bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunocytochemistry of Alcohol Dehydrogenase in the Rat Central Nervous System
Authors: Kerr Joanne T. , Maxwell David S. , Crabb David W.
Published: April 2006

A sensitive immunocytochemical method for the localization of alcohol dehydrogenase (ADH) in the rat brain is described. The method employs rat liver ADH isolated and purified with Cap‐Gapp affinity chromatography. Antiserum to rat liver ADH is generated in rabbits, and used in the peroxidase‐antiperoxidase immunocytochemical method. The method is compatible with both light and electron microscopic methods of tissue preparation. In the present report we describe the identification of ADH in neurons of the mammillary bodies, periaqueductal gray, and the cerebral and cerebellar cortices of normal adult rats. In all brain tissues examined, the enzyme is limited to neuronal cytoplasm, and only to some neurons. The restriction of the enzyme to a limited percentage of neurons in the central nervous system may help to account for the difficulty in demonstrating the enzyme in whole brain homogenates, as the dilution of enzyme‐bearing cytoplasm with a large volume of enzymatically inactive tissue would reduce the specific activity of the enzyme to near the limit of detectability. In the cerebellar cortex, the enzyme is found only in Purkinje cell cytoplasm. In the other regions examined, we are unable to identify by other criteria a specific neuronal class that consistently displays ADH reactivity. The reactive cells seem to be generally midrange in size and bipolar or multipolar in configuration. The presence of ADH in certain neurons leads us to speculate that intraneuronal ethanol metabolism may lead to focal accumulation of acetaldehyde. The intracellular presence of this toxin may in turn help to account for brain dysfunction in acute ethanol intoxication, and the neuropathology of chronic alcohol abuse.
Investigations of the Role of Protein Kinase C in the Acute Sedative Effects of Ethanol
Authors: Deitrich Richard A. , Bludeau Pequita A. , Baker Rodney C.
Published: April 2006

The activity of protein kinase C (PKC) in whole brain and brain areas of mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute ataxic effect of ethanol has been investigated. The cytosolic and membrane fractions of whole brain PKC activities are significantly less in LS mice than in SS mice. There are significant differences in PKC activity between brain areas in both the SS and LS lines. Ethanol given in ataxic doses results in significantly increased amounts in PKC activity in whole brain cytosolic fractions and in some brain areas but egually in both SS and LS mice. Ethanol added in vitro reduced enzyme activity slightly in SS brain membranes, suggesting that the mechanism of the increase in PKC activity seen after in vivo administration is indirect. These results indicate that PKC is not involved in the mechanism whereby LS and SS mice differ in alcohol sensitivity.

Direct intracerebroventricular (ICV) injection of phorbol myristate acetate (PMA), an activator of PKC, resulted in increased sleep times in both SS and LS mice. ICV injection of PMA also caused a more marked decrease in body temperature in LS than in SS mice. The half‐life of PMA in brain was determined to be 9.6 hr and no metabolites could be detected.

At limiting calcium concentrations, PMA added in vitro activated PKC equally well in both lines. However, PMA given ICV did not alter the level of PKC as determined in vitro.

Administration of phorbol myristate‐acetate intraperitoneally (i.p.) to LS mice increased their sleep time response to ethanol and caused a prolonged depression of temperature when given alone. Similar treatment of SS mice caused no change or a decreased sleep time and a smaller temperature drop as compared to LS mice. There was no effect of i.p.‐administered PMA or PMA plus ethanol on PKC activity in whole brain cytosol or membrane fraction except for a decreased activity in membranes of SS mice given PMA alone. It was found that only small amounts of PMA given i.p. reached the brain. There appears to be different mechanisms by which phorbol esters alter sleep time in these mice, one via a central effect which is not related to why LS and SS mice differ and one via a peripherial effect that may be related to the SS and LS differences.
Penetration of Ethanol into the Male Reproductive Tract
Authors: Salonen Iiris , Eriksson C. J. Peter
Published: April 2006

We studied the pharmacokinetics of ethanol in the rat rete testis fluid, interstitial fluid, seminiferous tubules, epididymal fluid, and whole testis after 0.75 g/kg and 1.5 g/kg intraperitoneal injections. Ethanol concentration in these tissues was compared to that in capillary and arterial blood. The data was characterized by fitting to a mathematical model. The highest ethanol concentrations in orbital capillary blood were measured 10 min after the injections. Ethanol content in testis homogenate and interstitial fluid did not generally differ from that of orbital blood. However, in rete testis fluid the highest ethanol values were measured at 60 min by the 1.5 g/kg dose and at 30 min by 0.75 g/kg. Ethanol values before this differed from those of capillary blood and interstitial fluid (p < 0.05–0.001). In seminiferous tubules, the highest ethanol concentration was reached at 20 min, and ethanol content was in general lower than in orbital blood (p < 0.001–0.01). Ethanol levels in epididymal fluid were comparable to capillary blood. The transportability factor from the model for rete testis was low, which indicates a barrier of penetration of ethanol from blood. In addition, water contents of testicular compartments were calculated. The area under the curve values of rete testis and seminiferous tubules were approximately 10 and 30%, respectively, smaller than that of interstitial fluid, for example. Therefore, the germ cells are somewhat better protected from ethanol than the interstitial cells.
Clinical Significance of Serum Antibodies Against Alcohol‐Altered Hepatocyte Membrane in Alcoholic Liver Disease
Authors: Izumi Namiki , Sakai Yoshinori , Koyama Wataru , Hasumura Yasushi
Published: April 2006

