bluuebunny/crossref_metadata_2025 huggingface dataset:
Monoamine Oxidase and Homovanillic Acid in Boys with Predispositions to Substance Abuse
Authors: Gabel Stewart , Stadler John , Bjorn Janet , Shindledecker Richard , Bowden Charles L.
Published: April 2006

Both dopaminergic dysregulation and abnormalities in monoamine oxidase (MAO) have been postulated as etiological factors in substance abuse. This study assessed whether MAO activity differed in sons of substance‐abusing fathers compared with sons of nonsubstance‐abusing fathers. It also assessed the levels of homovanillic acid (HVA), the metabolite of dopamine, and MAO in a group of substance‐using/‐abusing boys compared with peers without this history In the same setting. Sixty‐five boys admitted to a residential center were evaluated on blood tests for HVA and MAO, and on a series of diagnostic instruments and questionnaires designed to elicit information about parental substance abuse and about the subject's own substance use/abuse. The results indicated tentatively that younger (< 12.0 years) sons of substanceabusing fathers had higher levels of MAO than younger sons of nonsubstanceabusing fathers. Levels of MAO in older (12.0 years) sons of substance‐abusing and nonsubstance‐abusing fathers did not differ. Boys with histories of significant use/abuse of substances themselves had significantly higher MAO levels and significantly lower HVA levels than peers of the same age without substance use/abuse histories.
Differences in Recent Life Events between Alcoholic and Depressive Nonalcoholic Suicides
Authors: Heikkinen Martti E. , Aro Hillevi M. , Henriksson Markus M. , Isometsä Erkki T. , Sarna Seppo J. , Kuoppasalmi Kimmo I. , Lönnqvist Jouko K.
Published: April 2006

The purpose of this study was to investigate the main differences in recent life events preceding suicide between alcoholic and depressive nonalcoholic suicide victims, how much these differences were sex‐ and age‐dependent, and how social support varied between these groups.

Using the psychological autopsy method, retrospective best‐estimate diagnoses by DSM‐III‐R criteria were assigned to a randomized 16.4% sample (n= 229) of suicide victims drawn from a 1‐year total nationwide suicide population (n= 1,397) in Finland. Life events during the last 3 months (32 items) and social support (6 items) of 75 suicide victims with alcohol abuse/dependence diagnoses were compared with those of 69 nonalcoholic depressive victims.

Among male suicides, the alcoholics had experienced more separations and family discord, financial trouble, and unemployment, whereas the depressives had experienced more somatic illness. Among females, adverse interpersonal events had been common in both alcoholic and depressive victims. Among the alcoholics, unlike the depressives, the number of adverse interpersonal life events had not diminished with increasing age. Living alone had been twice as common among the alcoholic suicides and, in these cases, recent separation, unemployment, and financial trouble were remarkably common, suggesting a concurrent stressor effect.

Our results confirm and extend the earlier findings of excess interpersonal stressors among alcoholic suicides compared with depressive suicides. The findings suggest that multiple adverse life events and living alone need to be taken into account in clinical practice when assessing psychosocial stress and suicidal danger in alcoholism.
Comparison of Different Methods for Detecting Carbohydrate‐Deficient Transferrin
Authors: Sillanaukee P. , Löf K. , Härlin A. , Mårtensson O. , Brandt R. , Seppä K.
Published: April 2006

Different methods for detecting carbohydrate‐deficient transferrin (CDT) were compared. In addition, their efficiency for detecting alcohol abuse among men not having clinical evidence of liver disease was studied in controls (n= 26), weekend (n= 16) and daily (n= 12) heavy drinkers, and alcoholics (n= 28). Comparisons were made between anion‐exchange separation of iron‐saturated transferrin (Tf) by microcolumns (CDTect) and by the Fast Protein Liquid Chromatography (FPLC% and FPLC‐MG), followed by doubleantibody radioimmunoassay of collected fractions. Tf fractions with pl ± 5.7 were also measured by two different isoelectric focusing (IEF) methods, followed by immunofixation (SA‐IEF‐CDT and IEFCDT‐TOT), the latter method being used also for detection of asialotransferrin (IEF‐CDT‐AS). The cut‐off was 20 units/liter for CDTect, 4.4% of total Tf for SA‐IEF‐CDT, and the mean + 2 sd of the control group for FPLC‐MG (as mg/liter of Tf), FPLC‐%, IEF‐CDT‐TOT, and IEF‐CDT‐AS (all as percentage of Tf). The overall accuracies (combining sensitivity and specificity) for detecting heavy drinkers of CDTect, FPLO (mg/liter), FPLC (%), SA‐IEF‐CDT, IEF‐CDT‐TOT, and IEF‐CDT‐AS were 63%, 59%, 61%, 74%, 57%, and 63%, respectively; for detecting alcoholics, 87%, 83%, 81%, 89%, 67%, and 76%, respectively. In conclusion, the methods were in rather good agreement with each other. Diagnostic characteristics among heavy drinkers and correlations between methods differed slightly, probably depending on the ability of different methods to separate and detect asialo‐, monosialo‐, and disialotransferrin. The overall accuracy among alcoholics was similar using each of the methods tested. The same was true among heavy drinkers, although SA‐IEF‐CDT had the highest sensitivity and overall accuracy among this group, making the method slightly better than the other ones.
A Double‐Blind, Placebo‐Controlled Pilot Study to Evaluate the Efficacy and Safety of Oral Nalmefene HCI for Alcohol Dependence
Authors: Mason Barbara J. , Ritvo Eva C. , Morgan Robert O. , Salvato Femando R. , Goldberg Gloria , Welch Bruce , Mantero‐Atienza Emilio
Published: April 2006

