bluuebunny/crossref_metadata_2025 huggingface dataset:
Vasodilatory State of Decompensated Cirrhosis: Relation to Hepatic Dysfunction, Ascites, and Vasoactive Substances
Authors: Friedman Howard S. , Cirillo Nicholas , Schiano Frank , Nathan Paul , Khan Sultan , Rosero Hugo , Vaseghi Mehdi , Sacchi Terrence , Vasavada Balendu , Bjornson Loring
Published: April 2006

The objective of this study was to determine the relations between the hallmark circulatory finding of decompensated cirrhosis, a reduced systemic vascular resistance (SVR), and the indices of hepatic decompensation, the accumulation of ascites, and the concentrations of various vasoactive substances.

At a university‐affiliated teaching hospital, eighteen hospitalized patients with cirrhosis and 18 age‐ and sex‐matched healthy subjects were used. This was a case‐control study.

Measurements included cardiac dimensions and indices derived from echocardiograms and Doppler studies, abdominal ultrasound estimates of ascites, indices of hepatic function, and various serum (S) and urinary (U) substances.

Results showed that cirrhotics had increased left atrial and left ventricular dimensions, left ventricular mass, heart rate, cardiac output (CO), transvalvular velocities, and a decreased SVR. SVR was related to hepatic dysfunction, as reflected by an abnormal prothrombin time ratio (r= ‐0.64, p= 0.006), and also related to overall severity of liver disease as estimated by the Child‐Pugh score (r= ‐0.53, p = 0.044). Although cirrhotics with ascites generally had a reduced SVR, estimates of ascites were directly related to SVR (r = 0.57, p = 0.03) and inversely related to CO (r= ‐0.53, p= 0.04). Concentrations of S and U digoxin‐like immunoreactive substance (DLIS) were also increased, but the concentrations of S glucagon and estradiol were not elevated. The accumulations of S and U DLIS, S glucagon, and S estradiol were all related to hepatic dysfunction. S estradiol was also related to SVR (r = ‐0.55, p= 0.04), but this was only evident with S estradiol expressed as a logarithm and did not emerge as significant on a multivariate analysis.

The reduced SVR observed in decompensated cirrhosis is related to various indices of hepatic dysfunction. Certain substances that accumulate in cirrhosis (such as DLIS, glucagon, and estradiol) do not explain the vasodilatation observed. Although ascites in decompensated cirrhosis generally signifies a vasodilated state, a reduced SVR may be found even before ascites is clinically evident, and tense ascites may actually obscure this finding.
Stress, Depression, Irrational Beliefs, and Alcohol Use and Problems in a College Student Sample
Authors: Camatta Clorinda D. , Nagoshi Craig T.
Published: April 2006

One‐hundred thirty‐five alcohol‐using college students completed a questionnaire on their levels of alcohol use, moderate‐to‐severe problems with alcohol use, the Eysenck 1.7 measure of impulsiveness and venturesomeness, the Zung depression scale, the “Hassles and Uplifts” scale of life stresses, and a scale of proneness to irrational beliefs. Impulsivity and venturesomeness were significantly correlated with quantity‐frequency of alcohol use, but not with the occurrence of alcohol use problems; whereas depression, stress, and irrational beliefs were significantly correlated with alcohol problems, but not with alcohol use. Multiple regression analyses indicated that the effect of stress on alcohol problems was mediated by depression, whereas the effect of depression, in turn, was mediated by irrational beliefs.
Ethanol Elevates Fetal Serum Glutamate Levels in the Rat
Authors: Karl Peter I. , Kwun Richard , Slonim Alfred , Fisher Stanley E.
Published: April 2006

Glutamate is an important excitatory neurotransmitter. However, a sustained elevation of glutamate in the extracellular space may be toxic to neurons. Because the blood‐brain barrier is incomplete in the developing fetus, an elevation of fetal serum glutamate could expose the immature, growing brain to potentially toxic levels of extracellular glutamate. Chronic ethanol consumption during pregnancy is associated with an increased risk for a complex array of congenital anomalies, including alterations in the CNS, a hallmark of the fetal alcohol syndrome. Some central nervous system changes appear to involve the glutamate receptor, including reduced number and altered function. One mechanism for receptor downregulation may be a sustained elevation in extracellular glutamate. We hypothesize that chronic ethanol exposure during pregnancy leads to an elevation in fetal serum glutamate. When rats were fed ethanol‐containing liquid diet throughout pregnancy, growth retardation of fetuses was observed at sacrifice (gestation day 20). Within each group, ethanol‐fed, pair‐fed, and ad libitum chow‐fed, serum glutamate levels were generally higher in the fetus than in the dam. Ethanol treatment had no effect on fetal or maternal serum glutamine, a reciprocal metabolite of glutamate. In contrast, ethanol treatment increased serum glutamate levels in the fetal serum by nearly 50%, compared with either of the control groups. Maternal serum glutamate was not affected. The finding of ethanol‐induced elevation of fetal serum glutamate suggests that the developing brain might be concurrently exposed to elevated levels of extracellular glutamate. Chronic exposure to elevated glutamate during critical periods of brain development may contribute to the pathogenesis of the fetal alcohol syndrome.
Human Stomach Class IV Alcohol Dehydrogenase: Molecular Genetic Analysis
Authors: Cheung Brenda , Anderson Jasen K. , Holmes Roger S. , Beacham Ifor R.
Published: April 2006

