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D M Goldberg

Publications and source records attributed to D M Goldberg.

At least 19 recordsLinked to original sources
PubMed1997

Genetic markers of alcohol abuse.

In this paper, we review the current status of genetic markers for the development of alcohol abuse. Family, twin, half-sibling and adoption studies of alcoholic subjects suggest that the heritability of liability to alcoholism is at least 50%. These findings have fuelled intensive investigation in the fields of neurology, biochemistry, genetics and molecular biology aimed at the identification of markers for the risk of alcoholism. The most promising of these are discussed in detail. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) polymorphisms, specifically the ADH3*1, ADH2*2, and ALDH2*2 genotypes appear to confer a protective effect against alcoholism, most notably in Oriental subjects. Caucasian alcohol abusers and their first-degree relatives exhibit depressed platelet monoamine oxidase activity, the degree of which is greater in Type II than Type I alcoholics. Electrophysiological characteristics of alcoholics and those at risk for developing alcoholism have also been identified, including the reduced amplitude of the event-related brain potential and, after ethanol ingestion, characteristic EEG alpha-wave activity. Lower platelet adenylate cyclase activity is seen in alcoholics compared to controls, presumably as a result of over-expression of an inhibitory G-protein. Markers related to other signal transduction pathways of the central nervous system including the serotoninergic, muscarinic and dopaminergic systems are also discussed. In this group of markers, the putative association between the inheritance of the AI allele of the D2 dopamine receptor and the susceptibility to alcoholism provides the most dramatic illustration of the challenges presently existing in this field of scientific investigation. Current limitations in the definition, diagnosis and classification of alcoholism, the confounding influences of race and gender on association studies, as well as the statistical approach of linkage studies are discussed as they relate to the endeavor to uncover valid genetic markers for the risk of alcoholism.

Alcoholism↗
PubMed1997

Resveratrol: a molecule whose time has come? And gone?

OBJECTIVES: Resveratrol (3,5,4'-trihydroxystilbene) is the parent compound of a family of molecules, including glucosides and polymers, existing in cis and trans configurations in a narrow range of spermatophytes of which vines, peanuts and pines are the prime representatives. Its synthesis from p-coumaroyl CoA and malonyl CoA is induced by stress, injury, infection or UV-irradiation, and it is classified as a phytoalexin anti-fungicide conferring disease resistance in the plant kingdom. RESULTS: In vitro, ex vivo and animal experiments have shown that it possesses many biological attributes that favour protection against atherosclerosis, including antioxidant activity, modulation of hepatic apolipoprotein and lipid synthesis, inhibition of platelet aggregation as well as the production of pro-atherogenic eicosanoids by human platelets and neutrophils. Red wine represents its main source in the human diet, and it has been proposed as a major constituent of the polyphenol fraction to which the health benefits of red wine consumption have been attributed. CONCLUSIONS: The past several years have witnessed intense research devoted to its measurement in wine and the factors likely to promote its enrichment in this beverage. Up to the present, conclusive evidence for its absorption by human subjectsin biologically significant amounts is lacking, and it is questionable (but not yetexcluded) that its powerful and beneficial in vitro activities are reproduced as a consequence of sustained moderate red wine consumption.

Acyltransferases↗
PubMed1997

Biochemical tests in diseases of the intestinal tract: their contributions to diagnosis, management, and understanding the pathophysiology of specific disease states.

Biochemical testing plays a major role in the complete evaluation of patients with suspected or established intestinal disease. We have classified these tests according to the medium in which they are performed: breath tests, including isotopic and nonisotopic tests, fecal tests, urine tests, serum tests, tissue tests, and other tests. The principles of various tests are outlined, and the role of each test in the evaluation of particular gastrointestinal disorders is discussed.

Biochemistry↗
PubMed1997

Wine as a biological fluid: history, production, and role in disease prevention.

Wine has been part of human culture for 6,000 years, serving dietary and socio-religious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high-density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl-CoA derivatives. Polymeric aggregation gives rise, in turn to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low-density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo-oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signalling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans.

Animals↗
PubMed1996

Method to assay the concentrations of phenolic constituents of biological interest in wines.

