bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol‐Preferring and Nonpreferring Rats Display Different Levels of Neurofilament Proteins in the Ventral Tegmental Area
Authors: Guitart Xavier , Lumeng Lawrence , Li Ting‐Kai , Nestler Eric J.
Published: April 2006

Previously, different levels of neurofilaments (NF) in the ventral tegmental area (VTA) have been identified in Sprague‐Dawley rats treated chronically with morphine or cocaine and in drug‐naive Lewis and Fischer 344, inbred strains that differ behaviorally in several ways, including alcohol, opiate, and cocaine preferences. These findings led us to examine whether rat lines that have been selectively bred for a difference in alcohol preference, the alcohol‐preferring (P) and nonpreferring (NP) rats, also express different levels of NFs in the VTA. We found by use of back phosphorylation and immunolabeling procedures that the VTA of the P rat contains 20–50% lower levels of the three major types of NF proteins‐NF‐200, NF‐160, and NF‐68—compared with the VTA of the NP rat. No strain difference in NF levels was seen in the substantia nigra (which like the VTA is a major dopaminergic nucleus in brain), locus coeruleus (which is a major noradrenergic nucleus in brain), or spinal cord (which is enriched in NF proteins). In contrast to NFs, no P‐NP line differences were found in VTA levels of tyrosine hydroxylase, which is also regulated by chronic morphine and cocaine treatments in Sprague‐Dawley rats and shows prominent Lewis‐Fischer strain differences, specifically in this brain region. The results provide additional support for the possibility that levels of NFs in the VTA may be related to preference for alcohol and other drugs of abuse.
Ethanol Increases K+ Conductance in Human T‐Cells
Authors: Oleson Dorothy R. , DeFelice Louis J. , Donahoe Robert M.
Published: April 2006

Ethanol increased the open probability of a K channel in cultured human T‐cells. Single‐channel currents were studied using the patch‐clamp technique in cell‐attached configuration. Ethanol increased the number of simultaneously active channels and subsequent current maxima at concentrations of 35 and 50 mM from control levels of 3.2 to 4.6 pA and 8.4 PA, respectively. Current responses were elicited by a 80 mV hyperpolarizing pulse following adjustment to the same resting potential. The channel was K‐selective as determined by the reversal potentials under different Na‐K gradients. When the pipette contained 155 mM K, single‐channel currents had a slope conductance of 28 pS and a reversal potential of ‐4.3 mV. Baseline current levels often shifted in a negative direction during the application of ethanol, indicating a hyperpolarization of the membrane potential and an increase in channel activity.
Diet and Ethanol Modulate Immune Responses in Young C57BL/6 Mice
Authors: Watzl Bernhard , Lopez Maria , Shahbazian Masoud , Chen Guanjie , Colombo Lucas L. , Huang Dennis , Way Dennis , Watson Ronald R.
Published: April 2006

Chronic ethanol (ETOH) ingestion adversely affects the immunocompetence of alcohol abusers. ETOH directly impairs host defense mechanisms and indirectly modulates immunocompetence by interfering with the nutritional status of the alcoholic. It is not clear from the current literature, however, to what extent ETOH, nutritional status, or the combination of the two factors modulates immune mechanisms in chronic alcoholics. To date, most animal studies investigating the immunotoxicity of ETOH have neglected the dietary factors, which may have masked additional immunotoxic effects of ETOH. To examine these dietary factors, we fed mice three liquid ETOH diets with different dietary sufficiencies for 7 weeks and investigated various immune responses. Spleen cell number and secretions of immunoreactive interleukin‐2 and tumor necrosis factor were totally independent of the diet, being affected only by ETOH. Body, spleen, and thymus weights, interferon‐γ secretion, and natural killer cell and phagocytic activities were modulated by ETOH as well as by diet. Natural killer cell and phagocytic activities were also directly affected by the nutritional quality of the diet. These results suggest that animal diets used in experimental studies of ETOH‐induced immunomodulation must be planned and controlled carefully in order to single out the direct effects that ETOH has on the host defense system.
Ethanol‐Induced Oxidative Stress and Nutritional Status
Authors: Bondy Stephen C. , Pearson Kristi R.
Published: April 2006

The ability of dietary ethanol, administered over a 10‐day period, to elevate production rates of reactive oxygen species and to alter glutathione levels has been determined in both liver and cerebellum, a brain region known to be susceptible to ethanol‐induced damage. Two groups of ethanol‐consuming rats were used. One set of treated animals that received an all‐liquid ethanol‐containing diet experienced weight gain, and this gain was matched in a pair‐fed control group. The other ethanol‐treated group that had free access only to solid chow and water containing ethanol lost weight during the exposure period. The corresponding control group that received unlimited water and chow was allowed to gain weight normally. In animals that lost weight as a consequence of ethanol in the drinking water, evidence of oxidative stress was enhanced relative to that in animals receiving ethanol by way of the liquid diet. This latter set gained weight, despite higher blood ethanol levels than the group that lost weight. An excess pre‐oxidant condition prevailed in the liver and cerebellum of the ethanol‐dosed malnourished group. In the case of liver, this difference may relate to a greater lability of iron‐containing proteins in the rats that experienced weight loss, leading to the appearance of low molecular weight iron in the cytosol.
Antagonism of Alcohol‐Induced Suppression of Rat Testosterone Secretion by an Inhibitor of Nitric Oxide Synthase
Authors: Adams Michael L. , Forman Joel B. , Kalicki Joelle M. , Meyer Edward R. , Sewing Bryan , Cicero Theodore J.
Published: April 2006

