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Biomedical subjects

I Diamond

Publications and source records attributed to I Diamond.

At least 73 records · Page 4Linked to original sources
PubMed1991

The role of adenosine and adenosine transport in ethanol-induced cellular tolerance and dependence. Possible biologic and genetic markers of alcoholism.

Acute exposure to ethanol in culture inhibits adenosine uptake into cells, thereby increasing the concentration of extracellular adenosine. Extracellular adenosine then reacts with adenosine A2 receptors to stimulate intracellular cAMP production. During prolonged exposure to ethanol, the increase in cAMP is followed by the development of heterologous desensitization of receptors coupled to adenylyl cyclase via Gs, the stimulatory GTP-binding protein. Ethanol-induced heterologous desensitization appears to be due to a reduction in mRNA and protein for G alpha s, a subunit of Gs. This is an example of cellular dependence on ethanol. The important implication of these findings is that a selective inhibitory effect of ethanol on adenosine uptake can lead to desensitization of diverse receptors coupled to cAMP production. Such changes could contribute to the pleiotropic effects of ethanol in the brain and other organs. Prolonged exposure to ethanol also alters the nucleoside transport system. While ethanol inhibits adenosine uptake into naive cells, ethanol no longer inhibits adenosine uptake into cells that have adapted to ethanol. This resistance to ethanol inhibition appears to be a form of cellular tolerance to ethanol. Thus, there appears to be a synergism between ethanol-induced heterologous desensitization of receptor-stimulated cAMP production (cellular dependence) and resistance to ethanol inhibition of adenosine uptake (cellular tolerance), because both lead to reduced intracellular levels of cAMP. Our studies on cAMP signal transduction in cell culture are directly relevant to the pathophysiology of human alcoholism. Heterologous desensitization of cAMP production is demonstrable in lymphocytes taken from actively drinking alcoholics; this measurement appears to be a biologic marker of active alcohol consumption. In addition, regulation of adenosine receptor-dependent cAMP production may be altered in patients at risk to develop alcoholism because of genetic factors. Thus, lymphocytes from alcoholics cultured many generations in the absence of ethanol show increased adenosine receptor-dependent cAMP production and increased sensitivity to ethanol-induced heterologous desensitization. These persistent phenotypic abnormalities in cell culture could be used as genetic markers for alcoholism. Studies are under way to test this possibility.

Adenosine↗
PubMed1991

cAMP-dependent protein kinase regulates inhibition of adenosine transport by ethanol.

Ethanol inhibits adenosine uptake, thereby increasing the concentration of extracellular adenosine. Elevation of extracellular adenosine increases intracellular cAMP concentration via activation of adenosine A2 receptors. Extracellular adenosine is also required for the subsequent development of ethanol-induced heterologous desensitization. Here we report that activation of cAMP-dependent protein kinase is necessary for inhibition of adenosine uptake by ethanol and for the consequent accumulation of extracellular adenosine. Ethanol does not inhibit adenosine uptake in mutants of the S49 cell line that lack receptor-stimulated cAMP production (unc cells) or cAMP-dependent protein kinase activity (kin- cells). Forskolin, which bypasses the receptor-coupling defect in unc cells to increase cAMP levels, restores inhibition of adenosine uptake by ethanol. In contrast, in kin- cells forskolin did not restore inhibition of adenosine uptake by ethanol, despite similar increases in cAMP levels. Taken together, these results suggest that cAMP-dependent protein kinase phosphorylates a component of the nucleoside transporter, thereby regulating the sensitivity of adenosine transport to ethanol.

Adenosine↗
PubMed1990

Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter.

