Gerard , Chokshi Reena V. , Rosen Valerie C.
Published: April 2006

Background: Prior studies that examined the effects of alcohol on Continuous Performance Test (CPT) performance have resulted in inconsistent outcomes. Most studies that examined the effects of alcohol on concentrated attention tasks (like the CPT) found little effect of alcohol on performance measures, even when doses that exceeded 0.8 g/kg were used. One likely reason for these inconsistencies is the varying difficulty (and sensitivity) of the task used, and as a result, comparisons between studies are difficult. This study is one in a series that examines the effects of alcohol on attention by using a difficult version of the CPT (Immediate and Delayed Memory Task—IMT/DMT). Our purpose for these studies has been two‐fold, examining the effects of alcohol (1) on concentrated attention (i.e., correct detections) and (2) on errors (i.e., commission errors) previously correlated with impulsive behaviors. The first is important because previous studies have shown little effect of alcohol on attention, and the second is important because commission errors have been related to impulsive behaviors.

Methods: In the IMT/DMT, participants respond to a briefly displayed number when it is identical to the one displayed before it. The procedure includes immediate and delayed conditions where successive stimuli to be matched are delayed by 0.5 sec or by 3.5 sec. The three stimulus types included target (identical match), catch (four of five digits match), and filler (no match) stimuli. Twenty subjects completed this task after consuming either a placebo drink or a drink that contained 0.5 g/kg or 1.0 g/kg of alcohol on different days.

Results: The main findings were that (1) alcohol decreased the percentage of correct identifications of target stimuli; (2) alcohol increased the percentage of commission errors in relation to the number of correct target responses; and (3) alcohol decreased discriminability whereas response bias became more conservative.

Conclusions: These results clearly demonstrated a time‐course effect of the 1.0 g/kg alcohol dose on attention, impulsivity, discrimination, and response criteria when a variety of dependent measures are used.
Binge Ethanol Consumption Causes Differential Brain Damage in Young Adolescent Rats Compared With Adult Rats
Authors: Crews Fulton T. , Braun Christopher J. , Hoplight Blair , Switzer Robert C. , Knapp Darin J.
Published: April 2006

Background:Adolescents respond differently to alcohol than adults. Furthermore, binge drinking in young adolescents is becoming increasingly common.

Methods:To determine if the effects of binge drinking on brain damage are different in juveniles compared with adults, the effects of a 4 day binge ethanol treatment (e.g., 4 days of 4 times per day 15% ethanol intragastrically, approximately 9–10 g/kg/day ethanol) were investigated in adolescent‐juvenile rats (JVN) 35 days old and compared with adult (ADT) rats 80 to 90 days old. Brain damage was measured by using the amino cupric silver stain of de Olmos et al. (1994).

Results:Significant brain damage was found in both groups. The olfactory bulbs were equally damaged in both groups; however, the associated frontal cortical olfactory regions were damaged only in JVN. The anterior portions of the piriform and perirhinal cortices also were damaged only in JVN rats. Quantitation of silver‐stained frontal areas in binge ethanol‐treated JVN rats ranged from 400% to 1260% of control values. For example, in anterior perirhinal cortex, silver stain increased from 48 ± 14 to 444 ± 114 (mm2× 103argyrophilic area;p< 0.01) in JVN control and binge ethanol‐treated animals, respectively. In contrast, posterior perirhinal cortex showed greater damage in adults, being 236 ± 76 vs. 875 ± 135 (mm2× 103argyrophilic area;p< 0.005) in JVN and ADT, respectively.

Conclusions:The young‐adolescent brain shows differential sensitivity to alcohol‐induced brain damage compared with adults.
Serotonergic Modulation of Ethanol‐Induced Electrophysiological Depression in Young and Aged Rats
Authors: Jeng Churn‐Hueih , Chou Jenny R. , Hoffer Barry J. , Wang Yun
Published: April 2006

Background: Ethanol (EtOH)‐induced electrophysiological depressions in cerebellar Purkinje neurons have been shown to be potentiated by exogenously applied serotonin (5HT). In this study, we determined whether this modulatory action can be activated by endogenous release from presynaptic serotonergic terminals, and whether such a response is altered by age or rat strain.