To examine whether nitric oxide (NO) mediates the suppression of testosterone secretion by alcohol (ethanol), adult male rats were pretreated with a NO synthase inhibitor, NG‐nitro‐L‐arginine methyl ester (NAME), then treated with alcohol. Serum and testicular interstitial fluid (TIF) testosterone concentrations, serum luteiniring hormone (LH) concentrations, blood alcohol concentrations (BAC), and TIF volumes were measured 2 hr after alcohol treatment at a time of peak effects of alcohol and NAME on testosterone secretion. Pretreatment with NAME (30 or 100 mg/kg, subcutaneous) 30 min before alcohol treatment (0.5–3 g/kg, intraperitoneal) completely blocked the alcohol‐induced suppression of testosterone secretion into the general circulation and into TIF without significantly altering blood alcohol concentrations (BAC) or TIF volumes. These results support the hypotheses that NO synthase inhibitors can antagonize alcohol induced suppression of testicular steroidogenesis, that alcohol interacts with arginine‐NO synthase systems that regulate testicular steroidogenesis, and that NO is involved in mediating alcohol's testicular and reproductive effects.
Measurement of Hemoglobin‐Acetaldehyde Adduct in Alcoholic Patients
Authors: Lin Renee C. , Shahidi Samin , Kelly Timothy J. , Lumeng Carey , Lumeng Lawrence
Published: April 2006

A sensitive and specific test for chronic alcohol abuse is useful in the diagnosis and management of alcoholic patients. Herein, we report the measurement of hemoglobin‐acetaldehyde adducts (Hb‐AA) in alcoholic patients by a sandwich ELISA using different antibodies. Keyhole limpet hemocyanin (KLH), a peptide consists of eight amino acid residues (8‐pep, V1 to K8) at the N‐terminus of βchain‐of human sickle‐cell Hb and a segment of HbA β‐chain consists of 11 amino acids rich in lysine or K (11‐pep, G56‐K66) were incubated with acetaldehyde and NaCNBH3 to form protein‐AAs. 8‐Pep‐AA and 11‐pep‐AA were individually conjugated to unmodified KLH as the carrier. Anti‐protein‐AA lgGs were raised in rabbits using these three protein‐AA immunogens. When anti‐KLH‐AA IgG was‐used in ELISA, optical densities for alcoholic patients and controls were 0.311 ± 0.124 and 0.147 ± 0.042 (means ± SD, n= 40/group, p < 0.001), respectively. Using mean value ± 2 SD of controls as the cut‐off, sensitivities to detect alcoholic patients were 78, 75, and 43%, respectively, when anti‐KLH‐AA, anti‐11‐pep‐AA, and anti‐8‐ pep‐AA were used. Correlation among optical densities obtained from the first two lgGs was excellent (R2= 0.905). We conclude that:(1) Hb‐AA has the potential of being a good marker for alcohol abuse, and (2) the site of Hb that is modified by acetaldehyde in vivo is‐ primarily located in a surface‐accessible domain near the center of the βchain of HbA where several lysine residues are clustered.
Alcohol Beverage Price Spectra: Opportunities for Substitution
Authors: Treno Andrew J. , Nephew Thomas M. , Ponicki William R. , Gruenewald Paul J.
Published: April 2006

This study examines the range of beer, wine, and spirits prices in the State of California using data from a survey of on‐ and off‐premise retail establishments. It is argued that alcohol price is best understood in terms of spectra, which reflect the range of available prices rather than individual price indices. Specific findings indicate that most price variability is due to premise type and beverage‐by‐premise‐type interactions. Smaller effects on price are found for brand and geographical region as indicated by area code. The implications of these findings for future research into the demand for alcohol are discussed.
A Longitudinal Examination of the Relationships Among Stress, Coping Strategies, and Problems Associated with Alcohol Use
Authors: Johnson Valerie , Pandina Robert J.
Published: April 2006

This study examined the longitudinal relationships among family history of alcoholism (FH+), stress levels, utilization of coping methods, and alcohol‐related problems. Data used in this study were obtained from a nonclinical sample of subjects who were originally interviewed when they were 12, 15, or 18 years of age and followed‐up twice more at 3‐year intervals for a longitudinal sample size of 1270. Although a greater percentage of females in this sample reported a FH+ background as well as higher levels of stress, they tended to utilize positive coping strategies more often and reported fewer numbers of alcohol problems than males. In general, younger subjects who reported high levels of stress experienced more alcohol‐related problems regardless of coping method chosen. In older subjects, the effect of stress on problems appeared to be buffered when coupled with the use of support seeking. Subjects whose stress preceded problems exhibited no significant difference from subjects whose problems preceded stress and symptom‐free and “stressed‐only” subjects were not significantly different from each other in number of problems at time 3, suggesting that a direct effect of stress alone on alcohol‐related problems is questionable.
Detection of Relapses in Alcohol‐Dependent Patients: Comparison of Carbohydrate‐Deficient Transferrin in Serum, 5‐Hydroxytryptophol in Urine, and Self‐Reports
Authors: Carlsson A. Voltaire , Hiltunen A. J. , Beck O. , Stibler H. , Borg S.
Published: April 2006