A partial human stomach alcohol dehydrogenase (ADH) encoding cDNA has been isolated, cloned, and sequenced, which contains 222 nucleotides encoding amino acid residues 227–299 of the ADH subunit. The amino acid sequence deduced from this cDNA was highly homologous with the rat stomach class IV ADH sequence recently reported (81.1% sequence identity). Homology with other human ADH classes was also observed: class I, 58.1% sequence identity; class II, 39.2% sequence identity; class III, 55.4% sequence identity; and class V, 50.0% sequence identity. These results support a proposal that the isolated cDNA encodes a partial sequence for human stomach class IV ADH. This sequence retains val294 for all other human ADH classes reported, as compared with an ala294 at this position reported for rat class IV ADH. This ala residue may contribute to the very high Km values with ethanol for the latter enzyme. In addition, three substitutions are reported for key residues in the coenzyme binding site: 251, gln/ser; 260, gly/asn; and 261, gly/asn, which may contribute to the weak coenzyme binding properties reported for human class IV ADH.
Quantitative Changes in G Proteins Do Not Mediate Ethanol‐Induced Downregulation of Adenylyl Cyclase in Mouse Cerebral Cortex
Authors: Tabakoff Boris , Whelan James P. , Ovchinnikova Larissa , Nhamburo Patson , Yoshimura Masami , Hoffman Paula L.
Published: April 2006

Our prior work, and the work of others, demonstrated that chronic administration of ethanol to cells in culture or to mice resulted in decreased responsiveness of adenylyl cyclase (EC4.6.1.1) to a number of stimulatory agents. In this study, we substantiated the ethanol‐induced changes in cerebral cortical adenylyl cyclase activity in alcohol‐tolerant and alcohol‐dependent mice, and we examined whether chronic ethanol treatment of mice altered the quantity of heterotrimeric guanine nucleotide‐binding regulatory proteins (G proteins) in cerebral cortex and other mouse brain areas. Amounts of various G protein subunits‐including the α subunits of Gs (Gsα), G1α1–3Goα and β subunits‐were examined by Western blot analysis. There was no change in quantity of these G protein subunits in cerebral cortex, hippocampus, or cerebellum of ethanol‐fed mice, compared with controls. In striatum of ethanol‐fed mice, small increases in G1α1, and Goα were observed, but these changes could not explain the ethanol‐induced desensitization of adenylyl cyclase in brain areas such as the cerebral cortex. Forskolin activation of cerebral cortical adenylyl cyclase activity showed two components of activation, with high and low “affinity” for forskolin. Ethanol treatment caused a decrease in the efficacy of forskolin for both components, whereas the EC50 of forskolin for each component did not change. Adenylyl cyclase activity measured in the presence of manganese was also diminished in cortical membranes of ethanol‐treated mice. Our results indicate that chronic ethanol treatment does not cause quantitative changes in G proteins which correlate with ethanol‐induced changes in cortical adenylyl cyclase activity. The ethanol‐induced reduction in adenylyl cyclase activity could be observed using agents (forskolin and manganese) that directly activate the catalytic unit of this enzyme. Thus, our results suggest that chronic ethanol treatment may alter the activity of the catalytic unit of adenylyl cyclase.
Ethanol's Effect on Tissue Polyamines and Ornithine Decarboxylase Activity: A Concise Review
Authors: Shibley Ivan A. , Gavigan Michael D. , Pennington Sam N.
Published: April 2006

An extraordinarily diverse literature describes the cellular/tissue systems in which the molecular effects of both acute and chronic alcohol exposure seem to be mediated by changes in polyamine levels and/or ornithine decarboxylase (ODC) activity. The single unifying factor that links most of these studies is that they all, in some way, involve tissues that are undergoing relatively rapid cell division. Non‐dividing cells expressing the NMDA receptor are a notable exception in that ethanol and the polyamines seem to act via discrete regions of that receptor. Under most cellular conditions, ODC activity is a reflection of the relative tissue polyamine content, and an increase in ODC activity and polyamine content seems to be one of the early events in the progression of quiescent cells toward cell division. Thus, it is not surprising that ethanol, which has been widely reported to delay cell division, should be found to interact with the ODC/ polyamine pathway. Perhaps the most unique aspect of these studies is the fact that, with rare exception, both acute and chronic ethanol exposure have been found to slow growth and to lower tissue polyamine (putrescine) content. Furthermore, in most studies, the ethanol‐induced suppression of cell division could be overcome by the administration of exogenous putrescine. These data suggest that the ethanol‐induced suppression of cell division resulted from the loss of putrescine. In addition, because the cells were able to respond to the exogenous putrescine, the studies suggest that the signaling pathway remained intact beyond the polyamine synthesis step. Increased ODC activity (and polyamines?) has been reported during the perinatal and postnatal periods in fetal animals exposed to ethanol during early development. Although not examined in all models, the perinatal/postnatal increase in fetal ODC activity may be a compensatory response to an initial loss of ODC activity, as the organism attempted to overcome the alcohol‐induced growth suppression.
Use of Repeated Measures in an Analysis of Ethanol‐Induced Loss of Righting Reflex in Inbred Long‐Sleep and Short‐Sleep Mice
Authors: Markel Paul D. , DeFries John C. , Johnson Thomas E.
Published: April 2006

We present a repeated‐measures analysis of ethanol‐induced loss of righting reflex (LRR) in Inbred Long‐Sleep (ILS) and Inbred Short‐Sleep (ISS) strains of mice and their F1 and F2 cross progeny. Mice were administered a 4.1 g/kg intraperitoneal dose of ethanol at two times, 7–10 days apart. Repeatability is nonsignificant in ILS, ISS, and F, mice, but is highly significant (0.47, p < 0.01) in the F2 mice. Mean LRR does not differ between trials 1 and 2, with the exception of the ISS strain in which the interaction of sex with LRR sensitization is significant. This two‐trial method leads to increased accuracy of genotype assessment for pharmacological or behavioral traits where trial 1 does not influence the outcome of trial 2. The repeated‐measures design facilitates novel analyses of the duration of LRR, and results suggest that most environmental variance for LRR is due to nonreplicable influences.
Alteration of [3H]MK‐801 Binding Associated with the JV‐Methyl‐d‐Aspartate Receptor Complex by Acute Ethanol in Rat Cortex and Hippocampus In Vitro
Authors: Spuhler‐Phillips Karen , Gonzalez Jose , Randall Patrick K. , Leslie Steven W.
Published: April 2006