We describe a reversed-phase HPLC method that uses gradient elution and diode array detection to quantitate eight biologically active phenolic constitutions of wine: the cis and trans isomers of resveratrol and their glucosides, catechin, epicatechin, quercetin, and rutin. ODS Hypersil served as the stationary phase; the gradient was formed by acetic acid, methanol and water. Each analysis required an equilibration period of ten minutes and a run time of fourty minutes for completion. Satisfactory peak resolution was achieved following direct injection of a 20-muL sample, and validation was accomplished by on-line spectral comparisons with known standards. Excellent linearity was obtained for all constituents, and the detection limits ranged from 30 mug/L (trans-resveratrol) to 1.5 mg/L (catechin). Recoveries approximated 100% range (95.2-105.5%), and the method provided good precision, with coefficients of variation between 1.17 and 3.38%. All of the phenolics measured were reasonably stable in opened wines protected against sunlight for up to 1 week at room temperature or 4 degrees C, but most showed losses of 10-40% when stored for 6 weeks at either temperature.

Antioxidants↗
PubMed1996

Wine: does the colour count?

The objective of this study was to determine whether phenolic constituents present in red wine and grape juice modulate plasma lipid and lipoprotein concentrations in healthy human subjects. All subjects consumed in random order 375 ml of red or white wine per day or 500 ml of two different grape juices (high and low phenols) per day for periods of 4 weeks separated by 2-week periods of abstention while continuing normal activity and food intake, and their normal lives in a community setting. The subjects were 24 healthy males aged 26-45 years screened by clinical examination and laboratory tests to exclude hypertension, diabetes mellitus, hyperlipidemia and obesity, among others. Fasting blood was collected at the beginning and end of each beverage schedule for analysis of lipids and lipoproteins. Changes in plasma lipids and lipoproteins in response to each beverage were measured to determine whether these were altered by red wine and grape juice phenolics independently of the effects of ethanol. Both grape juices had virtually no effect. Red and white wines raised plasma HDL-cholesterol and apo A-I and apo A-II concentrations as well as the apo A-I:apo B ratio to a similar extent. Red wine also raised plasma triglyceride and total cholesterol concentrations. Neither wine affected plasma apo B or apo (a) concentrations. The favourable effects of wines in modulating plasma lipid and lipoprotein concentrations are probably due to their alcohol content and cannot be reproduced by grape juices.

Adult↗
PubMed1996

Wines and grape juices as modulators of platelet aggregation in healthy human subjects.

To test the hypothesis that red wine, by virtue of its relatively high concentration of polyphenols, is more protective against atherosclerosis and coronary heart disease (CHD) than white wine, and that grape juice enriched in one of these, trans-resveratrol, may share some of these properties, studies were performed on 24 healthy males aged 26-45 years. Each consumed the following beverages for periods of 4 weeks: red wine, white wine, commercial grape juice and the same grape juice enriched with trans-resveratrol. Apart from the last beverage, 2 weeks abstinence was maintained before commencing the schedule. Blood was taken at the beginning and end of each schedule to determine plasma thromboxane B2 (TxB2) concentration and the IC50 (concentration required for 50% aggregation) for ADP and thrombin-induced platelet aggregation. White wine (P < 0.05) but not red wine increased the IC50 for ADP. Both wines increased the IC50 for thrombin (P < 0.02 and P < 0.001, respectively) and also lowered plasma TxB2 concentrations (P < 0.01 and P < 0.025, respectively). Neither grape juice altered ADP-induced aggregation or TxB2 concentrations, but the commercial juice lowered the IC50 for thrombin (P < 0.001) whereas the resveratrol-enriched juice caused a dramatic increase (P < 0.001). In vitro experiments demonstrated that the aggregation of fresh washed human platelets by ADP and thrombin was moderately reduced by both grape juices, strongly by red wine and not at all by white wine. The synthesis of TxB2 by platelets from labelled arachidonate was stimulated by commercial grape juice, slightly enhanced by resveratrol-enriched juice and strongly inhibited by red wine with white wine having little effect. Platelets from subjects consuming the commercial juice had a higher ratio of cyclo-oxygenase to lipoxygenase product formation and those consuming the resveratrol-enriched juice a lower ratio than during the control period. We conclude that trans-resveratrol can be absorbed from grape juice in biologically active quantities and in amounts that are likely to cause reduction in the risk of atherosclerosis. The failure of red wines (which have a 20-fold excess of polyphenols over white wines) to show any advantage suggests that, in vivo, ethanol is the dominant anti-aggregatory component in these beverages which are more potent than grape juices in preventing platelet aggregation in humans.

Adult↗
PubMed1995

Beyond alcohol: beverage consumption and cardiovascular mortality.

