Nonalcoholic Controls Research Articles

Wine and Grape Juice Modulate Interferon-y-induced Neopterin Production and Tryptophan Degradation in Human PBMC

Abstract Population-based studies suggest moderate and regular consumption of alcoholic beverages and especially of red wine to reduce morbidity and mortality from coronary heart disease. These beverages may interfere with immune activation cascades crucial in the pathogenesis of coronary heart diseases. Neopterin concentrations in human body tluids were found to increase in the course of coronary heart disease indicating the activity of the atherogenetic process. In this study, human peripheral blood mononuclear cells (PBMC) stimulated with mitogens phytohaemagglutinin and concanavalin A were exposed to red and white wines, to ethanol and to grape juice as a non-alcoholic control in vitro. Neopterin production and tryptophan degradation were measured in supcrnalants. Both biochemical effects are induced by Th 1-type cytokine interferon-y and allow monitoring of immune actnation. In stimulated PBMC increased production of neopterin and degradation of tryptophan was observed Red and white wines, as well as grape juice inhibited these stimulation-induced effects, higher concentrations being more cffective. Ethanol had comparably small if any effect, Red and white wines as well as grape juice down regulate cytokine-mediated effects in PBMC. Most likely, antioxidant ingredients of wine and grape juice such as resveratrol are capable of interfering with immunologic pathways which appear to be of relevance, e g.. in the pathogenesis of cardiovascular disease.

Polymorphisms of the dopamine D2 receptor, serotonin transporter, and GABA A receptor β 3 subunit genes and alcoholism in Mexican-Americans

The etiology of alcohol dependence is a complex interaction of psychosocial and biologic factors. To study the impact of genetic factors that play an important role in an individual's vulnerability to alcohol abuse and dependence, we examined the genetic variations of the major neurotransmitter genes, including the dopamine D2 receptor ( DRD2) TaqI A, B, and -141C insertion/deletion ( Ins/Del) polymorphisms, the serotonin transporter–linked polymorphic region ( 5-HTTLPR), and the gamma-aminobutyric acid A (GABA A) receptor β 3 subunit gene ( GABRβ3), for 130 Mexican-American alcoholic men and 251 nonalcoholic control subjects (105 men and 146 women). The genotype frequency for the DRD2 -141C Ins/Del allele was significantly different between alcoholic and control subjects ( P = .007). The frequency of the 5-HTTLPR short ( S) allele was significantly higher in alcoholic individuals (61.5%) than in nonalcoholic control subjects (52.8%; P = .021). When smokers were excluded from both control and alcoholic groups, the association between the DRD2 -141C Ins allele, as well as between the 5-HTTLPR S allele, and alcoholism became significant at both genotypic and allelic levels. No positive association was found between alcoholism and the DRD2 TaqI A or B, or the GABRβ3, genotype. Our findings indicate that the DRD2 -141C Ins allele and the 5-HTTLPR S allele are genetic risk factors for alcoholism in Mexican-Americans, and that smoking modulates the association between genetic risk factors and alcoholism.

Alcoholism-related phenotypes and genetic variants of the CB1 receptor

Neurotransmitter release of GABAergic and glutamatergic neurons may be significantly influenced by cannabinoid CB1 receptors located at presynaptic nerve terminals. GABA and glutamate have been reported to be involved in the pathogenesis of severe alcohol withdrawal-induced seizures and delirium tremens. The aim of this study is to test the potential influence of a bi-allelic cannabinoid receptor gene (CNR1) polymorphism (G1359A) on severe alcohol withdrawal syndromes. Based upon a sample size estimation, 196 subjects meeting DSM IV and ICD10 criteria for alcohol dependence and 210 non-alcoholic controls were recruited for study. CB1 polymorphisms were determined using polymerase chain reaction (PCR). History of alcohol withdrawal-induced delirium tremens, seizures and other alcohol withdrawal-related phenotypes were obtained using the SSAGA (Semi-Structured Assessment of Genetics in Alcoholism). Data were corroborated with information from the inpatients' clinical files. Allele frequencies of the CNR1 G1359A polymorphism were within the range reported by previous studies. After correcting for multiple testing, no association of the A- or G-allele of CNR1 polymorphism with a history of alcohol withdrawal-induced seizures was detected. In addition, no significant relationships with other alcoholism-related phenotypes were found. This study failed to confirm an earlier report of a potential role of a CNR1 polymorphism in the pathogenesis of delirium tremens.