Chronic exposure to ethanol results in heterologous desensitization of receptors coupled to adenylyl cyclase via Gs, the stimulatory guanine nucleotide regulatory protein. Ethanol-induced accumulation of extracellular adenosine is required for the development of heterologous desensitization (Nagy, L. E., Diamond, I., Collier, K., Lopez, L., Ullman, B., and Gordon, A. S., Mol. Pharmacol., in press). To understand the mechanism underlying ethanol-induced increases in extracellular adenosine, we examined the interaction of ethanol with the adenosine transport system in S49 lymphoma cells. We found that ethanol inhibited nucleoside uptake without affecting deoxyglucose or isoleucine transport. Inhibition of adenosine uptake was due to decreased influx via the nucleoside transporter. Thus, ethanol-induced increases in extracellular adenosine appear to be due to inhibition of adenosine influx. After chronic exposure to ethanol, cells became tolerant to the acute effects of ethanol, i.e. ethanol no longer inhibited uptake. Consequently, ethanol no longer increased extracellular adenosine concentrations. Taken together with our previous studies, these results suggest that ethanol inhibition of adenosine influx leads to an increase in extracellular adenosine which causes an initial increase in intracellular cAMP levels and subsequent development of heterologous desensitization of cAMP signal transduction.

Adenosine↗
PubMed1990

The uses and users of population projections in Australia.

"It is widely recognized that population projections are increasingly used in formulating policy in many public and private sectors. However, little information exists on the nature of the projections or their users. This paper reports the results of a survey conducted to rectify this situation. The results confirm that the applications of projections are very broad and that the prime area of increase has been in small-area projections. At this level many users make their own projections rather than use official projections and the paper reviews the methodology used to make these projections. A number of suggestions are made for improving communication between national and subnational producers and local users." The geographical focus is on Australia.

Australia↗
PubMed1990

Chronic ethanol-induced heterologous desensitization is mediated by changes in adenosine transport.

Chronic exposure of cultured cell lines to ethanol results in a heterologous desensitization of receptors coupled to adenylate cyclase via GS, the stimulatory guanine nucleotide regulatory protein. This heterologous desensitization is accompanied by a decrease in alpha S, the GTP-binding subunit of GS. Ethanol-induced accumulation of extracellular adenosine is required for the development of heterologous desensitization. To determine the mechanism underlying the ethanol-dependent increase in extracellular adenosine, we investigated the effects of ethanol on the nucleoside transporter responsible for the bidirectional transport of adenosine into and out of the cell. We found that ethanol specifically and non-competitively inhibited nucleoside uptake. Inhibition of adenosine uptake was primarily due to decreased influx via the nucleoside transporter. Thus, ethanol-induced increases in extracellular adenosine appear to be due to inhibition of adenosine influx. After chronic exposure to ethanol, cells became tolerant to the acute effects of ethanol, i.e. ethanol no longer inhibited uptake and, consequently, no longer increased extracellular adenosine concentration. Taken together with our previous studies, these results suggest that acute ethanol inhibition of adenosine influx leads to an increase in extracellular adenosine which in turn activates adenosine A2 receptors to increase cyclic AMP levels, leading to desensitization of receptor-dependent cyclic AMP signal transduction after chronic exposure to ethanol. We next determined whether the same effects of ethanol also occur in alcoholics. We isolated lymphocytes from alcoholics and non-alcoholics and found that alcoholics had a 75% decrease in basal and adenosine receptor-stimulated cyclic AMP production compared with non-alcoholics. To determine whether these differences were due to exposure to ethanol in vivo or to a possible genetic difference between alcoholics and non-alcoholics, we grew lymphocytes in culture in the absence of ethanol. Adenosine receptor-stimulated cyclic AMP levels were higher in alcoholics than non-alcoholics. Moreover, cultured cells from alcoholics were more sensitive to the effects of chronic alcohol on cyclic AMP signal transduction than cells from non-alcoholics. Our results suggest that the cyclic AMP signal transduction system may reflect a genetic alteration in alcoholics and that studies in cultured lymphocytes may allow us to identify individuals at risk of developing alcoholism.

Adenosine↗
PubMed1990

Maternal education and child immunization.

This article explores the hypothesis that formal education of women results in increased child survival because of greater knowledge of the protective function of the major childhood immunizations. Education is also associated with greater awareness of proper immunization schedules. Irrespective of mother's formal education level, specific immunization knowledge is associated with an increased likelihood of using immunization. The Indonesian analysis is important as a model for preventive health campaigns among other populations with low education levels among women.

Adult↗
PubMed1989

Personality profile and affective state of patients with inflammatory bowel disease.