A dozen studies have been published showing that opiate antagonists suppress alcohol drinking in animals, and two independent placebo‐controlled, double‐blind clinical trials of naltrexone found this agent was associated with decreased alcohol craving and consumption in alcohol‐dependent patients. Nalmefene is a newer opiate antagonist that has a number of potential advantages over naltrex‐one in the treatment of alcoholism, including no dose‐dependent association with liver toxicity and more effective binding to central opiate receptors. Consequently, a double‐blind pilot study was conducted to gather preliminary data on the safety and efficacy of nalmefene for reducing alcohol consumption in alcohol‐dependent subjects. Twenty‐one alcohol‐dependent subjects meeting admission criteria were randomly assigned to 12 weeks of double‐blind treatment with 40 mg nalmefene, 10 mg nalmefene, or placebo, resulting in 7 patients/treatment group. Nalmefene was well tolerated, with no serious adverse drug reactions. The 40 mg group had a significantly lower rate of relapse (p 0.05), and a greater increase in the number of abstinent days/week (p 0.09), than the other treatment groups. A significant decrease in the number of drinks/drinking day was noted for both nalmefene groups (p 0.04), but not for placebo. These results were supported by parallel decreases in ALT. These pilot data provide preliminary support for the hypotheses that nalmefene can be safely given to alcoholics, and that nalmefene may have a role in reducing alcohol consumption and preventing relapse, particularly at the 40 mg level. A full‐scale study is underway to confirm these preliminary findings.
Women, Alcohol, and Red Cells
Authors: Seppä Kaija , Sillanaukee Pekka
Published: April 2006

Alcohol abuse is known to increase erythrocyte mean cell volume mainly as a consequence of direct toxic effect on the developing red cell. The influence of alcohol on other red cell parameters is unclear. The objective of this cross‐sectional survey was to examine the consequences of different alcohol amounts on red cell parameters among women.

We compared red cell parameters between female alcoholics, heavy drinkers, and controls. Controls (n= 138) and heavy drinkers (n= 65) consisted of consecutive 40‐ and 45‐year‐old women participating in the health screening, and alcoholics (n= 73) of consecutive women coming to a detoxification clinic.

Alcoholics had significantly smaller erythrocyte counts (p < 0.01), and higher erythrocyte mean cell volume values (p < 0.001), reticulocyte counts (p < 0.01), and red cell distribution width values (p < 0.001) than controls. No difference between these groups was found, however, in hemoglobin distribution width value. The only red cell difference between controls and heavy drinkers was erythrocyte mean cell volume, which was significantly higher among heavy drinkers (p < 0.001). In alcoholics, red cell distribution width values were even more often increased (in 44%) than erythrocyte mean cell volume values (in 34%). This increase in red cell distribution width was not solely explained by iron deficiency or liver disease.

Chronic alcohol abuse not only affects erythrocyte mean cell volume values, but also leads to anisocytosis seen in blood count as an increased red cell distribution width value.
Predictors of Mortality in Alcoholic Women: A 20‐Year Follow‐Up Study
Authors: Smith Elizabeth M. , Lewis Collins E. , Kercher Carman , Spitznagel Edward
Published: April 2006

Very little is known about the factors that predict mortality in female alcoholics. This study investigates these predictors in 103 female alcoholics who were psychiatrically hospitalized between 1967 and 1968 and followed for over 20 years. The findings showed that age, benders, and/or delirium tremens, comorbidity, and 3‐year posttreatment drinking status were associated with time to death. That older alcoholics and those with pathological drinking within 3 years after treatment had a significantly shorter time to death was not surprising. However, the association of benders with mortality indicated that women may be very sensitive to short periods of high concentrations of alcohol. Comorbidity also had an intriguing effect in that women with a history of depression were more likely to survive. The predictors of mortality in these female alcoholics differed from those of the male alcoholics in this sample. These differences will be discussed in future publications.
The Subchronic Effects of the TRH Analog TA‐0910 and Bromocriptine on Alcohol Preference in Alcohol‐Preferring Rats: Development of Tolerance and Cross‐Tolerance
Authors: Mason George A. , Rezvani Amir H. , Grady Danny R. , Garbutt James C.
Published: April 2006

In a previous study, we showed that a single injection of the thyrotropin‐releasing hormone analog TA‐0910 dose‐dependently reduced alcohol intake in alcohol‐preferring (P) rats and increased their water intake over a 24‐hr period. In the present study, the effects of seven consecutive, once‐daily injections of TA‐0910 (0.75 mg/kg, ip) on alcohol preference were determined. P rats developed tolerance to the attenuating effects of TA‐0910 on alcohol intake within 3–5 days. Following the development of tolerance to TA‐0910, rats were injected with the dopamine agonist bromocriptine (0.5 mg/kg, sc). In the presence of tolerance to TA‐0910, the attenuating effect of bromocriptine on alcohol intake was reduced. When rats were made tolerant to the attenuating effects of bromocriptine, they exhibited tolerance to the attenuating effects of TA‐0910. These findings indicate that tolerance to the effects of TA‐0910 on alcohol intake occurs and suggest dopamine involvement in the mechanism of action of TA‐0910 in reducing alcohol intake in P rats.
Effects of Ethanol Feeding on the Interaction of Rat Hepatocytes with Laminin Peptides
Authors: Xu Dongsheng , Sorrell Michael F. , Clemens Dahn L. , Casey Carol A. , Tuma Dean J.
Published: April 2006

