bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Alcohol Abuse in Neurological Patients: Variables of Clinical Relevance to the Accuracy of the %CDT‐TIA and CDTect Methods
Authors: Bråthen Geir , Bjerve Kristian S. , Brodtkorb Eylert , Helde Grethe , Bovim Gunnar
Published: April 2006

Objectives: Alcohol‐related neurological diseases are encountered frequently. Early diagnosis is essential, because minimal intervention effectively reduces hazardous alcohol consumption and may prevent permanent neurological damage. Carbohydrate‐deficient transferrin (CDT) is a valuable tool for the identification of alcohol abuse, but for unselected patient populations, reduced test accuracy has been reported. Recently, factors other than alcohol use have been shown to influence CDT levels. Our aim was to identify clinically relevant factors that might reduce test accuracy.

Material and Methods : We included 397 neurological patients consecutively hospitalized for seizures, ischemic stroke, or sciatica and 87 patients who attended routine outpatient controls for epilepsy. Blood samples were analyzed for CDT by using two commercially available tests, %CDT‐TIA and CDTect. All patients underwent a semistructured clinical interview that included a record of the reported ethanol consumption during the last 8 days, and all completed the Alcohol Use Disorders Identification Test (AUDIT). Current medication, medical history, and demographic information also were obtained.

Results: Both tests were elevated in female antiepileptic drug users, compared with others who reported no recent ethanol intake. A higher number of false‐positive cases was seen for CDTect than for %CDT. Various combinations of CDT and γ‐glutamyltransferase improved sensitivity, but at the cost of reduced specificity. Variables that predicted the variation of CDT included antiepileptic drug use, sex, body mass index, and smoking. Total transferrin levels were reduced significantly in postmenopausal women, whereas a falling trend was seen for CDTect. Transferrin alterations caused a higher number of false‐positive results for CDTect than for %CDT. The area under the receiver operating characteristics curve for women was higher for CDTect than for %CDT, and for %CDT, the area under the receiver operating characteristics curve was higher for men than for women.

Conclusion: The accuracy of CDT for detection of alcohol abuse in neurological patients was generally low, particularly for women. Combination variables of CDT and γ‐glutamyltransferase did not increase test accuracy. Variables that were associated with higher CDT levels included female sex, antiepileptic drug use, transferrin alterations, and possibly low body mass index. When factors known to cause poor accuracy in particular patient groups are appreciated, CDT may be a good adjunct to the clinical examination.
Injury Risk Among Medically Identified Alcohol and Drug Abusers
Authors: Miller Ted R. , Lestina Diane C. , Smith Gordon S.
Published: April 2006

Background: Although nonfatal injury prevalence is higher among substance abusers than in the general population, few studies have estimated the injury risk for clinically recognized substance abusers. The extant studies, moreover, analyze rates of visits for injury treatment rather than rates of injury events. This study estimates the excess risk of medically treated and hospitalized nonoccupational injury for people under age 65 with medically identified substance abuse problems and private health care coverage.

Method: We conducted a retrospective cohort study by using medical claims data from Medstat Systems, Inc., with a longitudinal database of health care claims for 1.5 million people with health care coverage from 70 large corporations. Claims histories for anyone who had an alcohol‐related or drug‐related primary or secondary diagnosis during 1987 to 1989 were analyzed. A random sample was selected from the remaining people without a substance abuse diagnosis in their medical records. Injury rates were compared among groups. We used logistic regression to estimate odds of medically treated and hospitalized injury, controlling for demographics.

Results: Medically identified substance abusers had an elevated risk of injury in a 3‐year period; alcohol and drug abusers had the highest risk (58%), followed by drug‐only abusers (49%), alcohol‐only abusers (46%), and controls (38%). Alcohol and drug abusers were almost four times as likely to be hospitalized for an injury in a 3‐year period when compared with controls. Injury risks were elevated substantially more for female then male substance abusers.

Conclusions: This study greatly improves on available information about the risk of injury for drug and multiple‐substance abusers. Medically identified substance abusers, especially adult women, have a higher probability of injury, more hospitalized injuries, and more injury episodes per person injured than nonabusers. More aggressive identification and subsequent treatment of female substance abusers appear warranted.
Reduced Seizure Threshold and Hippocampal Cell Loss in Rats Exposed to Alcohol During the Brain Growth Spurt
Authors: Bonthius Daniel J. , Woodhouse Justin , Bonthius Nancy E. , Taggard Derek A. , Lothman Eric W.
Published: April 2006

Background: Epilepsy is a prominent sign of neurologic dysfunction in some children with fetal alcohol syndrome (FAS). However, it is unknown whether the epileptic disorders in these children are directly due to the neuroteratogenic effects of alcohol or to some other factor accompanying maternal alcoholism. The hippocampus is vulnerable to alcohol‐induced pathologic changes, and dysfunction of the hippocampus often manifests as epilepsy. We examined the effect of alcohol exposure during development on the seizure threshold and examined the relationship between alteration of seizure threshold and alcohol‐induced neuronal loss from the hippocampus.