The Eysenck Personality Inventory and Hospital Anxiety and Depression scale were administered to 80 patients undergoing medical treatment for long standing inflammatory bowel disease: 22 patients were studied before the diagnosis was established and 40 patients with diabetes mellitus served as controls. High neuroticism and introversion scores were more prevalent in the patients with inflammatory bowel disease than controls (p less than 0.05) and these characteristics were as prominent in patients before diagnosis as in established cases. Introversion scores increased with the duration of disease (r = 0.51). Depression was uncommon, occurring only in patients with active chronic disease. Patients believed there was a close link between personality, stress and disease activity. Fifty six of the patients recognised factors that initiated the disease and in 42 this was thought to be a stressful life event or a 'nervous personality'.

Affect↗
PubMed1989

Adenosine is required for ethanol-induced heterologous desensitization.

Recent evidence suggests that ethanol initially causes an increase in receptor-dependent cAMP levels, followed by heterologous desensitization of receptors coupled to GS after chronic exposure. Here we investigated the role of adenosine in mediating these responses. We found that ethanol caused accumulation of extracellular adenosine in NG108-15 and S49 lymphoma cells. This adenosine activated adenosine receptors to increase intracellular cAMP levels. The addition of adenosine deaminase, to degrade accumulated extracellular adenosine, or isobutyl-methylxanthine, an adenosine receptor antagonist, completely blocked ethanol-induced increases in cAMP levels in NG108-15 cells. Chronic exposure of NG108-15 and S49 wild type cells to ethanol resulted in heterologous desensitization of adenosine receptor- and prostaglandin E1 receptor-dependent cAMP signal transduction. Coincubation of NG108-15 and S49 wild type cells with adenosine deaminase and ethanol for 48 hr prevented heterologous desensitization. Moreover, mutant S49 cells, which are unable to transport adenosine, did not accumulate extracellular adenosine after incubation with ethanol and did not develop ethanol-induced heterologous desensitization. Our results suggest that adenosine is an important mediator of both the acute and chronic effects of ethanol on cAMP signal transduction.

Adenosine↗
PubMed1988

Chronic ethanol causes heterologous desensitization of receptors by reducing alpha s messenger RNA.

One of the biochemical results of ethanol exposure is a change in the amount of the intracellular second messenger cyclic AMP (cAMP) produced in response to receptor stimulation. In general, acute ethanol exposure increases the amount of cAMP produced on stimulation of receptors coupled to the enzyme adenylyl cyclase via the GTP-binding protein Gs, whereas chronic ethanol exposure has the opposite effect (results for receptors coupled via Gi have been more variable). We previously reported that adaptation to continuous ethanol exposure reduces receptor-stimulated cAMP production by 25-35% in a neuroblastoma cell line (NG108-15), and an even greater reduction of 75% was observed in lymphocytes taken from actively-drinking alcoholics. This reduction in receptor-stimulated cAMP levels was recently confirmed in platelets from alcoholics. None of these studies, however, determined whether more than one receptor coupled to adenylyl cyclase activity was affected in the same cell. Here we report that chronic ethanol exposure causes desensitization of heterologous receptors coupled to Gs as cAMP production mediated by prostaglandin E1 as well as by adenosine is reduced by approximately 30% in NG108-15 cells. We show that, after chronic ethanol exposure, the activity of the alpha subunit of Gs is decreased by 29%, the amount of alpha s protein is decreased by 38.5%, and alpha s messenger RNA is decreased by 30%. Thus, cellular adaptation to ethanol involves a reduction in alpha s mRNA and, as a consequence, reduced cAMP production by heterologous receptors coupled to Gs. Such changes in cAMP production may account for the tolerance and physical dependence on ethanol in alcoholism.

Cyclic AMP↗
PubMed1988

Cultured lymphocytes from alcoholic subjects have altered cAMP signal transduction.