Evidence of apoptosis in chronic alcoholic skeletal myopathy

Apoptosis is a common mechanism of programmed cell death that has been implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in cardiac muscle. The relationship between skeletal and cardiac muscle damage in alcoholism led us to consider the possible role of apoptosis in the pathogenesis of skeletal myopathy. We prospectively evaluated apoptosis in skeletal muscle biopsies of 30 consecutively selected male high-dose well-nourished chronic alcohol consumers and 12 nonalcoholic controls. Alcohol consumption, evaluation of muscle strength by myometry, and deltoid muscle biopsy with immunohistochemical and morphometric analysis were performed. Apoptosis was assessed by TUNEL, BAX, and BCL-2 immunohistochemical assays. Chronic alcoholics compared with controls showed a significantly higher apoptotic index in TUNEL (2.35% ± 0.25% versus 0.18% ± 0.03%, P < 0.001), BAX (9.16% ± 2.00% versus 0.66% ± 0.22%, P < 0.001), and BCL-2 muscle assays (8.08% ± 0.20% versus 0.83% ± 0.20%, P = 0.001), respectively. In addition, these apoptotic indexes were higher in alcoholics with skeletal myopathy compared with in those without skeletal myopathy (3.04% ± 0.36% versus 1.65% ± 0.26%, P = 0.004 for TUNEL; 17.00% ± 2.78% versus 1.33% ± 0.22%, P < 0.001 for BAX; and 15.13% ± 3.2% versus 1.03% ± 0.33%, P < 0.001 for BCL-2 assays, respectively). We conclude that apoptosis is present in the skeletal muscle of high-dose alcohol consumers, mainly in those affected by myopathy. However, the specific pathogenic mechanism of apoptosis in chronic skeletal myopathy in alcoholics remains to be elucidated.

Serum hyaluronate correlates with histological progression in alcoholic liver disease.

Chronic alcohol consumption may lead to the development of liver cirrhosis. Serum concentrations of hyaluronate were suggested as a predictor in chronic liver disease, but its power to distinguish between severity of fibrosis and inflammation had not been assessed. In order to evaluate hyaluronate as a marker to detect early stages of alcoholic liver disease and to establish a possible correlation with hepatic histology, serum concentrations were measured by radioimmunoassay in 87 patients with biopsy-proven fatty liver, fatty liver and mild fibrosis, fatty liver and inflammation, severe fibrosis and inflammation, and cirrhosis, and in 12 non-alcoholic control subjects. In addition, serum hyaluronate was determined in 40 non-cirrhotic alcoholic patients with either a normal serum aspartate aminotransferase (AST) or an AST elevated at least two-fold. Serum hyaluronate increased significantly with advanced stages of alcoholic liver disease, while levels in patients with fatty liver were elevated only slightly without reaching significance. Hyaluronate correlated well with histological stage and was highly sensitive for detecting fibrosis in general and perivenular fibrosis as an indicator of progression to cirrhosis. Hyaluronate levels were not influenced by AST levels. Serum hyaluronate is a good predictor of the presence of even moderate hepatic fibrosis in alcoholic liver disease, justifying its clinical use to assess morphological alterations of the liver in alcoholics.