Methods: Extracellular 5HT levels in cerebellar cortex were measured in real time by in vivo chronoamperometry, by using Nafion‐coated carbon fiber electrodes, in anesthetized young (3–5 months old) or aged (18–24 months old) Sprague Dawley and Fischer 344 rats. Some animals were prelesioned with 5,7 dihydroxytryptamine (5,7 DHT). Single unit electrophysiological activity was recorded from cerebellar Purkinje neurons. Serotonin or its presynaptic antagonist methiothepin was applied directly to cerebellar neurons through multibarrel pipettes.

Results: Local application of methiothepin dose‐dependently induced 5HT overflow in young Sprague Dawley and Fisher 344 rats. Methiothepin‐induced 5HT release was decreased significantly in aged or 5,7 DHT‐lesioned rats. Local application of methiothepin or 5HT potentiated EtOH‐induced electrophysiological depression of Purkinje neurons in young animals of both strains. Methiothepin‐potentiated, EtOH‐elicited neuronal inhibition was reduced greatly in aged or 5,7 DHT‐lesioned rats. Serotonin‐facilitated EtOH responses were reduced in the aged Sprague Dawley rats.

Conclusions: EtOH‐induced electrophysiological responses in cerebellum can be facilitated by endogenous 5HT release by using a 5HT autoreceptor antagonist. Such actions are attenuated in aged rats perhaps through a presynaptic serotonergic mechanism.
A Characterization of Approach and Avoidance Learning in High–Alcohol‐Drinking (HAD) and Low–Alcohol‐Drinking (LAD) Rats
Authors: Blankenship Matthew R. , Finn Peter R. , Steinmetz Joseph E.
Published: April 2006

Background: This study was undertaken as one of a series of experiments designed to examine basic behavioral characteristics present in rats bred specifically for alcohol preference. The basic premise for these experiments has been the idea that alcohol‐preferring and ‐nonpreferring rats may differ in basic activation and inhibition control mechanisms that govern behavior and that different lines of alcohol‐preferring rats may demonstrate differential deficits in behavioral activation and behavioral inhibition tendencies. In the present experiment, conditioned approach and avoidance behaviors were studied in alcohol‐naïve high–alcohol‐drinking (HAD), low–alcohol‐drinking (LAD), and N/NIH rats to evaluate behavioral activation in this line of rats.

Methods: High alcohol drinking (HAD1), low alcohol drinking (LAD1), and N/Nih stock rats were trained to press a response bar during a tone signal to avoid a mild foot shock or receive a food reward. In addition, HAD2 and LAD2 rats, independently‐bred replicate lines of the HAD1/LAD1 rats, were trained on the avoidance task.

Results: Although the HAD1 rats easily learned the appetitive version of the bar‐pressing task, they did not learn the avoidance response. The LAD1 and N/Nih rats learned both the approach and the avoidance tasks normally. Similar to HAD1 rats, the HAD2 rats did not learn the avoidance response whereas LAD2 rats showed significant avoidance performance levels.

Conclusions: The present data demonstrated that both HAD1 and HAD2 rats had a rather specific behavioral activation deficit: although they easily learned to press a bar to receive food reinforcement, they did not learn to press the bar to avoid a foot shock. We speculate that this failure to learn the avoidance response may be related to heightened anxiety in the HAD rats and that this excessive anxiety may lead to the development of high levels of alcohol consumption in these selectively bred rats.
Reliability and Concurrent Validity of DSM‐IV Subclinical Symptom Ratings for Alcohol Use Disorders Among Adolescents
Authors: Bailey Susan L. , Martin Christopher S. , Lynch Kevin G. , Pollock Nancy K.
Published: April 2006

Background: The concurrent validity of subclinical ratings for psychiatric symptoms can help refine symptom definitions and threshold criteria. However, virtually no research has examined subclinical ratings for DSM‐IV symptoms in psychiatric diagnostic interviews. This study examined the frequency, reliability, and concurrent validity of subclinical ratings for 11 symptoms of alcohol use disorders among adolescents.

Methods: Subjects were 239 male and 164 female adolescents ages 14 to 18 recruited from treatment and community sources. Symptoms and diagnoses were made with an adapted version of the Structured Clinical Interview for the DSM‐IV.

Results: Subclinical ratings showed acceptable to high interrater reliability. The proportion of subclinical ratings tended to decrease with increasing levels of alcohol problems. For 10 of the 11 symptoms, subjects with subclinical ratings were distinguished from those with absent and/or those with present ratings. Subjects with subclinical ratings were often distinct from those with present ratings but less often distinct from those with absent ratings.