This paper reviews epidemiological investigations which have identified an inverse relationship between alcohol consumption and death from coronary heart disease: evidence from studies of mixed populations as well as of single-sex populations have, on the whole, demonstrated that this relationship is independent of sex or age. This 'cardioprotective effect' of alcohol can be explained, at least in part, by ethanol-related increases in high density lipoprotein cholesterol and reduced platelet coagulability. With certain beverages, especially red wine, phenolic compounds may provide additional protection by altering eicosanoid metabolism in favour of increased prostacyclin and decreased thromboxane synthesis, as well as antioxidant functions which prevent the peroxidation of low-density lipoprotein. Trans-resveratrol, a tri-hydroxy stilbene present in the skins of specific grape cultivars, is a constituent of certain red wines which may play a crucial role in modulating lipoprotein metabolism, eicosanoid synthesis, oxidation and coagulation. Preliminary studies using the human hepatoma cell line HepG2 are described, demonstrating that this compound has no effect upon cell viability or overall protein synthesis in these cells, and at high concentrations DNA synthesis as measured by radioactive thymidine incorporation is enhanced. Reduced intracellular concentration and secretion of apolipoprotein B have been shown to occur in response to resveratrol although a clear dose-dependency has not yet been demonstrated. The mechanisms underlying these changes as well as the effects upon the synthesis and secretion of other apolipoproteins are under active investigation in our laboratory.

Alcohol Drinking↗
PubMed1995

The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease.

A number of lines of evidence suggest that red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease (CHD) mortality. This protection over and above that due to ethanol itself may be explained by phenolic components with which red wines are richly endowed. We have studied the effects of the trihydroxy stilbene trans-resveratrol on human platelet aggregation and on the synthesis of three eicosanoids from arachidonate by platelets, i.e. thromboxane B2 (TxB2), hydroxyheptadecatrienoate (HHT) and 12-hydroxyeicosatetraenoate (12-HETE). These effects were compared with the actions of other wine phenolics (quercetin, catechin and epicatechin) and antioxidants (alpha-tocopherol, hydroquinone and butylated hydroxytoluene). trans-Resveratrol and quercetin demonstrated a dose-dependent inhibition of both thrombin-induced and ADP-induced platelet aggregation, whereas ethanol inhibited only thrombin-induced aggregation. The other compounds tested were inactive. trans-Resveratrol also inhibited the synthesis of TxB2, HHT, and to a lesser extent 12-HETE, from arachidonate in a dose-dependent manner. Quercetin inhibited only 12-HETE synthesis, and hydroquinone caused slight inhibition of TxB2 synthesis, the remaining compounds being ineffective. De-alcoholized red wines inhibited platelet aggregation; their ability to inhibit the synthesis of TxB2 but not that of 12-HETE from labelled arachidonate by washed human platelets was proportional to their trans-resveratrol concentration. These results are consistent with the notion that trans-resveratrol may contribute to the presumed protective role of red wine against atherosclerosis and CHD.

Arteriosclerosis↗
PubMed1995

Factors affecting the regulation of apo B secretion by liver cells.

The concentration of apo B is an important risk factor for atherosclerosis, and thus its reduction is associated with a reduction in CHD mortality. In order to reduce apo B concentrations effectively, we must understand how plasma apo B concentration is regulated. Apo B is synthesized, assembled, and secreted by the liver, controlling this process will reduce the number of particles that eventually enter the plasma compartment. The assembly of apo B into a VLDL particle is a complex process which occurs through several stages: peptide synthesis, translocation, accumulation of lipid, and transport through the secretory pathway. Multiple control points regulate the synthesis and secretion of apolipoproteins. Modulation of transcription, translation and intracellular degradation represent independent regulatory mechanisms. The ability of the lipoprotein to bind cotranslationally to lipid appears to be crucial to the formation of a secreted particle. This process may be regulated solely by MTP, or may be modified by the activity of the lipid-synthesizing enzymes. A great deal of evidence supports the role of TG and CE synthesis, although the relative importance of these two lipids is a source of major controversy. In summary, all the lipoprotein components can be limiting for apo B and VLDL synthesis when their availability is substantially decreased. The rate-limiting component in vivo has still not been identified. By understanding how lipoprotein synthesis and assembly are regulated, it should become possible to design new ways of altering these processes in a beneficial manner.

Animals↗
PubMed1995

Does wine work?

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Antioxidants↗
PubMed1994

Education in clinical biochemistry: the Canadian scene.