Increased TUNEL positive cells in human alcoholic brains

Alcohol-sensitive neuronal cell loss, which has been reported in the superior frontal cortex and hippocampus, may underlie the pathogenesis of subsequent cognitive deficits. In the present study, we have used the TUNEL labeling to detect the DNA damage in human alcoholic brains. Seven out of eleven alcoholics exhibited TUNEL-positive cells in both superior frontal cortex and hippocampus, which were co-localized with GFAP immunoreactivity. In contrast, almost no positive cells were detected in the non-alcoholic controls. None of the TUNEL-positive cells showed any typical morphological features of apoptosis or necrosis. TUNEL-positive cells observed in the present study may indicate DNA damage induced by ethanol-related overproduction of reactive oxygen species.

Craving for alcohol and pre-attentive processing of alcohol stimuli

The present study was designed to test the hypothesis of unconscious attending to alcohol-related information in alcoholics experiencing a high level of craving for alcohol. Subjects included a group of alcoholics ( n=34) divided by a median split on a craving measure into two groups labeled as ‘high craving’ ( n=18) and ‘low craving’ ( n=16) alcoholics, and a non-alcoholic control group ( n=39). The cardiovascular reactions of these groups were compared after their exposure to masked and unmasked alcohol and control stimuli. As expected the ‘high craving’ alcoholics showed an immediate heart rate deceleration after exposure to masked and non-consciously accessible alcohol pictures. The ‘high craving’ alcoholics reported a small but significant increase in difficulty resisting a drink after exposure to masked alcohol pictures. When the alcohol pictures were presented unmasked a significant increase was found in both high and low craving alcoholics on consciously expressed urges, fidgeting and reduced coping with temptation to drink. The ‘high craving’ alcoholics had lower tonic heart rate variability compared to the control group and the level of craving was positively associated with salivation during the exposure to all picture types. The findings generally support the psychobiological theory of craving, which suggests that the uncontrollability of the craving experience is rooted in unconscious processing of drug-related information.

Activation of hepatic macrophage contributes to hepatic necrosis after post-ischemic reperfusion in alcoholic fatty liver

Fatty livers are vulnerable to ischemia/reperfusion (I/R) injury. We investigated the role of hepatic macrophages in the I/R injury in the fatty liver. Rats with alcoholic or nonalcoholic fatty liver were subjected to hepatic warm ischemia for 30 min. A bolus of gadolinium chloride (GdCl 3) was injected intravenously twice before I/R to block hepatic macrophage activity. Alcoholic fatty liver developed more extensive hepatic necrosis with neutrophil infiltration in association with a higher production of cytokine-induced neutrophil chemoattractant (CINC)-1, a potent neutrophil chemokine in rat, after I/R than the nonalcoholic fatty liver or control liver without steatosis. Hepatic apoptosis after I/R increased to a similar degree (3-fold) in each of the two fatty liver models, compared with the control liver. Alcoholic fatty liver exposed to I/R showed a rapid increase in nuclear factor-kappa B (NF-κB) binding activity. The GdCl 3 pretreatment significantly reduced NF-κB binding activity, CINC-1 level and necrosis in alcoholic fatty liver, despite no significant decrease in the extent of apoptosis. Our results suggest that the activation of hepatic macrophages in alcoholic fatty liver may contribute to hepatic necrosis after I/R, and that the apoptosis might be less dependent on the macrophage activity.

Nutritional deficiencies in German middle-class male alcohol consumers: relation to dietary intake and severity of liver disease

The purpose of the present study was to compare the nutrient intake and the nutritional status between German middle-class alcohol consumers and non-drinkers. Cross-sectional study using patients with different stages of alcoholic liver disease (ALD) and healthy volunteers. Southern Germany. Seventy-six hospitalized German middle-class alcohol consumers with different stages of alcoholic liver disease (ALD) and 22 healthy control subjects. Subjects and controls were nutritionally assessed and mineral and vitamin content was measured in blood and urine. When compared with controls, alcohol consumers had significantly higher intakes of total calories, but intake of non-alcoholic calories did not differ between groups (P<0.05). Among drinkers, there was a decrease in percentage of energy derived from protein and fat and a significant increase in carbohydrates (P<0.05). With the exception of vitamin E, micronutrient intake of alcoholics was equal to that of controls; however, blood vitamin (vitamin C, retinol, lycopene, alpha- and gamma-carotene) and trace element (selenium, zinc) concentrations of alcohol-drinking patients were lower than those of non-drinkers. From the results of this study it is concluded that in German middle-class male alcohol consumers the status of several micronutrients is disturbed, although dietary intake hardly differs from that in non-alcoholic controls.

