Alcohol, Wine, and Health

Alfred A. de Lorimier, M.D., Geyserville, Califomia

Reprinted on this Web site with the permission of the American Journal of Surgery. Manuscript submitted June 19, 2000, accepted in revised form August 7, 2000, and published November, 2000, Vol. 180, pp. 357-361.

BACKGROUND:  For the past 20 years numerous epidemiological studies have correlated the consumption of alcohol and a variety of disease states: overall mortality, arteriosclerotic vascular diseases, hypertension, cancers, peptic ulcer, respiratory infections, gall stones, kidney stones, age-related macular degeneration, bone density, and cognitive function.

METHODS:  A review of these articles reveals that each of these studies has compared the outcome of individuals at various levels of alcohol consumption with that of abstainers.

RESULTS:  Each analysis has identified a U-shaped or J-shaped curve of reduced relative risk for a given disease state compared with abstainers. A clear definition of consumption in moderation becomes evident: for men it should not exceed 2 to 4 drinks per day, and for women it should not exceed 1 to 2 drinks per day.

CONCLUSIONS:  Alcohol by itself has favorable effects on the level of high-density lipoprotein cholesterol, and inhibition of platelet aggregation. Wine, particularly red wine, has high levels of phenolic compounds that favorably influence multiple biochemical systems, such as increased high-density lipoprotein cholesterol, antioxidant activity, decreased platelet aggregation and endothelial adhesion, suppression of cancer cell growth, and promotion of nitric oxide production. Am J Surg. 2000; 180:357-361. 0 2000 by Excerpta Medica, Inc.

My wife and I have been growing wine grapes in the Alexander Valley in Sonoma County since 1972, and we started de Lorimier Winery in 1986. So, you should understand that I have a conflict of interest in presenting a subject of wine and health. However, I have tried to be as objective as possible in relating the ensuing data on alcohol, specifically wine, and health. The space limitations of this journal do not permit an in-depth analysis of the enormous literature on this subject.

It is important that a distinction is made between use in moderation of beverage alcohol and abuse of alcohol. Today, more than two thirds of Americans, at some time, drink beverage alcohol and in moderation. But we must also acknowledge that perhaps 5% of those who drink alcohol become addicted to it. Another 5% of the drinking population fail to adhere to moderation and cause considerable havoc in terms of accidents and injuries, spousal abuse, lawlessness, and so forth. All of us in medicine are acutely aware of the ravages that follow the abuse of alcohol, and I do not wish to minimize the toll this abuse takes on our society.

For the 60% who drink sensibly, however, are there any positive attributes to alcohol or wine? For the past 20 years there has been an enormous outpouring of scientific papers linking a favorable effect of drinking beverage alcohol and a variety of disease states: atherosclerotic vascular disease (cardiovascular mortality, stroke incidence, peripheral vascular disease, and diabetes), hypertension, cancer , peptic ulcer, upper respiratory infections, gall stones, kidney stones, age-related macular degeneration, bone density, and cognitive function.

In all of these papers drinkers are compared with non, drinkers or abstainers. In this review, particular attention was paid to studies that distinguished lifetime abstainers from those who were former drinkers or "sick quitters." In addition to having abstainers for comparison with those who consume alcohol, a correction should be made for associated cofounders such as age, sex, race, smoking, blood pressure, diabetes, body mass index, serum cholesterol, plasma concentrations of low-density liproprotein (LDL), high-density lipoprotein (HDL), and apolipopro, teins, regular vigorous exercise, regular aspirin use, and social class. Most of the published reports reviewed here have used the Cox proportional,hazards model to adjust for many of these multiple risk factors simultaneously. It will be noted that the conclusion of most of these studies reveals a U-shaped or J-shaped curve of risk of a given disease state and alcohol consumption, compared with nondrinkers (Figure). That is, abstainers are considered the control population with a risk of 1. If overall mortality is to be studied, the death rate of those who drink a given amount of beverage alcohol per day becomes the numerator, and the death rate of the abstainers is the denominator. The result provides the relative risk of drinkers related to the level of consumption. And from this information there is a clear definition of moderation. That is, men who consume 1 to 4 drinks per day and women who drink 1 or 2 drinks per day have a lower risk of a disease state compared with nondrinkers or with those who consume an excess of 4 drinks.

