Alcohol and alcoholism (Oxford, Oxfordshire). Supplement最新文献

Ethanol inhibits the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal systems, but the mechanism of the inhibition has not been elucidated. Previous work, using primary cultures of rat cerebellar granule cells, showed that both exposure to alcohol and activation of protein kinase C (PKC) by the phorbol ester PMA reduced the potency of the co-agonist, glycine, to enhance NMDA receptor function (measured as an increase in intracellular Ca2+), resulting in inhibition of the NMDA response at low glycine concentrations. Inhibition of NMDA receptor function by PMA and ethanol could also be overcome by PKC antagonists, implicating PKC in the inhibitory effect of ethanol. We have now compared the effects of ethanol and PKC activation of NMDA receptor function in primary cultures of rat cerebral cortical cells. The receptor in these cells was much less sensitive to ethanol inhibition, and the inhibition was not overcome by high concentrations of glycine. Furthermore, PMA treatment resulted in an increased response to NMDA at low glycine concentrations. The results indicate that PKC does not mediate ethanol inhibition of NMDA receptor function in cerebral cortical cells, and that the mechanism of ethanol inhibition can vary among brain regions and/or cell types. Possible determinants of the differing mechanisms of ethanol's actions include the subunit composition of the NMDA receptor and/or the isoforms of PKC present in the different cells.

Acetaldehyde, an intermediate in ethanol metabolism, has been shown to react with proteins to produce both stable and unstable adducts. These modified proteins are immunogenic, leading to the production of anti-adduct antibodies. In this report we describe studies carried out to determine whether anti-adduct antibodies could be used as a marker of alcohol abuse. We have used ELISAs to measure plasma immunoreactivity with unmodified and acetaldehyde-modified bovine serum albumin in groups of female and male social drinkers, heavy drinkers and alcoholics. When total immunoreactivity with the unmodified and acetaldehyde-modified proteins was measured it was found that each of the groups exhibited elevated reactivity with the modified protein as compared to the unmodified. Similar results were obtained when IgM immunoreactivity was measured. However, when IgA immunoreactivity was measured the reactivity with the modified protein was more greatly elevated in the heavy drinking and alcoholic groups than in the social drinking groups. There was no evidence of IgG reactivity with modified protein in any of the groups. These data suggest that elevated IgA reactivity with acetaldehyde-modified proteins may be a marker for high alcohol intake.

Evidence suggests that liver disease per se may contribute to the cognitive and motor impairments encountered in chronic alcoholics. Neuropathologic studies reveal astrocytic changes (Alzheimer type II astrocytosis) in the brains of alcoholic cirrhotic patients who died in hepatic coma. Pathophysiologic mechanisms responsible for hepatic (portal-systemic) encephalopathy in alcoholics include the loss of neuron-astrocytic metabolic trafficking as well as selective alterations of serotoninergic and dopaminergic function. In addition, there is evidence to suggest that endogenous ligands for both central-type (GABA-related) and "peripheral-type" (astrocytic) benzodiazepine receptors are implicated in the pathogenesis of hepatic encephalopathy in these patients. Chronic liver disease may also interfere with brain thiamine homeostasis and thus contribute to the pathogenesis of the Wernicke-Korsakoff syndrome in chronic alcoholism.

Alteration of microcirculatory status and aberration of the autonomic nervous activity are thought to play an important role in the pathogenesis of ethanol-induced organ damages. Recently, the significant roles of nitric oxide and endothelin in the regulation of the pancreatic microcirculatory system and its disturbances have also been discovered. The present study was undertaken to clarify the histochemical and biochemical alteration of the cholinergic and adrenergic nerves. NADPH diaphorase and nitric oxide synthase activities, markers of nitroxergic nerves, and endothelin immunoreactivity as well as binding sites of 125 I-endothelin, were also studied in the pancreas of rats fed for three months with the Lieber-DeCarli's ethanol-containing liquid diet. In the rats fed ethanol, the histochemical and biochemical activities of the cholinergic nerves gradually increased, compared with the control rats. Monoamine fluorescence and NADPH diaphorase histochemical activity were also markedly enhanced in the ethanol-treated group. The results suggest that the activation of cholinergic and adrenergic nerves and increased NO synthesis are involved in the pathogenesis of ethanol-induced pancreatic injury.

The development of the nervous system is partly regulated by growth factors, especially by members of the fibroblast growth factor family (FGF) family. Both the proliferation and differentiation of neuronal precursor cells within the developing neural tube appear to depend upon appropriate stimulation with FGF-1 or FGF-2. Recently, it has been shown that cells residing in the sub-ventricular zone of adult brains have characteristics of neuronal precursors: they can respond to FGF-2 by proliferation and FGF-1 induces neuronal differentiation. Thus, it appears that the adult central nervous system has the potential to replace damaged neurons if the precursor cell can be stimulated with the appropriate growth factor. Exposure of the embryo to alcohol appears to diminish the proliferation of the ventricular layer and subsequently reduced the number of neurons generated. This suggests that alcohol may inhibit FGF action, and exogenous administration of factors may provide a mechanism for stimulating or overcoming deficits resulting from such exposure.