Laminin, a complex glycoprotein of the extracellular matrix, contains a number of biologically active sites. These sites are involved in cell growth, attachment, differentiation, and gene expression. Our previous studies have shown that chronic ethanol consumption by rats impairs hepatocyte attachment to various components of the extracellular matrix including laminin. In this study, three synthetic peptides (PA22‐2, YIGSR, and RGD) that correspond to three distinct functional sites on the laminin molecule were used to investigate the effect of ethanol consumption on their cognate receptors. Initially, varying concentrations of each peptide were incubated with isolated hepatocytes from ethanol‐fed and pair‐fed control rats. These hepatocytes were then assayed for the ability to attach to laminin. The results Indicated that all three peptides effectively inhibited laminin‐mediated cell adhesion: the degree of inhibition appeared similar between pair‐fed controls and ethanol‐fed animals. Of the three peptides, PA22‐2 showed the most dramatic inhibition of attachment. Therefore, we investigated the ability of hepatocytes to attach directly to PA22‐2 itself. Attachment of hepatocytes from ethanol‐fed animals to PA22‐2 was impaired by 30% after 4 days and 90% by 14 days. Conversely, no significant difference in attachment to the entire laminin molecule was observed in ethanol‐fed animals at these early time points. These results indicated that the ethanol‐induced impairment of hepatocyte attachment to laminin may be caused by the decreased interaction of hepatocytes with specific functional sites on the laminin molecule and that specific receptors on the hepatocyte may be affected differently. Because laminin has been shown to influence cell proliferation, differentiation, and gene expression, this defect could potentially result in structural and functional changes of the hepatocytes.
Delayed Pro‐Opiomelanocortin Activation after Ethanol Intake in Man
Authors: Ekman Ann‐Charlotte , Vakkuri Olli , Vuolteenaho Olli , Leppäluoto Juhani
Published: April 2006

To elucidate the effect of ethanol on the secretion of ACTH and β‐endorphin (BE) as the representatives of the pro‐opiomelanocortin (POMC) system, as well as cortisol as the hypophyseally regulated peripheral hormone, we measured concentrations of serum ethanol and plasma ACTH, BE, and cortisol at 1‐ to 4‐hr intervals for 12 hr after administration of 0.5 and 1.0 g ethanol/kg of body weight and placebo drinks between 1900–1945 hr to nine healthy volunteers according to a double‐blind, cross‐over design.

Plasma ACTH, BE, and cortisol showed an expected diurnal rhythm with the highest levels at 0700 hr. Intake of ethanol had no statistically significant effects on plasma ACTH up to 0700 hr in the morning. The higher dose caused increased levels of BE at 0100 hr and both doses at 0200 hr. Plasma cortisol at 0400 hr was higher in subjects receiving 1.0 g ethanol/kg than in those receiving placebo (p < 0.05). Our present observation that plasma ACTH was unchanged after ethanol intake, but plasma BE was increased at 0100‐0200 hr may be due to the fact that our BE antiserum cross‐reacts with β‐lipotropin, which has a considerably longer half‐life than ACTH or BE, and also to the long sampling interval. Thus, the POMC system may have been stimulated after ethanol intake. The nocturnal rise of plasma cortisol levels at 0400 hr, 2‐3 hr after the peak in plasma BE, may be caused by the increased secretion of POMC. Because the ethanol dose of 1.0 g/kg body weight stimulated the POMC system but the 0.5 g/kg body weight did not, we conclude that higher ethanol doses induce increases in stress hormone secretion.
Acute Ethanol Exposure Suppresses the Repair of O6‐Methylguanine DNA Lesions in Castrated Adult Male Rats
Authors: Wilson David M. , Tentler John J. , Carney James P. , Wilson Teresa M. , Kelley Mark R.
Published: April 2006

Alcohol has clearly been associated with an increase of cancers in numerous tissues, including the respiratory tract, colon, rectum, liver, but especially the esophagus, larynx, pharynx, and mouth. Alcohol alone has not been shown to be a mutagen until it is converted to acetaldehyde and, therefore, alcohol presumably acts as a cocarcinogen. Previous data has shown that alcohol concentrations of 2% or greater inhibits DNA repair, and in light of the widespread consumption of alcoholic beverages with alcohol contents ranging from 4 to 5% (beer and wine coolers) to 50% (whiskey), interest in determining the mechanism(s) responsible for alcohol‐induced carcinogenesis has heightened. Although previous studies, in intact rats, have investigated the effects of chronic alcohol exposure on some aspects of DNA repair, we have begun to address the effects of acute or “binge” alcohol exposure on mammalian DNA repair. Toward this end, we report the inhibition of O6‐methylguanine‐DNA methyltransferase (MGMT) by a single intraperitoneal injection of 30% ethanol in adult male castrated rats. This inhibition lasted for at least 24 hr. We also observed a dose‐response effect of ethanol on MGMT activity, again only in the castrated rats. The finding of ethanol's effect on MGMT activity in castrated and not intact rats implies a hormonal component of MGMT DNA repair response, which has only been alluded to in past research.
Flow Cytometric Analysis of Lymphocyte Subsets of Mice Maintained on an Ethanol‐Containing Liquid Diet
Authors: Hsiung Linda , Wang Joseph , Waltenbaugh Carl
Published: April 2006