ALCOHOL AND CARDIOVASCULAR MORTALITY

Coronary heart disease is the leading cause of death in the age group 45 years and older, with the average age of first infarction in the 50s for men and 10 years later for women. It is estimated that this year there will be 1.1 million Americans who will suffer a myocardial infarction. Typically one third of these people die at the time of the first infarction. There are now more than 50 publications showing that moderate alcohol consumption is associated with a reduced incidence of myocardial infarction as well as coronary heart disease mortality by a factor of 20% to 50% less than abstainers or very light drinkers in both men and women. This is particularly true for those individuals with one or more risk factors for cardiovascular diseases, such as hypercholesterolemia, hypertension, cigarette smoking, obesity, diabetes mellitus, and low HDL levels. 1-5

Figure. A typical U-shaped or J-shaped curve of relative risk for adverse health effects for alcohol or wine consumers compared with nondrinkers. Nondrinkers are assigned a risk of 1, and drinkers are plotted according to level of consumption. The relative risk equals number of events (eg, myocardial infarction) among drinkers divided by number of events among nondrinkers. Note that the relative risk of adverse health events for drinkers is lower than that for nondrinkers when consumption is between 1 and 4 drinks per day, whereas consumption exceeding 4 drinks results in an increased risk above that of nondrinkers.

Camargo et al' have also reviewed the Physicians' Health Study of 22,071 men on the incidence of angina and myocardial infarction. Consistent with the reduced cardiac mortality associated with moderate alcohol consumption, this study found that men who consumed 2 drinks per day had a 56% lower risk of angina and a 47% lower risk for myocardial infarction.4 This same population of physicians were in a trial of aspirin, and it has been noted that the decreased risk of myocardial infarction with moderate al. cohol intake may be even stronger with those taking low-dose aspirin.

STROKE

The third leading cause of death in the United States is cerebral vascular disease. There are two categories of stroke: ischernic stroke from cerebrovascular occlusion and hemorrhagic stroke. Hemorrhagic stroke may be an intracerebral hemorrhage or a subarachnoid hemorrhage. The actual incidence of stroke is probably underestimated because of "silent strokes." In autopsy studies of individuals where brain infarcts were found, only 27% had clinical evidence of a stroke. Ischemic stroke accounts for 70% to 85% of all strokes.6 Moderate alcohol consumption is associated with a relative risk of ischemic stroke 20% to 50% less than that of nondrinkers.' When the level of consumption rises more than 3 to 5 drinks per day, the risk of ischemic stroke begins to rise above that of nondrinkers.1 Wine has been noted to be associated with lower risk, while there was no difference in risk with beer and spirits drinkers. 1,7

However, there is evidence that alcohol increases the risk of both intracerebral and subarachnoid hemorrhagic stroke. When more than 3 "units" per day are consumed, the risk of hemorrhagic stroke is reported to increase two to three times that of nondrinkers. In the long-term follow-up of 22,071 male physicians in the Physicians Health Study there was a 21% reduction in total stroke for moderate drinkers and there was no association between alcohol consumption and hemorrhagic stroke. 8 Overall, in comparison with nondrinkers and heavy drinkers, when consumption is maintained in moderation, the reduced risk from ischemic stroke far outweighs the risk of hemorrhagic stroke.