Conclusions: For most of the DSM‐IV alcohol use disorder symptoms, subclinical ratings appear to be reliable and valid and provide information beyond dichotomous symptom classifications for adolescents. Threshold criteria appear to be appropriate in many cases, but boundaries between absent and subclinical ratings are “fuzzy.” Practical and research implications are discussed.
Heavy Drinking, Alcohol Dependence, and Injuries at Work Among Young Workers in the United States Labor Force
Authors: Veazie Mark A. , Smith Gordon S.
Published: April 2006

Background: To determine whether heavily drinking and alcohol‐dependent workers are at higher risk of occupational injury, we analyzed the nationally representative cohort of people enrolled in the National Longitudinal Survey of Youth since 1979.

Methods: This analysis was restricted to the 8569 respondents in the 1989 annual interview (age 24–32) who were employed during the 6 months before the interview. We studied occupational injuries (excluding sprains or strains) reported within 6 months of the interview in 1989 (cross‐sectional analysis) and 1990 (prospective analysis).

Results: Among current drinkers, significant two‐fold increases in the odds of injury for one or more episodes of heavy drinking were reduced to an odds ratio (OR) of 1.2 (95% confidence interval [CI] = 0.7, 2.1) in the cross‐sectional analysis and an OR of 1.6 (CI 1.0, 2.8) in the prospective analysis after adjustment for confounding. No dose‐response relationship with the frequency of heavy drinking was found. Alcohol‐dependent respondents were not at higher risk of injury in the cross‐sectional (OR = 1.1, CI 0.7, 1.8) or prospective (OR = 1.3, CI 0.8, 2.2) analyses after adjustment for confounding.

Conclusions: For young U.S. workers, common occupational injuries (excluding sprains and strains) may not be strongly associated with alcohol dependence. Confounding by other risk factors may explain much of the association between being a heavy drinker and occupational injuries in this population.
Increased Distractibility by Task‐Irrelevant Sound Changes in Abstinent Alcoholics
Authors: Ahveninen Jyrki , Jääskeläinen Iiro P. , Pekkonen Eero , Hallberg Anja , Hietanen Marja , Näätänen Risto , Schröger Erich , Sillanaukee Pekka
Published: April 2006

Background: Chronic alcoholism is accompanied by “frontal” neuropsychological deficits that include an inability to maintain focus of attention. This might be associated with pronounced involuntary attention shifting to task‐irrelevant stimulus changes and, thereafter, an impaired reorienting to the relevant task. The neural abnormalities that underlie such deficits in alcoholics were explored with event‐related potential (ERP) components that disclosed different phases of detection and orienting to stimulus changes.

Methods: Twenty consecutive abstinent male alcoholics (DSM‐IV) and 20 age‐matched male controls (healthy social drinkers) were instructed to discriminate equiprobable 100 and 200 msec tones in a reaction‐time task (RT) and to ignore occasional, either slight (7%) or wide (70%), frequency changes (hypothesized to increase RT) during an ERP measurement.

Results: In the alcoholics, we found pronounced distractibility, evidenced by a RT lag (p < 0.01) caused by deviants, that correlated (Spearman ρ= 0.5) with a significantly enhanced (p < 0.01) amplitude of mismatch negativity (MMN) to deviants. Significantly increased RT lag for trials subsequent to deviants (slight p < 0.001, wide p < 0.05) in the alcoholics suggested impaired reorienting to the relevant task. The MMN enhancement also predicted poorer hit rates in the alcoholics (Spearman ρ= 0.6–0.7). Both the MMN enhancement and pronounced distractibility correlated (Spearman ρ= 0.4) with an early onset of alcoholism.

Conclusions: Attentional deficits in the abstinent alcoholics were indicated by the increased distractibility by irrelevant sound changes. The MMN enhancement suggested that this reflects impaired neural inhibition of involuntary attention shifting, being most pronounced in early‐onset alcoholics.
Ethanol Inhibits Insulin Receptor Tyrosine Kinase
Authors: Seiler Andrea E. M. , Henderson Aaron , Rubin Raphael
Published: April 2006

Background: Ethanol inhibits insulin‐like growth factor‐I (IGF‐I) and insulin signaling in various cell types. The tyrosine autophosphorylation of the IGF‐I and insulin receptors appears to be a target for ethanol, as well as other receptor tyrosine kinases.

