bluuebunny/crossref_metadata_2025 huggingface dataset:
Working Memory Impairments in Alcohol‐Dependent Participants Without Clinical Amnesia
Authors: Ambrose Margaret L. , Bowden Stephen C. , Whelan Greg
Published: April 2006

Background: The delayed alternation (DA) task is highly sensitive to the deficits of nonhuman animals with alcohol‐related brain damage. DA is thought to measure working memory which serves as a temporary store for processing of information. However, performance on this type of task has only been investigated in alcohol‐dependent humans with severe cognitive deficits. The aim of the current study was to e‐plore the validity of DA as a test sensitive to alcohol‐related brain damage by manipulating storage and processing components in three versions of the task. It was hypothesized that alcohol‐dependent people would perform worse than control participants and that their deficits would be more pronounced in DA versions with ma‐imal working memory demands.

Methods: A sample of 12 alcohol‐dependent participants without Wernicke‐Korsakoff syndrome was compared with a sample of 12 nonalcohol‐dependent controls on three versions of DA. These versions, in order of increasing working memory demand, were single alternation (LR), double alternation (LLRR), and asymmetric alternation (LRRR). DA was administered on a personal computer and performance measured by the number of trials taken to reach criterion.

Results: Alcohol‐dependent participants, compared with the control participants, took more trials to reach learning criterion on DA on all versions when analyzed together (p= 0.002). Performance on DA was also found to deteriorate with increased working memory demands in both groups of participants (p < 0.001). However, the deficits of alcohol‐dependent participants were most pronounced on the DA task with moderate (LLRR) as opposed to extreme (LRRR) working memory demands.

Conclusions: The results indicate that both storage and processing demands are necessary for task performance and demonstrate sensitivity of DA to alcohol‐related brain injury.
Maintaining Intentional Control of Behavior Under Alcohol
Authors: Grattan Karen E. , Vogel‐Sprott M.
Published: April 2006

Background: This research used a process dissociation paradigm to measure the influence of controlled and automatic processes on a word‐stem completion task when correct performance under alcohol was positively reinforced, or had no particular consequence. It was predicted that the impairing effect of alcohol on controlled processes that govern intentional control of behavior would be resisted when drinkers were reinforced for performing well.

Methods: Four groups of eight male drug‐free social drinkers initially studied a list of words. Two of the groups then received 0.56 g/kg alcohol (A) and two received a placebo (P) before the stem‐completion task was performed. During the task, the correct responses of one pair of A and P groups were reinforced (money and verbal approval) whereas no reinforcement was provided to the other pair.

Results: As predicted, under alcohol, the influence of controlled processes that govern intentional responses was greater when reinforcement was provided than when it was absent (p= 0.005). Without reinforcement, controlled processes in the A group were lower than the P control group (p= 0.01). In contrast, the A and P groups that received reinforcement did not differ (p= 0.142). Controlled processes in the P groups were not affected by reinforcement (p= 0.65). In addition, the influence of automatic processes was not affected by alcohol or by reinforcement (p > 0.781).

Conclusions: Positive reinforcement for behavior under alcohol increases the influence of controlled processes. These results suggest that the degree to which intentional control is retained under alcohol depends on the consequence of behavior in the situation. It seems that controlled processes enable drinkers to intentionally display the behavior that is rewarded.
Neurochemical Characteristics Associated With Ethanol Preference in Selected Alcohol‐Preferring and ‐Nonpreferring Rats: A Quantitative Microdialysis Study
Authors: Katner Simon N. , Weiss Friedbert
Published: April 2006

Background: Rodent lines selected for alcohol preference and nonpreference have been used extensively to determine the neurobiological basis of alcohol‐seeking behavior. Evidence suggests that innate differences in the mesolimbic dopamine and serotonin systems may contribute to disparate alcohol‐seeking behaviors between these selected lines. Therefore, the purpose of this study was to identify neurochemical characteristics which may predict ethanol preference in selected alcohol‐preferring and ‐nonpreferring rats [high–alcohol‐preferring (HAD), low–alcohol‐preferring (LAD), Alko alcohol (AA), Alko nonalcohol (ANA), Wistar].

Methods: Basal release of dopamine (DA) and serotonin (5‐HT) in the nucleus accumbens of ethanol‐naive rats was analyzed for its relationship with subsequent measures of ethanol preference. Initially, basal extracellular DA and 5‐HT levels were measured by “no‐net‐flux” quantitative microdialysis. Subsequently, the dopaminergic response to systemic ethanol administration (1.5 g/kg; intraperitoneal) was determined. After completion of the neurochemical tests, the rats received unlimited two‐bottle, free‐choice access to 10% (w/v) ethanol and water in the home cage for 28 days.

Results: Analysis of the data across individual animals revealed that extracellular dopamine levels ([DA]e;r=+ 0.64;p < 0.006) and the percent of baseline increase in DA (%incrDA;r=+ 0.77;p < 0.001) due to ethanol were significant predictors of ethanol preference. Comparison of the data between genetic lines yielded a significant relationship between preference and %incrDA (r=+ 0.87;p < 0.05). Analysis of the data across animals within each line and their respective control line determined that in the AA/ANA line pair (r=+ 0.67;p < 0.03) and Wistar line (r=+ 0.66;p < 0.03) %incrDA was a significant predictor of preference. In the HAD/LAD line pair, %incrDA (r=+ 0.56;p < 0.005) and [DA]e (r=+ 0.86;p < 0.004) were significant predictors of ethanol preference.