Methods: Rat pups received 0.85, 2.5, or 3.75 g/kg of alcohol via intragastric intubation daily over postnatal days (PD) 4–9. An intubated control and a suckle control group were also included. To assess the effect of a single day of alcohol exposure, an additional group received 3.75 g/kg of alcohol on PD 4 alone. Behavioral seizure thresholds were determined by intravenous infusion of the proconvulsant, pentylenetetrazol (PTZ), on PD 31 or on PD 90. In addition, electrographic seizure thresholds were determined by recording extracellular field potentials from the dentate gyrus. The number of hippocampal CA1 pyramidal cells, CA3 pyramidal cells, and granule cells of the dentate gyrus were determined by stereology.

Results: Daily exposure to alcohol resulted in a dose‐dependent decrease in the seizure threshold and in the selective loss of CA1 pyramidal cells. Reduction in the seizure threshold was significantly correlated with loss of CA1 pyramidal cells. Recordings of extracellular field potentials confirmed the alcohol‐induced reduction in seizure threshold, demonstrated that PTZ‐induced seizures involve hippocampal‐parahippocampal circuitry, and provided evidence that the hippocampal formation is the generator of the PTZ‐induced seizures in alcohol‐exposed animals.

Conclusions: These findings demonstrate that exposure of the developing brain to alcohol can permanently reduce the threshold for both behavioral and electrographic seizures and can selectively kill hippocampal CA1 pyramidal cells. Both the pathologic findings and the physiologic recordings support the concept that the reduced seizure threshold in alcohol‐exposed animals is due to hippocampal pathology.
Increased Circulating Leptin Levels in Chronic Alcoholism
Authors: Nicolás J. M. , Fernández‐Solà J. , Fatjó F. , Casamitjana R. , Bataller R. , Sacanella E. , Tobías E. , Badía E. , Estruch R.
Published: April 2006

Background: Malnutrition seen in chronic alcoholics is partly due to reduced energy intake. Leptin is a peptide hormone implicated in the regulation of appetite and expenditure of energy. The prevalence and significance of abnormal circulating leptin levels in alcoholics, as well as the relationship of these levels with nutritional status, liver disease, and ethanol consumption, remain uncertain.

Methods: Serum leptin levels were measured in 60 active asymptomatic alcoholics, 20 active alcoholics with cirrhosis of the liver, 20 abstinent alcoholics, and 60 controls. Nutritional status and ethanol consumption also were assessed.

Results: In the control group, circulating leptin levels (mean 4.7 ± 0.3 μg/liter) correlated with body fat stores. Despite showing a lower fat area of the arm, active alcoholics had significantly higher leptin levels than the controls (p < 0.001), regardless of the presence of cirrhosis. By contrast, none of the abstinent alcoholics showed hyperleptinemia. In the multivariate regression analysis, the fat area of the arm (p < 0.001), the lifetime ethanol consumption (p= 0.007), and the number of cigarettes smoked per day (p= 0.02) were found to be independent factors that influenced leptin levels in active alcoholics. After we adjusted for age, fat area of the arm, and tobacco consumption, a significant correlation was observed between lifetime consumption of ethanol and serum leptin concentrations (r= 0.36, p < 0.001).

Conclusions: Circulating leptin levels are increased in a dose‐dependent manner in chronic alcoholism, regardless of nutritional status or the presence of compensated liver disease.
Effect of Repeated Exposure to Alcohol on the Response of the Hypothalamic‐Pituitary‐Adrenal Axis of the Rat: II. Role of the Length and Regimen of Alcohol Treatment
Authors: Rivier Catherine , Lee Soon
Published: April 2006

Background: Prior exposure to alcohol alters the adrenocorticotropin hormone (ACTH) response to a second drug challenge administered several days later. We used three models of alcohol treatment to investigate the mechanisms that may be involved in this phenomenon.

Methods: Adult male rats were exposed to alcohol vapors daily for 3 days (4–4.5 hr/day) and then were exposed to shocks or an intragastric injection of alcohol 7 days later (group A); were injected daily with alcohol (4.5 g/kg intragastrically) for 3 days and then exposed to shocks or an intragastric injection of alcohol 7 days later (group B); or were exposed to alcohol vapors for 6 days and exposed to shocks or an intragastric injection 24 hr later (group C). Control animals were not exposed to the vapors or received the appropriate vehicle.

Results: Compared with animals administered the vehicle, rats of groups A and B that had been exposed to alcohol all exhibited a significantly decreased ACTH response to a second drug challenge. In contrast, their ACTH response to footshocks was statistically comparable to that of vehicle‐pretreated animals. Rats of group C that had been exposed to alcohol for 6 days also showed decreased ACTH release when injected with alcohol 7 days later while responding normally to shocks. Measurement of anterior pituitary pro‐opiomelanocortin indicated that alcohol pretreatment had produced a 54% increase of these transcripts in group C and a 27% decrease in group A. There were no changes in pituitary receptors type 1 for corticotropin‐releasing factor (CRFR1) in any of the groups.

Conclusion: Regardless of whether they are delivered shortly before an acute alcohol injection or several days earlier, alcohol vapors or injections interfere with the ACTH response to the drug but not to shocks. Our results also suggest that changes in ACTH responses may not be correlated directly with small changes in pituitary pro‐opiomelanocortin or CRFR1 mRNA levels.
Testing Genetic Susceptibility Loci for Alcoholic Heart Muscle Disease
Authors: Kajander Olli A. , Kupari Markku , Perola Markus , Pajarinen Jarkko , Savolainen Vesa , Penttilä Antti , Karhunen Pekka J.
Published: April 2006

Background: Although many heavy alcohol users have subclinical alcoholic heart muscle disease, only a very few develop severe dilated cardiomyopathy. Therefore, and because cardiac abnormalities correlate only weakly with the duration or quantity of drinking, individual susceptibility differences may exist. In this work we examined whether common gene variants previously associated with cardiac hypertrophy or altered alcohol metabolism could modify the effects of alcohol on the heart.