Alcoholic patients often have impaired immune function, yet little is known about the precise mechanism(s) of this impairment. We have previously shown that ethanol consumption by mice alters copolymer‐specific humoral and cellular immune responses. In this study, we asked whether alcohol consumption by mice would phenotypically alter lymphocyte populations. Female C57BL/6 mice were fed a nutritionally complete liquid diet containing 35% ethanol‐derived calories for up to 8 days. As controls, mice either were fed a liquid control diet that isocalorically substitutes sucrose for ethanol or remained on a standard solid diet and water ad libitum. Although mice fed ethanol‐containing liquid or pair‐fed control liquid diets have decreased numbers of spleen cells compared with solid diet controls, only the ethanol‐containing diet allowed normally nonresponder C57BL/6 spleen cells to make antibody responses to the poly(Glu50Tyr50) synthetic copolymer antigen. Flow cytometric analysis of splenic lymphocyte populations of mice on the ethanol‐containing diet shows an increase in the relative proportion of T‐lymphocytes as compared with mice on either solid or liquid control diets. No such change is seen for either B‐cell or natural killer cell populations in these same mice. Both liquid control and liquid ethanol diets caused a slight decrease in the CD4:CD8 ratios of splenic T‐lymphocytes. We see the relative percentage of T‐cells bearing the αβ‐cell receptor (TcR) increases in the spleens of liquid ethanol diet mice; a smaller increase TcRαβ usage is seen in the spleens of liquid control mice, compared with solid diet mice. Flow cytometric analysis shows that little, if any, difference exists in TcRγδ expression between the liquid ethanol and either the liquid control or solid diet groups. Preliminary analysis of TcRαβ subsets suggest that ethanol increases the percentage of T‐cells expressing Vβ5 and Vβ8, and decreases the percentage of Vβ11 expressing cells. These findings suggest that, in addition to modifying the immune response, ethanol alters the phenotypic expression of lymphocyte subsets.
Effect of Ethanol on Insulin‐Like Growth Factor‐II Release from Fetal Organs
Authors: Mauceri Helena J. , Lee Wei‐Hua , Conway Sonya
Published: April 2006

This study examines the effect of ethanol (ETOH) exposure and nutrient restriction on the release of insulin‐like growth factor (IGF)‐II from 18‐ and 20‐day explanted fetal organs. Fetuses were exposed to ETOH (E) in utero by feeding dams a 36% (calories derived from ETOH: 6.6% v/v) ETOH liquid diet. Control fetuses were offsprings of dams either pair‐fed (P) a control liquid diet or ad libitum (A) fed a standard pelleted lab chow. Brain, heart, kidney, liver, lung, muscle, and placenta of fetuses from the same litter were pooled and explanted, and IGF‐II concentration in explanted media was analyzed by radioimmunoassay. Maternal and fetal weights were determined during pregnancy and at sacrifice, respectively, to evaluate the influence of ETOH on growth.

Both maternal and fetal weights were substantially reduced by ETOH on 18 and 20 days of gestation compared with both A and P controls. At 18 days of gestation, E fetuses (1.33 ± 0.03 g) weighed less than either A (1.47 ± 0.03 g) or P (1.54 ± 0.04 g) fetuses. By 20 days, A mean fetal weight (4.19 ± 0.23 g) was significantly greater than both P (3.74 ± 0.06 g) and E (3.28 ± 0.06 g) fetuses. IGF‐II concentration in media from 18‐day fetal explants was highest from E (brain, heart, liver, and placenta) and P tissues (kidney, lung, and muscle). IGF‐II in media from A tissues (except placenta) was lower than both E and P levels. A significant difference between treatments occurred in heart. By 20 days, IGF‐II levels were highest in media from all A tissues (except placenta). IGF‐II in media from E tissues (except lung) was lower than those from P tissues. A significant difference between treatments occurred in the brain.

With regard to the developmental pattern, IGF‐II release generally increased between 18 and 20 days of gestation, with the greatest increases occurring in A tissues. Increased secretion by P tissues was greater than that by corresponding E tissues, and tended to follow the A trend. On the other hand, E brain, kidney, and placenta released only slightly more IGF‐II at 20 days compared to 18 days, whereas E heart, liver, lung, and muscle released slightly less hormone.

This study suggests that even moderate nutrient deprivation influences the pattern of IGF‐II release from fetal organs, even though there is only a small decrease in overall body size. At the same level of nutrient deprivation, ETOH more dramatically alters both fetal weight and the pattern of IGF‐II release. Because IGFs are autocrine/ paracrine factors that influence growth, differentiation, and function, the reduced availability of IGF‐II may be one of the factors contributing to ETOH‐induced growth retardation and impaired functional capacity of some organ systems.
Tolerance to Ethanol Hypothermia in HOT and COLD Mice
Authors: Crabbe John C.
Published: April 2006

COLD and HOT mice have been selected to be sensitive or resistant, respectively, to the acute hypothermic effect of ethanol. Previous studies have found HOT mice to be relatively resistant to the development of tolerance to this effect, whereas COLD mice readily develop tolerance. By administering several doses of ethanol and recording multiple postdrug temperatures, in the current study we equated the selected lines for area under the curve describing initial hypothermic response over time, a measure reflecting both maximal hypothermia achieved and the duration of total hypothermic response. The dose‐response function for COLD mice was much steeper than that for HOT mice, and HOT mice recovered to baseline body temperatures more slowly. Doses were administered daily for 5 days. Both lines developed tolerance to ethanol hypothermia. The magnitude of tolerance developed was greater in COLD than in HOT mice. At higher doses, HOT mice showed a progressively enhanced hypothermic response over days (i.e., sensitization).
Fine T‐Cell Subsets in Alcoholics as Determined by the Expression of l‐Selectin, Leukocyte Common Antigen, and β‐Integrin
Authors: Cook Robert T. , Waldschmidt Thomas J. , Ballas Zuhair K. , Cook Brian L. , Booth Brenda M. , Stewart Barbara C. , Garvey Michael J.
Published: April 2006