Conclusions: Overall, these findings suggest that elevated extracellular levels of dopamine within the nucleus accumbens and a greater responsivity to enhancements in DA release by ethanol may be factors which contribute to high‐alcohol preference. Furthermore, the data suggest that alcohol may be more reinforcing in animals that exhibit an enhanced dopaminergic response to the first ethanol exposure, and that this effect may subsequently be associated with high–alcohol‐seeking behavior.
Genetic Determinants of Alcohol Addiction and Metabolism: A Survey in Italy
Authors: Pastorelli Roberta , Bardazzi Gabriele , Saieva Calogero , Cerri Annalisa , Gestri Donella , Allamani Allaman , Airoldi Luisa , Palli Domenico
Published: April 2006

Background: Although multiple genes are involved in alcoholism and can contribute differently to the risk of dependence and liver damage, no studies have investigated susceptibility to addiction in combination with susceptibility to liver damage due to differences in ethanol metabolism.

Methods: We evaluated the role of three polymorphic genes related to alcohol metabolism (CYP2E1) and, possibly, dependence (DRD2 and SLC6A4 promoter) in a series of 60 alcoholics admitted to a specialized referral center in Florence, Italy. Eighteen had a diagnosis of liver cirrhosis. A control series of 64 blood donors were identified at the same hospital. Genotyping was done by polymerase chain reaction‐restriction fragment length polymorphism methods.

Results: No difference was found in the frequency of the CYP2E 1 Rsa I c2 allele (2.5% among alcoholics and 4.7% among controls) and the Dra I C allele (6.7% and 10.1%). Similarly, no difference was found in the frequency of the DRD2 A1 allele (15.8% and 13.3%) and the B1 allele (10.8% and 8.6%). The proportion of controls with a combined B1 genotype (B1/B1 or B1/B2) was significantly associated with smoking (p= 0.03). The distribution of the S and L allele of the SLC6A4 gene was similar in the two groups, with 15% and 14%, respectively, homozygous S/S carriers. A significant association, however, emerged in the group of alcoholics, with a five times higher risk for S/S carriers of developing cirrhosis (p < 0.05). This association with liver persisted even after exclusion of the subgrouped of 10 hepatitis C virus positive alcoholics.

Conclusions: Overall, our results provided no evidence of an increased susceptibility to develop alcoholism that was associated with the three genotypes investigated, either alone or in combination. An increased risk of developing liver cirrhosis for S/S homozygous carriers among alcohol‐dependent patients was observed for the first time.
Coronary Artery Disease Modifies Left Ventricular Remodelling due to Heavy Alcohol Consumption
Authors: Kajander Olli A. , Kupari Markku , Laippala Pekka , Penttilä Antti , Karhunen Pekka J.
Published: April 2006

Background: Coronary artery disease (CAD) and e‐cessive alcohol use can both damage the myocardium. Their combined effect on the heart muscle has not been characterized. We set out to assess whether the presence of CAD modifies the effects of chronic alcohol consumption on the left ventricular (LV) structure in middle‐aged men.

Methods: A postmortem e‐amination was performed on 700 Finnish men (age range, 33–70 years) who e‐perienced a sudden, nonhospital death. A coronary arteriography and measurement of the LV wall thickness, cavity area, and ratio by planimetry of transversal ventricular slices were done at the autopsy. The men were grouped by the most severe coronary artery diameter stenosis (<30%, 30–60%, >60%) and by daily alcohol dose (<12 g, 12–72 g, 72–180 g, >180 g) estimated by a structured interview of their lifetime partner.

Results: Analysis by ANCOVA, adjusted for age, body size, smoking, hypertension, and diabetes, showed a statistically significant interaction between the effects of coronary artery stenosis and daily alcohol dose on the LV cavity area (p= 0.037) and on the LV wall thickness/cavity area ratio (p= 0.018). In the group with <30% stenosis, the LV wall thickness/cavity area ratio (mean ± SEM) increased from 1.6 ± 0.2 mm/cm2 in men drinking <12 g/day to 6.2 ± 1.4 mm/cm2 in men drinking 72–180 g/day (p= 0.021). A similar trend was seen in men with 30–60% coronary stenosis (p= 0.32). By contrast, in men with >60% coronary stenosis, the LV wall thickness/cavity area ratio decreased with increasing daily alcohol use from 2.2 ± 0.3 to 1.4 ± 0.1 mm/cm2 (p= 0.27).

Conclusions: CAD modulates the effects of alcohol on the heart muscle. Heavy drinking results in concentric LV remodelling in men with no or only mild coronary artery stenoses whereas an opposite trend is seen in men with severe coronary artery obstructions. The mechanism of the interaction remains unknown.
Third Trimester Binge Ethanol Exposure Results in Fetal Hypercapnea and Acidemia but Not Hypoxemia in Pregnant Sheep
Authors: Cudd Timothy A. , Chen Wei‐Jung A. , Parnell Scott E. , West James R.
Published: April 2006

Background: The mechanisms by which maternal ethanol abuse during pregnancy causes neurodevelopmental injury in the fetus are not well understood. The purpose of this study was to use a chronically instrumented fetal sheep model system to determine if a binge pattern of ethanol e‐posure administered throughout the third trimester reduced fetal arterial partial pressure of o‐ygen (PaO2); a positive finding would support the hypothesis that fetal hypoxemia may play a role in mediating ethanol‐related birth defects.

Methods: Pregnant ewes received saline or 0.75, 1.25, 1.5, or 1.75 g/kg of ethanol intravenously over 1 hr beginning on day 109 of gestation (term = 145 days) for 3 consecutive days per week followed by 4 days without e‐posure. The fetuses were surgically instrumented on day 113, and e‐periments were performed on days 118 or 132, the 6th and the 12th ethanol e‐posure, respectively.