PERIPHERAL ATHEROSCLEROSIS

The ankle-brachial pressure index has been used to determine the severity of compromise involving lower extremity circulation. In the Edinburgh Artery Study a greater alcohol intake was related to a higher index, ie, less severe peripheral arterial insufficiency.9 This protective effect was more evident with consumption of wine than with beer or spirits. In another study of 22,000 male physicians consumption of alcohol of all types was associated with a lower risk of peripheral vascular disease." Kiechl et al 11 performed ultrasound imaging of the common and internal carotid arteries, and found that there was a J, shaped relationship in the progression of atherosclerosis and alcohol consumption.

UPPER DIGESTIVE TRACT CANCER

It is clear that tobacco is a very dominant carcinogen affecting the oropharynx, larynx, and esophagus. The combination of tobacco and alcohol extends the risk of these tumors substantially from 40% to 280% greater than that of abstainers." In each study, when the data were adjusted for cigarette smoking, there was a direct effect of alcohol. However, when the data were analyzed for the source of alcohol, this effect was stronger for spirits and beer than it was for wine." In the prospective cohort study of Gron, beck et al,14 those who consumed 7 to 21 drinks per week of beer and spirits had a relative risk 3 times that of abstainers. Those who drank more than 30% of their total intake as wine had a relative risk of 0.514 In a Spanish analysis of esophageal carcinoma it was found that spirits and beer along with cigarettes, but not wine, are the greatest risk factors. 15 Gammon et al 16 noted that the risk of esophageal squamous cell carcinoma was more than doubled with beer and tripled with liquor consumption, whereas drinkers of wine had a 40% reduced risk of all forms of esophageal and gastric cancers.

BREAST CANCER

There has been an intense interest and controversy about the association of alcohol and breast cancer. Some have shown a reduced risk or no risk of breast cancer with moderate alcohol intake. Other studies have shown a significant increased mortality from breast cancer in heavy drinkers. 3 In an analysis of six cohort studies, women consuming 30 to 60 g of alcohol daily were found to have a 41% higher relative risk than abstainers. 17 However, three of the six individual studies pooled for this analysis found that consumption of up to 15 grams of alcohol per day was associated with a slight decrease in the risk of breast cancer. In the Cancer Prevention Study, 238,206 women over the age of 30 years were followed up from 1982 through 1991. 12 The relative risk of breast cancer increased 20% with consumption of 1 drink per day and 50% with 2 to 3 drinks/day." Longnecker 18 performed a meta-analysis of 38 epidemiological studies from over 50 reports in the literature. He concluded that there was a dose-response relationship of alcohol and breast cancer, where the relative risk for 1 drink per day was 1; for 2 drinks per day, it was 1.24; and for 3 drinks per day, it was 1.38. He noted that the dose -response had a modest slope, which "leaves the causal role of alcohol in question. 18 The more recent Framingham Study determined that light consumption of wine, beer, or spirits is not associated with increased breast cancer risk. 19 Some studies, not all, have shown that increased estrogen levels in the blood and urine occur with drinking alcohol, and it is speculated that this might be the stimulus for breast cancer risk. 17 If there is an increased risk of breast cancer with consumption of alcohol, it should be noted that 1 woman in 25 would eventually die of this tumor. But in the big picture, 1 in 2 women will die of either heart disease or stroke. The subgroup of women aged 35 to 64 who are at low risk of heart disease, but who are at significant risk of breast cancer, could decrease their risk by reducing their alcohol consumption. 20 In the older women, the protective effect of alcohol consumption in reducing the risk of atherosclerotic disease outweighs the weak evidence for an increased risk of breast cancer.

HYPERTENSION

Many investigators note that consumption follows a U- or J-shaped curve, with the lowest pressures in those consuming I to 3 drinks per day. 21 Increasing consumption is associated with increasing blood pressure, particularly at high levels of intake. It has been suggested that the elevated blood pressures are pseudo-hypertension, since the usual associated complications of stroke, coronary heart disease, peripheral atherosclerosis, renal failure, or heart failure do not seem to follow. 22 Consumption in individuals with apparent essential hypertension follows the U-shaped curve or has no influence on the level of blood pressure in either treated or untreated hypertensive patients. 13 It should be noted that those who drink wine have lower levels of systolic blood pressure than abstainers. 24