Alcoholics admitted to the hospital solely for detoxication have been studied by flow cytometry to evaluate changes in the surface markers of peripheral blood leukocytes. As we have shown previously, such patients have an elevated percentage of CD8hl lymphocytes that are HLA DR+; we now demonstrate that they also have striking alterations in the quantitative relationships of the fine T‐cell subsets. Both CD4+ and CD8hl lymphocytes have a sharply reduced percentage of the l‐selectin+ CD45RA+ subset, increased percentages of the CD45RA‐subsets, and several other fine subset alterations. The fine subset profile suggests, according to current correlations of phenotype and function, that both CD4+ suppressor inducer and CD4‐dependent CD8+ suppressor effector cells are reduced, whereas other subsets, including CD8+ CTL or their precursors, are increased in relative percentages. Some of the phenotypic changes are reversible over the several days following withdrawal.

In other results, the percentage of CD8hl lymphocytes expressing CD11b (β‐integrin) is shown to be reciprocal with the percentage expressing l‐selectin both in normals and alcoholics. However, the regression function of CD11b vs. l‐selectin on CD8hl cells is different for the alcoholics than for the normals, indicating an abnormality in the regulation of the expression of these two adhesion markers. Taken together, this abnormality of adhesion molecules and the fine subset alterations previously described indicate widespread changes in the peripheral lymphocytes of currently drinking alcoholics. These changes suggest functional deficiencies that may include alterations of lymphocyte traffic and other adhesion‐dependent functions, and a shift in the balance of regulatory interactions.
Involvement of Protein Kinase C in Ethanol‐Induced Inhibition of NMDA Receptor Function in Cerebellar Granule Cells
Authors: Snell Lawrence D. , Tabakoff Boris , Hoffman Paula L.
Published: April 2006

Ethanol inhibits N‐methyl‐d‐aspartate (NMDA)‐stimulated increases in intracellular Ca2+ in cerebellar granule cells apparently by reducing the potency of glycine to act as a co‐agonist at the NMDA receptor. The inhibitory effect of ethanol on the NMDA response in these cells can be reversed not only by a high concentration of glycine, but also by the protein kinase inhibitors, staurosporine and calphostin C. We previously showed that activation of protein kinase C in cerebellar granule cells also resulted in inhibition of the NMDA response, and in decreased potency of glycine at the NMDA receptor. Furthermore, the inhibitory effects of ethanol and protein kinase C activation are not additive. These results suggest a role for protein kinase C in ethanol inhibition of NMDA responses in cerebellar granule cells. In contrast, although ethanol can inhibit the response to kainate in these cells in a “competitive” manner, this response is not affected by activation of protein kinase C.
Thrombosis and Fibrinolysis in Acute Myocardial Infarction
Authors: Eisenberg Paul R.
Published: April 2006

The development of coronary thrombosis in response to rupture of atherosclerotic plaques is the primary determinant of the evolution of stable atherosclerotic coronary disease to unstable ischemic syndromes and acute myocardial infarction. Activation of the tissue factor pathway of coagulation and adhesion of platelets are critical events in the initiation of thrombosis. However, subsequently, other factors may determine the extent of thrombosis by modulating the intensity of procoagulant and fibrinolytic activity. Marked procoagulant activity, attenuation of physiologic fibrinolytic activity, or both appear to be risk factors for myocardial infarction. The results of recent studies have provided considerable insight into potential mechanisms for thrombosis in response to rupture of atherosclerotic plaque and have identified potential novel antithrombotic interventions to inhibit the progression of coronary thrombosis.
Alcohol and Platelet Function
Authors: Rubin Raphael , Rand Margaret L.
Published: April 2006

Epidemiological studies have shown that moderate consumption of alcoholic beverages is inversely related to the incidence of the complications of coronary artery disease. The protective effect of ethanol may be partially attributable to an inhibitory effect of ethanol on platelets. This article summarizes the experimental observations that ethanol inhibits platelet responses to specific physiological agonists. In alcoholics, various platelet defects have been observed, but these may be influenced by metabolic factors rather than the presence of ethanol alone. The acute effects of ethanol on platelet functions both in vivo and ex vivo will be reviewed. Evidence will be presented demonstrating that ethanol added acutely in vitro inhibits phospholipase A2 in stimulated platelets. The interaction of ethanol with other signal transduction pathways will also be discussed.
Effects of Ethanol on the Contractile Function of the Heart: A Review
Authors: Thomas Andrew P. , Rozanski Dennis J. , Renard Dominique C. , Rubin Emanuel
Published: April 2006

Chronic ethanol consumption leads to a number of alterations in the contractile function of the heart and is a leading cause of cardiomyopathy. Ethanol also has an acute negative inotropic effect mediated by direct interaction with cardiac muscle cells, although this action is often masked by indirect actions resulting from enhanced release of catecholamines in vivo. This article reviews the effects of ethanol on the contractile function of the heart. The specific targets affected by ethanol in cardiac muscle cells are discussed in terms of potential mechanisms underlying the depressions of contractility resulting from both acute and chronic actions of ethanol.
Alcoholism and Myocardial Energy Metabolism
Authors: Cunningham Carol C. , Spach Priscilla I.
Published: April 2006