In this study, detection of relapses in male alcohol‐dependent patients by biochemical markers and self‐reports of alcohol consumption were examined. The patients were trying to stay abstinent from alcohol for 6 months. Four of 15 patients dropped out from treatment after 50–110 days. Ratios of urinary 5‐hydroxytryptophol (S‐HTOL)/5‐hydroxyindole‐3‐acetic acid and 5‐HTOL/creatinine were measured daily and serum carbohydrate‐deficient transferrin (CDT) once a week. Clinical ratings and self‐reports about alcohol consumption were performed three times a week. According to the self‐reports, 3 of the patients drank alcohol frequently, 5 of them sporadically, and 7 of the patients reported no alcohol intake at all. According to the 5‐HTOL marker, 4 of the patients drank alcohol frequently, and 11 of them sporadically. No one had all urinary levels of 5‐HTOL marker below the reference level. According to the CDT, 3 of the patients drank alcohol frequently, 3 sporadically, and in 9 of the patients no elevated levels of CDT were found. Elevated levels of CDT were preceded by increased values of 5‐HTOL marker. The combined results suggested that no one of the patients was totally abstinent from alcohol during the treatment period. The 5‐HTOL marker seemed to be useful to reveal recent alcohol drinking, and CDT proved to be useful to validate the patients' self‐reports. Together the two biochemical markers showed complementary properties in early detection of relapse and treatment monitoring.
Comparison of Blood Alcohol Concentrations After Beer and Whiskey
Authors: Roine Risto P. , Gentry R. Thomas , Lim Robert T. , Helkkonen Erkki , Salaspuro Mikko , Lieber Charles S.
Published: April 2006

To determine whether blood alcohol concentrations achieved by ingestion of various alcoholic beverages differ as a function of prandial state, healthy male volunteers, aged 24 to 48 years, were given the same amount of alcohol (0.3 g/kg) as different beverages. The alcohol was consumed in three prandial states: postprandial (1 hr after a meal, n= 10), prandial (during the meal, n= 10), and preprandial (after an overnight fast, n= 9). Each subject was tested with both beer and whiskey, and in the postprandial state also with wine and sherry, in a within‐subjects design. Blood alcohol concentrations were estimated by breath analysis for 4 hr or until concentrations reached zero. Peak blood alcohol levels were higher with beer than with whiskey in the postprandial and prandial conditions (p < 0.01), whereas the opposite was true in the preprandial state (p < 0.05). Similarly, the area under the blood alcohol curve was higher with beer in the prandial state (p < 0.05), and higher with whiskey in the preprandial condition (p < 0.01). Wine and sherry yielded peak concentrations intermediate between those of beer and whiskey in the postprandial state. The results indicate that a dilute alcoholic drink can yield either higher or lower blood alcohol levels than a concentrated beverage, depending on the prandial state.
Thiamin and Thiamin Phosphate Ester Deficiency Assessed by High Performance Liquid Chromatography in Four Clinical Cases of Wernicke Encephalopathy
Authors: Tallaksen C. M. E. , Bell H. , Bøhmer T.
Published: April 2006

The concentrations of thiamin and thiamin phosphate esters were determined by high performance liquid chromatography in four patients with clinical Wernicke encephalopathy. Three were alcohol abusers, and one had prolonged vomiting and anorexia. Thiamin and thiamin monophosphate were assessed in plasma and whole blood (four patients) and in cerebrospinal fluid (two patients) before and during thiamin treatment. Thiamin diphosphate was also assessed in whole blood in the four patients. Before treatment, thiamin mono‐phosphate was significantly decreased in all patients, and thiamin diphosphate in three. A poor increase in thiamin mono‐ and diphosphate was paralleled by a slow clinical improvement in one patient, while an increase in all thiamin compounds was observed in two patients with a rapid recovery. Thiamin monophosphate was a more sensitive marker of deficiency than thiamin diphosphate and un‐phosphorylated thiamin.
Alcohol, Injury, and Risk‐Taking Behavior: Data from a National Sample
Authors: Cherpitel Cheryl J.
Published: April 2006

The association of alcohol consumption and injury is well documented in the literature. It has also been suggested that alcohol consumption is associated with risk‐taking behaviors. No studies have reported the association of alcohol consumption and risk‐taking behaviors with injury across all injury types, however. Data were collected (1990) from a national probability household sample (n= 2058; weighted n= 1150) on: injuries that required treatment during the last year; quantity and frequency (Q‐F) of drinking; and behaviors associated with risk perception, risk‐taking/impulsivity, and sensation seeking. The injured (12% of the sample) were more likely to be male, younger, and to report moderate and heavy drinking and more frequent drunkenness compared with those with no injuries. They were also less likely to score high on risk perception and more likely to score high on risk‐taking/impulsivity and sensation seeking than those with no injuries. However, using logistic regression analysis to predict a treated injury during the last year, only the interaction term of gender by Q‐F was significant, with Q‐F a significant predictor of injury among males but not among females.
Alcohol and Estrogen Levels in Postmenopausal Women: The Spectrum of Effect
Authors: Gavaler Judith S. , Deal Stephen R. , Van Thiel David H. , Arria Amelia , Allar Marjorie J.
Published: April 2006

Compared with alcohol‐abstaining normal postmenopausal women, estradiol levels are known to be statistically increased in normal postmenopausal women who consume alcoholic beverages moderately, and to be even further increased in alcoholic postmenopausal women with cirrhosis. This study was undertaken to evaluate whether or not there is a spectrum of changes in levels of sex steroids and pituitary hormones associated with alcohol abstinence, alcohol use, and alcohol‐induced cirrhosis in the absence of current alcohol abuse. For levels of estradiol and testosterone, as well as for the estradiol to testosterone ratio, all three groups differed significantly from each other; for the pituitary hormones, levels in the abstainers and alcohol users were similar and statistically different from levels in the alcoholic cirrhotic women. Compared with the alcohol‐abstaining women, the relationships of age and estradiol with levels of the other hormones were disturbed for 4 of 11 correlations examined among the alcohol users, and for 9 of 11 correlations evaluated among the alcoholic cirrhotic women. These findings suggest that not only are hormonal relationships markedly disrupted among alcoholic cirrhotics, but also that alcoholic beverage consumption in the range of 0.1‐28 total weekly drinks results in detectable perturbations of the normal hormonal relationships expected in postmenopausal women.
Low‐Dose Thyrotropin‐Releasing Hormone Effects in Cognitively Impaired Alcoholics
Authors: Khan Arifulla , Mirolo Mary Helen , Claypoole Keith , Hughes Deborah
Published: April 2006