Results: Ethanol infusions resulted in peak blood ethanol concentrations of 80.8 ± 6.5, 182.5 ± 13.5, 224.4 ± 13.9, and 260.6 ± 20.0 mg/dl ± SEM (maternal) and 70.0 ± 5.9, 149.7 ± 9.0, 216.9 ± 14.0, and 233.3 ± 19.8 mg/dl ± SEM (fetal) in response to the 0.75, 1.25, 1.5, and 1.75 g/kg doses, respectively. Maternal and fetal heart rate and maternal blood pressure increased whereas fetal blood pressure decreased in a dose‐dependent manner in response to ethanol infusions. Maternal and fetal arterial pH decreased and arterial partial pressures of carbon dio‐ide increased in response to ethanol infusions. Maternal PaO2 decreased whereas fetal PaO2 did not change in response to ethanol infusions.

Conclusions: A binge ethanol e‐posure paradigm, three consecutive days per week throughout the third trimester at ethanol doses that created blood ethanol concentrations commonly achieved by human ethanol abusers, resulted in changes in maternal and fetal heart rate, changes in blood pressure, hypercapnea, acidemia, and maternal, but not fetal, hypo‐emia. We conclude that in an ovine model system, ethanol doses that create blood ethanol concentrations as high as 260 mg/dl do not result in fetal hypo‐emia. Remaining issues to address with this model system are whether neurodevelopmental injuries that are associated with maternal ethanol abuse are mediated by a reduction in fetal cerebral blood flow, fetal hypercapnea, or acidemia.
Identifying Maternal Self‐Reported Alcohol Use Associated With Fetal Alcohol Spectrum Disorders
Authors: Barr Helen M. , Streissguth Ann P.
Published: April 2006

Background: The incidence of Fetal Alcohol Syndrome (FAS) has been estimated at 1 to 3 per 1000 live births. Fetal Alcohol Spectrum Disorders (FASD) (which include FAS) are estimated to occur in about 1 in 100 births. Cessation of drinking during pregnancy can improve the outcome even if the unborn child is already affected. For individuals born with FASD, an early diagnosis appears to be a protective factor against secondary disabilities. A quick screening tool to identify newborn children at risk has been elusive.

Methods: A simple descriptive presentation is offered that shows where 36 individuals with FASD were found from among the many patterns and amounts of prenatal alcohol use that were reported by a sample of 1439 pregnant women whose offspring were later e‐amined within the first 7 years of life.

Results: Individuals with FASD (i.e., those with FAS, fetal alcohol effects, alcohol‐related neurodevelopmental disorder) were found within two aggregates of alcohol scores that together recommend a set of three to four alcohol questions. Within this derivation sample, one scoring of the questions yields almost 78% sensitivity and 97% specificity for FASD. Another scoring of the same instrument yields 100% sensitivity with 90% specificity.

Conclusions: These new data may facilitate early identification of offspring who may be most in need of early intervention, namely those born with FASD.
Approaches to Understanding the Neurobiological Regulation of Ethanol Self‐Administration: A Young Investigators Forum
Authors: Czachowski Cristine L. , Slawecki Craig J. , Grahame Nicholas J. , Thiele Todd E. , Katner Simon N.
Published: April 2006

The article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The co‐chairs were Cristine L. Czachowski and Craig J. Slawecki. The presentations were (1) Behavioral assessment of ethanol seeking and self‐administration, by Cristine L. Czachowski; (2) Electrophysiological measures of ethanol preference and reinforcing efficacy, by Craig J. Slawecki; (3) Genetic differences in locomotor sensitization and reward phenotypes associated with bidirectional selection for alcohol preference in mice, by Nicholas J. Grahame; (4) Transgenic and knockout mouse models: Powerful tools for investigating the neurobiology of alcoholism, by Todd E. Thiele; and (5) Neurochemical characteristics that may predict ethanol preference in selected P and NP rats: A quantitative microdialysis study, by Simon N. Katner.
The Role of Craving in Alcohol Use, Dependence, and Treatment
Authors: Flannery Barbara A. , Roberts Amanda J. , Cooney Ned , Swift Robert M. , Anton Raymond F. , Rohsenow Damaris J.
Published: April 2006

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer and chair was Barbara A. Flannery, and the co‐chairs were Barbara A. Flannery and Helen Pettinati. The presentations were (1) Animal models of alcohol craving and relapse, by Amanda Roberts; (2) Real‐time field assessment of alcohol craving, by Ned Cooney; (3) Medications and alcohol craving, by Robert Swift; (4) The assessment of craving: Insights from the clinic and clinical laboratory studies, by Raymond Anton; (5) A comparison of three alcohol craving questionnaires, by Barbara Flannery; (6) and Assessing posttreatment urge to drink, by Damaris Rohsenow.
Neurotoxicity and Neurocognitive Impairments With Alcohol and Drug‐Use Disorders: Potential Roles in Addiction and Recovery
Authors: Bowden Stephen C. , Crews Fulton T. , Bates Marsha E. , Fals‐Stewart William , Ambrose Margaret L.
Published: April 2006

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organisers/chairs were Stephen C. Bowden and Fulton T. Crews. The presentations were (1) Age, genetic and other factors that increase risk of alcoholism also increase alcohol‐induced neurotoxicity, by Fulton T. Crews; (2) A neurocognitive moderation model of addictions treatment response, by Marsha E. Bates; (3) The relationship of neurocognitive impairment and longitudinal treatment outcome among substance‐abusing patients, by William Fals‐Stewart; and (4) Treatment of cognition in detoxifying alcohol‐dependent participants, by Margaret L. Ambrose.
The Synthesis and Secretion of Fatty Acid Ethyl Esters From HepG2 Cells Are Stimulated by Lipoproteins and Albumin
Authors: Hasaba Ali , Laposata Michael
Published: April 2006

Background: Fatty acid ethyl esters (FAEEs) are nonoxidative metabolites of ethanol produced by the esterification of fatty acids and ethanol. FAEEs have been implicated as mediators of ethanol‐induced organ damage in vivo and in vitro. They are detectable in the blood and in many organs after ethanol ingestion, and on this basis they are useful markers of ethanol intake in living patients as well as subjects at autopsy. FAEEs found in human plasma after ethanol ingestion bind to lipoproteins and albumin.