The clinical significance of serum antibodies against alcohol‐altered rabbit hepatocytes was evaluated in 91 patients with alcoholic liver disease. Patients were divided into two groups according to the presence or absence of those antibodies at the time of first admission, and their clinical, biochemical, and histological findings were compared. In 38 seropositive patients, the total amount of ethanol consumption as well as serum activity of glutamate‐oxaloacetate transaminase, serum levels of total bilirubin, gamma‐globulin, IgG, and IgA were all significantly higher than in 53 seronegative patients. In addition, the extent of fibrosis, alcoholic hyalin, cholestasis, and lymphocytic and polymorpholeukocytic infiltrations in the liver were all significantly greater in the seropositive patients. Histological changes were compared in the 16 patients who continued to drink alcohol and who received repeated liver biopsies. Seven out of eight patients who were seropositive at the time of the first liver biopsy showed histological deterioration, whereas one of the eight seronegative patients showed a slight progression. These results suggest that the presence of serum antibodies against alcohol‐altered liver cell membrane delineates a group of alcoholic patients with severe, advanced liver disease characterized by a tendency to progress with continued alcohol ingestion.
Cerebral Cortical Morphology and Behavior in Rats Following Acute Prenatal Ethanol Exposure
Authors: Kotkoskie Lois A. , Norton Stata
Published: April 2006

Cerebral cortical morphology and early motor development were evaluated in offspring from ethanol‐exposed mothers, pairfed control mothers and ad libitum control rats. Ethanol‐exposed rats received a total dose of 18 g/kg of ethanol by intubation on gestational Days 14 and 15, a critical period of development of the cerebral cortex. Pairfed control mothers received isocaloric sucrose on gestational Days 14 and 15 and were pairfed to ethanol‐exposed animals from gestational Day 12 through gestational Day 20. Ethanol‐exposed offspring weighed significantly less than control offspring from postnatal Day 7 through postnatal Day 28. Ethanol‐exposed offspring also showed significant delays in reflex suspension (time an animal maintained its grip on a crossbar) and continuous corridor (number of turns in 5 min). The thickness of the cerebral cortex of ethanol‐exposed offspring was significantly different from ad libitum and pairfed control offspring on postnatal Day 1. However, only Layer V and total cortical thickness were affected in ethanol‐exposed offspring on postnatal Day 28. The results of this study indicate that ethanol exposure during a critical period of development causes alterations in central nervous system development and developmental delays.
Specific Cognitive Impairment in Sons of Early Onset Alcoholics
Authors: Tarter Ralph E. , Jacob Theodore , Bremer Deborah L.
Published: April 2006

Cognitive and behavioral functioning in school‐aged sons of early onset alcoholics, late onset alcoholics, normal social drinking fathers, and depressed fathers were compared on a battery of neuropsychological measures. Sons of early onset alcoholics performed more poorly than offspring of the normal fathers on tests measuring attention and verbal intellectual capacity, but were not significantly different from sons of late onset alcoholic fathers. Sons of normal and late onset alcoholics were not distinguishable from each other.
Combined Upper and Lower Gastrointestinal Endoscopy: A Prospective Study in Alcoholic and Nonalcoholic Cirrhosis
Authors: Rabinovitz Mordechai , Kumar Shashi , Kajani Mirza , Van Thiel David H. , Gavaler Judith S.
Published: April 2006

Upper gastrointestinal hemorrhage is one of the more important complications of cirrhosis. Most of the available data regarding the prevalence of upper and lower gastrointestinal sites of bleeding in cirrhotic patients have been obtained in individuals with alcoholic cirrhosis evaluated in the course of an acute gastrointestinal bleeding episode. Few data exist, however, as to the prevalence of either potential bleeding sites or of normal endoscopic findings in hemo‐dynamically stable individuals with cirrhosis of any etiology.

Five hundred ten cirrhotic subjects, who were evaluated for possible liver transplantation (OLTx) between January 1985 and June 1987, were included in this study. Seventy‐five had alcoholic cirrhosis and 435 had nonalcoholic cirrhosis of various etiologies. Of these 510 patients, 412 underwent combined upper and lower gastrointestinal endoscopy and 98 underwent upper gastrointestinal endoscopy alone.

Gastritis, gastric and duodenal ulcer disease were found significantly (each at least p < 0.025) more often in patients with alcoholic liver disease than in those with nonalcoholic liver disease. The prevalence of the various lower gastrointestinal lesions in both groups was similar. Of particular interest is the fact that in alcoholic cirrhotics, the prevalence of gastritis, gastric ulcer and duodenal ulcer disease was unrelated to the degree of portal hypertension, whereas in the nonalcoholic cirrhotics the prevalence of gastritis and duodenal ulcer disease but not gastric ulcer disease was associated significantly with the degree of portal hypertension as assessed by the presence or absence of large esophageal varices, ascites, and hepatic encephalopathy.
Paternal Alcohol Consumption: Effects on Ocular Response and Serum Antibody Response to Pseudomonas aeruginosa Infection in Offspring
Authors: Berk Richard S. , Montgomery Ilene Nowicki , Hazlett Linda D. , Abel Ernest L.
Published: April 2006