The cognitive effects of a low dose of thyrotropin‐releasing hormone (TRH) (2.0 mg, IV) were evaluated in 18 chronic alcoholic patients who exhibited memory dysfunction secondary to chronic alcohol abuse. The study used a double‐blind crossover design that compared cognitive functions in patients with 2.0 mg of TRH IV as compared with a placebo. TRH was chosen because of its ability to enhance cholinergic transmission. Only minimal effects were seen with TRH. Patients with a shorter duration of alcohol use (mean of 16 years) performed significantly better with TRH as compared with placebo on a test involving verbal learning and memory. Those with a more chronic history of alcohol abuse (mean of 27 years) did not show such a response. All of the subjects showed cardiovascular response to TRH. Factors that may have contributed to the results of our study are discussed. It is our impression that future studies evaluating the cognitive effects of TRH in chronic alcoholics need to include an evaluation of the functional activity of TRH in the brain.
Heart Rate as an Index of Stress Response in Alcohol Administration Research: A Critical Review
Authors: Sayette Michael A.
Published: April 2006

Heart rate has been a widely used measure in experimental investigations of alcohol and stress. Meaningful interpretations from this measure, however, may be threatened due to methodological problems. This article critically reviews alcohol administration studies that have utilized heart rate as an index of stress response. Potential confounds stemming from the use of heart rate are identified and suggestions for its future use are presented. Implications for highrisk studies are discussed. It is concluded that (a) the amount of time provided for the absorption of an alcohol or placebo beverage is highly correlated with postdrink heart rate change, (b) the magnitude of this postdrink heart rate change is highly associated with the probability of finding a subsequent stress response dampening effect, and (c) offspring of alcoholics appear to manifest a heightened heart rate response to alcohol, which may account for apparent enhanced stress response dampening effects among these subjects.
Immune Function in Offspring of Nonhuman Primates (Macaca nemestrina) Exposed Weekly to 1.8 g/kg Ethanol during Pregnancy: Preliminary Observations
Authors: Grossmann Angelika , Astley Susan J. , Liggitt H. Denny , Clarren Sterling K. , Shiota Faith , Kennedy Bryan , Thouless Margaret E. , Maggio‐Price Lillian
Published: April 2006

A preliminary investigation of immune host response was conducted in a group of fetal alcohol‐exposed nonhuman primates (Macaca nemestrina) who were part of a broader ongoing study of ethanol teratogenicity. The mothers of the offspring received weekly oral doses of ethanol (1.8 g/kg) for the first 3 or 6 or the entire 24 weeks of gestation. A control group received sucrose solution weekly throughout pregnancy. Four of the 18 ethanol‐exposed animals (22%) died or were euthanized after infectious disease or failure to thrive during the first year of life; none of the seven control animals dled. This imbalance in survival prompted the present review of immune function in the remaining offspring. Parameters assessed included: (1) white blood cell count (WBC), (2) peripheral blood leucocyte subsets (CD4+, CD8+, CD20+, and CD11c+), (3) T‐cell proliferation after activation with phytohemagglutinin (PHA), staphylococcus enterotoxin B (SEB), and tetanus toxoid (TT), (4) phagocytic activity of monocytes, and (5) serum immunoglobulin levels and serum antibody titers after TT vaccination. Mean T‐cell proliferation to TT was significantly decreased (p= 0.01) in all ethanol‐exposed animals relative to controls, with near‐significant decreases (p= 0.06) in response to SEB in the ethanol‐exposed animals. Lymphocyte proliferation in response to PHA was not altered. Ethanolexposed animals had significantly lower TT titers than controls after initial vaccination and booster. WBC, leukocyte subsets, serum immunoglobulins, and monocyte phagocytic activity were not significantly different from control values. These preliminary observations suggest that T‐cell proliferation and antigen‐specific memory responses may be altered in offspring exposed to weekly doses of ethanol in utero and warrant further evaluation for confirmation.
Cloning and Expression of the Full‐Length cDNAS Encoding Human Liver Class 1 and Class 2 Aldehyde Dehydrogenase
Authors: Zheng Chao‐Feng , Wang Thomas T. Y. , Weiner Henry
Published: April 2006

The amino acid sequences of both human class 1 and 2 aldehyde dehydrogenase (ALDH) and the sequences of the genes coding for them are known. Based on this sequence data, we designed primers and isolated the full‐length cDNAs encoding both isozymes from a human liver mRNA pool. cDNAs were subcloned in the plasmid pT7‐7 and expressed in Escherichia coli with a yield of ˜3 mg ALDH protein/liter of cell culture, although only one‐third of the enzyme was soluble. The soluble recombinantly expressed ALDHs were purified to homogeneity using a hydroxyacetophenone‐Sepharose affinity column. The mitochondrial isozyme had a subunit molecular weight of 55 kDa, an isoelectric point of 4.9, and a specific activity of 1.10 units/mg, which were in good agreement with that from the native enzyme. The expressed cytosolic isozyme had the same subunit molecular weight (55 kDa) and pl (5.4) as that reported for the native enzyme and had a specific activity of 0.26 units/mg. The expressed mitochondrial isozyme could be recognized by antibodies raised against rat mitochondrial ALDH, whereas the cytosolic isozyme could be recognized by antibody raised against horse cytosolic ALDH.
Impact of Chronic Alcoholism on the Aging Rat: Changes in Nutrition, Liver Composition, and Mortality
Authors: Mendenhall C. L. , Rouster S. D. , Roselle G. A. , Grossman C. J. , Ghosn S. , Gartside P.
Published: April 2006