We investigated the effect of ethanol on specific binding of [3H]MK‐801 to the intrachannel phencyclidine (PCP) receptor site, as an index of change in the functional response of the N‐methyl‐d‐Aspartate (NMDA)‐associated ion channel. Saturation binding experiments were performed on synaptic membrane homogenates from adult rat cortex and hippocampus. [3H]MK‐801 binding assays were conducted under conditions of basal, 10 μm glutamate, or 10 μm glutamate + 30 μm d‐serine, with and without 50 or 100 mm ethanol. Association experiments of [3H]MK‐801 binding (5 nm) were conducted under conditions of 0 or 10 μm glutamate, with varying concentrations of glycine (0.01, 0.10, and 10 μm) with and without 100 mm ethanol. Ethanol (50 and 100 mm) significantly decreased the percentage of high‐affinity (open‐channel state) MK‐801 receptors with a concomitant increase in percentage of low‐affinity receptors, but did not change high‐ and low‐affinity constants of the two binding states. An ethanol‐induced increase in the closed‐channel receptor density in basal and activated conditions was suggested by the saturation experiments. Association experiments further explained this finding, in that ethanol (100 mm) significantly decreased fast component (open‐channel) [3H]MK‐801 binding in conditions of glycine (0.01–10 μm) only and activated conditions of glutamate + glycine (0.01–0.10 μm). However, the observed fast and slow kinetic rate constants of [3H]MK‐801 binding, as well as total specific binding (fast + slow components), were not altered. Thus, ethanol seems to act as a noncompetitive antagonist upon the gating mechanism of, and ligand access to, the NMDA‐coupled ion channel. These findings support previous observations of ethanol selectively reducing NMDA‐activated calcium influx, and reducing the frequency and duration of ion channel opening in electrophysiological studies. Similar to previous reports on NMDA‐stimulated calcium influx and [3H]MK‐801 binding, glycine (at the maximal concentration of 10 μm), in the presence of 10 μm glutamate, was found to reverse ethanol inhibition of fast component binding.
Differential Sensitivity of NMDA Receptor‐Mediated Synaptic Potentials to Ethanol in Immature Versus Mature Hippocampus
Authors: Swartzwelder H. Scott , Wilson W. A. , Tayyeb M. I.
Published: April 2006

Pharmacologically isolated, NMDA receptor‐mediated population EPSPs (pEPSPs) were evoked from area CA1 of hippocampal slices using electrical stimulation of the Schaffer collateral/commissural fiber pathway. Slices were prepared from rats aged 20–25 or 80–100 days. The inhibitory effects of a range of ethanol concentrations were assessed. While ethanol antagonized NMDA‐mediated pEPSPs in slices from both age groups, it was significantly more potent against pEPSPs from immature versus mature hippocampi. In slices from mature animals, significant and consistent reduction of pEPSPs was observed only with the highest ethanol concentration (100 mm), whereas 10, 30, or 100 mm significantly reduced the amplitude of pEPSPs in slices from immature animals. These results indicate that NMDA‐mediated synaptic activity in the hippocampus is more sensitive to the effects of ethanol in immature versus mature animals.
Effect of Ethanol, Propanol, Butanol, and Catalase Enzyme Blockers on β‐Endorphin Secretion from Primary Cultures of Hypothalamic Neurons: Evidence for a Mediatory Role of Acetaldehyde in Ethanol Stimulation of β‐Endorphin Release
Authors: Reddy B. V. , Boyadjieva N. , Sarkar D. K.
Published: April 2006

Previously, we have shown that low closes of ethanol (12.5–100 mm) and acetaldehyde (12.5–50 μm), but not salsolinol, enhanced immunoreactive β‐endorphin (IR‐β‐EP) secretion from fetal hypothalamic neurons in primary culture. In this study, the effects of ethanol, propanol, and butanol, as well as the effect of catalase inhibitors on IR‐β‐EP secretion were studied in vitro to determine the role of membrane fluidization and ethanol metabolism on ethanol‐induced IR‐β‐EP secretion. The primary cultures of fetal hypothalamic neurons were maintained for 8–9 days in chemically defined medium and treated for 5 hr with ethanol (50 mm), propanol (25 and 50 mm), and butanol (25 and 50 mm). Determination of hourly secretion of IR‐β‐EP from the cultures revealed that only 50 mm ethanol caused stimulation of IR‐β‐EP secretion, whereas propanol and butanol did not alter IR‐β‐EP response at any given concentration. Pretreatment of these cultures with the catalase inhibitors, 3‐amino‐1,2,4 ‐triazole (3‐AT; 1, 5, and 10 mm), caused a dose‐dependent inhibition of ethanol‐stim‐ulated IR‐β‐EP secretion, but did not inhibit dibutyryl cAMP (dcAMP)‐stimulated IR‐β‐EP secretion. Another catalase inhibitor, sodium azide (5 mm), also inhibited ethanol‐stimulated IR‐β‐EP secretion. Measurement of acetaldehyde production in cultured cells and media after ethanol or dcAMP treatments revealed that cultured cells produce acetaldehyde only after ethanol treatment and at levels of acetaldehyde (8–24 μm) that are known to evoke IR‐β‐EP release. The catalase inhibitor 3‐AT (10 mm) treatment reduced ethanol‐evoked acetaldehyde production. These results suggest for the first time that the catalase‐H2O2 system is functional in the cultured hypothalamic neurons and is involved in mediation of ethanol's effects on IR‐β‐EP secretion via conversion of alcohol to acetaldehyde.
Divergence of Ethanol and Acetaldehyde Kinetics and of the Disulfiram‐Alcohol Reaction between Subjects with and without Alcoholic Liver Disease
Authors: Wicht Francis , Fisch Hans‐Ulrich , Nelles Joachim , Raisin Juergen , Allemann Peter , Preisig Rudolf
Published: April 2006