Male Swiss‐Webster mice that consumed liquid alcohol diets containing 25, 20, 15, 10, 5, or 0% ethanol‐derived calories (EDC) for 7 weeks were bred to untreated females that were not exposed to alcohol diets. Males receiving the 20–0% EDC diets were pair‐fed to those consuming the 25% EDC diet. At approximately 60 days of age, male offspring were challenged with 108 colony forming units of Pseudomonas aeruginosa onto the scarified cornea of one eye. The ocular response was then evaluated macroscopically for 4 weeks. Male offspring sired by alcohol‐consuming fathers exhibited more severe ocular infection at 24 hr postinfection compared with mice sired by control fathers and, after 8 days postinfection, more corneas of the 25% EDC‐sired progeny perforated than did the other groups. At 30 days after infection, serum immunoglobulin titers (IgM, IgG, IgA) specific to P. aeruginosa were determined by ELISA. Although the majority of the mice were unable to restore corneal clarity within 30 days postinfection, a strong serum IgG response was detected in pooled sera from those animals tested. Offspring were reinfected in the contralateral control eye at 30 days postprimary infection. Most control animals were able to restore corneal clarity in the contralateral control eye within 30 days postinfection, but less than a third of the alcohol‐sired offspring did so. Again, the pooled sera that was tested indicated a strong humoral response, despite differences in corneal clarity. These studies indicate an increased susceptibility to infection and an impairment in restoration of corneal clarity in offspring sired by alcohol‐consuming males, which does not appear to be mediated by serum antibody mechanisms.
Concentration of Vitamin B6 and Activities of Enzymes of B6 Metabolism in the Blood of Alcoholic and Nonalcoholic Men
Authors: Fonda Margaret L. , Brown Stephanie G. , Pendleton Mary W.
Published: April 2006

The purpose of this study was to compare concentrations of vitamin Be compounds and the activities of enzymes that synthesize or catabolize pyridoxal 5′‐phosphate in the plasma and erythrocytes of nonalcoholic and alcoholic subjects. Blood was obtained from male nonalcoholics and chronic alcoholics with minimal liver damage and normal hematology. Plasma, erythrocyte, and urinary B6 compounds were analyzed by high performance liquid chromatography, and pyridoxal phosphate was also measured enzymatically. Erythrocyte pyridoxine kinase and pyridoxine phosphate oxidase and erythrocyte and plasma pyridoxine phosphate phosphatases were assayed. Plasma pyridoxal phosphate concentration was significantly lower in the alcoholics (31.3 ± 3.6 nmol/liter) than in the nonalcoholics (58.7 ± 7.5 nmol/liter). The concentrations of the other B6 compounds in plasma, erythrocytes, and urine were not different in the two groups. Plasma alkaline pyridoxine phosphate phosphatase activity was significantly higher in the alcoholics (4.05 = 0.36 nmol/(h · mg)) than in the nonalcoholics (3.01 ±0.18 nmol/(h · mg)). The activities of erythrocyte kinase, oxidase, and phosphatases were not significantly different in the two groups. The relationship of plasma pyridoxal phosphate concentration to its metabolites and the activities of the enzymes involved in its metabolism was determined. Plasma pyridoxine phosphate phosphatase activity assayed at pH 9.0 or 7.4 correlated negatively with plasma pyridoxal phosphate concentration. The low pyridoxal phosphate concentration observed in the plasma of the alcoholic subjects may in part be related to increased plasma phosphatase activity.
Prenatal Exposure to Ethanol Alters the Synthesis and Glycosylation of Proteins in Fetal Hepatocytes
Authors: Renau‐Piqueras Jaime , Sancho‐Tello María , Cervellera Rafael Báguena , Guerri Consuelo
Published: April 2006

In the present work we have studied the effect of prenatal exposure to alcohol on the synthesis, glycosylation, and transport of proteins in fetal hepatocytes isolated from 21–day‐old fetuses derived from control and chronic alcoholic rats. Protein synthesis was evaluated both in a cell‐free system and in hepatocytes after (35S)methionine and (3H)leucine incorporation, respectively. Glycosylation was assessed using (3H)mannose and (3H)galactose as precursors. Protein synthesis was significantly decreased in treated hepatocytes. In control hepatocytes, quantitative electron microscope autoradiography showed that both (3H)leucine and (3H)mannose incorporation occur first in the rough endoplasmic reticulum (rER). Later the silver grains appeared over the Golgi apparatus, and, finally there was a transport towards the cell periphery. After pulse, silver grains corresponding to (3H)galactose incorporation appeared over the Golgi apparatus. The label then moved to the hepatocyte periphery. Alcohol treated hepatocytes showed a retention of grains over the Golgi apparatus with a diminution in the label at the cell periphery. These results indicate that prenatal exposure to alcohol induces a decrease in the synthesis of proteins in the hepatocyte as well as an alteration in the process of glycosylation and/or transport of secretory proteins.
Apolipoprotein A1 is a Serum and Tissue Marker of Liver Fibrosis in Alcoholic Patients
Authors: Bedossa Pierre , Poynard Thierry , Abella Annie , Aubert Alain , Pignon Jean‐Pierre , Naveau Sylvie , Leluc Robert , Lemaigre Guy , Martin Etienne D. , Chaput Jean‐Claude
Published: April 2006

The aim of this study was to assess the specific correlation of apolipoprotein‐Al to hepatic fibrosis in alcoholic patients. Four hundred eighty two patients were prospectively included with serum measurement of apolipoprotein‐Al within 10 days before liver biopsy. Pathologic features were semiquantitatively assessed by two observers. In 28 patients liver biopsy was used for histomorphometric assessment of fibrosis and immunohistochemical labeling of apolipoprotein‐Al. Serum apolipoprotein‐Al was negatively correlated to semiquantitative score of fibrosis (r=‐0.50; p < 0.001), independently of the scores of steatosis and alcoholic hepatitis (r=‐0.44; p < 0.001) and of the value of serum albumin, bilirubin, and prothrombin time (r=‐0.22; p < 0.001) and independently of the nutritional parameters (r=‐0.29; p < 0.009). The mean value of apolipoprotein‐Al decreased according to the grade of fibrosis from 220 ± 6 mg/dl (mean ± SEM) to 110 ± 8 mg/dl. Serum apolipoprotein‐Al was negatively correlated to the percentage of fibrosis (r=‐0.70; p < 0.001) in the biopsies morphometrically assessed. The labeling was superimposed to the extracellular matrix. In conclusion, this study shows that decrease of apolipoprotein‐Al is a serum and tissue marker of liver fibrosis independently of steatosis, alcoholic hepatitis, liver function tests, and nutritional parameters.
Low Basal Levels of Cortisol Distinguish Detoxified Alcoholics With Major Depressive Disorder from non‐MDDs
Authors: Halbreich Uriel , Castaneda Richardo , Galanter Marc
Published: April 2006