Methods: In this study, we used a hepatoblastoma cell model (HepG2) to determine if lipoproteins or albumin stimulates the synthesis and/or secretion of FAEEs from HepG2 cells. Because FAEEs have been shown to decrease HepG2 cellular proliferation and protein synthesis, their removal from cells potentially could reestablish normal cell activity.

HepG2 cells were incubated with 100 mM ethanol and 6 nM 3H oleic acid to generate 3H‐FAEEs within the cells. Dose response and time course studies were performed by using low density lipoproteins, high density lipoproteins, and albumin as FAEE acceptors.

Results: The results indicate that FAEEs are extracted efficiently by each of these FAEE carriers and that FAEE synthesis also is stimulated by the addition of FAEE carriers to the extracellular medium.

Conclusion: These observations indicate that lipoproteins and albumin can extract ethyl esters from HepG2 cells and thereby may limit alcohol‐induced liver damage.
Effects of Acamprosate on Ethanol‐Seeking and Self‐Administration in the Rat
Authors: Czachowski Cristine L. , Legg Brooke H. , Samson Herman H.
Published: April 2006

Background: Acamprosate (calcium acetyl homotaurinate) has been used clinically to treat relapse in alcoholics. In rats, it has been shown to decrease ethanol, but not water, self‐administration after ethanol deprivation.

Methods: To further investigate the effect of acamprosate on reinforced behaviors in rats, the present experiment used: (1) both ethanol and sucrose reinforcer solutions to better assess the distinct effects of acamprosate on ethanol‐directed behaviors, and (2) an operant model that procedurally separates the “cost” to begin drinking from consuming the reinforcer solutions to dissociate the effects of acamprosate on appetitive versus consummatory processes. In daily sessions (5 days/week), rats (n= 6/group) were trained to make 30 lever‐press responses to gain access for 20 min to a sipper tube containing either ethanol (10%) or sucrose (3%). After stable responding, acamprosate treatment was given. Three doses were tested (50, 100, and 200 mg/kg/injection, intraperitoneally), one dose per week. Each week, a total of four injections were given (21 and 2 hr before the operant sessions over 2 consecutive days).

Results: At these doses, acamprosate had no effect on the measures of appetitive responding for either solution. However, all doses reliably decreased ethanol consumption on the 2nd day of treatment (from an average of 0.83 to 0.63 g/kg). Analysis of the pattern of ethanol consumption showed that the effects of acamprosate occurred after the onset of a normal pattern of intake, as measured by lick rate and size of the initial bout of drinking, which suggested that acamprosate is most effective when combined with the pharmacological effects of ethanol. Sucrose intake was unaffected by all acamprosate treatments, which indicated that the treatment effects were specific to ethanol and not due to a general decrease in consummatory behavior.

Conclusions: Overall, these results suggest that acamprosate is effective at reducing total ethanol intake, but may not reliably alter subjects propensity to begin a drinking bout as measured by this model. However, whether this applies to the clinical use of acamprosate, where other types of reinforcement may also precipitate relapse drinking, is not certain.
Ethanol‐Induced Increased Surface‐Localized Fibrinolytic Activity in Cultured Human Endothelial Cells: Kinetic Analysis
Authors: Abou‐Agag Laila H. , Tabengwa Edlue M. , Tresnak Jennifer A. , Wheeler Crystal G. , Taylor Kenneth B. , Booyse Francois M.
Published: April 2006

Background: Moderate alcohol consumption is associated with reduced risk for coronary heart disease and this cardioprotection may be due, in part, to increased fibrinolysis. We have previously demonstrated that low concentrations of ethanol (0.1%, v/v) induce the short‐term (<1 hr) and sustained, long‐term (24 hr) increase in surface‐localized fibrinolytic activity; it up‐regulates t‐PA, u‐PA, and the candidate plasminogen receptor (PmgR), annexin II, and gene transcription in cultured human umbilical vein endothelial cells (HUVECs). These studies describe the short‐ and long‐term effects of low concentrations of ethanol on the kinetics of cell‐bound 125I‐labeled Glu‐plasminogen (Glu‐Pmg) activation by receptor (R)‐bound t‐PA, resulting in increased fibrinolytic activity in cultured HUVECs.

Methods: Live cultured HUVECs were incubated with varying concentrations of Glu‐Pmg (0.25–2 μM) and ethanol (0.025–0.1%, v/v) (in the presence of Aprotinin and α2‐antiplasmin) and the direct activation of cell‐bound 125I‐labeled Glu‐Pmg quantitated by measurement of 125I‐labeled Mr 20 kDa plasmin light‐chain, after reduction/SDS‐PAGE. The effects of ethanol on 125I‐labeled Glu‐Pmg and t‐PA ligand binding were determined by Scatchard analysis (Bmax, sites/cell).

Results: Cell‐bound t‐PA (endogenous/exogenous) activation of cultured HUVEC‐bound 125I‐labeled Glu‐Pmg (short‐ and long‐term) obeyed Michaelis‐Menten kinetics, both in the absence/presence of low ethanol, as shown by Lineweaver‐Burke plot analysis. In the short‐term, ethanol (at 0.1%) increased the Vmax (2.5‐fold), kcat (2‐fold) and the apparent kcat/Km (4‐fold), commensurate with a significant decrease in the apparent Km (6‐fold) and increase in 125I‐labeled Glu‐Pmg ligand binding, Bmax (2‐fold). In the long‐term, ethanol increased the Vmax (2‐ to 3‐fold), kcat (2.5‐fold), apparent kcat/Km (5‐fold), and B max (2‐fold) for 125I‐labeled Glu‐Pmg ligand binding, without significantly affecting the apparent Km.