The science of Immunology, since its beginnings around the year 1900, has expanded to encyclopaedic dimensions and has had enjoyed two "golden ages," in the early 1900s and after the 1950s. By way of illustration, as many as 23 of the present total of 157 Nobel Laureates received their award for discoveries relevant to immunology, including the first in 1901 to Emil von Behring for the use of immune serum in the treatment of disease. The Nobel awards in Immunology will be used as theme points for the text of this lecture. In fact, this paper asks you to imagine a series of six lectures on Contemporary Concepts delivered at various times between 1900 and the present, specifically 1905, 1930, 1960, 1970, 1980 and today, May 1994.

Comparative neuropsychology involves the study of brain-behavior relationships by applying experimental paradigms, used extensively in animal laboratories, for testing human clinical populations. Popular paradigms include delayed reaction tasks, discrimination and reversal learning tasks, and matching- and nonmatching-to-sample. Such tasks were perfected on experimental animals having well defined brain lesions, and adapted for the sensory and motor capabilities of human neurological patients. By holding task requirements constant for human and nonhuman primates, analogous measures can be made of neurobehavioral deficits associated with specific brain damage. Human and nonhuman primates solve many so-called animal-learning tasks, in similar ways. Moreover, many tasks, despite their apparent simplicity, already have proven to be sensitive to cognitive impairments after brain damage in humans and nonhumans alike. An important advantage of using paradigms from comparative neuropsychology, in conjunction with standard clinical neuropsychological assessments, is that the simplicity of the tasks makes them manageable for patients with severe cognitive impairments. In addition, since the tasks do not require linguistic strategies for performance, the problems can be solved by patients whose language skills are compromised. An example of the application of comparative neuropsychology to clinical populations is given: patients with a history of long term alcohol abuse were tested on delayed reaction paradigms, and the findings have been useful in clarifying the contribution of damaged frontal cortical-subcortical brains systems to their cognitive impairments.

Alcohol affects the liver through metabolic disturbances associated with its oxidation. Redox changes produced by the hepatic alcohol dehydrogenase pathway affect lipid, carbohydrate and protein metabolism. Ethanol is also oxidized in liver microsomes by the ethanol-inducible cytochrome P4502E1, resulting in ethanol tolerance and selective hepatic perivenular damage. Furthermore, P4502E1 activates various xenobiotics, explaining the increased susceptibility of the heavy drinker to the toxicity of anesthetics, commonly used medications (i.e. isoniazid), analgesics (i.e. acetaminophen), and chemical carcinogens. Induction of microsomal enzymes also contributes to vitamin A depletion, enhances its hepatotoxicity and results in increased acetaldehyde generation from ethanol, with formation of protein adducts, glutathione depletion, free-radical-mediated toxicity, and lipid peroxidation. Chronic ethanol consumption strikingly enhances the number of hepatic collagen-producing activated lipocytes. Both in vivo (in our baboon model of alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and activated lipocytes) ethanol and/or its metabolite acetaldehyde increase collagen accumulation and mRNA for collagen. Gender differences are related, in part, to lower gastric ADH activity (with consequent reduction of first pass ethanol metabolism) in young women, decreased hepatic fatty acid binding protein and increased free-fatty acid levels as well as lesser omega-hydroxylation, all of which result in increased vulnerability to ethanol. Elucidation of the biochemical effects of ethanol are now resulting in improved therapy: in baboons, S-adenosyl-L-methionine attenuates the ethanol-induced glutathione depletion and associated mitochondrial lesions, and polyenylphosphatidylcholine opposes the ethanol-induced hepatic phospholipid depletion, the decrease in phosphatidylethanolamine methyltransferase activity and the activation of hepatic lipocytes, with full prevention of ethanol-induced septal fibrosis and cirrhosis; its dilinoleoyl species also increases collagenase activity in lipocytes. The efficacy of this compound in man is now being studied in randomized multicenter clinical trials.

Alcoholic liver disease evolves from fatty change through alcoholic hepatitis to alcoholic cirrhosis. Its development is associated with an excess mortality both in relation to the presence of liver disease and to other complications of alcohol abuse. In the majority of patients fatty liver is a benign lesion which will reverse completely following abstinence from alcohol. Continued drinking is associated with the eventual development of cirrhosis in approximately 20% of individuals. Survival rates of 70% are reported both at 2 years and at 10 years. Alcoholic hepatitis is a precirrhotic lesion; progression to cirrhosis is observed more commonly in women, in individuals with severe disease and in those who continue to drink. Thirty-day mortality rates of less than 20% are observed in patients with mild to moderate disease but exceed 40% in individuals with severe liver injury. Corticosteroids may improve short term survival in a small subgroup of patients with severe alcoholic hepatitis. Survival rates of 55 to 60% are reported both at 2 years and at 10 years. Survival is significantly reduced in women and in the elderly and is adversely affected by the presence of severe liver injury, evolution to cirrhosis and continued drinking. Two-thirds of patients with alcoholic cirrhosis present with decompensated disease; 15% will develop hepatocellular carcinoma. Survival rates at 5 years vary from zero to 80%; 60 to 90% of individuals die of their liver disease. Survival is adversely affected by the presence of decompensated disease, superimposed alcoholic hepatitis, continued drinking and the development of hepatocellular carcinoma. The advent of hepatic transplantation, which has a 5-year survival rate in excess of 70%, will influence these survival figures.