A review of the effects of chronic ethanol consumption on myocardial energy metabolism in animal models reveals that alterations in cardiac function are not accompanied by changes in the levels of the high‐energy metabolites, ATP, and creatine phosphate. There are minor alterations in mitochondrial ultrastructure and function that appear to be accentuated by lowered nutrient intake. Observations to date indicate that, in animal models, there is an interaction between chronic ethanol consumption and caloric deprivation in eliciting alterations in myocardial energy metabolism. Furthermore, ethanol‐related ultrastructural changes and depressed mitochondrial function are much more demonstrable in liver than in heart, suggesting strongly that the myocardium is less susceptible to the deleterious effects of alcohol than is the liver.
Acetate‐Mediated Effects of Ethanol
Authors: Israel Y. , Orrego H. , Carmichael F. J.
Published: April 2006

Ethanol has been shown to increase markedly portal blood flow, primarily by increasing intestinal blood flow. This effect of ethanol is reproduced by acetate, infused at rates equivalent to those leading to endogenous acetate production following ethanol administration. The physiological mediator, adenosine, is also known to increase markedly intestinal and portal tributary blood flow. We have shown that adenosine receptor blockade with 8‐phenyltheophylline completely abolishes the effects of ethanol, acetate, and adenosine on intestinal and portal blood flow, suggesting that increases in adenosine tone may constitute a common mechanism mediating the actions of both ethanol and acetate on the splanchnic vasculature.

Studies are also presented that show that acetate administration has marked effects on central nervous system function. On two tests, motor coordination and anesthetic potency, both ethanol and acetate showed similar effects. The effects of acetate were fully abolished by 8‐phenyltheophylline. The effects of ethanol were partially blocked by 8‐phenyltheophylline, with a greater effect of this blocker being seen at low doses of alcohol.

Whereas ethanol at low doses increased locomotor activity in mice, acetate markedly reduced it. The effect of acetate on locomotion was fully reversed by the adenosine receptor blocker 8‐phenyltheophylline, whereas the activating effect of ethanol on locomotion was markedly enhanced by this blocker. These data suggest that the actions of ethanol on locomotor activity normally result from the combination of a direct stimulatory effect of ethanol per se and an inhibitory effect of acetate, produced endogenously from ethanol. When the latter effect of acetate is abolished by adenosine receptor blockade, the activating effect of ethanol is fully expressed.

These data demonstrate that acetate is not an inert molecule and that some actions of ethanol may be partially or fully mediated by acetate.
Sleepiness and Ethanol Effects on Simulated Driving
Authors: Roehrs Timothy , Beare David , Zorick Frank , Roth Thomas
Published: April 2006

Twelve healthy young men were assessed in each of four experimental conditions presented in a Latin Square design: 8‐hr time in bed (TIB) and placebo, 4‐hr TIB and placebo, 8‐hr TIB and ethanol, and 4‐hr TIB and ethanol. After consuming ethanol (0.6 g/kg) or placebo (0900–0930 hr) with 20% supplements at 1030 and 1100 hr, subjects were tested for sleepiness (Multiple Sleep Latency Test at 1000, 1200, 1400, and 1600 hr) and divided attention (1030 hr) performance on day 1, and for simulated driving and divided attention (1000–1200 and 1400–1600 hr) performance on day 2. In the morning testing, with breath ethanol concentrations (BECs) averaging 0.049%, sleepiness was increased, divided attention reaction times increased (on both days), and simulated driving performance was disturbed in the ethanol and 4‐hr TIB relative to placebo. Similarly in the afternoon, with BECs averaging 0.013%, the ethanol and 4‐hr TIB condition increased sleepiness and disrupted divided attention and simulated driving performance. The results show that sleepiness and low‐dose ethanol combine to impair simulated automobile driving, an impairment that extends beyond the point at which BEC reaches zero. They provide a possible explanation for the incidence of alcohol‐related automobile accidents at low BECs.
Detection of Reduced Acetaldehyde Protein Adducts Using a Unique Monoclonal Antibody
Authors: Klassen Lynell W. , Tuma Dean J. , Sorrell Michael F. , McDonald Thomas L. , DeVasure Jane M. , Thiele Geoffrey M.
Published: April 2006

Acetaldehyde (AA), the major product of alcohol metabolism, has been shown to bind to proteins in vivo and form chemical adducts. These AA‐protein adducts have been shown to alter protein structure and function and may result in tissue damage. Recent reports have shown that polyclonal antibodies can be produced that recognize proteins modified in vitro with AA in the presence of sodium cyanoborohydride (NaCNBH3), a strong reducing (R) agent. Antibodies prepared in this way have been shown to recognize proteins in the livers of rats fed alcohol chronically. Because multiple AA‐protein adducts can be recognized by polyclonal antisera, and a variety of adducts may be formed in vitro or in vivo, this study was designed to develop monoclonal antibodies specific for proteins modified by AA. In addition, adducts formed under R conditions are probably chemically different than those formed under nonreducing (NR) conditions, and monoclonal antibodies may provide the specificity required to distinguish these chemical differences. Balb/c mice were immunized with bovine brain tubulin that was modified by treatment with 5 mM AA for 7 days under NR conditions. Sera from immunized animals were tested for antibody activity to the immunogen (protein‐NR) and for cross‐reactivity to protein‐R and unmodified protein. Although the highest serum antibody titers were seen toward the NR adduct, antibodies to the R adduct were also detected. This activity difference was independent of the carrier protein, because NR and R bovine serum albumin, keyhole limpet hemocyanin, and actin also gave similar results when used as the adducted protein. Surprisingly, all the monoclonal antibodies (RT1.1, RT1.2, RT1.3, and RT1.4) produced by hybridomas generated from spleen cells from NR‐tubulin immunized mice recognized the R and not the NR adduct. One of these hybridomas (RT1.1) produces an lgG2b antibody that reacts with all tested proteins that have been modified with AA under chemical R conditions. Because of its monoclonal specificity, this antibody may be useful in probing for the presence of R AA‐protein adducts made both in vitro and in vivo.
Ethanol Effects on Embryonic Craniofacial Growth and Development: Implications for Study of the Fetal Alcohol Syndrome
Authors: Weston Wayde M. , Greene Robert M. , Uberti Michelle , Pisano M. Michele
Published: April 2006