Methods: We studied 700 middle‐aged male victims of sudden death who underwent a medicolegal autopsy. In addition to routine postmortem examination, the weights and the cavity and wall dimensions of the left and right ventricle were measured. Coronary artery stenoses were determined from a silicone rubber cast of the arteries. Alcohol consumption and cardiovascular risk factors were assessed by a structured interview of the spouse. The following gene polymorphisms were determined by using polymerase chain reaction restriction fragment length polymorphism and solid‐phase minisequencing techniques: angiotensin converting enzyme I/D, angiotensin II type 1 receptor 1166A/C, aldosterone synthase −344C/T, alcohol dehydrogenases 2 and 3, acetaldehyde dehydrogenase 2, and cytochrome P‐450 2E1 Dra I, Pst I, Rsa I, and Msp I.

Results: The most consistent effects of alcohol (p < 0.05) were a higher total heart weight and a larger right ventricle size with increasing daily drinking. However, these and other effects of alcohol were statistically fully independent of the studied genotypes.

Conclusions: The gene polymorphisms selected for and analyzed in our study are unlikely to modify the effects of alcohol on the heart. Other unknown factors determine the individual susceptibility to alcoholic heart muscle disease.
Do Ethanol and Deuterium Oxide Distribute Into the Same Water Space in Healthy Volunteers?
Authors: Norberg Åke , Sandhagen Bo , Bratteby Lars‐Eric , Gabrielsson Johan , Jones Alan Wayne , Fan Hu , Hahn Robert G.
Published: April 2006

Background: The volume of distribution at steady state for ethanol (Vss) is thought to be identical to the total body water (TBW). We compared a two‐compartment pharmacokinetic model with parallel Michaelis‐Menten and first‐order renal elimination with the classical one‐compartment zero‐order elimination model. Ethanol concentration‐time profiles were established for breath, venous blood, and urine. The values of Vss obtained for ethanol were compared with TBW determined by deuterium oxide dilution.

Methods: Sixteen healthy volunteers each received a 30‐min intravenous infusion of ethanol on two occasions. Ethanol was measured in breath by a quantitative infrared analyzer and in blood and urine by headspace gas chromatography. Deuterium oxide was given as an intravenous injection and measured in serum by isotope‐ratio mass spectrometry. Components of variation were calculated by ANOVA to determine the precision of the estimates of Vss and TBW.

Results: Mean TBW, determined by deuterium oxide dilution, was 44.1 ± 3.9 liters (±SD) for men, corresponding to 0.61 liters/kg, and 37.4 ± 3.2 liters for women, or 0.54 liters/kg. Estimates of Vss from blood‐ethanol pharmacokinetics were 87.6% of TBW according to isotope dilution and 84.4% for breath analysis with the two‐compartment model. This compares with 95.1% and 95.4% for blood and breath alcohol, respectively, when the classical zero‐order kinetic analysis is used. The precision of the estimates of Vss and TBW was between ±1.56 and ±2.19 liters (95% confidence interval).

Conclusions: Ethanol does not distribute uniformly into the TBW. The precision of measuring Vss by ethanol dilution was comparable to estimates of TBW by isotope dilution. Results of noninvasive breath ethanol analysis compared well with use of venous blood for estimating Vss. The sophisticated two‐compartment model was much superior to the classical one‐compartment model in explaining the total concentration‐time course of intravenously given ethanol.
Variations on the CAGE Alcohol Screening Questionnaire: Strengths and Limitations in VA General Medical Patients
Authors: Bradley Katharine A. , Kivlahan Daniel R. , Bush Kristen R. , McDonell Mary B. , Fihn Stephan D.
Published: April 2006

Background: Several variations on the CAGE alcohol screening questionnaire have been recommended. This report evaluates modifications and additions to the CAGE.

Methods: Alcohol screening questionnaires were evaluated in male VA general medicine patients (n= 227; mean age, 65.8). Mailed questionnaires included two scoring options for the CAGE (standard and last‐year time frames), questions about quantity and frequency of drinking, two questions about episodic heavy drinking, and the question “Have you ever had a drinking problem?” Main analyses compared alcohol screening questions, at various cut‐points, to a gold standard of hazardous drinking during the past year (≥14 drinks/week or ≥5 drinks on an occasion) and/or DSM‐III‐R alcohol abuse or dependence, based on standardized interviews.

Results: The CAGE questionnaire with a past‐year time frame was much less sensitive (0.57 vs. 0.77) but more specific (0.82 vs. 0.59) than the standard CAGE for detecting hazardous drinking during the past year and/or DSM‐III‐R alcohol abuse or dependence. An eight‐item questionnaire that included the standard CAGE was most sensitive (0.92) but had low specificity (0.50). A single question about the frequency of drinking ≥6 drinks on an occasion, included in the eight‐item questionnaire, was both relatively sensitive (0.77) and specific (0.83).