Source Monitoring in Alcoholism

Recent research on the neural bases of source memory suggests that this type of memory is relevant to the neuropsychological assessment of neurobehavioral disorders. Source memory refers to the ability to discriminate the origin or source of information (e.g., did I think of the idea or did I read about it). We examined source monitoring in abstinent alcoholic patients (N = 53) and nonalcoholic controls (N = 34) and report significant impairments in the alcoholic patients' ability to remember the source of recently presented information. Decrements in source memory were uncorrelated with alcoholic patients' neuropsychological deficits on the Wisconsin Card Sorting Test or the Benton Facial Recognition Test. Using qualitative measures of brain CT scans in a subsample of 39 alcoholic patients, we found that source memory was correlated with Sylvian fissure ratings in the left hemisphere. We propose that source memory decrements are another area of neuropsychological functioning affected in chronic alcoholism. Tasks of source memory may offer the neuropsychologist a valuable new tool for evaluating cognitive functions in neurobehavioral disorders.

Executive Dysfunction and Clinical Outcome in Chronic Alcoholics

Background The purpose of this study was to investigate which of 12 neuropsychological tests predict alcoholic patients’ alcohol‐specific and/or alcoholic‐nonspecific outcome. Our hypothesis was that the ecologically valid neuropsychological tests that measure executive function are better predictors of alcoholics’ functional outcome.Methods We administered 12 neuropsychological tests to chronic alcoholics. Included in the tests were tasks of Reaction Time, Symbol Digit Modalities, Figure Position, Digit Span, Block Design, Trail Making, and six subtests of a battery called the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Previous investigators have suggested that the BADS has ecological validity. Twenty‐two male alcoholics were compared with 15 nonalcoholic control subjects on these neuropsychological measures 7 weeks after detoxification. Two functional outcome indices, i.e., resumption of drinking and occupation, were evaluated 18 months after discharge.Results The total profile score and the score on three of the six subtests of the BADS were lower in alcoholics than in nonalcoholic controls. Alcoholics’ performance on the BADS predicted alcohol‐nonspecific outcome (occupation) but not alcohol‐specific (drinking) outcome. In contrast, other neuropsychological tests did not predict either of the two outcome indices.Conclusions The BADS total profile score is related to alcohol‐nonspecific outcome but not to alcohol‐specific outcome.

A laboratory-based investigation of relations among video lottery terminal (VLT) play, negative mood, and alcohol consumption in regular VLT players

Thirty regular video lottery terminal (VLT) players were randomly assigned to 90 min of VLT play or a control activity (viewing a movie) to examine the impact of VLT play on alcohol use. Ratings of dysphoric mood were taken at baseline, midactivity, and postactivity. Alcoholic and nonalcoholic control beverages were available throughout. As hypothesized, those in the VLT condition were more likely to consume alcoholic than nonalcoholic control beverages (i.e., 73% drank alcohol and 20% drank control beverages), whereas no such preference for alcohol was observed in the movie control condition (i.e., 40% drank alcohol and 47% drank control beverages). Consistent with predictions derived from Steele and Josephs' [J. Abnorm. Psychol. 97 (1988) 196; Am. Psychol. 45 (1990) 921.] attention allocation model, VLT condition participants who drank alcohol showed increases in dysphoric effect over the course of testing. No such changes in negative mood were observed in VLT participants who did not consume alcohol or in movie control participants regardless of whether they drank alcohol. An observed temporal pattern of greater drinking during the early phase of VLT play indicated that the relation between alcohol use and dysphoric affect among VLT condition participants could not readily be explained by drinking to relieve dysphoria induced by VLT losses. Clinical and policy implications are discussed.