Fetal alcohol syndrome (FAS), which is brought about by maternal consumption of ethanol during pregnancy, is a major public health problem. To gain understanding of the etiology of this condition, a number of teratological studies have been performed in different animal systems to develop an animal model for FAS. The C57BL/6J mouse strain has been described as susceptible to the teratogenic effects of ethanol, whereas the ICR (CD‐1) strain is considered relatively insensitive. We have compared the effects of ethanol on DNA and protein synthesis in cultured embryonic palate mesenchymal cells from both strains to determine if the reported differential sensitivity to ethanol is reflected in differences in ethanol's effects on cell behavior. Chronic exposure to 200 mM ethanol for 48 hr had a strong inhibitory effect on DNA synthesis in palate cells derived from both the C57BL/6J and ICR strains and a significant effect on protein synthesis in C57BL/6J palate cells. When we attempted to verify strain differences in susceptibility to ethanol teratogenesis, we were not able to observe an increased incidence of birth defects due to ethanol in either strain. High doses of ethanol (5.8 g/kg, administered by intraperitoneal injection on gestational day 8) resulted in death in both C57BL/6J and ICR mice. A lower dose (4.8 g/kg) caused decreased fetal weight and increased resorption in both strains, but did not bring about FAS‐like craniofacial dysmorphology in either strain. It appears, therefore, that whereas ethanol can significantly affect the behavior of cells derived from craniofacial tissue, these effects cannot be correlated with sensitivity to ethanol teratogenesis in the mouse system. In view of these results, we suggest that the suitability of the mouse model for FAS be reviewed.
Statistical Approaches in Alcohol Research: A Comparative Survey of Two Major Alcohol Journals with Four Major Psychiatric Journals
Authors: Kirisci Levent , Tarter Ralph E. , Moss Howard
Published: April 2006

This study surveyed and compared the statistical methods used in two major alcohol journals with those used in four major psychiatric journals. The alcohol specialty journals were Alcoholism: Clinical and Experimental Research and Journal of Studies on Alcohol. The psychiatry journals studied were the American Journal of Psychiatry, British Journal of Psychiatry, Archives of General Psychiatry, and Acta Psychiatrica Scandinavca. The aim of this study was to examine the extent to which alcohol researchers use statistical methods and their level of statistical sophistication. A second aim focused on the extent to which alcohol researchers are attentive to design and sample size issues. Comparisons between papers published in the four psychiatry journals and the two alcohol specialty journals published in 1990 revealed that the percentage of articles without any numerical results was substantially different among the journals: 21% of the psychiatry journals and 7% in the alcohol journals. There was a significant difference in favor of the alcohol journals with respect to frequency of intermediate statistical techniques. The number of papers published in the two alcohol journals using 20 or fewer subjects was similar to the four psychiatric journals. However, the alcohol journals contained more articles in which >400 subjects were studied.
Severity and Treatment of Alcohol Withdrawal in Elderly Versus Younger Patients
Authors: Brower Kirk J. , Mudd Sharon , Blow Frederic C. , Young James P. , Hill Elizabeth M.
Published: April 2006

We conducted a retrospective chart review of older (n= 48; mean age = 69) and younger (n= 36; mean age = 30) patients who were admitted to residential/inpatient treatment for alcohol withdrawal and dependence. Although the two age groups did not differ in terms of recent drinking history, the elderly group had significantly more withdrawal symptoms for a longer duration than the younger group. The elderly group also had more symptoms of cognitive impairment, daytime sleepiness, weakness, and high blood pressure. Finally, no significant differences were found between age groups in either the dosage or number of days of detoxification medication, although a trend was found for more days of medication in the elderly. We conclude that alcohol withdrawal may be more severe in elderly than in younger persons. Accordingly, treatment may take longer and should target the specific profile of symptoms that characterize alcohol withdrawal in the elderly.
Maternal Drinking During Pregnancy: Attention and Short‐Term Memory in 14‐Year‐Old Offspring—A Longitudinal Prospective Study
Authors: Streissguth Ann P. , Sampson Paul D. , Olson Heather Carmichael , Bookstein Fred L. , Barr Helen M. , Scott Mike , Feldman Julie , Mirsky Allan F.
Published: April 2006