Despite standardization, marked interindividual variation in the severity of the disulfiram‐alcohol reaction (DAR) has been observed. We studied the DAR in 51 consecutive alcoholics with (n= 16) and without (n= 35) significant alcoholic liver disease. Clinical signs of the DAR were much weaker in the patients with compared with those patients without liver disease. Because acetaldehyde is thought to be the main cause of the DAR, we studied ethanol and acetaldehyde kinetics in 13 patients (6 females, 7 males) with alcoholic liver disease (documented by biopsy, clinical and/or radiological findings, and by quantitative liver function) [galactose elimination capacity (GEC) 4.2 ± SD 1.0 mg/min/kg; aminopyrine breath test (ABT) 0.14 ± 0.10% dose × kg/mmol CO2] and 13 age‐ and sex‐matched controls (alcoholics without significant liver disease, GEC 7.1 ± 0.7; ABT 0.81 ± 0.35). Clinical signs of acetaldehyde toxicity during the DAR (flush, nausea, tachycardia, and blood pressure drop) were absent in alcoholic liver disease, but clearly evident in controls. Blood ethanol kinetics were similar in both groups, Cmax and area under the concentration‐time curve (AUC) being 6.27 ± 1.82 and 368.9 ± 72.9 mmol × min/liter in alcoholic liver disease, and 6.62 ± 1.71 and 377.6 ± 124.5 in controls, respectively. In contrast, there was a strong (p < 0.001) difference in Cmax and AUC of acetaldehyde, respective values being 33.46 ± 21.52 and 1463.8 ± 762.5 μmol × min/liter in alcoholic liver disease, and 110.87 ± 56.00 and 4162.0 ± 2424.6 in controls. We hypothesize that the lack of disulfiram‐induced acetaldehyde retention in the alcoholic liver disease group may be due to decreased formation of disulfiram metabolites.
Increased Cell Death and Reduced Neural Crest Cell Numbers in Ethanol‐Exposed Embryos: Partial Basis for the Fetal Alcohol Syndrome Phenotype
Authors: Cartwright Martina M. , Smith Susan M.
Published: April 2006

Fetal alcohol syndrome (FAS) is characterized by growth retardation, craniofacial malformations, and heart and neural defects; the cellular and molecular mechanism(s) responsible for ethanol's teratogenicity remains unknown. Although the phenotype suggests that prenatal ethanol exposure perturbs neural crest cell development, direct proof that these cells are an in utero target is still lacking. Previous research suggested that cranial neural crest cells are eliminated by ethanol‐induced apoptosis. We tested this hypothesis using a chick embryo model of FAS. A single dose of ethanol, chosen to achieve a concentration of 35–42 mg/dl, was injected in ovo at gastrulation and resulted in growth retardation, craniofacial foreshortening, and disrupted hindbrain segmentation. Ethanol exposure enhanced cell death within areas populated by cranial neural crest cells, particularly in the hindbrain and craniofacial mesenchyme. In contrast, control embryos had limited cell death within these regions. Subsequent immunolabeling with neural crest cell‐specific antibody revealed that ethanol treatment resulted in fewer neural crest cell numbers, whereas neural crest migration patterns were unaffected by ethanol. These results suggest that prenatal ethanol exposure leads to loss of cranial neural crest cells. Such a loss could result, in part, in the phenotype characteristic of FAS.
Ethanol Suppresses Mycobacteria tuberculosis‐Induced mRNA for Nitric Oxide Synthase in Alveolar Macrophages, In Vivo
Authors: Greenberg Stan , Xie Jianming , Kolls Jay , Nelson Steve , Didier Peter , Mason Carol
Published: April 2006

Acute ingestion of alcohol [ethanol (ETOH)] adversely affects the immunocompetence of both naive individuals as well as chronic alcohol abusers. An increased incidence and severity of tuberculosis is found in chronic alcohol abusers. Nitric oxide (NO) produced by alveolar macrophages (AMs) may play a role in the in vitro killing of Mycobacterium avium and Mycobacterium tuberculosis (MTB). Moreover, tumor necrosis factor‐α (TNF‐α) is believed to be a primary cytokine mediator of NO production by AMs. Recent studies from our laboratory demonstrated that ETOH suppressed endotoxin‐induced increases in both TNF‐α and NO in AMs, in vivo. We tested the postulate that acute ingestion of ETOH can interfere with myco‐bacteria‐induced upregulation of the NO system in AMs, in vivo. We show that heat‐killed M. avium complex (MAC) and human virulent MTB instilled into rat lungs rapidly increased mRNA for inducible NO synthase II (iNOS) of AMs in fluid obtained by bronchoalveolar lavage (BAL fluid). This was associated with production of reactive nitrogen intermediates [(RNIs); NO2‐ and NO3‐] in BAL fluid, lung homogenate, and AMs in the absence of a significant increase in BAL fluid TNF‐α. A single dose of ETOH (5.5 g/kg, ip) administered 30 min before intratracheal administration of MAC or MTB attenuated both MAC and MTB‐induced increases in RNI in BAL fluid, lung, and AMs, and the increase in mRNA for iNOS. Thus, mycobacteria upregulate iNOS mRNA and enhance RNI production by AMs without any increase in the production of TNF‐α. Moreover, ETOH attenuates mycobacteria‐induced upregulation of mRNA for iNOS and RNI production in the absence of ETOH‐mediated suppression of TNF. Speculatively, ETOH‐mediated inhibition of the AM NO system may offer an explanation for the increased severity of mycobacterial infections in alcoholics.
Ethanol Consumption Reduces the Cytolytic Activity of Lymphokine‐Activated Killer Cells
Authors: Gallucci Randle M. , Meadows Gary G.
Published: April 2006