The adverse effects of chronic alcohol consumption (mean 6.68 g/kg/d) were assessed in 150 male Sprague‐Dawley rats over their life span (25 months). Evaluations were performed at 2, 3, 8, 13, 19, and 25 months of age for changes in nutrition status, biochemical tests for liver injury, compositional changes in liver, and hepatic regenerative capacity. In spite of nearly identical caloric intake, alcohol treatment was associated with nutritional levels 10‐30% lower than controls.

Maximal changes were observed at the two extremes of ages (2‐3 months and 19‐25 months). Hence, a nutritional contribution to other adverse changes could not be excluded. Fatty compositional increases (triglycerides) occurred early (5‐fold increases after 1 month of treatment) then declined to levels only slightly above controls. Biochemical tests on sera for liver injury (AST and total bilirubin) were consistently higher with alcohol treatment. Regenerative capacity measured by [3H]thymidine uptake after partial hepatectomy was initially elevated in the alcoholic then rapidly declined beyond 7 months of age. In control animals, an age‐related decline was also observed but occurred later beyond 12 months of age. Consistent with these adverse effects, ethanol diet survival was poorer than the pair‐fed control groups by 15% (median survival for alcoholics, 17 months vs. 20 months in controls).
Production of Antibodies That Recognize the Heterogeneity of Immunoreactive Sites in Human Hemoglobin Chemically Modified by Acetaldehyde
Authors: Lin Renee C. , Shahidi Samin , Lumeng Lawrence
Published: April 2006

Human hemoglobin (Hgb) was incubated with acetaldehyde under two different conditions: (a) in the presence of 250 mM acetaldehyde for 1 hr then reduced with 100 mM NaCNBH3 for an additional 4 hr at room temperature; and (b) in the presence of 500 mM acetaldehyde for 10 days at room temperature and then reduced with 1 mM NaBH4 for 1 hr. It was found that 44% and 27% of free amino groups in Hgb‐acetaldehyde adduct (AA) remained unmodified when Hgb was treated under conditions (a) and (b), respectively. SDS‐PAGE analysis revealed that the molecular weight of Hgb‐AA(a) [Hgb modified under condition (a)] was slightly greater than that of unmodified Hgb and extensive protein cross‐linking had occurred in Hgb‐AA(b) [Hgb modified under condition (b)]. Electrophoresis on agarose gel showed the order of negative charge was Hgb‐AA(b) > Hgb‐AA(a) > unmodified Hgb. Polyclonal antibody raised in rabbits using keyhole limpet hemocyanin as the carrier protein modified by acetaldehyde under condition (a) [i.e., KLH‐AA(a)] preferentially recognized Hgb‐AA(a), whereas antibody raised using KLH‐AA(b) as the immunogen recognized only Hgb‐AA(b). In conclusion, antibodies raised with protein‐AA antigens produced under different conditions recognize different epitopes.
Ethanol Metabolism in Deermice: Role of Extrahepatic Alcohol Dehydrogenase
Authors: Ito Daisuke , Lieber Charles S.
Published: April 2006

The relative contributions to ethanol metabolism of extrahepatic alcohol dehydrogenase (ADH) and of liver microsomes were assessed in deermice, which lack hepatic low Km ADH (ADH‐). In vitro kinetic studies showed the existence of high Km (>1 M) ADH activity in the liver and kidney, and an enzyme with intermediate Km in the gastric mucosa (Km= 133 mM), whereas the low Km ADH was missing. With deuterated ethanol, ADH‐ deermice showed a significant exchange of reducing equivalents that had been equated with ethanol metabolism by others, whereas we found a poor correlation between the rate of exchange and the rate of metabolism. In vitro studies with subcellular fractions, isolated hepatocytes, and tissue slices revealed that neither liver, nor kidney, nor stomach from ADH‐ deermice contributed to exchange of reducing equivalents. These findings clearly indicated that the ADHs with high or intermediate Km of the tissues studied are not responsible for the exchange. Furthermore, gastrectomized ADH‐ deermice still showed an exchange of reducing equivalents, thereby dissociating exchange from gastric ADH activity. Moreover, pretreatment with cimetidine (50 mg/kg body weight), an inhibitor of gastric ADH, did not alter the rate of total ethanol elimination when ethanol was given intraperitoneally. In conclusion, when ethanol is given parenterally, the microsomal ethanol‐oxidizing system rather than gastric ADH is a major pathway of ethanol oxidation in ADH‐ deermice, whereas both pathways contribute significantly to the metabolism of orally administered ethanol.
Carbohydrate‐Deficient Transferrin During 3 Weeks' Heavy Alcohol Consumption
Authors: Salmela Katja S. , Laitinen Kalevi , Nyström Mikael , Salaspuro Mikko
Published: April 2006