A large and compelling experimental literature has documented the adverse impact of prenatal alcohol exposure on the developing brain of the offspring. This is the first report of adolescent attention/ memory performance and its relationship with prenatal alcohol exposure in a population‐based, longitudinal, prospective study (n= 462) involving substantial covariate control and “blind” examiners. Prenatal alcohol exposure was significantly related to attention/memory deficits in a dose‐dependent fashion. A latent variable reflecting 13 measures of maternal drinking was correlated 0.26 with a latent variable representing 52 scores from 6 tests measuring various components of attention and short‐term memory performance. The number of drinks/occasion was the strongest alcohol predictor. Fluctuating attentional states, problems with response inhibition, and spatial learning showed the strongest association with prenatal alcohol exposure. A latent variable reflecting the pattern of attention/memory deficits observed at 14 years correlated 0.67 with a composite pattern of deficits previously detected on neurobehavioral tests administered during the first 7 years of life. The 14‐year attention/memory deficits observed in the present study appear to be the adolescent sequelae of deficits observed earlier in development. As is usual in such studies, not all exposed offspring showed deficits.
Allele Frequencies of the Preproenkephalin A (PENK) Gene CA Repeat in Asians, African‐Americans, and Caucasians: Lack of Evidence for Different Allele Frequencies in Alcoholics
Authors: Chan Rebecca J. , McBride Andrew W. , Thomasson Holly R. , Ykenney Abi , Crabb David W.
Published: April 2006

Evidence from animal models and from recent reports on the efficacy of the opioid antagonist naltrexone in the treatment of alcoholism suggests that the endogenous opioid systems may play a role in alcohol seeking behavior. The gene encoding preproenkephalin A (PENK) is flanked at its 3’end by a polymorphic (CA)n. repeat. We determined the allele frequencies for this locus in samples of Chinese and Atayal living in Taiwan, Caucasians living in the United States and Byelorussia, and African‐Americans living in the United States. We compared the allele frequencies of nonalcoholics in each population with those of alcoholics with or without alcohol‐induced organ pathology. There was no difference in allele frequencies within any racial group when alcoholics with or without organ pathology were compared; there was also no difference in allele frequency between nonalcoholics and alcoholics within the two Asian populations, Caucasians, or African‐Americans. There were highly significant differences in the frequency of the various length polymorphism between the Asian, Caucasian, and African‐American samples.
Regulatory Potential of Ethanol and Retinoic Acid on Human Monocyte Functions
Authors: Szabo Gyongyi , Puppolo Maria , Verma Bikash , Catalano Donna
Published: April 2006

Retinoic acid (RA), a metabolic product of vitamin A, has been shown to affect a variety of immune functions, including monocytes. Monocyte functions and mediator production are also modulated by ethanol exposure. This study demonstrates that therapeutic doses of RA (0.1–10 μM) significantly increase transforming growth factor‐β (TGFβ) production both in THP‐1, human myelomonocytic cells, and in human peripheral blood monocytes. We have previously reported TGFB induction by ethanol in human Mø. Combination of RA stimulation with acute in vitro ethanol treatment, however, resulted in significantly lower Mø TGFβ production than TGFB levels induced by RA alone (p < 0.003). Down‐regulation of Mø TGFβ production by ethanol was tested at the concentration range of 25–150 mM and occurred both at high and low RA concentrations (10–0.1μM). In contrast to its inhibitory effect on RA‐induced Mø TGFβ production, ethanol augmented TGFB production induced by mura‐my1 dipeptide (20 μg/ml), suggesting that ethanol can either up‐ or down‐regulate Mø TGFB production, depending on the costimulatory factors. RA also induced a moderate increase in Mø tumor necrosis factor‐α (TNFα) production, which was down‐regulated by ethanol both at the level of secreted and cell‐associated TNFα. In addition to regulation of cytokine production, both RA and ethanol decreased expression of CD4 on THP‐1 cells. The degree of inhibition of CD4 expression by RA was more significant than by ethanol, but RA‐induced decrease in CD4 expression was not significantly affected by the combined stimulation with ethanol. These results provide further evidence for the immunoregulatory potential of nutritional and dietary factors, such as RA and ethanol, on the immune functions of human monocytes.
Agonist‐Stimulated and Basal Phosphatidylethanol Formation in Neutrophils from Alcoholics
Authors: Lundqvist Christofer , Alling Christer , Aradottir Steina , Gustavsson Lena
Published: April 2006

Phospholipase D has been shown to be a key enzyme in the signal transduction systems involved in neutrophil activation. In the presence of ethanol, the enzyme catalyzes a transphosphatidylation reaction through which phosphatidylethanol is formed instead of the normal product phosphatidic acid. The effects of ethanol on the formation of phosphatidylethanol and phosphatidic acid was studied in neutrophils from human alcoholics in vitro. Neutrophils were isolated and cellular lipids were labeled with [3H]oleate, whereafter the cells were preincubated with cytochalasin B. Subsequently, cells were stimulated with the chemotactic peptide formyl‐Met‐Leu‐Phe in the presence of ethanol concentrations ranging from 0 to 200 MM. In the presence of ethanol, both neutrophils from alcoholics and controls produced phosphatidylethanol, with a concomitant reduction of the production of phosphatidic acid. The amounts of phosphatidylethanol and phosphatidic acid formed were dependent on the concentration of ethanol. In neutrophils from alcoholics, a higher apparent Km for the phospholipase D‐mediated transphosphatidylation reaction was noted (58 MM ethanol compared with 28 mM in controls). The in vivo mass of phosphatidylethanol in recently drinking alcoholics was also analyzed in neutrophils. Measurable phosphatidylethanol levels (average 5.6 pmol/106 neutrophils) were found in alcoholics up to 23 hr after the last intake of ethanol. Thus, in addition to the ethanol‐induced changes in the normal production of phosphatidic acid, phosphatidylethanol accumulated in vivo in alcoholics may be expected to influence neutrophil function.