PEPTIC ULCERS

Helicobacter pylori infection stimulates gastrin production, which results in high acid secretion; and it suppresses gastric somatostatin secretion, which is inhibitory to acid production. Recent prospective cohort analyses indicate that intake of alcohol was not associated with development of peptic ulcer, and that the odds ratio for moderate alcohol consumption was lower than in those who almost never drank. 25 Furthermore, it has been noted that the adjusted odds of an H pylori infection in those who drank 50 to 75 g of alcohol per week was one third that who drank less or abstained." Wine has been shown to be bactericidal for Escherichia coli, Salmonella, Shigella, and H pylori. 17

UPPER RESPIRATORY INFECTION

There has been a supposition that both smoking and consumption of alcohol suppress resistance to virus infection. In a controlled experiment, volunteers were given intranasally either saline or a low infectious dose of one of five respiratory viruses. Thirty one percent of the virus, exposed subjects developed respiratory illness. Nonsmokers who consumed alcohol had a lower risk of respiratory illness. 28 In this group, increased alcohol consumption was related to decreased susceptibility to clinical colds. Smokers were not protected at any level of alcohol intake.

GALL STONES

More than 80% of gallstones are composed dominantly of cholesterol. Consumption of alcohol is associated with a decreased risk of gall stone formation 10% to 50% less than that for abstainers. 29

KIDNEY STONES

An analysis of 45,289 men in the Health Professionals Follow-up Study reveals that increasing fluid intake does diminish the risk of stones. Following correction for many confounders, it was concluded that for each 240 ml, serving consumed daily, the risk of stone formation decreased according to the type of beverage: caffeinated coffee by 10%, decaffeinated coffee by 10%, tea 14%, beer 21%, and wine by 39%. In a similar study of 81,093 women in the Nurse's Health Study, the results of fluid intake and the influence of beverage type were essentially identical .30 The diminished risk of urinary stone formation associated with alcohol beverages has been corroborated in less controlled studies.

AGE RELATED MACULAR DEGENERATION

Age-related macular degeneration (AMD) is the most common cause of blindness in adults older than 65 years. It is a bilateral progressive disease affecting central vision and impairs the affected person's ability to read. Alcohol was suspected as a contributing factor in the development of AMD. This motivated an analysis of alcohol and AMD from the National Health and Nutrition Examination Survey-1 (NHANES-1). There was a significant, negative association of alcohol consumption with AMD. This was particularly significant for wine. 31

BONE DENSITY

There are now at least nine studies showing that, in the older population, there is a direct correlation with the consumption of alcohol and preservation of bone density in men and women. In most studies the type of alcohol beverage was not analyzed, but in one there was a trend for wine to be more protective than other beverages. 32 There is a lower incidence of bone fractures in the elderly who consume moderate amounts of alcohol. 33

COGNITIVE FUNCTIONING

Cognitive decline in aging is most commonly due to Alzheimer's disease and vascular dementia from multiple cerebral infarcts. Some investigators have considered heavy alcohol to be one of many causes of dementia. Unlike chronic alcohol abuse, a number of publications show that cognitive function is actually better in moderate drinkers than in abstainers; or abusers. 34 In a prospective cohort study involving 3 ,767 residents over the age of 65 years from around Bordeaux, France, moderate wine drinkers showed a strikingly reduced odds ratio of 0.18 for Alzheimer's disease and dementia compared with nondrinkers. 35 In the Atherosclerotic Risk in Communities (ARIC) study involving 14,000 middle-aged adults, moderate drinkers were noted to have higher cognitive scores than nondrinkers. 36 In the Framingham Heart Study 1,800 men and women were given eight cognitive tests, and it was noted that women who were moderate drinkers had a superior performance to abstainers. 37 The relationship of alcohol and cognition was weaker in men. In another study of World War II white male veterans, it was found that light drinking appears to be beneficial to cognitive performance." There is speculation that the antioxidant effects of red wine might have a role in preventing the peroxidations typical of aging.