To study the effect of controlled heavy drinking of 60 g ethanol/day for 3 weeks on carbohydrate‐deficient transferrin (CDT), a commercial double antibody kit (CDTect™) was used. By the end of the third drinking week, a statistically significant increase in the mean CDT level was observed. When compared to AST and γ‐glutamyltransferase, CDT was a more informative marker. However, only in 2 of the 10 volunteers did CDT exceed the upper normal level (20 units/liter) recommended by the manufacturer. This indicates that the sensitivity of CDT to detect heavy drinking is lower than that previously reported. The higher accuracy has in general been obtained in studies comparing healthy controls with a low alcohol consumption to alcoholics with an alcohol consumption higher than that used in the present experiment. Our results suggest that it remains to be established whether CDT, although better than AST and γ‐glutamyltransferase, will provide a clinically useful tool in identifying heavy drinkers in populations covering a wide range of alcohol consumption.
Nosological Comparisons of DSM‐III‐R and DSM‐IV Alcohol Abuse and Dependence in a Clinical Facility:Comparison with the 1988 National Health Interview Survey Results
Authors: Hasin Deborah S. , Grant Bridget
Published: April 2006

The purpose of this study was to compare DSM‐III‐R and proposed formulations of DSM‐IV diagnoses of alcohol use disorders in a clinical sample with the same assessment methods used in a large national survey previously reported. Issues included the number of symptoms required for abuse and dependence diagnoses, the effects of requiring evidence of physiological dependence to make the dependence diagnosis (Option 1 vs. Option 2), whether to require a duration criterion, and the concept of alcohol abuse. The diagnostic criteria proposed in the 1991 DSM‐IV options book were the criteria investigated in this study. Concordance between DSM‐III‐R and DSM‐IV was closest when the form of DSM‐IV used was most similar to DSM‐III‐R. The duration criterion had much less effect on a dependence diagnosis in this clinical sample than in the general population. DSM‐IV Option 2 for alcohol dependence excluded a number of cases from the dependence diagnosis who received such a diagnosis under DSM‐III‐R and DSM‐IV Option 1. Abuse continued to function as a residual category, especially noticeable under increasingly restrictive definitions of dependence, and was rare in both the clinical and general population sample. Implications of the findings for research and other purposes are discussed.
Prognostic Validity of Short‐Term Abstinence in Alcoholism
Authors: Yates William R. , Reed David A. , Booth Brenda M. , Masterson Brian J. , Brown Keith
Published: April 2006

A demonstrated period of abstinence is often viewed as a good prognostic sign in alcoholism. For example, short‐term abstinence one factor often considered important as a selection criteria for alcoholics who are being evaluated as liver transplant candidates. However, the prognostic validity of short‐term abstinence is unclear. We evaluated the effects of 3 and 6 months of abstinence on readmission rates in a series of 299 alcoholics following discharge from inpatient treatment. Readmission rates were stratified using 3‐factor model of alcoholism severity. This 3‐factor model defined groups with 1‐year readmission rates, ranging from 15.8% to 62.7%. Short‐term abstinence did not have strong effects on readmission rates for the most severe alcoholics, nor did short‐term abstinence produce clinically significant reduction for readmission rates for the least severe alcoholics. We conclude that short‐term abstinence has minimal effect on prognosis for alcoholics with various levels of baseline severity.
Relationship Between Age and Drinking Patterns and Drinking Problems Among Japanese, Japanese‐Americans, and Caucasians
Authors: Higuchi Susumu , Parrish Kiyoko M. , Dufour Mary C. , Towle Leland H. , Harford Thomas C.
Published: April 2006

Comparing alcohol consumption patterns by age and gender among Japanese in Japan and Japanese‐Americans and Caucasians in the United States, this study examined the associations between age and both heavy drinking and social problems using logistic regression for each ethnic group of male current drinkers. As reported in previous studies of Caucasians, men drink more alcohol than women, older respondents are more likely than younger ones to be abstainers, and the percentages of heavier drinkers and problem drinkers are higher among the young than among older people. Although Japanese‐Americans reported consuming less alcohol than Caucasians, their drinking patterns by age were similar:among both United States populations, younger respondents are at higher risk for drinking problems than older respondents, even when alcohol consumption and sociodemographic variables are controlled by logistic regression. However, this association of age and drinking patterns and drinking problems is not universal. Japanese men consumed more alcohol and had a higher proportion of heavier drinkers in the middle age groups; the association between age and drinking problems also varied in this group. In addition to aging, sociocultural factors such as drinking norms probably account for the differences in drinking behavior among different age groups. This study may stimulate further cross‐cultural comparison of drinking patterns and problems.
In Vivo Pharmacodynamic Studies of the Disulfiram Metabolite S‐Methyl N,N‐Diethylthiolcarbamate Sulfoxide:Inhibition of Liver Aldehyde Dehydrogenase
Authors: Hart Bruce W. , Faiman Morris D.
Published: April 2006