Conclusion: The CAGE questionnaire with a past‐year time frame was an insensitive alcohol‐screening test. An eight‐item augmented version of the standard CAGE was the most sensitive. A question about the frequency of drinking ≥6 drinks on an occasion performed better than the standard CAGE, which made it the optimal brief screening test for at‐risk drinking.
Acute Effects of Ethanol on Steroidogenic Acute Regulatory Protein (StAR) in the Prepubertal Rat Ovary
Authors: Srivastava Vinod K. , Hiney Jill K. , Dearth Robert K. , Dees W. Les
Published: April 2006

Background: Steroidogenic acute regulatory protein (StAR) is a 30 kDa mitochondrial protein that plays an essential role in steroid hormone biosynthesis by facilitating delivery of cholesterol across the mitochondrial membrane, where side chain cleavage occurs to initiate ovarian steroidogenesis. Because ethanol (EtOH) suppresses estradiol secretion in prepubertal female rats, we evaluated the effects of EtOH on prepubertal ovarian StAR.

Methods: At 0700 hr, 28‐day‐old female rats were gavaged with saline or a 3 g/kg dose of EtOH. At 0800 hr, half of each of these two groups was treated with 15 IU of pregnant mare serum gonadotropin (PMSG). At 1000 hr, a 2 g/kg dose was administered to maintain moderately elevated blood alcohol levels. At 1600 hr, all of the animals were killed by decapitation, and blood and ovaries were collected for measurement of serum pregnenolone and estradiol and for ovarian StAR gene and protein expression.

Results: Northern blot analysis showed two major transcripts of 3.8 and 1.7 kb of ovarian StAR mRNA. The ovaries from EtOH‐treated rats showed decreased (p < 0.01) basal expression of both 3.8 and 1.7 kb StAR transcripts. PMSG‐stimulated animals showed a more than 4‐fold increase (p < 0.001) in the levels of both transcripts, when compared with ovaries from animals that received saline or EtOH only. Conversely, in EtOH‐treated animals, the PMSG‐stimulated expression of the 1.7 kb transcript was blocked, and the increase in the 3.8 kb StAR transcript was blunted (p < 0.05 vs. PMSG). Western blot analysis revealed that EtOH exposure also depressed (p < 0.01) the basal expression of StAR protein. PMSG‐stimulated animals showed an increase (p < 0.001) in levels of StAR protein, and this was blocked (p < 0.01) by EtOH. These changes observed in ovarian StAR mRNA and protein were paralleled by changes in serum pregnenolone and estradiol. Specifically, acute EtOH exposure suppressed (p < 0.05) the basal levels of both steroids. Furthermore, PMSG‐stimulated animals showed an increase in the production of pregnenolone (p < 0.05) as well as estradiol (p < 0.01), and EtOH blocked this stimulatory action of PMSG on both steroids.

Conclusion: These results demonstrate for the first time that EtOH is capable of altering ovarian StAR expression, which contributes to the detrimental effect this drug has on ovarian steroidogenesis during prepubertal development.
A Retinoic Acid Receptor Antagonist Suppresses Brain Retinoic Acid Receptor Overexpression and Reverses a Working Memory Deficit Induced by Chronic Ethanol Consumption in Mice
Authors: Alfos Serge , Boucheron Catherine , Pallet Véronique , Higueret Denise , Enderlin Valérie , Béracochéa Daniel , Jaffard Robert , Higueret Paul
Published: April 2006

Background: Chronic ethanol consumption induces disorders in the biosynthesis of retinoic acid, an active derivative of vitamin A. Recent evidence suggests that an alteration in the retinoic acid signaling pathway leads to impairments in learning and memory in adult mice. We have previously shown that chronic ethanol consumption in mice produces an increased expression of the brain retinoic acid receptor β (RARβ) mRNA. These results prompted us to examine whether suppressing the overexpression of retinoid receptors in alcohol‐treated mice by RAR antagonist administration would reverse their cognitive impairment.

Methods: After 10 months of ethanol consumption (12% v/v in drinking water), C57BL/6 mice were submitted to a working memory task in a T‐maze. Then, mice of the control and the ethanol‐treated groups received an RARβ antagonist (CD2665 0.6 mg/kg) for 22 days. The behavioral effect of CD2665 administration was evaluated on a spontaneous alternation task and the neurochemical effect was measured by quantifying the mRNA expression of RARα, RARβ, retinoid X receptor (RXRβ/γ) and tissue transglutaminase (tTG; a retinoic acid‐target gene).

Results: Mice submitted to ethanol treatment exhibited a progressive decrease in spontaneous alternation rates over successive trials. Moreover, these mice displayed an increased expression of brain RARβ and RXRβ/γ mRNA, together with an increased level of tTG mRNA and enzymatic activity. The administration of CD2665 to alcohol‐treated mice totally reversed the working memory deficit and suppressed the overexpression of brain RARβ, RXRβ/γ and tTG mRNA, whereas the same treatment in control mice decreased only the RARβ mRNA level without affecting memory performance.

Conclusion: These data point to the potential role of the retinoid signaling pathway in memory processes and suggest that the overexpression of brain RARβ and RXRβ/γ could be responsible, at least in part, for some memory impairments observed during chronic ethanol consumption.
Bone Marrow Triglyceride Accumulation and Hormonal Changes During Long‐Term Alcohol Intake in Male and Female Rats
Authors: Wezeman Frederick H. , Gong Zhaodi
Published: April 2006

Background: Chronic alcohol consumption may influence the metabolism of adipocytes, the most abundant stromal cell phenotype in bone marrow, and promote bone marrow triglyceride accretion.