Basal plasma levels of cortisol and its suppression by dexamethasone were measured in 60 inpatient alcoholics 12–13 days after detoxification. Both hypothalamic‐pituitary adrenal system parameters were essentially within normal limits in most patients–those who did not meet criteria for major depressive disorder (n=43) as well as those who met criteria for MDD per their episode (11–17). Basal levels of cortisol below 7 μg/dl distinguished alcoholics without MDD from those who met criteria for MDD per current episodes.
Early Onset of Nonalcoholic Cirrhosis in Patients with Familial Alcoholism
Authors: Arria A. M. , Tarter R. E. , Williams R. T. , Van Thiel D. H.
Published: April 2006

The etiology of many forms of liver disease is largely unknown. Recent research has identified certain immunogenetic factors which may play a role in the progression of alcoholic cirrhosis as well as autoimmune forms of cirrhosis. In this study we examined the role of familial alcoholism and HLA status in determining age of liver disease onset. Patients with biopsy‐proven nonalcoholic autoimmune cirrhosis and having a history of familial alcoholism experience an earlier age of onset of liver disease than patients without a family history of alcoholism. The same result was true for patients with alcoholic liver disease. This effect may be more prominent in females. Subjects with HLA B‐8 also had a younger age of onset of nonalcoholic autoimmune liver disease. The presence of a family history of alcoholism in conjunction with the presence of HLA B‐8 and DR‐3 also was related to an earlier age of disease onset. These findings suggest that the susceptibility to develop alcoholism and nonalcoholic autoimmune liver disease may be transmitted conjointly and point to potential fruitful areas of research for identifying individuals at risk for developing cirrhosis as well as detecting genetic markers for alcoholism.
Effects of Ethanol on an Intestinal Epithelial Cell Line
Authors: Nano J. L. , Cefai D. , Rampal P.
Published: April 2006

The effect of exposure of an intestinal epithelial cell line to various concentrations of ethanol [217 mm (1%) to 652 mm (3%)] during 24, 48, and 72 hr was investigated in vitro using a rat intestinal epithelial cell line (IRD 98). Incubation of these cells in the presence of ethanol significantly decreased cell growth. This inhibition was accompanied by a strong increase in cellular protein. Stimulation of specific disaccharidases, gamma‐glutamyl transferase, and aminopeptidase activities by ethanol was dose‐ and time‐dependent. Ethanol induces a change in the relative proportions of the different lipid classes synthesized; triglycerides, fatty acids, and cholesterol esters were preferentially synthethysed. Our findings show that cell lines are good models for investigation of the effects of ethanol, and that alcohol considerably modifies the functions of intestinal epithelial cells.
Nighttime Hypoxemia Is Increased in Abstaining Chronic Alcoholic Men
Authors: Vitiello Michael V. , Prinz Patricia N. , Personius Janelle P. , Nuccio Maureen A. , Koerker Richard M. , Scurfield Raymond
Published: April 2006

Previously we reported that abstaining chronic alcoholic men demonstrated significantly more nighttime hypoxemia than a control group. Here, we report a replication employing a larger sample of abstaining chronic alcoholics and a more appropriate control group than that used in the previous study. Forty‐seven males, 48.4 ± 1.7 years of age (mean ±SEM), reporting 24.8 ± 1.5 years of heavy alcohol use, comprised the abstaining alcohol group. Thirty‐five age‐and weight‐matched males, 50.3 ± 1.7 years were the control group. The alcohol group had significantly more nighttime oxygen desaturations below 90% than did the control group (16.9 ± 3.3 vs. 6.2 ± 1.4, F= 7.8, p < 0.01), with significantly higher percentages of individuals in the alcohol group manifesting more than 10 or 20 oxygen desaturations below 90%. Regression analyses within the alcohol group revealed that severity of alcohol abuse, but not age, body mass index, days abstinent, or smoking significantly predicted levels of nighttime hypoxemia. These results confirm our original observation of increased nighttime hypoxemia in abstaining chronic alcoholic men and suggest that long‐term alcohol abuse may be a risk factor for development of sleep apnea.
Low Doses of Ethanol Reduce Neurotensin Levels in Discrete Brain Regions from LS/Ibg and SS/Ibg Mice
Authors: Erwin V. Gene , Jones Byron C. , Radcliffe Richard
Published: April 2006

