Health effects of moderate alcohol consumption: a paradigmatic risk factor.
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Alcohol Drinking↗
Biomedical subjects
D M Goldberg
Publications and source records attributed to D M Goldberg.
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↗
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↗
More on antioxidant activity of resveratrol in red wine.
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Aged↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Models of neoplasia and their diagnostic implications: a historical perspective.
In comparison with normal cells, cancer cells have an enhanced ability to trap both nitrogen and energy; an enhanced operation of the glycolytic and direct oxidative pathways, leading to accumulation of lactate and increased production of NADPH; and a greater content of lysosomal hydrolases. These changes represent a reprogramming of gene expression, which, at its most specific, is accompanied by the reappearance in the cell and ultimately in the body fluids of oncodevelopmental proteins not normally found in mature adult tissues. The most florid stage of this reprogramming leads to the metastatic phenotype, which confers upon the cancer cell the ability to stimulate angiogenesis, invade the bloodstream and lymphatic vessel, and arrest and proliferate in distant tissues. The diagnostic implications of these phenotypic changes are illustrated for cancer of the cervix uteri and cancer of the colon. We also review the classical theories of neoplasia, including the cellular anoxia concept of Warburg, the deletion hypothesis of Potter, and various other mechanisms emphasizing genomic derepression and impaired immunity. The critical steps in chemical carcinogenesis are described, and the Vogelstein-Lane model is presented, emphasizing the stepwise and cumulative genomic changes affecting chromosomes 5q, 17p, 18q, and gene amplification of chromosome 12 as well as genomic instability resulting from reduced DNA methylation. The main consequences of these genomic alterations include overexpression or activation of oncogenes such as c-myc and k-ras, together with mutation or functional inactivation of suppressor genes such as p53. Finally, the implications of these findings for diagnosis and management are illustrated by reference to recent investigations in cancers of the breast, colon, and bladder, in which these genomic alterations can be detected by examination of appropriate cellular material and by detection in serum of antibodies to the p53 gene product.
History, 20th Century↗
Outcome survey of auditory-verbal graduates: study of clinical efficacy.
Audiologists must be knowledgeable about the efficacy of aural habilitation practices because we are often the first professionals to inform parents about their child's hearing impairment. The purpose of this investigation was to document the status of graduates of one aural habilitation option; auditory-verbal. A consumer survey was completed by graduates from auditory-verbal programs in the United States and Canada. Graduates were queried regarding degree and etiology of hearing loss, age of onset, amplification, and educational and employment history, among other topics. Results indicated that the majority of the respondents were integrated into regular learning and living environments.
Adolescent↗
Enzymes as agents for the treatment of disease.
The replacement of genetically deficient enzymes in patients with inherited metabolic disorders by infusion of purified enzymes or by organ transplantation has had very limited success, although good results with bone marrow transplantation have been obtained in some patients with mucopolysaccharidosis, Gaucher disease and inherited immunodeficiency diseases. Genetic engineering of the patient's lymphocytes may ultimately render these approaches redundant, at least for some of these diseases. Treatment of chronic pancreatic insufficiency and of disaccharidase deficiency with oral enzymes can be very effective; therapy can be monitored in the latter by measuring the breath hydrogen excretion and in the former by a range of tests of which stool chymotrypsin assay is the most convenient. Treatment of acute myocardial infarction by intracoronary perfusion of thrombolytic enzymes can improve both cardiac function and long-term survival if given early enough. Successful reperfusion can be identified by changes in the kinetics of serum enzyme release and clearance, especially for the isoenzymes and isoforms of creatine kinase. In cancer chemotherapy, L-asparaginase has long been a useful adjunct in the treatment of acute lymphoblastic leukemia, but recent experience suggests a role in acute nonlymphoblastic leukemia as well.
Asparaginase↗
Modulation of lipoprotein production in Hep G2 cells by fenofibrate and clofibrate.
Fenofibrate and other fibrate derivatives are commonly used to treat hyperlipidemia. It is not yet clear how they exert their modulatory effects on plasma lipoproteins. To investigate whether these drugs act on the liver to primarily inhibit very low density lipoprotein production, we utilized the highly differentiated human hepatoma cell line, Hep G2. At concentrations greater than 15 micrograms/mL, fenofibrate caused a 30% decrease in secreted apolipoprotein B (apo B) after 4 days of treatment. Pulse-chase studies demonstrated that this was not due to inhibition of apo B synthesis. Triglyceride synthesis by fenofibrate-treated Hep G2 cells was decreased by 30%, and the amount secreted into the medium was reduced by 50%. At a low concentration of drug (5 micrograms/mL), triglyceride secretion was reduced markedly while apo B secretion remained unchanged. Thus, apo B secretion is less sensitive to fenofibrate than the synthesis and secretion of triglyceride, and may be secondary to changes in the latter. Fenofibrate has also been shown to raise plasma high density lipoprotein concentrations. We found that low concentrations of fenofibrate caused a 20-101% increase in secreted apolipoprotein AI (apo AI), and pulse-chase immunoprecipitation studies showed that this was due to an increase in apo AI synthesis. Fenofibrate was compared to clofibrate to investigate whether their relative effects on lipoprotein production in Hep G2 cells were comparable to their relative effects on plasma lipoproteins. Both fibrates decreased the secretion of apo B to the same extent, but only fenofibrate increased apo AI secretion. Fenofibrate was more effective than clofibrate in inhibiting the secretion of lipids by these cells. Thus, the known effects of fenofibrate on plasma lipoproteins can be attributed to its direct modulation of lipoprotein synthesis in the liver cell. Hep G2 cells may thus be useful in testing the relative efficacy of fibric acid derivatives in vitro.
Apolipoproteins A↗
Enzyme-linked immunosorbent assay to measure apolipoproteins AI and B secreted by a human hepatic carcinoma cell line (Hep G2).
We describe an enzyme-linked immunosorbent assay (ELISA) to measure apolipoproteins AI and B secreted by Hep G2 cells and in cell homogenates. These assays utilize commercially available polyclonal antibodies, affinity-purified to improve their specificity, thereby achieving a dramatic increase in the sensitivity of the assay. These affinity-purified antibodies were also more sensitive than a series of monoclonal antibodies tested. We achieved a sensitivity of 0.4 ng in the apo AI assay, and a sensitivity of 5 ng in the apo B assay. By these methods, we measured secretion rates by Hep G2 cells of 358 +/- 41 ng/mg cell protein/hr for apo B and 137 +/- 8 ng/mg cell protein/hr for apo AI. These assays also allowed the measurement of intracellular apolipoproteins and thus can be used to facilitate investigations of human lipoprotein metabolism in cell culture systems.
Amino Acids↗
Apolipoprotein synthesis and secretion in Hep G2 cells: effects of monensin and cycloheximide.
Hep G2 cells were used to study the relationship between apolipoprotein synthesis and secretion, as revealed by their interaction with agents modulating these processes. Cycloheximide inhibited the secretion of both apolipoproteins (apo) AI and B, but the reduction in apo AI secretion was evident at earlier times. Monensin also inhibited secretion of apo AI and apo B, but only apo AI accumulated intracellularly. Pulse-chase studies showed that, at concentrations of monensin that had no effect on total protein synthesis, apo B synthesis was specifically inhibited. Triacylglycerol synthesis was inhibited to the same extent as apo B synthesis, but this preceded the latter inhibition and unlike apo B there was an accumulation of intracellular triglyceride. These results suggest that distinctive mechanisms modulate the synthesis and secretion of apo AI and apo B, and that apo B synthesis can be specifically inhibited by mechanisms that initially block triglyceride production.
Apolipoprotein A-I↗