Ethanol (20% w/v) given to female C57BL/6 mice in their drinking water reduces splenic natural killer (NK) cell cytolytic activity after 2, 4, and 10 weeks of consumption. This reduction is transient because the levels of NK cell cytotoxicity from ethanol‐consuming mice are nearly equal to those of water‐drinking mice after splenocytes were incubated in 1000 lU/ml of recombinant interleukin‐2 (rlL2) for 16–18 hr. In this study, mice were given 20% w/v ethanol in the drinking water for 2 weeks. Splenic NK cells were enriched up to 88% by negative selection based on surface expression of NK1.1. Enriched NK cells were expanded in HL2 for 6 days. Lymphokine‐activated killer (LAK) cells from both ethanol‐consuming and water‐drinking mice were <95% NK1.1+. LAK cell cytolytic activity was significantly lower against NK‐insensitive P815 mastocytoma [6.67 ± 2.18 vs. 17.21 ± 1.8 lytic units (LUs), p < 0.01], moderately NK‐sensitive B16 melanoma (25.3 ± 6.6 vs. 66.2 ± 14.2 LU, p < 0.05), and NK‐sensitive YAC‐1 lymphoma targets (80.5 ± 34.7 vs. 177.0 ± 43.6 LU, p < 0.005) in cells from ethanol‐consuming mice compared with water‐drinking controls. Ethanol consumption did not affect the morphology or phenotype of LAK cells with respect to surface expression of NK1.1, B220, CD3, CD25, CD11a, CD54, CD45RB, or class I major histocompatibility complex.
A Double‐Blind, Placebo‐Controlled Study of Nortriptyline and Bromocriptine in Male Alcoholics Subtyped by Comorbid Psychiatric Disorders
Authors: Powell Barbara J. , Campbell Jan L. , Landon Jennifer F. , Liskow Barry I. , Thomas H. Mikel , Nickel Elizabeth J. , Dale Tamara M. , Penick Elizabeth C. , Samuelson Stephen D. , Lacoursiere Roy B.
Published: April 2006

This double‐blind, placebo‐controlled, 6‐month follow‐up treatment study investigated the efficacy of bromocriptine and nortriptyline in attenuating drinking behavior and psychiatric symptoms in 216 male alcoholic patients subtyped by comorbid psychiatric disorder(s). Three well‐defined subtypes were examined: alcoholism only, alcoholism + affective/anxiety disorder, and alcoholism + antisocial personality disorder. It was hypothesized that both medications would relieve negative affective symptoms associated with alcohol use and would be particularly effective for the affective/anxiety subgroup. Contrary to our predictions, the only significant effects found were with the antisocial personality disorder patients who were receiving nortriptyline. One interpretation of the results was that nortriptyline may have reduced impulsive drinking in the antisocial personality disorder subgroup by actions on serotonergic neurotransmission.
Autonomic Reactivity and Alcohol‐Induced Dampening in Men at Risk for Alcoholism and Men at Risk for Hypertension
Authors: Conrod Patricia J. , Pihl Robert O. , Ditto Blaine
Published: April 2006

Both sons of male alcoholics with multigenerational family history of male alcoholism (MFH) and sons of essential hypertensives (HTs) exhibit elevated psychophysiological reactivity to stress when compared with male controls (FH‐). MFHs also demonstrate a significant baseline heart rate increase and stress‐response dampening following alcohol consumption. The present study investigates the specificity of this alcohol‐induced psychophysiological response pattern by testing these two risk groups in a shock response paradigm, both sober and alcohol‐intoxicated. A repeated measures analysis of variance on sober and alcohol‐intoxicated heart rate reactivity yielded a significant risk by alcohol interaction, indicating that alcohol consumption led to a greater decrease in reactivity in the MFH group compared with the HT and FH‐ groups. Similar results were obtained for muscle tension measures. MFHs also displayed greater increases in resting baseline heart rate and muscle tension when alcohol intoxicated. The results may reflect a sensitivity to negatively and positively reinforcing effects of alcohol specific to individuals with multigenerational familial histories of alcoholism.
Patterns of Cognitive Impairment among Alcoholics: Are There Subtypes?
Authors: Tivis Rick , Beatty William W. , Jo Nixon Sara , Parsons Oscar A.
Published: April 2006

The mild generalized dysfunction hypothesis of alcohol abuse's deleterious effects on cognitive processes has gained support from a number of studies in which detoxified alcoholics have a lower mean performance level than peer controls on a variety of neuropsychological tests. This approach might obscure consistent but different patterns of preserved and impaired cognitive performance among subgroups of alcoholics, suggestive of alternative hypotheses. To test this possibility, neuropsychological test data from two large, independent samples of alcoholics (sample 1, n= 143; sample 2, n= 130) and controls (sample 1, n= 97; sample 2, n= 83) were subjected to separate centroid hierarchical cluster analyses. For both samples, the majority of alcoholics (94% and 94%) exhibited a pattern of impaired verbal and nonverbal performance and deficits in memory and perceptual motor skill, with normal motor skill. The alcoholics who did not fit this pattern showed more severe or wide‐ranging impairments. These findings indicate that empirical support for the mild generalized dysfunction hypothesis of alcoholics' cognitive deficits is not an artifact of averaging.
Pathways into Risk: Temperament and Behavior Problems in Three‐ to Five‐Year‐Old Sons of Alcoholics
Authors: Jansen Roger E. , Fitzgerald Hiram E. , Ham Hazen P. , Zucker Robert A.
Published: April 2006