Studies were designed to examine the previously proposed hypothesis that some of the pharmacological actions of ethanol are mediated by neurotensinergic processes. Neurotensin‐immunoreactivity (NT‐ir) was extracted from various brain regions and shown by high performance liquid chromatography to possess the same retention time as authentic bovine NT1‐13. The highest levels of NT‐ir were observed in the hypothalamus with intermediate levels in the midbrain and striatum and lowest levels in the frontal cortex. Levels of NT‐ir were higher in hypothalamus and midbrain from long‐sleep (LS) than from short‐sleep (SS) mice. Ethanol, in vivo, produced a dose‐dependent decrease in NT‐ir in several brain regions; low doses, 1.5 to 3.0 g/kg, but not high doses, 4.1 g/kg, of ethanol significantly decreased NT‐ir in hypothalamus, midbrain, and striatum of LS and SS mice. Levels of NT‐ir in the frontal cortex were not altered by ethanol administration. Ethanol‐induced decreases in NT‐ir were of rapid onset with a maximum decrease in 5 min after intraperitoneal (i.p.) injection, and they were of long duration with levels remaining depressed for 4 hr. These findings show that subhypnotic, intoxicating doses of ethanol enhance NT release, in vivo, and support the hypothesis that some of ethanol's actions are mediated by neurotensinergic systems.
Detoxification of Alcoholics: Improving Care by Symptom‐Triggered Sedation
Authors: Wartenberg Alan A. , Nirenberg Ted D. , Liepman Michael R. , Silvia Loretta Y. , Begin Ann M. , Monti Peter M.
Published: April 2006

This study evaluated a staff training program on alcohol detoxification. Training consisted of didactic presentations on the pathophysiology of alcohol withdrawal syndrome and information on use of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA‐A). Treatment course was assessed on 100 patients admitted before or after the training. Whereas 73% of patients were given drug therapy before, only 13% of patients received drug therapy after. Significantly more benzodiazepine was administered before training (M = 108.48 mg) than after training (M = 42.97 mg). After excluding those who received no drug therapy, patients who received benzodiazepine after the training received significantly higher amounts of benzodiazepine (M = 252.50 mg) than those who received drug before (M = 144.64 mg). The average number of hours from the first benzodiazepine dose to the last was reduced from 13 to 5 hr. Clinical implications of matching patient symptomatology with appropriate drug therapy, thus preventing both over‐ and under‐treatment for alcohol withdrawal symptoms, are discussed.
Angiotensin Converting Enzyme Inhibitors Reduce Alcohol Consumption: Some Possible Mechanisms and Important Conditions for Its Therapeutic Use
Authors: Lingham T. , Perlanski E. , Grupp L.A.
Published: April 2006

Alcoholism is a prevalent problem of contemporary society, yet there are virtually no clinically effective drugs for the management of this disorder. A previous study demonstrating the ability of angiotensin‐converting enzyme (ACE) inhibitors to attenuate voluntary alcohol intake in rats prompted the suggestion that these drugs, currently marketed for the treatment of hypertension, may also be useful in dealing with human alcohol abuse. The present experiments explored in more detail the effect and possible mechanisms of action of this class of drug on alcohol consumption in rats. Experiment one demonstrated that Abutapril, a new ACE inhibitor, significantly reduced alcohol intake and that this effect could not be blocked by either an ANG II or an opiate receptor antagonist suggesting that neither the peripheral renin‐angiotensin system (RAS) nor the endogenous enkephalins are involved in the ability of ACE inhibition to attenuate alcohol intake. Experiments two and three showed that ACE inhibition effectively reduced alcohol drinking faster in animals with elevated RAS activity and not at all in animals with suppressed RAS activity indicating that initial levels of RAS activity may determine the speed and ability of ACE inhibition to attenuate alcohol intake. ACE inhibitors may reduce alcohol intake by elevating a nonapeptide fragment or by elevating central ANG II levels. The assessment of this class of drugs to reduce alcohol intake in humans should include a monitoring of the initial level of activity in the reninangiotensin system since this may be a predictor of the effectiveness of treatment with the ACE inhibitors.
Alcohol‐Induced Neuronal Loss in Developing Rats: Increased Brain Damage with Binge Exposure
Authors: Bonthius Daniel J. , West James R.
Published: April 2006

A rat model of third trimester fetal alcohol exposure was used to determine whether a smaller daily dose of alcohol can induce more severe microencephaly and neuronal loss than a larger dose, if the small dose is consumed in such a way that it produces higher blood alcohol concentrations (BACs). The possibility of regional differences within the developing brain to alcohol‐induced neuronal loss was also investigated. Sprague‐Dawley rat pups were reared artificialty over postnatal Days 4–10 (a period of rapid brain growth similar to that of the human third trimester). Two groups received a daily alcohol dose of 4.5 g/kg, administered either as a 5.1% solution in four of the 12 daily feedings or as a 10.2% solution in two of the 12 feedings. A third group received a higher daily dose (6.6 g/kg) administered as a 2.5% solution in every feeding. Gastrostomy and suckle controls were also reared. On postnatal Day 10, the animals were perfused, and brain weights were obtained. In the hippocampal formation, cell counts were made of the pyramidal cells of fields CA1 and CA2/3, the multiple cell types of CA4 and the granule cells of the dentate gyrus. In the cerebellum, Purkinje cells and granule cells were counted in each of the ten lobules of the vermis. The lower daily dose (4.5 g/kg) condensed into two or four feedings produced high maximum BACs (means of 361.6 and 190.7 mg/dl, respectively) and significant microencephaly and cell loss, relative to controls. The higher daily dose (6.6 g/kg), administered continuously, resulted in low BACs (mean of 39.2 mg/dl) and induced no microencephaly or cell loss. Regional differences in neuronal vulnerability to alcohol were evident. In the hippocampus, CA1 neuronal number was significantly reduced only by the most condensed alcohol treatment, while CA3, CA4, and the dentate gyrus populations were not reduced with any alcohol treatment. In the cerebellum, some lobules suffered significantly greater Purkinje cell loss and granule cell loss than did others. The regions in which Purkinje cells were most mature at the time of the alcohol exposure were the most vulnerable to Purkinje cell loss.
Ethanol Oxidation by Deermice Mitochondria under Physiologic Conditions
Authors: Inatomi Nobuhiro , Ito Daisuke , Lieber Charles S.
Published: April 2006