Association of a CB1 Cannabinoid Receptor Gene ( CNR1) polymorphism with severe alcohol dependence

Due to the involvement of the endogenous cannabinoid system in brain reward mechanisms a silent polymorphism (1359G/A; Thr453Thr) in the single coding exon of the CB1 human cannabinoid receptor gene ( CNR1) was analysed in 121 severely affected Caucasian alcoholics and 136 most likely non-alcoholic controls. The observed frequency of the A allele was 31.2% for controls and 42.1% for alcoholics with severe withdrawal syndromes ( P=0.010). Post-hoc exploration indicated that this allelic association resulted from an excess of the homozygous A/A genotype in patients with a history of alcohol delirium ( P=0.031, DF 2), suggesting s an increased risk of delirium (OR=2.45, 95% CI 1.14–5.25). This finding suggests that the homozygous genotype CNR1 1359A/A confers vulnerability to alcohol withdrawal delirium.

Epidemiological and histopathological study of relevance of Guizhou Maotai liquor and liver diseases.

To explore the relevance of Maotai liquor and liver diseases. Epidemiological study was conducted on groups of subjects, each consisting of 3 subjects from the Maotai liquor group consisting of 99 individuals and one from the non-alcoholic control group consisting of 33 individuals. Liver biopsy was performed on 23 volunteers from Guizhou Maotai Distillery who had a constant and long history of drinking Maotai liquor. Experimental histopathological study was conducted as follows: sixty male Wistar rats were divided into 3 groups randomly and fed with Maotai liquor, ordinary white wine, and physiological saline respectively for a period of 8 and 12 weeks. The rats were sacrificed in batches, then serum ALT, AST, TBil, and AKP were measured. Rat livers were harvested to measure the liver indexes, GSH, and MDA. Histopathological examinations were also performed. Another eighty mice were randomly divided into 4 groups and fed with Maotai (at different dosages of 10 ml.kg(-1) and 20 ml.kg(-1)), ethanol, and physiological saline. The animals were sacrificed after 4 weeks and serum ALT was determined. Then the livers were harvested and liver indexes and MDA were measured. The incidence rate of hepatic symptoms, splenomegaly, liver function impairment, reversal of Albumin/Globulin and increased diameter of portal veins in the Maotai liquor group were 1.0% 1/99 , 1.0% 1/99 , 1.0% 1/99 , 1.0% 1/99 , 0 0/99 and 0 0/99 , 0 0/99 ,0 0/99 , 0 0/99 , 0 0/99 , respectively. There was no significant difference between the Maotai group and the non-alcoholic control group P>0.05 . Various degree of fatty infiltration of hepatocytes was found in the 23 volunteers receiving liver biopsy, but there was no obvious hepatic fibrosis or cirrhosis. A comparison was made between the Maotai liquor group and the ordinary white wine group. It was found that hepatic MDA in rats and mice were 0.33+/-0.10 and 0.49+/-0.23 respectively in Maotai group and 0.61+/-0.22 and 0.66+/-0.32 in the ordinary white wine group; MDA had an obvious decrease in the Maotai liquor group (P<0.05); hepatic GSH were 0.12 mg.g(-1)+/-0.06 mg.g(-1) in rats of the Maotai liquor group and (0.08+/-0.02)mg.g(-1) in white wine group, it was obviously increased in the Maotai liquor group (P<0.05). After the 20 rats had been fed with ordinary white wine for 8 weeks consecutively, disarranged hepatocyte cords, fatty infiltration of hepatocytes, and fibrous septa of varying widths due to hepatic connective tissues proliferation were observed; after 12 weeks, the fibrous tissue proliferation continued and early cirrhosis appeared. Compared with the ordinary white wine group, fatty infiltration was observed in the 8-week and 12-week groups, but no necrosis or fibrosis or cirrhosis was found in the Maotai liquor group (P<0.05). Maotai liquor may cause fatty liver but not hepatic fibrosis or cirrhosis, and it can strengthen lipid peroxidation in the liver.