Methods and Results: The effect of ethanol on purified recombinant insulin receptor kinase activity was examined. A noncompetitive inhibition was observed at pharmacologically relevant concentrations of ethanol. Both peptide substrate tyrosine phosphorylation and kinase autophosphorylation are inhibited by ethanol. Near equivalent inhibition of kinase activity was noted for 300 mM methanol, 150 mM ethanol, 20 mM 1‐propanol, and 10 mM 1‐butanol.

Conclusion: The findings identify a direct protein interaction site of ethanol, and provide insight into the mechanism by which ethanol inhibits receptor tyrosine kinase activity.
Gene Expression in Human Alcoholism: Microarray Analysis of Frontal Cortex
Authors: Lewohl Joanne M. , Wang Long , Miles Michael F. , Zhang Li , Dodd Peter R. , Harris R. Adron
Published: April 2006

Background: Changes in brain gene expression are thought to be responsible for the tolerance, dependence, and neurotoxicity produced by chronic alcohol abuse, but there has been no large scale study of gene expression in human alcoholism.

Methods: RNA was extracted from postmortem samples of superior frontal cortex of alcoholics and nonalcoholics. Relative levels of RNA were determined by array techniques. We used both cDNA and oligonucleotide microarrays to provide coverage of a large number of genes and to allow cross‐validation for those genes represented on both types of arrays.

Results: Expression levels were determined for over 4000 genes and 163 of these were found to differ by 40% or more between alcoholics and nonalcoholics. Analysis of these changes revealed a selective reprogramming of gene expression in this brain region, particularly for myelin‐related genes which were down‐regulated in the alcoholic samples. In addition, cell cycle genes and several neuronal genes were changed in expression.

Conclusions: These gene expression changes suggest a mechanism for the loss of cerebral white matter in alcoholics as well as alterations that may lead to the neurotoxic actions of ethanol.
Impairment in Eyeblink Classical Conditioning in Adult Rats Exposed to Ethanol as Neonates
Authors: Green John T. , Rogers Ronald F. , Goodlett Charles R. , Steinmetz Joseph E.
Published: April 2006

Background: Eyeblink classical conditioning is a learning task that engages well‐defined neural circuitry in the cerebellum and brainstem. Binge‐like exposure to alcohol during the neonatal brain growth spurt in rats produces neurotoxic effects on both the cerebellum and the brainstem. The precise localization of the neural substrates of eyeblink conditioning makes it an ideal task to study functional disruptions in the cerebellum and brainstem caused by early exposure to alcohol. The purpose of this study was to determine whether impairments in eyeblink conditioning caused by neonatal binge exposure to alcohol persist into adulthood, indicative of long‐lasting abnormalities in cerebellar and brainstem function.

Methods: Group Ethanol received alcohol doses of 5.25 g/kg/day via intragastric intubation on postnatal days 4–9. Group Sham Intubated underwent the intragastric intubation procedures on postnatal days 4–9 but did not receive any infusions. Group Nonintubated did not receive any intubations. When all rats were at least 3 months old, they were tested in either paired or unpaired eyeblink conditioning.

Results: Group Ethanol showed impaired eyeblink conditioning and some abnormalities in conditioned response timing. Control groups did not differ from each other.

Conclusions: The present data indicate that early exposure to alcohol has long‐term effects on eyeblink conditioning, perhaps through enduring effects associated with alcohol‐induced loss of Purkinje cells of the cerebellum.
Carbohydrate‐Deficient Transferrin (CDT) and HDL Cholesterol (HDL) Are Highly Correlated in Male Alcohol Dependent Patients
Authors: Szegedi Armin , Müller Matthias J. , Himmerich Hubertus , Anghelescu Ion , Wetzel Hermann
Published: April 2006

Background: Serum levels of total HDL cholesterol (HDL) are reportedly influenced by recent alcohol intake. We examined the correlation between HDL cholesterol and widely used markers of excessive alcohol intake, such as carbohydrate‐deficient transferrin (CDT), γ‐glutamyl‐transferase (GGT), or mean corpuscular volume of erythrocytes (MCV), of which CDT is thought to be the most specific.

Methods: Several serological markers [i.e., CDT, GGT, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), MCV, and HDL] were determined in 100 actively drinking male patients with alcohol dependence (DSM‐IV) and in 27 non‐alcohol‐dependent controls, according to routine procedures. Spearman‘s rank correlation coefficients were calculated.

Results: We found a highly significant positive correlation between HDL and CDT (rs= 0.55;p < 0.0005) in patients, but not in controls (rs= 0.13;p= 0.51). HDL was also positively correlated with GGT, ALAT, ASAT, and MCV only in patients.