EFFECT OF ALCOHOL AND ATHEROGENESIS

It is apparent that alcohol, by itself, affects cardiovascular events through an influence in the levels of lipoproteins in the blood. High levels of HDL cholesterol are associated with low risks of cardiovascular morbidity and mortality. 39 HDL cholesterol rises with the consumption of alcohol. Epidemiological studies have shown that those who consume alcohol moderately develop a lowering of LDL cholesterol levels. High concentrations of LDL cholesterol have not been associated with a risk of coronary heart disease in men who consumed 3 or more drinks a day. 40 In a controlled diet study of premenopausal women, consumption of alcohol over a 3-month period was associated with a decrease in LDL cholesterol 8%, increased HDL cholesterol 10%, and no change in lipoprotein(a).

BLOOD CLOTTING FACTORS

Alcohol has a direct effect on the status of the coagulation system. A low plasma fibrinogen level is associated with a low risk of coronary heart disease, even when LDL cholesterol concentrations are elevated. Alcohol consumption is inversely correlated with fibrinogen levels. There is a positive association between moderate alcohol intake and plasma concentrations of plasminogen and endogenous tissue type plasminogen activator antigen. Moderate consumption of alcohol also enhances postprandial fibrinolytic activity. Alcohol inhibits platelet aggregation. 39 An associated decrease in thromboxane A2 production has also been noted with consumption of alcohol. 39 It is apparent that, of the many factors that appear to account for a lower mortality in consumers of moderate alcohol, a substantial benefit might be derived from inhibited clot formation.

WINE, BEER, OR SPIRITS?

Does wine provide more health benefits than other beverage alcohol? There are numerous publications supporting the contention that wine confers greater protection than beer or spirits. 1,41 However, other analyses indicate that it is the alcohol that is protective, and there is no difference between wine, beer, or spirits. Cleophas 41 performed a meta-analysis of nine major cohort and case control studies on the relative risk of death or coronary heart disease and the type of alcohol beverage. He concluded that wine was 46no more effective than other alcoholic beverages ... [all. though the level of significance in the meta-analysis is slightly better for wine than for beer or spirits . . . ."42 Alcohol has been shown to have pro-oxidant effects, and it may increase oxidation of LDL cholesterol.

UNIQUE QUALITIES OF WINE

(Additional references for this section are available from the author.) There are components of wine, particularly red wine, that do not exist in spirits, and are in low concentrations in beer and malt whiskey. These compo~ nents are phenols: flavanoids, polyphenols, nonflavanoid phenols, and tannins. Examples of flavanoids are the anthocyanins, which give color to the wine, catechins, procyanidins, and quercetin. The dominant nonflavanoid phenol is resveratrol. These elements of wine have been identified as antioxidants, antimutagens, chelating catalytic metals, and free radical scavengers. The antioxidant effects of these phenols counter the pro-oxidant activity of alcohol. Wine polyphenols decrease platelet aggregation and adhesion to endothelium, increase HDL cholesterol independent of the alcohol content of wine, and inhibit the oxidation of LDL cholesterol. These compounds inhibit the cyclo-oxygenase and lipo-oxygenase of platelets and macrophages, thereby inhibiting clotting and the in, flammatory mediators in a developing atheroma.

The flavanoids are hydrogen donors that react with superoxide anions, hydroxyl radicals, and lipid peroxidation in vivo. In addition, resveratrol has been found to inhibit intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM,l) expression, which promote the adhesion of macrophages to endothelium and their entry into the intima, which promotes atherosclerotic plaque.

Flavanoids suppress cancer cell growth in vitro. Resveratrol inhibits cyclooxygenase ,2 (COX~2) gene transcrip~ tion. COX-2 is a factor favoring growth of cancers. Anthocyanins have been shown to inhibit growth of tumors in in-vitro studies against cultured human colon cancer cells (HCT-15) and human gastric cancer cells (AGS).