Conclusions: Low concentrations of ethanol induce the short‐ versus long‐term increase in surface‐localized fibrinolytic activity in cultured HUVECs via different mechanisms. Short‐term effects may be mediated by ethanol‐induced membrane conformational changes that simultaneously facilitate increased surface‐localized HUVEC PmgR availability and fibrinolytic protein/receptor interactions, resulting in the increased affinity of t‐PA for Glu‐Pmg and the accelerated activation of Glu‐Pmg (increased Bmax, decreased apparent Km). The long‐term effects may be attributed primarily to the ethanol‐induced increased availability of both newly synthesized t‐PA and PmgR and, hence, the accelerated activation of Glu‐Pmg (increased Bmax)
Altered Emotional Perception in Alcoholics: Deficits in Affective Prosody Comprehension
Authors: Monnot Marilee , Nixon Sara , Lovallo William , Ross Elliott
Published: April 2006

Background: Affective prosody is a nonlinguistic aspect of language that conveys emotion and attitude during discourse. It is a dominant function of the right hemisphere. Because skills associated with the right hemisphere have been found to be impaired in alcoholics, this study explored the possibility that affective prosodic functioning may be sensitive to the effects of alcohol due to heavy persistent drinking or prenatal exposure.

Methods: Subjects were aged 25 to 58 years. Twenty‐nine men and three women who met DSM‐IV criteria for an alcohol use disorder with a median of 39 days of sobriety, 11 men with a probable history of fetal alcohol exposure (FAexp), and 41 age‐matched control subjects of both sexes were tested by using the Aprosodia Battery. This instrument assesses affective prosodic comprehension (APC) across a range of verbal articulatory demands.

Results: The alcoholic group scored 2 SD below the control mean, and the FAexp group scored −5 SD regardless of whether they had ever been diagnosed with alcohol abuse. Despite their poor performance on APC, alcoholic and FAexp groups performed similarly to the control group on vocabulary, abstract reasoning, and an index of cognitive impairment that used the Shipley Institute of Living Scale. Multiple regression analyses that used nine alcohol use variables to model APC resulted in four significant contributors to the effect. These regressors were related to early exposure to ethanol and chronicity of alcohol abuse.

Conclusions: Alcoholics and FAexp subjects were significantly less accurate at APC compared with controls. These alcohol‐exposed subjects appear to be deficient in the ability to understand emotional valence in the speech of others, which results in errors of judgment that may impair social interactions.
Induction of Steady‐State Blood Alcohol Levels: Application to the Study of Within‐Session Alcohol Tolerance in Rats
Authors: Froehlich J. C. , Stewart R. B. , Li T.‐K. , Mosemiller A. K. , McCullough D. E. , Ho M. C. , Kisner J. M.
Published: April 2006

Background: The study of within‐session alcohol tolerance in the rat has been hampered by methodological difficulties related to the measurement of dependent variables at predictable blood alcohol concentrations (BAC) during a single session of alcohol exposure. This study characterizes a method for maintaining steady‐state blood alcohol levels over several hours in the rat, referred to as the “alcohol clamp.”

Methods: Wistar rats were implanted with an indwelling catheter in the carotid artery for blood sampling and another in the external jugular vein for alcohol infusion. To clamp BAC at a predetermined level, rats first were infused with a priming dose of alcohol to establish the desired or “target” BAC, followed by a continuous infusion of alcohol at a rate equal to that of alcohol metabolism in the rat. This maintained BAC at a constant level over time. BACs of 100, 200, or 300 mg% were maintained over several hours in separate groups of rats. The alcohol clamp was applied to the study of acute (within‐session) alcohol tolerance in rats selectively bred for high and low alcohol drinking. Alcohol‐induced hypothermia was used to index tolerance, and within‐session alcohol tolerance was defined as a return of body temperature toward baseline during the course of the alcohol infusion while BAC was maintained at a constant level.

Results: The continuous alcohol infusion procedure maintained BAC in a steady state throughout the 3 hr alcohol infusion session at each of the three target BAC levels. Alcohol infusion induced a drop in body temperature, followed by a return of temperature toward baseline during the course of infusion, which indicated the development of within‐session alcohol tolerance.

Conclusions: The continuous alcohol infusion procedure (alcohol clamp) maintained BAC in a steady state, both within and between subjects, across a wide range of blood alcohol levels. The alcohol clamp appears to be a useful tool for subsequent studies of within‐session alcohol tolerance in the rat.
Long‐Term Follow‐Up of a High School Alcohol Misuse Prevention Program's Effect on Students' Subsequent Driving
Authors: Shope Jean T. , Elliott Michael R. , Raghunathan Trivellore E. , Waller Patricia F.
Published: April 2006

Background: Alcohol‐related injuries, particularly motor vehicle, are an important cause of adolescent mortality. School‐based alcohol prevention programs have not been evaluated in terms of driving outcomes. This study examined the effects on subsequent driving of a high school‐based alcohol prevention program.

Methods: The Alcohol Misuse Prevention Study included a randomized test of the effectiveness of an alcohol misuse prevention curriculum conducted among 4635 10th‐grade students. Students were assigned to intervention (n= 1820) or control (n= 2815) groups and were followed for an average of 7.6 years after licensure, which typically occurred during or shortly after 10th grade. Outcomes examined included alcohol‐related and other serious offenses, and at‐fault, single‐vehicle, and alcohol‐related crashes.