Conclusions: HDL cholesterol, as a widely determined parameter, may represent a useful routine marker for recent excessive alcohol intake. High HDL cholesterol levels should alert clinicians to investigate a patient's recent pattern of alcohol consumption.
Effects of Acute, Moderate Ethanol Consumption on Human Platelet Aggregation in Platelet‐Rich Plasma and Whole Blood
Authors: Zhang Qing‐Hui , Das Kabita , Siddiqui Shahid , Myers Adam K.
Published: April 2006

Background: Platelet‐inhibitory effects of alcohol potentially contribute to the reduced risk of coronary heart disease associated with moderate drinking. However, few studies have directly examined the effects of acute consumption of a moderate dose of alcohol on aggregation of platelets from healthy human subjects. In the present study, we examined those effects, with the use of multiple platelet agonists and two aggregation measurement techniques, as part of an ongoing series of studies that evaluate the actions of ethanol on platelet function.

Methods: Human subjects consumed alcohol at a dose equivalent to one drink (0.25 ml/kg) or two drinks (0.5 ml/kg). One hour after ingestion, anticoagulated blood was collected and agonist‐induced aggregation of platelets was measured in both whole blood and in platelet‐rich plasma.

Results: Inhibition of aggregation by ethanol consumption was observed in whole blood (measured as maximum change in impedance) and reached statistical significance (p < 0.05) in the 0.5 ml/kg alcohol group for two collagen concentrations (0.625 and 1.25 μg/ml) as well as for the highest concentration of adenosine diphosphate tested (p < 0.05). Inhibition was 15.4%, 22.6%, and 10.5%, respectively, for these three situations. In platelet‐rich plasma, after consumption of 0.5 ml/kg ethanol, aggregation (measured as maximum change in optical density) in response to 1.25 μg/ml collagen was significantly inhibited (p < 0.05); no other significant inhibition was observed at either dose of alcohol in any other cases with platelet‐rich plasma. In comparison of male and female subjects, there was a statistically significant difference (p < 0.05) in the degree of inhibition by ethanol consumption (0.5 ml/kg) of whole‐blood platelet aggregation induced by collagen, whereby female aggregation was inhibited to a greater extent than male.

Conclusions: This study shows that alcohol, at physiologically relevant doses, below those investigated in most previous human studies, has a dose‐dependent inhibitory effect on platelet aggregation. Such an effect could potentially contribute to the beneficial effects of alcohol consumption against coronary artery disease. The inhibitory action is most readily measured with whole‐blood platelet aggregometry, with the use of collagen as the agonist. This observation is consistent with the view that alcohol reduces platelet sensitivity to thrombotic stimuli by inhibition of arachidonic acid release and, therefore, subsequent thromboxane synthesis.
Formation of Malondialdehyde Adducts in Livers of Rats Exposed to Ethanol: Role in Ethanol‐Mediated Inhibition of Cytochrome c Oxidase
Authors: Chen Juanjuan , Petersen Dennis R. , Schenker Steven , Henderson George I.
Published: April 2006

Background: Previous studies in our laboratory demonstrated that short‐term ethanol consumption by maternal rats increased the hepatic levels of 4‐hydroxynonenal (HNE) in both the adult and the fetus. Additionally, HNE inhibited cytochrome c oxidase (COX) by forming adducts with the enzyme subunits. The present study examined modification of COX by another major aldehydic lipid peroxidation product, malondialdehyde (MDA), and its role in COX inhibition by ethanol.

Methods and Results: It is demonstrated in vitro that MDA inhibits the activity of purified COX while forming adducts with the enzyme. Compared with HNE, MDA is a more potent inhibitor of COX. Overnight incubation at room temperature caused an 80% decrease in COX activity by MDA versus a 67% decrease by HNE. MDA produced marked inhibition of COX activity at physiologically relevant concentrations, e.g., 43% inhibition at 10 μM. Although our previous studies documented that HNE formed adducts primarily with subunit IV of COX via histidine residues, the current report showed that MDA forms adducts with both subunit IV and subunit V via lysine residues. Furthermore, both aldehydes induce carbonyl formation in subunit IV. The in vivo role of MDA in the impairment of COX by ethanol is assessed in both adult and fetal liver after maternal ethanol consumption.