Nitric oxide (NO) is stimulated by exposure to red wine and other red grape products, but not white wine, independent of alcohol. NO probably influences hemostatic mechanisms such as platelet-vessel wall (collagen) inter. action. And NO promotes vasorelaxation.

CONCLUSION

Consumption of alcohol in moderation has health benefits. Wine contains components that enhance those health benefits. However, it is inappropriate to advocate consumption of beverage alcohol for persons who are prone to addiction, who have religious reasons for abstaining, who are taking medication that adversely interacts with alcohol, who have repugnant reactions, and perhaps during pregnancy. It should be a priority in our educational system to define consumption in moderation and to deplore abuse of alcohol. 

REFERENCES

1. Stampfer MJ, Colditz G, Willett WC, et al. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. NEJM. 1988;319:267-273.

2. Gronbaek M, Deis A, Sorensen TIA, et al. Influence of sex, age, body mass index, and smoking on alcohol intake and mortality. BMJ. 1994;308:302-306.

3. Fuchs CS, Stampfer MJ, Colditz GA, et al. Alcohol consumption and mortality among women. NEJM. 1995;332:1245-1250.

4. Camargo CA, Stampfer MJ, Glynn RJ, et al. Moderate alcohol consumption and risk for angina pectoris or myocardial infarction in US male physicians. Ann Intern Med. 1997;126:372-375.

5. Renaud SC, Gueguen R, Schenker J, et al. Alcohol and mortality in middle-aged men from eastern France. Epidemiology. 1998; 9:184-188.

6. Reed DM, Resch JA, Hayashi T, et al. A prospective study of cerebral artery atherosclerosis. Stroke. 1988;19:820-825.

7. Truelsen T, Gronbaek M, Schnohr P, et al. Intake of beer, wine, and spirits and risk of stroke. The Copenhagen City Heart Study. Stroke. 1998;29:2467-2472.

8. Berger K, Ajani UA, Case CS, et al. Light-to-moderate alcohol consumption and the risk of stroke among U.S. male physicians. NEJM. 1999;341:1557-1564.

9. Jepson RG, Fowkes FG, Donnan PT, et al. Alcohol intake as a risk factor for peripheral arterial disease in the general population in the Edinburgh Artery Study. Eur J Epiderniol. 1995; 11:9 -14.

10. Camargo CA, Hennekens CH, Gaziano JM, et al. Prospective study of moderate alcohol consumption and mortality in US male physicians. Arch Intem Med. 1997;157:79-85.

11. Kieckl S, Willeit J, Rungger G, et al. Alcohol consumption and atherosclerosis: what is the relation? Prospective results from the Bruneck study. Stroke. 1998;29:900-907.

12. Thun M), Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly U.S. adults. NEJM. 1977; 337:1705-1714.

13. Anderson P, Cremon A, Paton A, et al. The risk of alcohol. Addiction. 1993;88:1493-1508.

14. Gronbaek M, Becker U, Johansen D, et al. Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract. BMJ. 1998;317:844-847.

15. Cayuela A, Vioque J, Bolumar F. Oesophageal cancer mortality: relationship with alcohol intake and cigarette smoking in Spain. J Epidemiol Comm Health. 1991;45:273-276.

16. Gammon MD, Schoenberg JB, Ahsan H, et al. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. J Nad Cancer Inst. 1997;89:1277-1284.

17. Smith-Warner S, Spiegelman D, Yaun S-S, et al. Alcohol and breast cancer in women-a pooled analysis of cohort studies. JAMA. 1998;279:535-540.

18. Longnecker M. Alcoholic beverage consumption in relation to risk of breast cancer: meta-analysis and review. Cancer Causes Control. 1994;5:73-82.

19. Zhang Y, Kreger BE, Dorgan JF, et al. Alcohol consumption and risk of breast cancer: the Framingham Study revisited. Am J Epidemiol. 1999;149:93-101.