S‐methyl N,N‐diethylthiolcarbamate sulfoxide (DETC‐MeSO) is proposed to be the metabolite of disulfiram responsible for the in vivo inhibition of liver low Km, aldehyde dehydrogenase (ALDH) in the rat. Studies were conducted in male Sprague‐Dawley rats and also in vitro using both rat liver mitochondrial and purified bovine mitochondrial low Km ALDH to investigate further the pharmacodynamic and pharmacokinetic characteristics of DETC‐MeSO. Administration of DETC‐MeSO to rats produced a rapid and maximal inhibition of liver mitochondrial low Km, ALDH within 2 hr, which was still inhibited 30% after 168 hr. After DETC‐MeSO treatment, the maximum plasma concentration of DETC‐MeSO was reached within 0.5 hr, with DETC‐MeSO being undetectable 2 hr after DETC‐MeSO dosing. Although a trace amount of DETC‐Me was detected in the plasma 0.5 hr after DETC‐MeSO administration to rats, this disappeared within 1 hr. When rats were treated with disulfiram, the maximal plasma concentration of DETC‐MeSO was found within 2 hr, with only a very small quantity of DETC‐MeSO still detectable after 8 hr. Rats also were given the disulfiram metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate‐methyl ester (DDTC‐Me), and S‐methyl N,N‐diethylthiolcarbamate (DETC‐Me), and plasma analyzed for DETC‐MeSO 2 hr after the administration of these metabolites. DETC‐MeSO was detected in plasma, further illustrating that DETC‐MeSO can be found in plasma after the administration of either disulfiram, or the subsequent in vivo metabolites DDTC, DDTC‐Me, or DETC‐Me. Rats treated with DETC‐MeSO and then challenged with ethanol exhibited an increase in blood acetaldehyde similar to that found from previous studies with disulfiram. In in vitro studies, incubation of rat liver mitochondria with 0.75 μM DETC‐MeSO inhibited rat liver mitochondrial low Km ALDH maximally within 2 hr, whereas purified bovine mitochondrial low Km ALDH was inhibited 90% and 99%, respectively, when incubated for 1 hr with 2 and 6 μM DETC‐MeSO. These studies with rats and purified bovine ALDH show that DETC‐MeSO is a potent inhibitor of mitochondrial low Km ALDH both in vivo and in vitro, providing additional evidence that DETC‐MeSO is the metabolite to which disulfiram must be bioactivated for liver ALDH to be inhibited.
Effects of Prenatal Exposure to Ethanol on the Number of Axons in the Pyramidal Tract of the Rat
Authors: Miller Michael W. , Al‐Rabiai Suad
Published: April 2006

We examined the effect of gestational ethanol exposure on the number of axons in the caudal pyramidal tract. Between gestational day (G)6 and G21, inclusive, pregnant rats were fed a liquid ethanol‐containing diet (Et), an isocaloric liquid control diet (Ct), or a diet of chow and water (Ch). On postnatal day 30, the offspring of these rats were killed and their caudal medullas were processed for electron microscopy. The overall size of the pyramidal tract and the space occupied by the axons was smaller in the Et‐treated rats than in the Ct‐treated rats. The myelinated axons were smaller and the myelin was thinner in the Et‐treated rats than in the Ct‐treated rats. These decreases produced an ethanol‐induced increase in the density of axons in the pyramidal tract. In particular, the density of myelinated axons (but not nonmyelinated axons) was greater in Et‐treated rats. The net result was that the estimated number of axons in the pyramidal tracts of the Et‐treated rats was not significantly different than the number in the Ch‐and Ct‐treated rats. The present data demonstrate that ethanol does not affect the absolute number of axons in the pyramidal tract. As a result of the ethanol‐induced microencephaly, however, the data translate into a relative increase in the number of pyramidal tract axons. This relative increase matches the ethanol‐induced increase in the density of corticospinal projection neurons that may result from the retention of a developmentally exuberant projection.
Acetalde hyde‐Induced Stimulation of Collagen Synthesis and Gene Expression Is Dependent on Conditions of Cell Culture: Studies with Rat Lipocytes and Fibroblasts
Authors: Maher Jacquelyn J. , Zia Shaheen , Tzagarakis Christina
Published: April 2006

Acetaldehyde has been proposed as a mediator of fibrogenesis in alcoholic liver disease, based in part on its ability to stimulate collagen synthesis by hepatic lipocytes in late primary or passaged culture. In this study, we examined the effect of acetaldehyde on rat lipocytes and fibroblasts at various stages of culture, in an effort to determine whether culture‐related events influence responsiveness to this compound. Lipocytes from normal rat liver were studied in primary culture at 3 and 7 days after plating; fibroblasts were studied in subculture, at subconfluent and confluent densities. Both cell types were incubated with 100 μM acetaldehyde for 24 hr followed by measurement of collagen synthesis and type I collagen gene expression. Acetaldehyde had no effect on lipocytes at either 3 or 7 days in primary culture. The inability of acetaldehyde to stimulate collagen synthesis in primary culture was not attributable to toxicity, because cell morphology and total protein synthesis were identical in both treated and untreated cultures. Fibroblasts exhibited a variable response to acetaldehyde that was dependent on cell density: subcon‐fluent cells contained similar amounts of type I collagen mRNA in both the presence and absence of acetaldehyde, whereas confluent cells exhibited a 2‐ to 3‐fold increase in collagen mRNA levels upon acetaldehyde exposure. To determine whether quiescent lipocytes would respond to acetaldehyde in a culture system that mimics the hepatic environment in vivo, lipocytes were plated in coculture with hepatocytes on a basement membrane gel and incubated with 20 mM ethanol for 72 hr. Direct communication between these two cell types did not provoke lipocyte activation, even in the setting of ethanol oxidation. We conclude from these experiments that acetaldehyde is not a primary stimulus to lipocyte activation in vivo. Acetaldehyde may enhance collagen synthesis by lipocytes, but its activity appears restricted to cells that have undergone a prior priming event in culture or in vivo. Of the many phenotypic changes that occur in lipocytes during the first week of primary culture, none sensitizes them to the fibrogenic effects of acetaldehyde.
The 5‐HT3 Antagonist MDL‐72222 Exacerbates Ethanol Withdrawal Seizures in Mice
Authors: Grant Kathleen A. , Hellevuo Kaisa , Tabakoff Boris
Published: April 2006