Chemical Pathology in Brain White Matter of Recently Detoxified Alcoholics: A 1H Magnetic Resonance Spectroscopy Investigation of Alcohol‐Associated Frontal Lobe Injury

Investigations have suggested that frontal lobe abnormalities are a prominent feature of the alcoholic brain, indicated by impaired neuropsychological performance on tests of frontal lobe function and by reduced frontal lobe volume in neuroimaging and neuropathological examinations. White matter compartment volume loss may underlie observed brain shrinkage and cognitive deficits associated with the frontal lobes, although the nature of this change has not been well-characterized. To investigate the susceptibility of frontal lobe white matter to alcohol-associated metabolic change and to understand the nature of alcohol-related white matter injury, 1H magnetic resonance spectroscopy (MRS) was used to measure concentrations of metabolites in frontal white matter (FWM) and parietal white matter (PWM) of recently detoxified alcoholics (RDA) and nonalcoholic controls (CON). Concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), myo-inositol (Ins), and creatine plus phosphocreatine (Cr) were measured in 37 RDA (mean age, 40.4 years; mean length of abstinence, 27.9 days) and 15 CON (mean age, 38.0 years). Analysis of variance (ANOVA) revealed a group by region of interest interaction for concentrations of NAA. Simple effects analysis revealed a significant 14.7% reduction in FWM NAA, while NAA levels in PWM were similar in RDA and CON. In addition, RDA had an 11.8% increase (averaged across both regions of interest) in brain white matter Ins relative to CON. Reductions in FWM NAA were associated with a longer drinking history in the RDA group, but this result was not found when both age and drinking history were used to predict the level of FWM NAA. Alcohol-associated reductions in FWM NAA may be the result of neuronal loss or dysfunction in the metabolism of NAA. While alcohol-induced oxidative stress may cause global brain impairments in the metabolism and subsequent reduction of NAA, the frontal lobes are particularly rich in excitatory amino acid pathways, and axonal damage or destruction secondary to glutamate-mediated excitotoxicity during alcohol withdrawal may cause frontal lobe-specific reductions in NAA. Elevations in brain white matter Ins may reflect astrocyte proliferation as well as an osmotic response to cell shrinkage.

Chemical Pathology in Brain White Matter of Recently Detoxified Alcoholics: A 1H Magnetic Resonance Spectroscopy Investigation of Alcohol-Associated Frontal Lobe Injury

Background: Investigations have suggested that frontal lobe abnormalities are a prominent feature of the alcoholic brain, indicated by impaired neuropsychological performance on tests of frontal lobe function and by reduced frontal lobe volume in neuroimaging and neuropathological examinations. White matter compartment volume loss may underlie observed brain shrinkage and cognitive deficits associated with the frontal lobes, although the nature of this change has not been well-characterized. Method: To investigate the susceptibility of frontal lobe white matter to alcohol-associated metabolic change and to understand the nature of alcohol-related white matter injury, 1H magnetic resonance spectroscopy (MRS) was used to measure concentrations of metabolites in frontal white matter (FWM) and parietal white matter (PWM) of recently detoxified alcoholics (RDA) and nonalcoholic controls (CON). Concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), myo-inositol (Ins), and creatine plus phosphocreatine (Cr) were measured in 37 RDA (mean age, 40.4 years; mean length of abstinence, 27.9 days) and 15 CON (mean age, 38.0 years). Results: Analysis of variance (ANOVA) revealed a group by region of interest interaction for concentrations of NAA. Simple effects analysis revealed a significant 14.7% reduction in FWM NAA, while NAA levels in PWM were similar in RDA and CON. In addition, RDA had an 11.8% increase (averaged across both regions of interest) in brain white matter Ins relative to CON. Reductions in FWM NAA were associated with a longer drinking history in the RDA group, but this result was not found when both age and drinking history were used to predict the level of FWM NAA. Conclusions: Alcohol-associated reductions in FWM NAA may be the result of neuronal loss or dysfunction in the metabolism of NAA. While alcohol-induced oxidative stress may cause global brain impairments in the metabolism and subsequent reduction of NAA, the frontal lobes are particularly rich in excitatory amino acid pathways, and axonal damage or destruction secondary to glutamate-mediated excitotoxicity during alcohol withdrawal may cause frontal lobe-specific reductions in NAA. Elevations in brain white matter Ins may reflect astrocyte proliferation as well as an osmotic response to cell shrinkage.