Methods: Male and female rats 35 days old were fed the Lieber‐De Carli liquid diet containing 36% of the calories as alcohol and were compared with pair‐fed rats given an isocaloric liquid diet in which maltose‐dextrin substituted for the calories supplied by alcohol. Other control rats were fed chow ad libitum. The rats were maintained on these diets for 64 days, after which the femurs were recovered and examined.

Results: End weights of male and female alcohol‐fed rats were significantly lower than both control groups. Femur diaphyseal bone marrow triglyceride levels were significantly increased in alcohol‐fed male and female rats compared with both control groups. Femur bone marrow cavity diameters were significantly increased and cortical thickness was significantly decreased by alcohol in both males and females. Serum insulin levels were significantly decreased by alcohol only in female rats compared with the ad libitum but not the pair‐fed control group, and insulin‐like growth factor‐1 levels were significantly reduced in male and female rats given the alcohol diet compared with both controls. Male testosterone and female estradiol levels remained unchanged. Male estradiol levels were significantly increased by alcohol compared with both controls, and female progesterone levels were significantly reduced by alcohol compared with pair‐fed rats. Whereas female leptin levels were unchanged by alcohol, male leptin levels were significantly increased by alcohol compared with pair‐fed rats.

Conclusions: Hormonal and growth factor changes during chronic alcohol consumption accompany triglyceride accumulation in diaphyseal bone marrow and may parallel the effects of alcohol on mesenchymal stem cells and the balance between osteogenic and adipogenic lineages and their cellular progenies.
ALDH2 Status, Alcohol Expectancies, and Alcohol Response: Preliminary Evidence for a Mediation Model
Authors: McCarthy Denis M. , Brown Sandra A. , Carr Lucinda G. , Wall Tamara L.
Published: April 2006

Background: A genetic variant in the alcohol‐metabolizing enzyme (aldehyde dehydrogenase;ALDH2*2 allele), common in individuals of Asian heritage, has been associated with both physiologic response to alcohol and alcohol consumption. Prior research has also demonstrated that those with ALDH2*2 alleles have lower positive alcohol expectancies than those without these alleles. This preliminary study was designed to test whether the level of response to alcohol is the mechanism by which ALDH2 status may affect alcohol expectancies.

Methods: Data were collected from 32 Asian American college students (14 women and 18 men). By use of a randomized, double‐blind design, participants were administered oral placebo and alcohol at separate laboratory sessions. Data included blood tests to establish ALDH2 status, questionnaire measures of demographic information and alcohol expectancy, and several physiologic measures collected after placebo and alcohol administration.

Results: ALDH2 status was related to alcohol response measures for both men and women. ALDH2 status was also related to tension reduction expectancies for women and to expectancies for cognitive behavioral impairment for men. In the male sample, the ALDH2/expectancy relationship was fully explained by the level of response to alcohol.

Conclusions: These results represent a first step in understanding the mechanisms by which genetic factors, such as ALDH2 status, can affect alcohol‐related learning.
Differential Expression of NPY and Its Receptors in Alcohol‐Preferring AA and Alcohol‐Avoiding ANA Rats
Authors: Caberlotto Laura , Thorsell Annika , Rimondini Roberto , Sommer Wolfgang , Hyytiä Petri , Heilig Markus
Published: April 2006

Background: Central neuropeptide Y (NPY) is known to control feeding and stress responses. Recently, it has been suggested that NPY also has a role in regulation of alcohol consumption.

Methods: NPY and NPY receptor expression in genetically selected alcohol‐preferring (AA), alcohol‐nonpreferring (ANA), and Wistar rats were investigated. Expression was assessed using in situ hybridization histochemistry with riboprobes specific for preproNPY, Y1, and Y2 receptors. Effects of central NPY administration on ethanol self‐administration were also examined in AA, ANA, and Wistar rats by using oral operant self‐administration.

Results: NPY mRNA expression was higher in ANA than in both AA and Wistar rats in the hippocampal CA region and dentate gyrus, whereas AA and Wistar did not differ from each other. No differences in NPY expression were found in the other regions analyzed: cingulate cortex, medial nucleus of the amygdala, arcuate, and paraventricular nuclei of the hypothalamus. Y1 receptor mRNA expression did not differ between the three lines. Y2 expression was higher in the dentate gyrus of both AA and ANA rats than in Wistar subjects. In the medial amygdala, Y2 mRNA was reduced in the AA line, compared to both ANA and Wistar rats. NPY injected intracerebroventricularly (1.5–3.0 nmol) did not affect operant ethanol self‐administration in any of the three lines examined.

Conclusion: The NPY system seems to differ in several respects between rat lines with different levels of alcohol preference. Differences observed within the hippocampus could be related to behavioral traits other than alcohol intake but it is also possible that elevated hippocampal expression of NPY in the ANA rats contributes to the low alcohol intake of this line. Aberrant NPY expression and/function within the amygdala complex could contribute to alcohol preference and constitute an anatomic substrate of the effects of NPY expression on alcohol intake observed previously in genetically modified animals.
Paternal Alcoholism and Toddler Noncompliance
Authors: Das Eiden Rina , Leonard Kenneth E. , Morrisey Sean
Published: April 2006

Background: This study examined the effect of fathers’ alcoholism and associated risk factors on toddler compliance with parental directives at 18 and 24 months of age.