Evidence suggests that a child with a difficult temperament, reared in an alcoholic family, is at high risk for the development of behavior problems that antedate the emergence of antisocial behavior, alcoholism, and coactive psychopathology. However, the causal linkage between difficult temperament and problem behavior in childhood, and antisociality and alcohol abuse in adulthood is far from certain, in part because few studies assess emergent behavior patterns in young children of alcoholics. In this study, we investigated the temperament‐behavior problem relationship in 191 3‐ to 5‐year‐old boys, 149 of whom were being reared in high‐risk alcoholic, low socioeconomic environments. Boys were classified as high in problem behavior or not based on standardized clinical cut‐off scores for Total Behavior Problems from the Child Behavior Checklist. Results indicated that boys rated in the clinical range for total behavior problems exhibited more characteristics of difficult temperament than boys who were not rated in the clinical range. Parents of the boys in the clinical group had significantly more alcohol‐related problems, higher levels of antisociality, and significantly lower levels of socioeconomic status, income, and education. Results are consistent with the supposition that the difficult temperament‐behavior problem relationship flourishes in the context of an antisocial, alcoholic family environment.
Thiamine Phosphatases in Human Brain: Regional Alterations in Patients with Alcoholic Cirrhosis
Authors: Rao L Raghavendra , Butterworth Roger F.
Published: April 2006

Activities of thiamine monophosphatase (TMPase) and thiamine diphosphatase (TDPase) were measured in homogenates of brain tissue obtained at autopsy from eight alcoholic cirrhotic patients who died in hepatic coma and nine controls matched for age and for postmortem delay interval and free from neurological or psychiatric disorders, hepatic disease, or other conditions of grossly impaired nutritional status. Enzyme activities were measured by standard spectrophotometric techniques. Both TMPase and TDPase were distributed unevenly in brain with highest activities being recorded in temporal cortex. Regional correlations between TMPase and TDPase, however, were poor. TDPase activities in brain tissue from alcoholic cirrhotic patients were significantly increased in 5 of 6 brain regions, by 26 to 153% (p < 0.05). TMPase activities in alcoholic cirrhotics, on the other hand, were unchanged in all brain regions, with the exception of caudate nucleus where they were increased by 70% (p < 0.05). These findings add to the substantial body of evidence suggesting that alcoholic liver disease is associated with abnormal thiamine status and with altered thiamine neurochemistry. Increased TDP degradation resulting from increased activities of TDPase could contribute to the pathophysiological mechanisms involved in alcohol‐related brain dysfunction.
Modulation of T‐Cell Adhesion Markers, and the CD45R and CD57 Antigens in Human Alcoholics
Authors: Cook Robert T. , Ballas Zuhair K. , Waldschmidt Thomas J. , Vandersteen Daniel , LaBrecque Douglas R. , Cook Brian L
Published: April 2006

Direct and indirect evidence indicates that T cells are altered in alcoholics. The most commonly reported changes under direct examination have been consistent with an increased level of activation as reflected by shifts in the ratio of common leukocyte antigen isoforms expressed at the cell surface, by increases in the expression of class II antigen, or by alterations in the expression of various adhesion molecules. Functional evidence for T‐cell abnormality includes loss of delayed hypersensitivity and a number of findings attributed to dysregulation of B cells by alcoholic T cells; these include the widely reported disturbances of immunoglobulin production in vivo and a range of abnormal responses when T and B cells are combined in vitro.

Detailed flow cytometric examination of T cells from alcoholics with or without active liver disease reveals a significant loss of l‐selectin CD8+ T cells, but not usually of CD4+ T cells. There is an inverse increase in the expression of CD11b on the CD8+ cells that have decreased L‐selectin+ percentages. Both CD8+ and CD4+ T cells in alcoholics display a significant loss of the CD45RA isoform and a gain of cells exhibiting the CD45RO isoform. Other surface alterations include increased expression of CD57, a marker most commonly associated on T cells with conditions of chronic increased antigenic exposure.

It is argued that these and other T‐cell alterations in alcoholics are cytokine‐driven in part and result in T‐cell differentiation states that are functionally inappropriate. The results of these alterations may include reductions in normal lymphocyte traffic, an increase in cell‐mediated cytotoxicity, and intermittent loss of normal suppressor functions for immunoglobulin production permitting increased autoantibody formation. Chronic excessive antigen exposure may contribute at other times to the development of abnormal regulatory suppression of the immune response.
Event‐Related Potentials in Alcoholic Men, Their High‐Risk Male Relatives, and Low‐Risk Male Controls
Authors: Hill Shirley Y. , Steinhauer Stuart , Locke Jeannette
Published: April 2006

A total of 217 adult male subjects were evaluated utilizing event‐related potentials (ERPs) elicited with two different auditory tasks (Counting and Choice Reaction). Ninety‐eight alcoholics from high‐density, multigenerational families were evaluated along with 39 first‐degree nonalcoholic relatives from the same high‐density families. Eighty controls, selected for low density of alcoholism in their extended families, were also studied. Using both conventional and topographic analyses, no significant differences in the amplitude of the P300 component could be found with either of the auditory tasks. No significant differences in amplitude of N250 were seen. The latency of N250 increased with increasing conditional probabilities (0.33,0.67, and 1.00), a trend that was amplified in the Counting task as compared with the Choice Reaction task. This prolongation in a task not requiring a reaction response (button press) tended to increase the latency more for alcoholics than controls or high‐risk nonalcoholic subjects. Age, lifetime, and recent drinking were treated as covariates in all analyses. The absence of P300 amplitude differences between adult high‐ and low‐risk subjects is discussed in the context of the much more reliable differences seen between high‐ and low‐risk children from the same high‐ and low‐density families, when evaluated with the same auditory tasks.
Is Alcohol‐Related Flushing a Protective Factor for Alcoholism in Caucasians?
Authors: Slutske Wendy S. , Heath Andrew C. , Madden Pamela A. F. , Bucholz Kathleen K. , Dinwiddie Stephen H. , Dunne Michael P. , Statham Dixie S. , Whitfield John B. , Martin Nicholas G.
Published: April 2006