Ethanol‐dependent mice were treated with the 5‐HT3 antagonist MDL 72222 after withdrawal from ethanol. Treatment with unit doses (0, 5.6, 10, and 17.0 mg/kg) of MDL 72222 at 0, 4, and 7 hr after withdrawal dose‐dependently exacerbated the severity of ethanol withdrawal seizures. Treatment with a single dose (17 mg/kg) of MDL 72222 at 5 hr after withdrawal also exacerbated the severity of ethanol withdrawal seizures. Ethanol naive mice treated with MDL 72222 (56 mg/kg) did not display any seizures. Treatment with another 5‐HT3 antagonist, ICS 205‐930 (23 and 46 mg/kg), or the 5‐ HT2 receptor antagonist ketanserin, did not affect ethanol withdrawal seizures. The findings suggest MDL 72222 selectively enhances sensitivity to withdrawal seizures following chronic ethanol exposure.
Drinking Outcomes of Alcohol Abusers Diagnosed as Antisocial Personality Disorder
Authors: Longabaugh Richard , Rubin Amy , Malloy Paul , Beattie Martha , Clifford Patrick R. , Noel Nora
Published: April 2006

Clinical research and wisdom suggest that alcoholics with antisocial personality (ASPs) disorders have poorer drinking outcomes after treatment than alcoholics without this disorder. The present study challenges this wisdom, suggesting that poor prognosis and response to treatment have been confounded by not covarying on pretreatment drinking measures. Thirty‐one ASPs are compared with 118 non‐ASPs randomly assigned to extended cognitive behavioral and relationship enhancement treatments. Thirteen to 18 months after treatment initiation, ASPs average more abstinent days than do non‐ASPs. Drinking intensity is a function of a patient‐treatment matching effect: ASPs treated with cognitive behavioral treatment (CB) drink less/drinking day than do either non‐ASPs treated in CB or ASPs treated in relationship enhancement. This finding is supportive of a comparable matching effect for CB and ASP found by Kadden et al. (1989). Examination of the process indicates that, irrespective of drinking index, ASPs respond poorly when they experience high posttreatment support for abstinence, whereas non‐ASPs respond better with support. We conclude that early pessimism for successful treatment of ASP alcoholic drinking outcomes may be unwarranted.
Carbohydrate‐Deficient Transferrin as a Measure of Immoderate Drinking: Remaining Issues
Authors: Allen John P. , Litten Raye Z. , Anton Raymond F. , Cross Gerald M.
Published: April 2006

A growing body of investigations demonstrate that elevated levels of carbohydrate‐deficient transferrin (CDT) effectively distinguishes alcoholics recently consuming large amounts of alcohol from light social drinkers or teetotalers. Nevertheless, important questions still remain concerning the value of CDT as a more generalized marker of alcohol consumption. Most important, the nature of the drinking pattern, including quantity and frequency, necessary to raise levels of CDT significantly remains unclear. Neither has research convincingly demonstrated that CDT is as accurate a marker for women, young adults, or non‐Caucasian ethnic groups as for White, middleaged men.

Whereas CDT might serve as a useful outcome measure in trials of alcoholism treatment effectiveness, current research suggests that CDT is of limited value in identifying problematic drinking in general medical or community settings in which a broad continuum of drinkers is represented. Combining CDT with other biochemical or self‐report screening measures may, however, improve sensitivity in these contexts.

At present, the most accurate laboratory technique to detect CDT seems to be isoelectric focusing. Additional research, however, is needed to resolve the issue of whether CDT is best quantitated as a simple value or if its ratio to total transferrin or non‐CDT results in higher predictive validity.
Residual Sedating Effects of Ethanol
Authors: Roehrs Timothy , Claiborue Deirdre , Knox Michele , Roth Thomas
Published: April 2006

To test for dose and duration effects of residual sedation, ethanol (0.0, 0.5, and 0.9 g/kg) was administered (at 0830, 1030, and 0730 hr, respectively) to 10 healthy, normal‐sleeping men, aged 21–35 years. The Multiple Sleep Latency Test was conducted at 0930, 1130, 1330, 1530, 1730, 1930, and 2130 hr, and a divided attention performance assessment was done at 1400, 1600, 1800, and 2000 hr. Breath ethanol concentration for both doses was 0.04% at 1130 hr, 0.01% at 1330 hr, and 0 at 1530 hr. A significant reduction in sleep latency was observed from 0930 to 1530 hr, but not thereafter. Divided attention performance overall was significantly impaired on the 1400‐hr test only. These data again showed residual sedation and suggest residual sedation is time limited and not affected in duration or intensity by dose.
Biases in the Diagnosis of Alcoholism by the Family History Method
Authors: Roy Marc‐André , Walsh Dermot , Prescott Carol A. , Kendler Kenneth S.
Published: April 2006

The authors explored the factors influencing the agreement of diagnoses of alcoholism obtained by a best‐estimate (BE) procedure versus those obtained by family history (FH) only, based on data from the Roscommon Family Study. The participants were first‐degree relatives of either schizophrenic subjects, subjects with affective disorders, or matched community controls. The FH information was obtained from first‐degree relatives of the participants, whereas the BE diagnoses included personal interview and medical records as well as FH information. Two types of error were distinguished: false‐negative FHs, who were diagnosed with alcoholism by BE but not by FH; and false‐positive FHs, who were diagnosed with alcoholism by FH but not by BE.

The risk of false‐negative FHs was increased by young age of the subject and male gender of the informant, and decreased by a history of previous hospitalization of the subject. Conversely, the risk for false‐positive FHs was increased by older age of the subject, male gender of the subject, female gender of the informant, and informant's diagnosis of alcoholism. Comorbid diagnosis of nonaffective psychosis increased the risk of both types of error. It is concluded that when validated against a BE diagnosis, the FH diagnosis of alcoholism is subject to several biases and that the FH method is not a satisfactory substitute for BE diagnoses.