The Canadian Health Care System is operated governmentally at the provincial level although the costs and benefits are similar in every province. Most physicians are remunerated on the 'charge per service' basis, but laboratory physicians (including medical biochemists) are among the few who are remunerated by salary. The training of medical biochemists is regulated by the Royal College of Physicians and Surgeons of Canada by means of a residency program of 4 years duration, following graduation from medical school and completion of the required internship. The training of clinical biochemists, whose functions overlap many of those attributable to medical biochemists, is regulated by the recently created Canadian Academy of Clinical Biochemistry through a certification process incorporating written and oral examinations approximately 1 year apart. Recognized and accredited training programs for clinical biochemists exist in several medical schools: these courses are of 2 (occasionally 3) years duration and entry to these programs requires a Ph.D. and, preferably, some post-graduate research experience. Details of both medical and clinical biochemistry training programs reveal a difference in emphasis and duration rather than in course content, with medical trainees required to spend at least 1 of their 4 training years in clinical disciplines relevant to the practise of biochemistry.

Biochemistry↗
PubMed1994

The effects of sertraline on nicotine self-administration and food-maintained responding in squirrel monkeys.

Recent reports suggested the involvement of serotonergic mechanisms in nicotine self-administration. The present study assessed the effects of sertraline, a selective serotonergic uptake inhibitor, on the reinforcing effects of i.v. nicotine (30 microgram/kg per injection) in squirrel monkeys responding under a fixed-ratio schedule. Nicotine (10-100 micrograms/kg per injection) produced a significant inverted U-shaped distribution on FR rate. Vehicle or sertraline (3, 6, 12, 24 mg/kg, p.o.) produced no changes in the response rates maintained by 30 micrograms/kg per injection i.v. nicotine, but sertraline produced non-significant increases response rates maintained by 10 micrograms/kg per injection nicotine and vehicle. In a separate group of monkeys, sertraline given in combination with i.m. doses of nicotine produced a significant dose-dependent decrease in responding maintained by food-pellet delivery. Thus, sertraline produced differential effects on response rates that may be related to (1) route of nicotine administration and (2) whether the behavior was maintained by nicotine or food. In addition, the results of the self-administration study suggest that sertraline would not disrupt well-maintained responding for nicotine.

1-Naphthylamine↗
PubMed1994

Enzymes and circulating proteins as markers of alcohol abuse.

The identification of alcohol abuse is an important social and clinical objective for which various biochemical procedures have been utilized, serum enzymes and circulating proteins being predominant. Tests are required to detect alcohol abuse as screening procedures in the general population as well as for the specific diagnosis of those presenting as hospital inpatients or outpatients, especially when liver disease is present or suspected. The amino-transferases are of limited value, although the mitochondrial isoenzyme of aspartate amino-transferase has been strongly advocated and is quite useful in detecting alcoholics among patients with liver disease. Gammaglutamyl transferase, by contrast, is raised in all forms of liver disease but can identify 30-50% of those consuming excessive amounts of alcohol before organic damage becomes manifest. Serum carbohydrate-deficient transferrin (CDT) is raised in many alcohol abusers without and most with liver damage, but is rarely elevated in other forms of liver disease. Haemoglobin-associated acetaldehyde, the newest biochemical index to be evaluated in alcoholics, is one of several adducts formed by the reaction of acetaldehyde with various proteins, and antibodies to these adducts may contribute, at least in part, to immunological tissue damage provoked by chronic excessive consumption of alcohol. Its assay is technically complex and it appears to be present in higher concentrations in heavy drinkers than in those who fulfill the criteria of addictive alcohol abuse. Many other markers have been introduced in the last decade but the search for a reliable index continues. CDT comes closest at the present time to matching the desired specificity, although it is of limited value in screening unselected non-hospitalized subjects.

Acetaldehyde↗
PubMed1993

Biochemical tests in the diagnosis of chronic pancreatitis and in the evaluation of pancreatic insufficiency.

Chronic pancreatitis (adults) and cystic fibrosis (children) are the most common diseases leading to exocrine pancreatic insufficiency that, when reduced to < 5% of normal function, is characterised by steatorrhoea. The pathogenesis of the former condition is outlined, and recent concepts are emphasized. Biochemical tests to detect pancreatic insufficiency and to identify pancreatic disease as the cause of steatorrhoea include: serum enzyme tests (lipase, amylase, trypsin); stool chymotrypsin; isotopic tests based upon the assimilation of [14C] lipids and starch or excretion of the isotope as breath CO2, as well as the dual-labelled Schilling test; oral function tests utilising substrates hydrolysed by pancreatic enzymes such as benzoyl tyrosyl-p-aminobenzoic acid and fluorescein dilaurate; and duodenal intubation studies following meal-induced or hormonal stimulation of the pancreas. The rationale for these tests and the cumulative clinical experience of their utility are reviewed. A recommended diagnostic strategy is briefly presented. The role of various biochemical procedures to evaluate the efficacy of pancreatic enzyme replacement therapy is also described.

4-Aminobenzoic Acid↗