Although alcohol‐related flushing seems to be a genetically influenced protective factor for alcoholism in some Asian groups, little is known about whether this is true for Caucasians. The evidence for alcohol‐related flushing as a protective factor for the development of alcoholism was examined in a sample of 5831 Australian twins (2041 men, 3790 women) who were administered a structured psychiatric interview. Twin correlations for self‐reported adverse alcohol reactions (e.g., “flushing or blushing” and “feeling very sleepy” after drinking 1 or 2 drinks) were modest, suggesting minimal contribution of genetic factors, but when corrected for reliability of measurement, were consistent with moderate heritabilities. In accord with studies examining Asian samples, we found that individuals who experienced adverse reactions after drinking small amounts of alcohol drank less often and slightly less per drinking occasion than those who did not experience adverse reactions. However, those who experienced adverse reactions were more likely to have symptoms of alcoholism and to report a parental history of alcohol problems. We conclude that self‐reported alcohol‐related flushing is not a protective factor for alcoholism in Caucasians and may be a risk factor.
Utility of Carbohydrate‐Deficient Transferrin as a Marker of Relapse in Alcoholic Patients
Authors: Rosman Alan S. , Basu Prithwijit , Galvin Kathryn , Lieber Charles S.
Published: April 2006

Carbohydrate‐deficient transferrin (CDT) has been proposed as a marker of alcoholism. However, its role in monitoring alcoholic patients for relapse has not been extensively studied. We therefore performed sequential serum CDT measurements using a microcolumn/radioimmunoassay method (Kabi Pharmacia, Piscataway, NJ) in 86 male alcoholics participating in a hepatitis vaccination program who were monitored for relapse using self‐report and collateral history (when available). The maximum serum CDT was significantly higher in patients who relapsed (n = 38) (33.1 ± 3.1 mg/liter), as compared with abstinent subjects with collateral verification (n= 39) (18.8 ± 1.3, p < 0.001) and abstinent patients without collateral verification (n= 9) (17.4 ± 1.3, p < 0.01). Using the manufacturer's currently recommended threshold of 20 mg/liter for males, serum CDT was elevated in 29 of 38 patients who relapsed (sensitivity 76.3%). In 16 (42.1%) of the relapsed patients, a serum CDT above this threshold preceded the patient's self‐report by at least 28 days. However, serum CDT exceeded 20 mg/liter in 10 of 48 patients who remained sober (specificity 79.2%); three of these patients had clinical and/or pathological evidence of cirrhosis. Using a threshold of 25 mg/liter, 21 of 38 patients who relapsed had an elevated serum CDT (sensitivity 55.3%); 12 (31.6%) of these patients had elevated serum CDT before self‐report. Only 4 of 48 subjects who remained sober had serum CDT levels that exceeded 25 mg/liter (specificity 91.7%); three of these patients had clinical and/or pathological evidence of cirrhosis. In conclusion, serial serum CDT testing detects relapses before self‐report in male subjects. Values between 20–25 mg/liter suggest relapse, but call for collateral verification, whereas CDT values above 25 mg/liter are usually diagnostic of relapse in the absence of cirrhosis.
Effect of Ethanol on Function of the Rat Heart and Skeletal Muscles
Authors: Pagala Murali , Ravindran Kadirimangalam , Amaladevi Bellamkonda , Namba Tatsuji , Grab David
Published: April 2006

The present study was undertaken to evaluate the acute effects of ethanol on responses of the rat heart and skeletal muscles both in vivo and in vitro. In the anesthetized rat, intravenous infusion of ethanol at 0.1–0.5 g/kg body weight (33–167 mm) decreased the breathing rate by 8–83%, heart rate by 4–52%, and QRS amplitude by 5–27%, and increased the P‐R interval by 1–49%. In the anterior tibialis muscle subjected to repetitive nerve stimulation at 100 Hz for 0.5 sec, ethanol at 0.1 g/kg increased the amplitude of the muscle action potential (AP) by 7%, whereas at 0.5 g/kg it decreased the muscle AP by 32%. The nerve‐evoked tetanic tension was reduced by 7–34% at 0.1–0.5 g/kg ethanol. In the isolated rat heart, perfusion of ethanol at 0.1–3.0% (22–651 mm) decreased the heart rate by 8–48% and QRS amplitude by 10–39%, and increased the P‐R interval by 5–61%. Left ventricular pressure was increased by 10% at 0.1 % ethanol, and decreased by 80% at 3.0% ethanol. In the isolated rat phrenic nerve‐diaphragm muscle preparation subjected to repetitive nerve stimulation at 100 Hz for 0.5 sec, 0.1–3.0% ethanol decreased the amplitude of the nerve AP by 5–89%, nerve‐evoked muscle AP by 2–96%, and peak tetanic tension by 1–87%. On repetitive direct muscle stimulation at 100 Hz for 0.5 sec, 0.1–3.0% ethanol decreased the amplitude of the muscle‐evoked muscle AP by 8–65%, and muscle‐evoked tetanic tension by 2–65%. These studies indicate that ethanol causes smaller reduction in responses of the heart and skeletal muscles at clinical concentrations, but marked reduction in these responses at higher concentrations due to direct action on excitability of these tissues. At higher concentrations, ethanol causes greater reduction in excitability of the skeletal muscle than of the heart.
Effects of Chronic Alcohol Abuse and HIV Infection on Brain Phosphorus Metabolites
Authors: Meyerhoff Dieter J. , MacKay Shane , Sappey‐Marinier Dominique , Deicken Raymond , Calabrese Giovanna , Dillon William P. , Weiner Michael W. , Fein George
Published: April 2006