Methods: Participants were 215 families with 12‐month‐old children, recruited through birth records, who completed assessments of parental substance use, family functioning, and parent‐child interactions at 12, 18, and 24 months of child age. Of these families, 96 were in the control group, 89 families were in the father‐alcoholic‐only group, and 30 families were in the group with two alcohol‐problem parents. Child compliance with parents during cleanup situations after free play was measured at 18 and 24 months. The focus of this paper is on four measures of compliance: committed compliance, passive noncompliance, overt resistance, and defiance.

Results: Sons of alcohol‐problem parents exhibited higher rates of noncompliance compared with sons of nonalcoholic parents. Sons in the two‐alcohol‐problem parent group seemed to be following a trajectory toward increasing rates of noncompliance. Daughters in the two‐alcohol‐problem parent group followed an opposite pattern. Other risk factors associated with parental alcohol problems also predicted compliance, but in unexpected ways.

Conclusions: Results indicate that early risk for behavioral undercontrol is present in the toddler period among sons of alcoholic fathers, but not among daughters.
Ethanol Inhibits Spontaneous Activity of Central Nucleus of the Amygdala Neurons but Does Not Impair Retention in the Passive‐Avoidance Task
Authors: Naylor Jennifer C. , Simson Peter E. , Gibson Benjamin , Schneider Allen M. , Wilkins Emily , Firestone Aaron , Choy Megan
Published: April 2006

Background: Behavioral studies using pharmacological manipulations that increase neuronal activity of the central nucleus of the amygdala (CeA) have implicated the CeA in enhancement of memory modulation. To date, however, there has been a dearth of studies investigating the effect of a drug that decreases CeA activity on memory modulation—a drug that inhibits the neuronal activity of the CeA might be expected to impair memory modulation. To determine whether ethanol inhibits CeA activity and, if so, whether decreased CeA activity is associated with impairment of memory modulation, this study investigated the effect of ethanol on spontaneous single‐unit activity of CeA neurons and retention in the passive‐avoidance task.

Methods: The effect of ethanol (0.35, 0.75, 1.5, 2.5 g/kg) was determined on spontaneously firing neurons in the CeA in urethane‐anesthetized rats by use of standard in vivo single‐unit electrophysiological recording techniques. Additionally, the effect of ethanol when administered immediately after training in a standard passive‐avoidance task was determined on retention the following day.

Results: Ethanol profoundly inhibited spontaneous CeA firing rates in urethane‐anesthetized rats at all doses tested. Maximal inhibition was related to dose. Each dose of ethanol significantly inhibited CeA activity within 15 min of administration; within 35 min of administration, 0.75 g/kg of ethanol inhibited CeA activity by 65.2%, and the highest dose (2.5 g/kg) produced nearly complete suppression of CeA activity (81.3%). Although ethanol markedly inhibited CeA activity, these same doses of ethanol failed to impair retention in the passive‐avoidance task: 0.35, 0.75, 1.5, and 2.5 g/kg of ethanol, administered immediately after training, failed to alter latency to step‐through the following day.

Conclusions: These results show that ethanol profoundly inhibits spontaneous CeA activity and suggest that inhibition of the CeA is not sufficient to impair retention in the passive‐avoidance task.
Alcohol Dehydrogenase‐2*2 Allele is Associated With Decreased Prevalence of Fetal Alcohol Syndrome in the Mixed‐Ancestry Population of the Western Cape Province, South Africa
Authors: Viljoen D.L. , Carr L.G. , Foroud T.M. , Brooke L. , Ramsay M. , Li T.K.
Published: April 2006

Background: Fetal alcohol syndrome (FAS) is particularly common among the mixed‐ancestry population of the Western Cape Province of South Africa and occurs at a frequency of 0.0392–0.0429 (39.2–42.9 of 1000) among 5‐ to 9‐year‐old school entrants. While FAS is clearly caused by an environmental insult, studies in twins and mice support a significant genetic contribution to risk for FAS. It is likely that the development of FAS following excessive alcohol exposure is influenced by genetic factors in both the mother and the child. Known polymorphisms of the alcohol dehydrogenase‐2 (ADH2) gene resulting in isozymes with different alcohol oxidizing capacities were investigated as possible candidates for influencing the risk for FAS.

Methods: Genotyping was undertaken for the ADH2 locus in 56 FAS‐affected children, their 56 mothers, and 178 control individuals of mixed ancestry from the same geographic region. The ADH2 alleles were analyzed for the three groups and the allele frequencies of the mother and FAS‐affected children were independently compared with the control group.

Results: The ADH2*2 allele was found to be significantly more common in the control group than in the mothers of FAS‐affected children (p= 0.025 ± 0.004) and in the FAS subjects (p= 0.025 ± 0.004). The ADH2*3 allele frequency was low and was not significantly different between the groups.

Conclusion: The ADH2*2 allele is significantly more common in control individuals, suggesting that it may either confer protection or be a marker for a protective effect against FAS among individuals of mixed ancestry in the Western Cape Province of South Africa.
Protein Binding of α‐Hydroxyethyl Free Radicals
Authors: Moncada Claudio , Israel Yedy
Published: April 2006

Background: The auto‐oxidation of ethanol is likely to proceed via the initial formation of hydroxyethyl radicals (HERs), the one‐electron oxidation product. In the laboratory, HERs can be generated by the Fenton reaction (H2O2+ Fe+2) in the presence of ethanol. We report studies on the binding of HERs to serum albumin, generated under Fenton and non‐Fenton conditions.