20. Longnecker M. Invited commentary: the Framingham results on alcohol and breast cancer. Am J Epidemiol. 1999;149:102-103.

21. Gillman WM, Cook N, Evans DA, et al. Relationship of alcohol intake with blood pressure. Hypertension. 1995;25:11061110.

22. Beevers DG, Maheswaran R. Does alcohol cause hypertension or pseudo-hypertension? Proc Nutr Soc. 1988;47:111-114.

23. Rabbia F, Veglio F, Russo R, et al. Role of alcoholic beverages in essential hypertensive patients. Alcohol Alcoholism. 1995;30:433439.

24. Nevill AM, et al. Modeling the associations of BMI, physical activity and diet with arterial blood pressure: some results from the Allied Dunbar National Fitness Survey. Ann Human Biol. 1997;24: 229-247.

25. Aldoori WH, Giovannucci EL, Stampfer MJ, et al. A prospective study of alcohol, smoking, caffeine, and the risk of duodenal ulcer in men. Epidemiology. 1997;8:420-424.

26. Brenner H, Rothenbacher D, Bode G, et al. Relation of smoking and alcohol and coffee consumption to active Helicobacter pylori infection: cross sectional study. BMJ. 1997;315:1489-1492. 27. Marimon JM, Bujanda L, Gutierrez-Stampa MA, et al. In vitro bactericidal effect of wine against Helicobacter pylori. Am J Gastroenterol. 1998;93:1392.

28. Cohen S, Tyrell DAJ, Russell MAH, et al. Smoking, alcohol consumption, and susceptibility to the common cold. Am J Public Health. 1993;83:1277-1283.

29. Simon JA, Grady D, Snabes MC, et al. Ascorbic acid supplement use and the prevalence of gallbladder disease. J CUn Epidemiol. 1998;51:257-265.

30. Curhan GC, Willett WC, Speizer FE, et al. Beverage use and risk for kidney stones in women. Ann Intem Med. 1998;128:534540.

31. Obisesan TO, Hirsch R, Kosoko 0, et al. Moderate wine consumption is associated with decreased odds of developing agerelated macular degeneration in NHANES-1. J Am Geriatr Soc. 1998;46:1-7.

32. Burger H, et al. Risk factors for increased bone loss in an elderly population. The Rotterdam Study. Am J Epiderniol. 1998; 147:87 1879.

33. Hoidrup S, et al. Alcohol intake, beverage preference, and risk of hip fracture in men and women. Am J Epiderniol. 1999; 149:9931001.

34. Launer Q, et al. Smoking, drinking and thinking. Am J Epidemiol. 1996;143:219-227.

35. Orgogozo J-M, Dartigues J-F, Lafont S, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol. 1997;153:185-192.

36. Cerhan JR, Folsom AR, et al. Correlates of cognitive function in middle-aged adults. Gerontology. 1998;44:95-105.

37. Elias PK, et al. Alcohol consumption and cognitive performance in the Framingham Heart Study. Am J Epiden-dol. 1999; 150: 580-589.

38. Cannelli D, et al. The effect of apolipoprotein E4 in the relationship of smoking and drinking to cognitive function. Neuroepidemiology. 1999;18:125-133.

39. Rinun EB, Williams P, Fosher K, et al. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ. 1999;319:1523-1528.

40. Hein HO, Suadicani P, Gyntelberg F. Alcohol consumption, serum low density lipoprotein cholesterol concentration, and risk of ischaemic heart disease: six year follow up in the Copenhagen Male Study.U. 1996;312:736-741.

41. Wannamethee SG, Shaper AG. Type of alcoholic drink and risk of major coronary heart disease events and all-cause mortality. Am J Public Health. 1999;89:685- 690.

42. Cleophas TJ. Wine, beer and spirits and the risk of myocardial infarction: a systemic review. Biomed Pharmacother. 1999;53:417423.