Results: Only serious offenses (which included alcohol‐related) had a significant treatment effect (statistically marginal) after we adjusted for sex, age, race, alcohol use/misuse, family structure, presence of prelicense offenses, age of driver licensure, and parental attitudes toward teen drinking. The effect was found only during the first year of licensure (estimated adjusted relative risk = 0.80, confidence interval = 0.63–1.01). Two first‐year serious offense interactions were found. The positive effect was strongest among the largest subgroup of students, those who were drinking less than one drink per week on average before the curriculum, compared with those who drank more than one drink per week (p= 0.009). The effect was also stronger for the small subgroup of students whose parents had not expressed disapproval of teens’ drinking, compared with those whose parents had disapproved (p= 0.004).

Conclusions: These findings suggest that a high school‐based alcohol prevention program can positively affect subsequent driving, particularly that of students who do not use alcohol regularly. The results highlight the need to start prevention efforts early and extend them beyond the initial exposure to driving. Programs should incorporate the differing backgrounds of the students.
Course of DSM‐IV Alcohol Dependence in a Community Sample: Effects of Parental History and Binge Drinking
Authors: Hasin Deborah , Paykin Andrea , Endicott Jean
Published: April 2006

Background: The role of positive family history in the etiology of alcohol dependence has been demonstrated repeatedly but little is known about the effect of this risk factor on the chronicity of alcohol dependence once it has begun.

Methods: We studied the effects of parental and sibling history in conjunction with frequency of binge drinking in a sample of 169 community residents who met criteria for DSM‐IV alcohol dependence at the baseline interview. Subjects were re‐interviewed approximately 1 year later and the status of their alcohol‐dependence disorders (remitted or chronic) was determined.

Results: Parental history of alcoholism was significantly related to chronicity of alcohol dependence, as was frequency of binge drinking.

Conclusions: Failure to find an effect for family history on chronicity would have suggested that the effect was transient, perhaps interacting with time‐limited environmental vulnerability. The finding of a positive relationship between family history and chronicity suggests that the relationship between familial/genetic background and alcohol dependence is stable.
Acetaldehyde Production and Other ADH‐Related Characteristics of Aerobic Bacteria Isolated From Hypochlorhydric Human Stomach
Authors: Väkeväinen Satu , Tillonen Jyrki , Blom Mikko , Jousimies‐Somer Hannele , Salaspuro Mikko
Published: April 2006

Background: Acetaldehyde is a known local carcinogen in the digestive tract in humans. Bacterial overgrowth in the hypochlorhydric stomach enhances production of acetaldehyde from ethanol in vivo after alcohol ingestion. Therefore, microbially produced acetaldehyde may be a potential risk factor for alcohol‐related gastric and cardiac cancers. This study was aimed to investigate which bacterial species and/or groups are responsible for acetaldehyde formation in the hypochlorhydric human stomach and to characterize their alcohol dehydrogenase (ADH) enzymes.

Methods: After 7 days of treatment with 30 mg of lansoprazole twice a day, a gastroscopy was performed on eight volunteers to obtain hypochlorhydric gastric juice. Samples were cultured and bacteria were isolated and identified; thereafter, their acetaldehyde production capacity was measured gas chromatographically by incubating intact bacterial suspensions with ethanol at 37°C. Cytosolic ADH activities, Km values, and protein concentration were determined spectrophotometrically.

Results: Acetaldehyde production of the isolated bacterial strains (n= 51) varied from less than 1 to 13,690 nmol of acetaldehyde/109 colony‐forming units/hr. ADH activity of the strains that produced more than 100 nmol of acetaldehyde/109 colony‐forming units/hr (n= 23) varied from 3.9 to 1253 nmol of nicotinamide adenine dinucleotide per minute per milligram of protein, and Km values for ethanol ranged from 0.65 to 116 mM and from 0.5 to 3.1 M (high Km). There was a statistically significant correlation (r= 0.64, p < 0.001) between ADH activity and acetaldehyde production from ethanol in the tested strains. The most potent acetaldehyde producers were Neisseria and Rothia species and Streptococcus salivarius, whereas nearly all Stomatococcus, Staphylococcus, and other Streptococcus species had a very low capacity to produce acetaldehyde.

Conclusions: This study demonstrated that certain bacterial species or groups that originate from the oral cavity are responsible for the bulk of acetaldehyde production in the hypochlorhydric stomach. These findings provide new information with the respect to the local production of carcinogenic acetaldehyde in the upper digestive tract of achlorhydric human subjects.
Prolonged Ethanol Treatment Enhances Lipopolysaccharide/Phorbol Myristate Acetate‐Induced Tumor Necrosis Factor‐α Production in Human Monocytic Cells
Authors: Zhang Zili , Bagby Gregory J. , Stoltz David , Oliver Peter , Schwarzenberger Paul O. , Kolls Jay K.
Published: April 2006

Background: Ethanol (EtOH) is known to alter host immune responses and cytokine production. Acute EtOH exposure can suppress tumor necrosis factor (TNF)‐α production, which attenuates pulmonary defense against infection. Previous studies in our laboratory show that acute EtOH inhibited TNF‐α production by a posttranscriptional process, namely suppression of TNF‐α‐converting, enzyme‐mediated, ectodomain shedding. However, chronic EtOH has been shown to augment TNF‐α production, and this has been associated with EtOH‐induced liver injury. To further characterize this paradoxical effect of EtOH on TNF‐α production, we developed an in vitro model by using Mono Mac 6 cells, a human monocytic cell line.

Methods: Mono Mac 6 cells were treated with EtOH (0–75 mM) for 1 to 7 days. TNF‐α production was induced by lipopolysaccharide and phorbol myristate acetate and quantitated by enzyme‐linked immunosorbent assay. Generation of reactive oxygen species (ROS) was assayed by using a specific fluorogenic reagent.