Sweet liking and family history of alcoholism in hospitalized alcoholic and non-alcoholic patients.

The present study was designed to test the hypothesis that preference for stronger sweet solutions may be associated with the genetic risk for alcoholism. Thirty-two male patients with alcohol dependence admitted for alcoholism in-patient treatment and 25 non-alcoholic control subjects were used in the study. Hedonic response to sweets was evaluated using the sweet preference test. Family history of alcoholism was evaluated using a Russian version of the Michigan Alcoholism Screening Test modified for the assessment of the alcohol-related behaviour of the subject's biological father. Similar to our previous findings, alcoholics were far more likely to prefer the highest offered sucrose concentration (0.83 M), compared to non-alcoholic controls. Such preference was determined by two factors: positive family history of alcoholism and alcoholic status. Statistically, these factors contributed to the likelihood of preferring sweet solutions independently. Therefore, the effects of these factors may enhance each other. These findings support the hypothesis that preference for a stronger sweet solution is associated with a paternal history of alcohol dependence and may reflect a genetic predisposition to alcoholism.

Expression, but not activity, of neuronal nitric oxide synthase is regionally increased in the alcoholic brain

The regional distribution of nitric oxide synthase (NOS) was investigated in alcoholic post-mortem brains compared with brains of non-alcoholic control individuals. Total enzyme activity in 28 brain regions was determined using the [(3)H]l-citrulline formation assay, whereas Western blot analyses were used for semi-quantitative measurement of the neuronal isoform of NOS (nNOS). In the alcoholic brain, nNOS protein expression was increased in the following regions: frontal cortex (85%), the cingulate gyrus (294%), the nucleus accumbens (54%), the entorhinal cortex (85%) and the thalamus (51%). These increases were, however, not associated with higher total NOS activity. Interestingly, nNOS protein content was increased in the frontal cortex and the nucleus accumbens, brain regions which are suggested to be involved in the dopaminergic mesolimbic reward system. It is concluded that upregulation of signal transduction pathways, such as the adenosine 3',5'-monophosphate and the protein kinase C-dependent pathway, due to stimulation of G-protein-coupled neurotransmitter receptor regulation, as a form of functional tolerance, could be responsible for increased nNOS protein expression, and downregulation of NOS enzyme activity in these brain regions.

This month in J Lab Clin Med: Issue highlights for October 2000

This month in J Lab Clin Med: Issue highlights for October 2000

Increased lipid and protein oxidation and DNA damage in patients with chronic alcoholism

Increased oxidative stress has been speculated to be one possible mechanism of ethanol toxicity. This study evaluates malondialdehyde (MDA) and protein carbonyl content in serum as markers of oxidative stress and DNA damage in lymphocytes in the same patients with chronic alcoholism. Patients with chronic alcoholism showed a significant increase in MDA levels and protein carbonyl content of their serum as compared with non-alcoholic control subjects. Increases in endogenous and H2O2-induced DNA damage were also observed in lymphocytes of patients with chronic alcoholism. In addition, there were significant correlations between endogenous and H2O2-induced DNA damage and serum MDA or protein carbonyl content in patients with chronic alcoholism. These results clearly indicate the presence of oxidative stress in patients with chronic alcoholism. (J Lab Clin Med 2000;136:287-91)