Methods: The generation of HER was determined by electron paramagnetic resonance spectroscopy. The formation of ethanol‐derived protein adducts was determined by 14C‐ethanol incorporation into serum albumin and by the binding of antibodies raised against HER adducts.

Results: We report that serum albumin, used as a model protein, is an effective trapping agent of HERs. In addition, HER radicals covalently bind to albumin to form acid stable adducts. Unexpectedly, we found that under aerobic conditions, the incubation of 50 mM ethanol and phosphate buffer (which contains iron traces) in the absence of the Fenton reagent yields HER radicals as shown by electron paramagnetic resonance spectroscopy and the formation of acid stable protein adducts that are recognized by antibodies raised against HER radical adducts.

Conclusions: Proteins (serum albumin used as a model) are avid trapping agents of HER. There are minimal requirements for the generation of HER, because in the presence of oxygen and a phosphate buffer that contains traces of iron, ethanol readily generates HERs. Thus, HER production is likely to occur in many tissues. The ability of proteins to bind this ethanol radical should be valuable in the diagnosis of alcohol abuse and may be relevant to some of the chronic effects of ethanol.
Carbohydrate Deficient Transferrin in Abstaining Patients With End‐Stage Liver Disease
Authors: DiMartini Andrea , Day Nancy , Lane Tonya , Beisler Amy T. , Amanda Dew Mary , Anton Raymond
Published: April 2006

Background: Carbohydrate deficient transferrin (CDT), a biochemical marker of chronic alcohol consumption, is used by researchers and clinicians alike in a variety of populations. Levels of CDT may be affected by certain types of medical illnesses and conditions. Thus the interpretation of CDT results may need to be carefully examined in these populations. Because CDT is synthesized, glycosylated, and secreted by the liver, the use of CDT values in patients with liver disease has been an area of focused interest.

Methods: We evaluated the CDT values of 79 abstaining patients with end‐stage liver disease. These patients were recruited from a liver transplant clinic while they were listed and waiting for transplantation. Patients were determined to be abstaining both by interview and by random blood alcohol levels in those with a diagnosis of alcoholic liver disease. The severity of the liver disease was categorized by the Child‐Pugh score. Correlations were determined between CDT values and liver enzymes, and Child‐Pugh scores and liver diagnosis.

Results: Nearly 50% of the patients had a CDT value of 2.6% or above, indicating a clinically positive value. There were strong correlations between CDT and a number of biochemical and physical variables, most importantly the Child‐Pugh score (r= 0.52, p= 0.000). Specific liver diseases were not associated with absolute CDT values. However, patients with hepatitis C (HCV) had a significantly higher chance of having a clinically positive CDT compared with patients with other types of liver diseases.

Conclusions: These results suggest that an elevated CDT value may not accurately represent alcohol consumption in patients with advanced liver disease. In fact, in such patients, the CDT may become a marker for the degree of liver impairment in alcoholic and nonalcoholic liver disease. CDT values should be viewed with caution in any patient with liver disease especially when the degree of cirrhosis reaches a Child‐Pugh score of C (total score of 10 or above).
Reduced Alloreactive T‐Cell Activation After Alcohol Intake is Due to Impaired Monocyte Accessory Cell Function and Correlates With Elevated IL‐10, IL‐13, and Decreased IFNγ Levels
Authors: Szabo Gyongyi , Mandrekar Pranoti , Dolganiuc Angela , Catalano Donna , Kodys Karen
Published: April 2006

Background: Immunosuppression associated with chronic alcohol use is characterized by reduced antigen‐specific T‐cell response and impaired delayed type hypersensitivity. Increasing evidence suggests in chronic alcohol consumption models that reduced antigen‐specific T‐cell proliferation is due to insufficient accessory cell function. Accessory cell function, a critical step in recognition of viral antigens, is reduced in chronic hepatitis C. The severity of hepatitis C is increased by alcohol consumption. Thus, we investigated the effects of alcohol consumption on accessory cell activity of monocytes in supporting alloreactive T‐cell proliferation.

Methods: Alloreactive T‐cell proliferation was evaluated in a one‐way mixed lymphocyte reaction (MLR). Mononuclear cells were isolated by Ficoll density gradient and monocytes by adherence. Alcohol (0.8 g/kg body weight, an equivalent of approximately three drinks) was given to nonalcohol‐consuming individuals and blood samples were collected before, 4 hr, or 18 hr after alcohol consumption. Alcohol in vitro was administered at concentrations of 25–100 mM.

Results: T‐cell proliferation in MLR was significantly reduced in the presence of physiologically relevant concentrations of alcohol in vitro (25–100 mM ethanol) (p < 0.05). In vivo alcohol consumption also depressed proliferation in the MLR when stimulator cells were obtained 4 hr after alcohol consumption. MLR was not decreased, however, in the presence of alcohol‐exposed responder cells and normal stimulator cells, suggesting that the accessory cell population and not T cells are affected by alcohol. Decreased accessory cell function was further evidenced by reduced superantigen‐induced (SEB) but not mitogen‐induced (PHA) T‐cell proliferation in samples obtained 18 hr after alcohol intake (35% reduction). Reduced accessory cell function was not due to changes in surface expression of monocyte costimulatory molecules (HLA class I, HLA‐DR, CD80, CD86, CD40). We found reduced IFNγ, elevated IL‐10, and unchanged IL‐4 levels during T‐cell proliferation in samples obtained 18 hr after alcohol consumption. Acute alcohol treatment resulted in increased IL‐13 in the MLR.