Results: Acute EtOH initially inhibited lipopolysaccharide/phorbol myristate acetate‐induced TNF‐α production in Mono Mac 6 cells. However, during chronic EtOH exposure, this inhibition was reversed gradually over time. By day 6 after EtOH treatment, Mono Mac 6 cells demonstrated significant up‐regulation of TNF‐α production. Moreover, chronic EtOH induced the generation of ROS in these Mono Mac 6 cells. Scavenging ROS by Mn(III)tetrakis(1‐methyl‐4pyridyl)porphyrin pentachloride and N‐acetyl‐L‐cysteine attenuated chronic EtOH‐enhanced TNF‐α production.

Conclusion: These results suggest that ROS induction is involved in EtOH‐enhanced TNF‐α production by monocytes. This study also provides insight into the mechanisms of alteration of TNF‐α production in different EtOH exposure settings.
Inhibition of Hematopoietic Progenitor Cell Proliferation by Ethanol in Human Immunodeficiency Virus Type 1 Tat‐Expressing Transgenic Mice
Authors: Prakash Om , Rodriguez Vicente E. , Tang Zhen‐Ya , Zhou Peng , Coleman Roy , Dhillon Gundeep , Shellito Judd E. , Nelson Steve
Published: April 2006

Background: A number of hematological abnormalities are associated with both human immunodeficiency virus type 1 (HIV‐1) infection and alcohol abuse. There is little information on how alcohol abuse might further influence the survival and growth of hematopoietic progenitors in HIV‐infected individuals in the presence of immune system abnormalities and anti‐HIV drugs. Because there is evidence that viral transactivator Tat itself can induce hematopoietic suppression, in this study we examined the role of ethanol as a cofactor in transgenic mice that expressed HIV‐1 Tat protein.

Methods: Tat transgenic mice and nontransgenic littermates were given ethanol (20% v/v) and the anti‐HIV drug 3′‐azido‐3′‐deoxythymidine (AZT; 1 mg/ml) in drinking water. Immunosuppression in mice was induced by weekly intraperitoneal injections of anti‐CD4 antibody. Hematopoiesis was examined by erythroid colony forming unit (CFU‐E) and granulocyte/macrophage colony‐forming unit (CFU‐GM) assays of the bone marrow progenitor cells.

Results: Administration of ethanol for 7 weeks resulted in a 50% decrease in the proliferative capacity of CFU‐E‐ and CFU‐GM‐derived progenitors from transgenic mice compared with that of ethanol‐treated nontransgenic controls. Similar decreases also were observed in transgenic mice treated with AZT or a combination of AZT and ethanol. Furthermore, ethanol and AZT were significantly more toxic to the granulopoietic progenitors (40–50% inhibition) than to the erythropoietic progenitors (10–20% inhibition) in Tat transgenic mice. Although a 10 day exposure of Tat transgenic and nontransgenic mice to a combination of ethanol and AZT had no suppressive effect on the erythropoietic and granulopoietic progenitor cells, there was a marked decrease (40–60%) in CFU‐GM in mice made immunodeficient by CD4+ T‐lymphocyte depletion. The ethanol‐treated Tat transgenic mice but not the nontransgenic littermates also showed a significant decrease (25%) in CFU‐GM.

Conclusion: Our in vivo study strongly suggests that ethanol ingestion in HIV‐1‐infected individuals, particularly those on antiretroviral drugs, might increase bone marrow toxicity and contribute to HIV‐1‐associated hematopoietic impairment.
A Rodent Model of Alcoholic Heart Muscle Disease and Its Evaluation by Echocardiography
Authors: Kim Shann D. , Beck Jennifer , Bieniarz Teresa , Schumacher Autumn , Piano Mariann R.
Published: April 2006

Background: Transthoracic echocardiography was used in a rodent animal model to determine whether long‐term alcohol consumption (8 and 12 months) was associated with the development of a dilated cardiomyopathy. We also investigated whether alcohol‐induced changes in cardiac structure corresponded to activation of the renin‐angiotensin system and the natriuretic peptide (NP) system.

Methods: Male rats received either the Lieber‐DeCarli liquid alcohol diet (EtOH) (9%v/v) (n= 8) or control diet (CON) (n= 8). Echocardiography (echo) was used to determine left‐ventricular (LV) dimensions, and isolated heart studies (Langendorff and atrium) were used to assess ex vivo contractility. Plasma and tissue angiotensin‐I converting enzyme (ACE) activity was measured. Gene expression, plasma, and tissue levels of the NPs were determined by northern blot analysis and radioimmunoassay, respectively.

Results: After 8 months of alcohol consumption, there was a trend for the end diastolic dimension, end systolic dimension, and LV mass to be greater in the 8 month EtOH group compared with the CON group. However, after 12 months of alcohol consumption, significant increases were found between the groups in several echo parameters. Tissue ACE activity (nmoles/min/mg protein) was greater in the 12 month EtOH group compared with the 12 month CON and 8 month EtOH group (p < 0.05). We found no differences between groups in gene expression (messenger RNA), plasma, and tissue levels of the NPs.

Conclusions: Echocardiography revealed that 8 to 12 months of alcohol consumption was associated with the development of a dilated cardiomyopathy. However, this was not preceded by an increase in tissue ACE activity, and these changes occurred in the absence of increased plasma and LV tissue levels of the NPs.
Ethanol Consumption and the Susceptibility of Mice to Listeria monocytogenes Infection
Authors: Salerno Joseph A. , Waltenbaugh Carl , Cianciotto Nicholas P.
Published: April 2006

Background: It is well known that excessive alcohol consumption correlates with increased infectious disease. However, the molecular microbiological and immunological bases for ethanol‐induced alterations in host defense are largely unknown.

Methods: To study the effect of alcohol consumption on the pathogenesis of intracellular bacteria, we examined the relative susceptibility of alcohol‐fed mice to a virulent strain of Listeria monocytogenes.