Mitochondria obtained from alcohol dehydrogenase‐positive or ‐ negative deermice do not oxidize significant amounts of ethanol at pH 7.4. A slight activity, equivalent to less than 0.3% of the elimination rate in alcohol dehydrogenase‐negative deermice was observed at pH 10; it was strongly inhibited by cyanide and thiourea, and was not dependent on exogenous NAD. Whereas ethanol oxidation by the cytosol of alcohol dehydrogenase‐positive deermice was timedependent, that of mitochondria from alcohol dehydrogenase‐negative deermice was not. These findings indicate that deermice mitochondria do not oxidize ethanol at physiological pH, and that the mitochondrial system is not likely to play a significant physiologic role.
Alcohol Consumption and Menstrual Distress in Women at Higher and Lower Risk for Alcoholism
Authors: Charette Lina , Tate Douglas L. , Wilson Allan
Published: April 2006

This study investigated whether alcohol consumption varied as a function of menstrual cycle, menstrual distress symptomatology, and global stress in nonalcoholic drinking young women at higher and lower (HR, LR) risk for alcoholism as assessed by family history. Eighty‐two normally menstruating women (52 LR and 30 HR) monitored their alcohol intake, physical and affective distress symptoms, and global stress level daily for two consecutive menstrual cycles. Subjects were unaware that their menstrual cycles were being monitored. The results confirmed the presence of increased physical distress symptomatology during the premenstrual and menstrual phases but did not show variation in negative affect or global stress throughout the menstrual cycle. High risk subjects were aware that they were at higher risk for alcoholism and consumed more alcohol. However, alcohol consumption was not related to the menstrual cycle, distress symptoms, or global stress. Subjects reported that they drank most frequently with others for pleasure enhancement and rarely for pain or tension‐reduction. Subjects also drank more on weekends than weekdays. These findings argue against the menstrual cycle as etiological in the development of alcoholism. It would appear that social factors influence alcohol consumption in young nonalcoholic women.
Alcoholism Treatment: A Ten‐Year Follow‐Up Study
Authors: Cross Gerald M. , Morgan Charles W. , Mooney Al J. , Martin Carolyn A. , Rafter John A.
Published: April 2006

Two hundred male and female patients, selected at random from all patients admitted to an inpatient alcoholism treatment facility in 1973–1974, were surveyed 10 years following treatment. Response rate was 80%, and a validity check was done. Of the 158 usable responses, 61% reported complete or stable remission of their alcoholism for at least 3 years prior to the survey and 84% reported stable psychosocial status. Successful outcome was possible regardless of severity of drinking history or psychosocial status. Seventy‐six percent (76%) of those still alive at follow‐up reported remission; at most, 23% of the deceased were reported in remission prior to death. Involvement in Alcoholics Anonymous (AA) predicted abstinence, suggesting successful outcome for patients who undergo a treatment regimen, which bridges patients into AA involvement. Of those respondents who continued to sponsor other AA members throughout the follow‐up period, 91% were in remission at the time of survey.
In Vivo Neutrophil Delivery in Men with Alcoholic Cirrhosis Is Normal Despite Depressed in Vitro Chemotaxis
Authors: MacGregor Rob Roy
Published: April 2006

Ten patients with far‐advanced Laennec's cirrhosis were studied for in vitro polymorphonuclear (PMN) chemotaxis and in vivo PMN delivery into modified skin windows. Random motility was similar for patient and control cells, but the patients' cells' mean chemotaxis to endotoxin‐activated homologous serum was only 38% of control. The poor response was due to a serum inhibitor which reduced chemotactic activity of control serum by 75.6% but had no effect on chemotaxis to N‐formyl‐methionyl‐leucyl‐phenylalanine. The level of inhibitor activity in each patient did not correlate with the severity of liver dysfunction. In spite of the universal presence of the chemotactic factor inhibitor in all patients' sera, their in vivo PMN delivery into skin chambers was similar to controls. Thus, patients with alcoholic cirrhosis appear able to deliver PMNs normally in response to local tissue injury.
Immunotoxicity of Alcohol in Young and Old Mice. I. In vitro Suppressive Effects of Ethanol on the Activities of T and B Immune Cells of Aging Mice
Authors: Chang M‐P. , Norman D. C. , Makinodan T.
Published: April 2006

A murine aging model was employed to assess effects of ethanol exposure on the T‐cell proliferative response to mitogenic stimulation and on the T cell‐dependent primary antibody response to sheep red blood cells (RBC) in vitro. Splenic cells from young (3–5 months) and old (28–32 months) BALB/c mice were first assessed for their ability to produce interleukin (IL) 2 and proliferate in response to mitogenic stimulation in the presence of various doses of ethanol. Then, splenic T blast cells from young and old mice, generated by Con A‐activation, were assessed for their IL2‐dependent proliferative capacity in the presence of various doses of ethanol. Finally, splenic cells of young and old mice were assessed for their ability to generate plaque‐forming cells (PFC) in response to sheep RBC in the presence of various doses of ethanol.