Conclusions: The results showed that: (1) there are significant increases in MDA levels in liver homogenate as well as mitochondria in both adult and fetal livers after ethanol exposure; (2) these MDA levels are in the nanomole/mg protein range, in contrast to picomole/mg protein range of HNE in identical setting; and (3) ethanol‐induced production of MDA is accompanied by enhanced formation of MDA adducts with COX. These findings suggest that MDA may play at least as equally an important role as HNE in ethanol‐induced inhibition of COX.
Pattern of Motor and Cognitive Deficits in Detoxified Alcoholic Men
Authors: Sullivan E. V. , Rosenbloom M. J. , Pfefferbaum A.
Published: April 2006

Background: Chronic excessive consumption of alcohol produces marked deficits in cognitive and motor abilities, although not all functions are affected to the same extent. Furthermore, although the occurrence of neuropsychological deficits in recently detoxified alcoholics is firmly established, the relative severity of these deficits, the specific neural systems that underlie the deficits, and their relationship to age and alcohol consumption variables either are less established or have proven elusive altogether.

Methods: We administered an extensive battery of neuropsychological tests, chosen for their known sensitivity to brain lesions in specific locations, to 71 recently (1 month) detoxified alcoholic men and 74 healthy controls who spanned the adult age range. Test scores were standardized to the controls for age and grouped a priori into composites that reflected performance in six functional domains: executive functions, short‐term memory, upper limb motor ability, declarative memory, visuospatial abilities, and gait and balance. Analogous verbal and nonverbal materials and left‐ and right‐hand upper limb motor tasks were used to test whether alcohol‐related deficits were greater for left or right hemisphere.

Results: Compared with controls, the alcoholics were impaired on executive functions, visuospatial abilities, and gait and balance even after we accounted for group differences in estimated premorbid IQ and education. Within the alcoholic group, the most salient deficits were in gait and balance and visuospatial abilities. No consistent lateralized deficit was observed across the four domains tested. Unlike the cognitive composites, the upper limb motor ability and gait and balance composites both showed increasing vulnerability to age, with an independent contribution to the gait and balance dysfunction from the amount of alcohol consumed over a lifetime.

Conclusions: The pattern of functional deficits implicates at least two principal neural systems: the cerebellar‐frontal system and the corticocortical system between the prefrontal and parietal cortices. In addition, age and amount of alcohol consumption were better predictors of motor than cognitive impairments.
Blunted Stress Cortisol Response in Abstinent Alcoholic and Polysubstance‐Abusing Men
Authors: Lovallo William R. , Dickensheets Stacey L. , Myers Dean A. , Thomas Terrie L. , Nixon Sara Jo
Published: April 2006

Background: This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM‐IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic‐pituitary‐adrenocortical (HPA) reactivity in recovering alcoholics.

Methods: Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20‐min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days.

Results: The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics.

Conclusions: The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.
Reliability and Validity of the Alcohol Use Disorders Identification Test (AUDIT) Imbedded Within a General Health Risk Screening Questionnaire: Results of a Survey in 332 Primary Care Patients
Authors: Daeppen Jean‐Bernard , Yersin Bertrand , Landry Ulrika , Pécoud Alain , Decrey Hedi
Published: April 2006

Background: Self‐administered, general health risk screening questionnaires that are administered while patients wait in the doctor's office may be a reasonable and timesaving approach to address the requirements of preventive medicine in a typical 10‐min medical visit. The psychometric characteristics of the Alcohol Use Disorders Identification Test (AUDIT) incorporated within a health questionnaire (H‐AUDIT) have not been examined.

Methods: The reliability and validity of the self‐administered AUDIT were compared between the H‐AUDIT and the AUDIT used as a single scale (S‐AUDIT) in 332 primary care patients.

Results: No major demographic or alcohol use characteristics were found between the 166 subjects who completed the H‐AUDIT and the 166 individuals who completed the S‐AUDIT. The test‐retest reliability of the 166 subjects who completed the H‐AUDIT [estimated by Spearman correlation coefficient at a 6‐week interval (0.88), internal consistency (total correlation coefficients for all items ranged from 0.38 to 0.69; Cronbach α index 0.85), and the sensitivity and specificity of the H‐AUDIT were used to identify at‐risk drinkers’ areas under receiver operating characteristic (0.77) and alcohol‐dependent subjects’ areas under receiver operating characteristic (0.89)] was similar to the same measurements obtained with the 166 individuals who completed the S‐AUDIT.

Conclusions: The AUDIT incorporated in a health risk screening questionnaire is a reliable and valid self‐administered instrument to identify at‐risk drinkers and alcohol‐dependent individuals in primary care settings.