Results: Based on lethal dose 50% determinations, survival curve analysis, and bacterial burden, alcohol consumption did not increase the susceptibility of C57BL/6, BALB/c, or A/J mice to systemic infection by strain EGD. Mice fed an ethanol‐containing liquid diet showed slightly reduced susceptibility to Listeria. Alcohol consumption modestly decreased bacterial numbers in the spleen but not the liver. We also found that mice fed a typical solid diet were more sensitive to EGD infection than were animals fed a control liquid‐containing diet.

Conclusions: This study indicates that alcohol consumption may not always increase infectious disease progression.
Effect of 4‐Methylpyrazole on Endogenous Plasma Ethanol and Methanol Levels in Humans
Authors: Sarkola Taisto , Eriksson C.J. Peter
Published: April 2006

Background: Endogenous methanol and ethanol levels are found in human blood. It is assumed that these compounds are derived mainly from microflora in the gastrointestinal tract and that the small amounts formed are consequently eliminated, mainly in the liver, by the alcohol dehydrogenase (ADH) pathway. The objective of the present study was to investigate the effect of 4‐methylpyrazole (4‐MP), a specific ADH inhibitor, on endogenous plasma methanol and ethanol levels in healthy women and men.

Methods: A double‐blind placebo‐controlled interventional study was carried out.

Results: A significant elevation in plasma endogenous ethanol and methanol levels was observed after intake of 4‐MP (10–15 mg/kg p.o.). For methanol levels, a linear increase from 20 ± 14 μmol/l before intake to 39 ± 22 μmol/l at 420 min from intake of 4‐MP (levels 20 ± 14 μmol/l and 14 ± 9 μmol/l during the corresponding placebo time points) was found. For ethanol, concentrations increased from levels below detection limit (i.e., < 5 μmol/l, determined by headspace gas chromatography) before intake to 30 ± 20 μmol/l at 195 min from intake of 4‐MP. A small increase in ethanol levels, to 13 ± 8 μmol/l, but not in methanol levels, was observed after the intake of lingonberry juice containing no ethanol or methanol. No sex differences in the ethanol and methanol levels before or after the intake of 4‐MP were found.

Conclusions: The present study provides conclusive evidence for a constant endogenous production as well as clearance of ethanol and methanol in humans. In addition, the study shows that the ethanol and methanol produced are, at least in part, eliminated by the ADH pathway.
Local Cerebral Glucose Utilization Rates in Alcohol‐Naïve High–Alcohol‐Drinking (HAD) and Low–Alcohol‐Drinking (LAD) Rats
Authors: Learn Jennifer E. , Smith Daniel G. , McBride William J. , Lumeng Lawrence , Li Ting‐Kai
Published: April 2006

Background: The present study compared baseline local cerebral glucose utilization (LCGU) values within reward‐relevant brain regions in alcohol‐naïve, adult male high–alcohol‐drinking (HAD) and low–alcohol‐drinking (LAD) rats from replicate lines 1 and 2.

Methods: 2‐[14C]Deoxyglucose ([14C]2‐DG) was injected (125 μCi/kg) intravenously during the rats’ dark cycle. Timed arterial blood samples were collected over 45 min and assayed for glucose as well as [14C]2‐DG content. Rats were then decapitated; their brains quickly removed and frozen in isopentane at −50°C. Coronal sections from each brain were apposed to film and exposed for 2 days. Image densities were analyzed using quantitative autoradiography.

Results: Data were collected from several key limbic (nucleus accumbens, ventral tegmental area, olfactory tubercle, amygdala, hippocampus, ventral pallidum, and septum), basal ganglia, cortical (medial prefrontal, frontal, parietal, temporal, occipital, entorhinal, pyriform, and cingulate), and subcortical (thalamus, habenula, and superior colliculus) structures. Because there were no significant differences between the replicates within each drinking line, data from the two replicates were combined to determine drinking line differences. When both replicate lines were combined, there were trends toward higher (approximately 15%) LCGU rates in HAD (n= 15) versus LAD (n= 16) rats within the parietal and occipital cortices, but neither of these line differences reached statistical significance (p < 0.01).

Conclusions: The findings suggested that, within the HAD and LAD replicate rat lines, the selection for alcohol preference did not lead to differences in functional brain activity, as measured with the 2‐DG method.
Patterns of Cognitive‐Motor Development in Children With Fetal Alcohol Syndrome From a Community in South Africa
Authors: Adnams Colleen M. , Kodituwakku Piyadasa W. , Hay Andrea , Molteno Chris D. , Viljoen Denis , May Philip A.
Published: April 2006

Background: Even though fetal alcohol syndrome (FAS) has been reported in nonwestern nations, there is a paucity of information on neurodevelopment in the affected children from those nations. This article reports on a study of cognitive‐motor development in a group of children with FAS from a community in the Western Cape Province in South Africa.

Methods: Thirty‐four children with FAS and 34 controls from grade 1 (school entry level) classes participated. The two groups comprised Afrikaans‐speaking children of mixed ancestry (South African Colored) and were matched for age, sex, and family income. The Griffiths Mental Development Scales were used to assess cognitive motor development of the participants.

Results: A multivariate analysis of covariance was performed to test the group effect on the combined Griffiths subscales adjusting for maternal education. The results showed a significant group effect. Follow‐up analyses revealed that a combination of four subscales (Speech and Hearing, Performance, Practical Reasoning, and Eye and Hand Coordination) primarily contributed to the overall effect. Although there was a marginal effect on the Personal‐Social subscale, no significant effect on the Locomotor (gross motor) subscale was found.

Conclusions: The results showed that the FAS group was markedly deficient only in higher‐order cognitive‐motor competencies.