The results revealed that ethanol has a much greater suppressive effect on old than young splenic T cells (10–15 times), as judged by their ability to proliferate in response to mitogenic stimulation. However, the magnitude of the difference in the suppressive effect is less when the cells are cycling (2 times). Furthermore, ethanol had only a minimal suppressive effect on IL2 production by T cells of both young and old mice, even at the concentration of 100 mm. These findings would suggest that the ethanol‐mediated suppression of T cell proliferation of both young and old mice is more likely due to an impairment of metabolic event(s) associated with or subsequent to the interaction of IL2 and IL2 receptor leading to cellular replication. The primary anti‐sheep RBC antibody responses of young and old spleen cells were also significantly suppressed, but the magnitude of suppression was comparable.
The HK/MBD Questionnaire: Factor Structure and Discriminant Validity with an Adolescent Sample
Authors: Windle Michael
Published: April 2006

A somewhat revised four‐factor structure emerged for the HK/MBD questionnaire with a sample of nonclinical adolescents. The three factors of hyperactivity/impulsivity, antisocial/oppositional behaviors, and learning problems largely retained their factor integrity, but a distinct peer dysfunction factor replaced attentional/socialization problems with the adolescent sample. Acceptable levels of internal consistency were found for three of the factors (excluding learning problems), and interrater reliability between adolescents and their primary caregivers was significant for all four factors. High factor intercorrelations were reported for hyperactivity/impulsivity and antisocial/oppositional behaviors. Differential predictive relations were found between the four factors and adolescent problem behaviors. Specifically, hyperactivity/impulsivity and antisocial/oppositional behaviors were most highly correlated with externalizing symptoms such as alcohol problems, delinquency, illicit drug use, and poor school performance. Peer dysfunction was most highly correlated with internalizing, depressive symptoms. Learning problems correlated most highly with poor school performance, and moderately with alcohol problems and depressive symptoms. There were no statistically significant differences in the strength of the interrelations between the factors of the HK/MBD questionnaire and adolescent problem behaviors for males and females.
Generation of Reactive Oxygen Species and Reduction of Ferric Chelates by Microsomes in the Presence of a Reconstituted System Containing Ethanol, NAD+ and Alcohol Dehydrogenase
Authors: Dicker Elisa , Cederbaum Arthur I.
Published: April 2006

Many of the toxic metabolic actions of ethanol on the liver have been ascribed to the enhanced cellular production of NADH, which arises as a consequence of the oxidation of ethanol by alcohol dehydrogenase (ADH). Experiments were conducted to evaluate whether NADH generated from a reconstituted system containing ethanol plus NAD+ plus ADH could interact with ferric chelates to promote microsomal lipid peroxidation and generation of a hydroxyl radical (OH)‐like species. In the presence of the reconstituted system and iron, microsomes produced • OH as assessed by the oxidation of • OH scavenging agents. This oxidation was inhibited by catalase and competitive • OH scavengers but not by superoxide dismutase. The ADH‐dependent microsomal production of • OH was effectively catalyzed by ferric‐EDTA and ‐diethylenetriamine pentaacetic acid (‐DTPA), but not by ferric‐ATP or ‐citrate. However, all these ferric chelates were reduced by the microsomes in the presence of the reconstituted system. Hydrogen peroxide (H2O2) was produced in the presence of ADH and appeared to be a limiting factor for the production of • OH. The reconstituted system also catalyzed microsomal lipid peroxidation, and the pattern of effectiveness of ferric chelates was opposite that of catalysis of • OH production. There was little effect by catalase, superoxide dismutase or dimethyl sulfoxide (DMSO) on the ADH‐dependent microsomal lipid peroxidation. The reconstituted system was characterized with respect to dependence on NAD+ and ADH; ethanol could be replaced by other alcohols, which are substrates for ADH. Pyrazole, a potent inhibitor of ADH, blocked the ability of the reconstituted system to interact with iron and microsomes to produce reactive oxygen species. The overall pattern of response of the ADH‐dependent reactions with respect to rates of reactions, catalytic effectiveness of ferric chelates and sensitivity to radical scavengers is similar to that found with a NADPH‐generating system. In view of the effectiveness of NADH derived from the oxidation of ethanol by ADH in reducing ferric chelates and promoting microsomal generation of reactive species, increased availability of cellular NADH as a consequence of ethanol oxidation could contribute to the development of oxidative stress and play a role in the toxic actions of ethanol to the liver.
Integration of Biological and Psychosocial Research on Alcoholism
Authors: Nathan Peter E.
Published: April 2006

This paper weighs the extent and potential of efforts to integrate biological and psychosocial research on alcoholism. It begins with a review of what is known in five crucial domains—pathophysiology, psychopathology, etiology and course, treatment, and prevention—that could facilitate this integration. It then considers, for the same five domains, the modest additional increments in knowledge that would markedly enhance the effectiveness of these integration efforts. The paper concludes with a brief discussion of how we might proceed from what we know to what we need to know in the further pursuit of biological‐psychosocial integration.
Emotional Perception and Memory in Alcoholism and Aging
Authors: Oscar‐Berman Marlene , Hancock Mary , Mildworf Bracha , Hutner Nancy , Weber Dorothy Altman
Published: April 2006

The ability to identify and recognize emotional materials was studied in 10 male alcoholic Korsakoff patients, 27 male non‐Korsakoff alcoholics, and 31 male nonalcoholic controls, across a wide age range (23 to 77 years). Stimulus materials were presented in two sensory modalities; the materials were photographs of faces expressing one of four emotions (happy, sad, angry, or neutral), and recordings of sentences with emotional intonations or semantic meanings expressing the same four emotions. Results of the experiments showed consistently severe deficits in emotional functions in the Korsakoff patients, but only minor alterations in the non‐Korsakoff alcoholics. Older subjects, whether or not they had a history of alcoholism, also exhibited significant deficits on most of the tasks. Results of the study did not provide strong support for the premature aging hypothesis of alcoholism, which suggests that alcoholism accelerates aging, beginning either at the onset of heavy drinking early in adult life, or later in life after the normal manifestations of aging have begun to appear. Results are related to brain mechanisms in emotional perception and memory functions.
Multiple Withdrawals from Chronic Ethanol “Kindles” Inferior Collicular Seizure Activity: Evidence for Kindling of Seizures Associated with Alcoholism
Authors: McCown Thomas J. , Breese George R.
Published: April 2006