We examined the effects of human immunodeficiency virus (HIV) infection and chronic alcohol consumption on cerebral phosphorus metabolites to determine if chronic alcohol abuse is a risk factor for the progression of neurological effects of HIV infection. We studied 15 HIV‐ alcoholics, 8 HIV‐ light/nondrinkers, 32 HIV+ alcoholics, and 41 HIV+ light/nondrinking men, with both HIV+ groups having similar CD4 lymphocyte counts. We used localized 31‐phosphorus magnetic resonance spectroscopy after magnetic resonance imaging to examine two brain volumes in superior white matter and subcortical gray matter. Chronic alcohol consumption was associated with reduced white matter concentrations of phosphodiester (PDE) and phosphocreatine (PCr). Also in the white matter, acquired immune deficiency syndrome (AIDS) and AIDS‐related complex (ARC) were associated with reduced concentrations of PDE and PCr, compared with both HIV‐ and clinically asymptomatic HIV+ subjects. Because no alcohol‐by‐HIV interactions were detected, the effects of HIV infection and alcohol abuse were cumulative. This is reflected in a successive decrease of white matter PDE and PCr concentrations in the order HIV‐ light/nondrinkers/HIV‐ alcoholics/HIV+ light/nondrinkers/HIV+ alcoholics. Subcortical gray matter PDE concentrations were lower in ARC/AIDS alcoholics than in HIV‐light/nondrinking individuals. These findings suggest altered brain phospholipid metabolites and energy metabolites with alcohol abuse and HIV infection. They demonstrate that the adverse metabolic effects of HIV on the brain are augmented by chronic alcohol abuse.
Low‐Level Hyperbaric Exposure Antagonizes Locomotor Effects of Ethanol and n‐Propanol But Not Morphine in C57BL Mice
Authors: Alkana Ronald L. , Davies Daryl L. , Mørland Jørg , Parker Elizabeth S. , Bejanian Marina
Published: April 2006

Low‐level hyperbaric exposure antagonizes a broad range of behavioral effects of ethanol in a direct, reversible, and competitive manner. This study investigates the selectivity of the antagonism across other drugs. C57BL/6 mice were injected with saline, ethanol, n‐propanol, or morphine sulfate, and then were exposed to 1 atmosphere absolute (ATA) air, 1 ATA helium‐oxygen gas mixture (heliox), or 12 ATA heliox. Locomotor activity was measured from 10 to 40 min following injection, N‐propanol produced a dose‐dependent depression of locomotor activity from 1.0 g/kg. Morphine produced a dose‐dependent stimulation of locomotor activity at doses of 3.75–12.0 mg/kg. Exposure to 12 ATA heliox significantly antagonized the locomotor depressant effects of 1.0 g/kg n‐propanol and 2.5 g/kg ethanol, without significantly affecting blood concentrations of these drugs measured at 40 min postinjection. Exposure to 12 ATA heliox did not significantly antagonize the locomotor‐stimulating effects of the two morphine doses tested (3.75 and 7.5 mg/kg). These findings suggest that exposure to 12 ATA heliox antagonizes the behavioral effects of intoxicant‐anesthetic drugs like ethanol and n‐propanol, which are believed to act via perturbation or allosteric modulation of functional proteins, but does not antagonize the effects of drugs like morphine, which act via more direct mechanisms. This demonstration of selective antagonism adds important support for the hypothesis that low‐level hyperbaric exposure is a direct mechanistic ethanol antagonist, with characteristics similar to a competitive pharmacological antagonist.
Attenuation of Glutamate‐Induced Neurotoxicity in Chronically Ethanol‐Exposed Cerebellar Granule Cells by NMDA Receptor Antagonists and Ganglioside GM1
Authors: Hoffman Paula L. , Lorio Karen R. , Snell Lawrence D. , Tabakoff Boris
Published: April 2006

Ethanol, acutely, is a potent inhibitor of the function of the N‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptor. After chronic exposure of animals to ethanol, however, the NMDA receptor in brain is upregulated. This upregulation is associated with the occurrence of ethanol withdrawal seizures. When cultured cerebellar granule neurons are exposed chronically to ethanol, the resulting upregulation of NMDA receptor function renders the cells more susceptible to glutamate‐induced neurotoxicity. The present studies show that chronic ethanol exposure produces an increase in NMDA receptor number in the cells, measured by ligand binding to intact cells. Glutamate‐induced excitotoxicity, both in control and ethanol‐exposed cells, is blocked by the same NMDA receptor antagonists previously shown to block ethanol withdrawal seizures in animals. In addition, glutamate neurotoxicity is blocked by acute (2‐hr) pretreatment of cells with ganglioside GM., or by chronic (3 days) treatment with the ganglioside. Acute ganglioside treatment does not interfere with the initial rise in intracellular calcium caused by glutamate, whereas this response is downregulated after chronic ganglioside treatment. These results suggest that therapeutic agents can be developed to block both ethanol withdrawal signs and the neuronal damage that accompanies ethanol withdrawal. Furthermore, chronic ganglioside treatment during ethanol exposure has the potential to prevent changes in the NMDA receptor that lead to withdrawal seizures and enhanced susceptibility to excitotoxicity.