Conclusion: These data suggest that even on one occasion moderate alcohol intake can reduce allostimulatory T‐cell activation via decreasing accessory cell function. Increased IL‐10 and IL‐13 plus the reduced IFNγ production after acute alcohol use are likely to contribute to both the reduced T‐cell proliferation and monocyte accessory cell function. These accessory cell mediated defects in T‐cell activation may result in impaired antiviral and antitumor immunity after moderate acute alcohol use.
Association of the ADH2*3 Allele With A Negative Family History Of Alcoholism in African American Young Adults
Authors: Ehlers Cindy L. , Gilder David A. , Harris Lilach , Carr Lucinda
Published: April 2006

Background: Two of the class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode for multiple isozymes that differ in their kinetic properties. Polymorphisms at both of these gene loci have been linked to alcoholism and/or alcohol‐induced disabilities in some populations. At the ADH2 locus, three polymorphisms are present (ADH2*1, ADH2*2, ADH2*3). ADH2*3 allele codes for a high Km and Vmax variant that has been reported to occur exclusively in African Americans and some tribes of Native Americans. In African Americans, the presence of the ADH2*3 allele is associated with protection from alcohol‐related birth defects. However, its relationship to risk for alcoholism in African Americans remains relatively unexplored.

Methods: The participants were 97 African American young adults (18–25 years old). A structured interview was used to gather information on demographics, psychiatric diagnoses, personal drinking and drug use history, and familial history of alcohol use disorders. A blood sample was obtained from each participant and leukocyte DNA extracted and genotyped for the presence of ADH2*3 alleles. The specific aim of the study was to investigate the associations between the presence of the ADH2* 3 allele and personal and family history of alcohol use/abuse.

Results: Thirty participants (31%) had at least one ADH2*3 allele and two were homozygous for the allele. A significant association between the presence of an ADH2*3 allele and a negative family history of alcoholism was uncovered (p < 0.04). No significant associations of an ADH2*3 allele with personal history of alcohol use disorders or with current drinking were found ; however, power to detect associations was limited in this population because half the population did not drink regularly.

Conclusions: Because family history of alcoholism is one of the best predictors of the development of alcohol use disorders, this pilot study suggests that, in this sample of African American young adults, the ADH2*3 allele may be associated with a lowered risk for the development of alcoholism.
Polyphenolics Increase t‐PA and u‐PA Gene Transcription in Cultured Human Endothelial Cells
Authors: Abou‐Agag Laila H. , Aikens Michael L. , Tabengwa Edlue M. , Benza Raymond L. , Shows Stephen R. , Grenett Hernan E. , Booyse Francois M.
Published: April 2006

Background: Moderate red wine consumption has been associated with a reduced risk for coronary heart disease, and this cardioprotection may be mediated, in part, by promoting fibrinolysis. This protection may be attributed to the combined or perhaps synergistic effects of alcohol and other red wine components (i.e., polyphenolics). These studies were carried out to determine whether individual phenolics (i.e., catechin, epicatechin, quercetin, and resveratrol) affect fibrinolytic protein (tissue‐type plasminogen activator [t‐PA] and urokinase‐type PA [u‐PA]) e‐pression and surface‐localized fibrinolytic activity in cultured human umbilical vein endothelial cells (HUVECs).

Methods: Cultured HUVECs were preincubated (1 hr, 37°C) in the absence or presence of varying concentrations of catechin, epicatechin, quercetin, and resveratrol (0.001–10 μM) and then were washed and incubated for various times in the absence of phenolics. Secreted t‐PA/u‐PA antigen (24 hr, enzyme‐linked immunoadsorbent assay) and mRNA [0–16 hr, reverse transcription‐polymerase chain reaction(RT‐PCR)] levels and fibrinolytic activity (direct activation of HUVEC‐bound 125I‐labeled glutamyl‐plasminogen, quantitation of 125I‐labeled M r 20 kDa plasmin light‐chain) were measured. Transient transfections of cultured HUVECs were carried out with the pt‐PA222/luc and pu‐PA236/luc promoter constructs, by using lipofectamine.

Results: Each of the phenolics similarly increased t‐PA and u‐PA antigen (2‐ to 3‐fold) and mRNA (3‐ to 4‐fold) levels, concomitant with an increase (2‐ to 3‐fold) in sustained (24 hr), surface‐localized fibrinolytic activity. Transcription inhibitor actinomycin D abolished the induction of t‐PA and u‐PA mRNA e‐pression by these phenolics. Transfections with the pt‐PA222/luc and pu‐PA236/luc promoter constructs showed 2‐ to 3‐fold and 2‐ to 4‐fold increases in luciferase activity for t‐PA and u‐PA, respectively.

Conclusions: These results demonstrate that each of these phenolics up‐regulates both t‐PA and u‐PA gene transcription, which results in the sustained increased e‐pression of surface‐localized fibrinolytic activity in cultured HUVECs. Wine phenolics increase fibrinolytic activity, independent of ethanol, and it is likely that the overall cardioprotective benefits associated with moderate red wine consumption are attributable to the combined, additive, or perhaps synergistic effects of alcohol and other wine components.