The present investigation tested the hypothesis that multiple withdrawals from chronic ethanol treatment “kindles” seizure activity. Two animal models of kindled seizure activity–electrical stimulation of the inferior collicular cortex or the amygdala–were used to evaluate this hypothesis. Four withdrawals from a 12‐day ethanol‐liquid diet regimen facilitated the seizure kindling rate in the inferior collicular cortex, when the stimulation was initiated 7 days after the last withdrawal. In contrast, four withdrawals from this chronic ethanol regimen significantly attenuated the rate of amygdaloid kindling. When the withdrawals were increased to six or 10 using a 5‐day chronic ethanol treatment schedule, the kindling rate in the inferior collicular cortex proved directly proportional to the withdrawal number. Continuous ethanol exposure over the same period as the 10 withdrawal group also facilitated the inferior collicular kindling rate, but not to the extent found in the 10 withdrawal group. As before, 10 withdrawals from the 5‐day chronic ethanol liquid diet treatment attenuated the rate of amygdaloid kindling. Thus, this kindling action of repeated ethanol withdrawals appears specific to seizures originating from the inferior collicular cortex, not the limbic system. These findings support a previous hypothesis for a kindling etiology of alcoholism related seizures.
Vagal Mediation of the Effect of Alcohol on Heart Rate
Authors: Newlin David B. , Byrne Evan A. , Porges Stephen W.
Published: April 2006

Alcohol (0.5 g/kg bodyweight) was administered in two sessions and placebo in a third session to normal, healthy social drinkers. A control group was administered a mixer (i.e., no alcohol) for each of the three sessions. The heart rate and vagal tone index (V) response patterns were different to alcohol than to the mixer or placebo. The treatments did not differentially influence pulse transit time. The results indicated that the acute effect of a moderate dose of alcohol on the heart is parasympathetically (i.e., vagally) mediated and has no significant direct sympathetic component.
Protein‐Acetaldehyde Adducts in Serum of Alcoholic Patients
Authors: Lin Renee C. , Lumeng Lawrence , Shahidi Samin , Kelly Timothy , Pound David C.
Published: April 2006

Enzyme‐linked immunosorbent assay (ELISA) was used to detect the presence of protein‐acetaldehyde adducts (‐AAs) in human serum samples. Two methods were compared: (1) direct ELISA: samples, rabbit anti‐hemocyanin‐AA IgG, and β‐galactosidase (β‐gal) conjugated goat anti‐rabbit serum IgG added to a 96‐well ELISA plate in a stepwise manner; and (2) two‐site or sandwich ELISA: serum samples added to an ELISA plate that had been precoated with anti‐hemocyanin‐AA IgG (the capture antibody) and incubated stepwise with biotinated anti‐hemocyanin‐AA IgG (the signal anti‐body) and avidin‐β‐gal conjugates. Serum protein‐AA levels were then assayed by bound β‐gal activities at OD405. When human hemoglobin (Hgb)‐AA was used as a model protein‐AA for the sandwich ELISA, the EC60 (estimated concentration that corresponds to 50% of the OD405 response range) was 7 ng/ml. Direct ELISA was less sensitive (EC50 of 120 ng/ml). Adding control human serum to Hgb‐AA increased the EC50 of the direct ELISA more than the sandwich ELISA. Intra‐ and interassay coefficients of variance for sandwich ELISA were both about 8%. Detection of Hgb‐AA by sandwich ELISA was highly specific. The above results with anti‐hemocyanin‐AA IgG were also obtained when anti‐myoglobin‐AA IgG was used in sandwich ELISA. Using sandwich ELISA and anti‐hemocyanin‐AA IgG, OD405 for sera of control subjects and alcoholic patients were 0.036 ± 0.033 (±SEM, n= 28) and 0.150 ± 0.088 (n= 28), respectively. Serum protein‐AAs reacted more strongly with anti‐myoglobin‐AA IgG than anti‐hemocyanin‐AA IgG. The data indicate that high titers of serum protein‐AAs are present in most alcoholic patients.
Are Women Drinking More Like Men? An Empirical Examination of the Convergence Hypothesis
Authors: Mercer Patricia W. , Khavari Khalil A.
Published: April 2006

The convergence hypothesis predicts that women's drinking levels are increasing and are approaching those observed in men. To test this hypothesis, drinking practices of women and men were assessed1 at a large urban university at two points in time, 1977 (n= 1711) and 1985 (n= 1045). Although women's ethanol intake remained the same, significant changes in patterns of drinking were seen. The mean annual volume of beer consumed by females in 1985 showed a 33.9% increase over the mean annual volume in 1977. “Binge” drinking increased for both sexes from 1977 to 1985. A decrease in women's rate of abstention was also observed. Convergence with male drinking patterns was noted for several drinking parameters. This convergence was demonstrated by decreases in the ratios of men's drinking to women's drinking for these measures. Women consumed more wine per occasion than men in 1985. When corrections were made for differences in body fluid, the data suggested that convergence was not a trend, but had in fact occurred. The findings have serious implications, particularly in the light of recent findings that women are at greater health risk than men when they imbibe ethanol.2