Previous work has shown that freshly isolated lymphocytes from alcoholic subjects show significantly reduced basal and adenosine receptor-stimulated cAMP levels. This decrease could be due to ethanol-induced cellular adaptation or to a genetic difference in the regulation of cAMP signal transduction. Therefore, we cultured human lymphocytes in defined medium without ethanol for 7-8 days and then examined differences in receptor-dependent cAMP accumulation between lymphocytes from alcoholic and nonalcoholic subjects. After four to six generations in culture without ethanol, lymphocytes from alcoholic subjects have significantly higher cAMP levels than do cells from nonalcoholic subjects. Thus, a difference in cAMP signal transduction is demonstrable in cells from alcoholic subjects grown without ethanol. We also found that cultured lymphocytes from both alcoholic and nonalcoholic subjects show a decrease in receptor-stimulated cAMP levels after exposure to 200 mM ethanol for 48 hr. To determine whether alcoholic subjects have increased sensitivity to ethanol, lymphocytes were exposed to only 100 mM ethanol for 24 hr. Under these conditions, receptor-dependent cAMP levels did not change in cells from nonalcoholic subjects. However, lymphocytes from alcoholic subjects showed a 39% decrease (P less than 0.003) in adenosine receptor-stimulated cAMP levels. Taken together, the results show that (i) chronic ethanol treatment in culture reproduces the suppression of cAMP levels found in circulating lymphocytes from alcoholic subjects and (ii) despite four to six cell divisions in culture without ethanol, lymphocytes from alcoholic subjects exhibit significantly increased adenosine receptor-dependent cAMP levels and increased sensitivity to chronic exposure to ethanol. These findings suggest that the suppression of cAMP levels observed in freshly isolated lymphocytes from alcoholic subjects results from both a direct effect of chronic exposure to ethanol and a genetic difference leading to altered cAMP signal transduction.

Adenosine Deaminase↗
PubMed1987

Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients.

Alcoholism causes serious neurologic disease that may be due, in part, to the ability of ethanol to interact with neural cell membranes and change neuronal function. Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the brain. Human lymphocytes also have adenosine receptors, and their activation causes increases in cAMP levels. To test the hypothesis that basal and adenosine receptor-stimulated cAMP levels in lymphocytes might be abnormal in alcoholism, we studied lymphocytes from 10 alcoholic subjects, 10 age- and sex-matched normal individuals, and 10 patients with nonalcoholic liver disease. Basal and adenosine receptor-stimulated cAMP levels were reduced 75% in lymphocytes from alcoholic subjects. Also, there was a 76% reduction in ethanol stimulation of cAMP accumulation in lymphocytes from alcoholics. Similar results were demonstrable in isolated T cells. Unlike other laboratory tests examined, these measurements appeared to distinguish alcoholics from normal subjects and from patients with nonalcoholic liver disease. Reduced basal and adenosine receptor-stimulated levels of cAMP in lymphocytes from alcoholics may reflect a change in cell membranes due either to chronic alcohol abuse or to a genetic predisposition unique to alcoholic subjects.

Adult↗
PubMed1986

Ethanol increases the expression of functional delta-opioid receptors in neuroblastoma x glioma NG108-15 hybrid cells.

Ethanol inhibits opioid peptide binding to the delta-opioid receptor. When neuroblastoma x glioma NG108-15 hybrid cells are grown with 25-200 mM ethanol, opioid receptor density increases up to 2-fold without a change in receptor affinity. Since changes in neurotransmitter receptor density may be important in neuronal adaptations to ethanol, we investigated the underlying mechanisms and functional consequences of this phenomenon. The opiate antagonist, naloxone, also increased opioid receptor number, but produced a smaller effect than ethanol with greater fractional inhibition of binding; long term enhancement of binding by ethanol is therefore not a simple function of acute receptor inhibition. Ethanol did not inhibit receptor down-regulation by etorphine, an opiate agonist, and therefore is not likely to increase receptor expression through interference with tonic down-regulation by endogenous opioid peptides. Ethanol increased opioid receptor expression in NG108-15 cells treated with actinomycin D, but not cycloheximide; hence, normal protein synthesis, but not DNA transcription, may be required for this response. The opioid receptors induced in ethanol-treated cells were subject to normal up-regulation by naloxone, down-regulation by etorphine, and acute inhibition of agonist binding by Na+. Etorphine maximally inhibits cyclic AMP accumulation in NG108-15 cells with only fractional occupancy of opioid receptors. Chronic ethanol exposure increased the receptor reserve for this response, resulting in a 3.5-fold increase in the potency of etorphine for inhibiting phenylisopropyladenosine-stimulated cyclic AMP accumulation. Neuronal adaptation to ethanol may involve changes in the density of receptors that regulate cellular levels of cyclic AMP.

Cell Line↗