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Flavonoids are polyphenolic antioxidants naturally present in vegetable foods. Some flavonoids, such as quercetin, inhibit carcinogenesis in rodents, but their effect in humans is unknown. We measured the flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin in foods and assessed flavonoid intake in 1985 by dietary history in 738 men aged 65-84 years without a history of cancer, who were then followed for five years. Mean flavonoid intake was 25.9 mg/day. The major sources of flavonoid intake were tea at 61% and vegetables and fruits (mainly onions, kale, endive, and apples) at 38%. Between 1985 and 1990, 75 men developed cancer (all sites) and 34 men died from cancer. Flavonoid intake in 1985 was not associated with incidence of all-cause cancer (p for trend = 0.54) or with mortality from all-cause cancer (p for trend = 0.51). Flavonoid intake was also not associated with risk of cancers of the alimentary and respiratory tract (p for trend = 0.92). Adjustment for age, body mass index, smoking, physical activity, and vitamin C, vitamin E, beta-carotene, and dietary fiber intake did not change the relative risks. A high intake of flavonoids from vegetables and fruits only was inversely associated with risk of cancer of the alimentary and respiratory tract (relative risk of highest vs. lowest tertile = 0.51, 95% confidence interval 0.25-1.05); these results suggest the presence of other nonvitamin components with anticarcinogenic potential in these foods. We conclude that intake of flavonoids, mainly from tea, apples, and onions, does not predict a reduced risk of all-cause cancer or of cancer of the alimentary and respiratory tract in elderly men. The effect of flavonoids on risk of cancer at specific sites needs further investigation in prospective cohort studies.

The value of self-rated health in predicting mortality and the incidence of chronic diseases was studied in a cohort of 783 elderly Dutch men in the Zutphen Study. In 1985, 48% of the men felt "healthy," while 12% felt "moderately healthy" or "not healthy." As of 1990, 23% of the 783 men had died. Survival analysis showed that self-rated health was highly predictive of subsequent 5-year mortality from all causes (p < 0.001). When adjusted for the presence of major chronic diseases, age, medication use, smoking, alcohol consumption, physical activity, body mass index, systolic blood pressure, serum cholesterol, education, marital status, and family history of chronic diseases, the relative risk for "moderately healthy" or "not healthy" men compared with "healthy" men was 2.7 (95% confidence interval (CI) 1.8-4.3). Analysis of cause-specific mortality revealed that self-rated health was associated with cardiovascular mortality (crude relative risk (RR) = 2.7), but this finding resulted mainly from confounding by baseline prevalence of cardiovascular diseases (adjusted RR = 1.9, 95% CI 0.9-3.8). However, self-rated health was an independent risk factor for cancer mortality (adjusted RR = 4.2, 95% CI 1.9-9.4) and mortality due to other causes (adjusted RR = 3.0, 95% CI 1.2-7.8). Self-rated health did not independently predict the incidence of chronic diseases. This suggests that self-rated health especially affects fatality from chronic diseases rather than their onset, and this issue should be pursued further.

Flavonoids are polyphenolic antioxidants naturally present in vegetables, fruits, and beverages such as tea and wine. In vitro, flavonoids inhibit oxidation of low-density lipoprotein and reduce thrombotic tendency, but their effects on atherosclerotic complications in human beings are unknown. We measured the content in various foods of the flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin. We then assessed the flavonoid intake of 805 men aged 65-84 years in 1985 by a cross-check dietary history; the men were then followed up for 5 years. Mean baseline flavonoid intake was 25.9 mg daily. The major sources of intake were tea (61%), onions (13%), and apples (10%). Between 1985 and 1990, 43 men died of coronary heart disease. Fatal or non-fatal myocardial infarction occurred in 38 of 693 men with no history of myocardial infarction at baseline. Flavonoid intake (analysed in tertiles) was significantly inversely associated with mortality from coronary heart disease (p for trend = 0.015) and showed an inverse relation with incidence of myocardial infarction, which was of borderline significance (p for trend = 0.08). The relative risk of coronary heart disease mortality in the highest versus the lowest tertile of flavonoid intake was 0.42 (95% CI 0.20-0.88). After adjustment for age, body-mass index, smoking, serum total and high-density-lipoprotein cholesterol, blood pressure, physical activity, coffee consumption, and intake of energy, vitamin C, vitamin E, beta-carotene, and dietary fibre, the risk was still significant (0.32 [0.15-0.71]). Intakes of tea, onions, and apples were also inversely related to coronary heart disease mortality, but these associations were weaker. Flavonoids in regularly consumed foods may reduce the risk of death from coronary heart disease in elderly men.

Objective: To compare the association of habitual fish intake with 17-yr mortality of coronary heart disease between normoglycemic and glucose intolerant elderly subjects., Research Design and Methods: In 1971, 272 men and women, 64-87 yr of age, were examined in a general practice in the town of Rotterdam, The Netherlands. Glucose intolerance (impaired glucose tolerance or diabetes mellitus) was observed in 83 subjects, and 189 subjects were found to be normoglycemic and free of clinically diagnosed diabetes mellitus. Information on usual dietary intake was obtained using the cross-check dietary history method., Results: Fish consumption was found in 58.7% of the normoglycemic population and in 62.4% of the glucose intolerant population. Among normoglycemic subjects, the age- and sex-adjusted 17-yr mortality for coronary heart disease was 10.9/1000 person-yr for those who ate fish and 25.1/1000 person-yr for those who did not. For the glucose intolerant population, the rates were 20.6/1000 and 31.2/1000 person-yr, respectively. Adjusted for age, sex, body mass index, smoking, alcohol use, intake of energy, polyunsaturated fat, and carbohydrates, the risk ratio for normoglycemic population was 0.34 (95% confidence interval: 0.16-0.72). For glucose intolerant subjects, an adjusted risk ratio of 0.80 (95% confidence interval: 0.31-2.05) was observed., Conclusions: These results suggest that in a glucose intolerant population the possible protective effect of fish intake on coronary heart disease may be smaller than in normoglycemic subjects.

The association between diet and the 25-year incidence of chronic nonspecific lung diseases (CNSLD) was studied in 793 middle-aged men in the town of Zutphen, the Netherlands, in 1960-1985. During follow-up, 232 new cases of CNSLD were identified. The incidence rate was 14.1 per 1,000 person-years. Habitual food intake was assessed by the cross-check dietary history method. The intake of linoleic acid was positively associated with the incidence of CNSLD. The relative risk was 1.55 (95% confidence interval (Cl) 1.11-2.16), comparing the highest with the lowest quartile of intake of linoleic acid, independent of potential cofounders (age, cigarette smoking, body mass index, and energy intake). Alcohol consumers showed a significantly lower risk than did non-consumers (relative risk (RR) = 0.72, 95% Cl 0.55-0.95) after adjustment for confounders. In addition, fruit intake was inversely related to incidence of CNSLD (RR = 0.73, 95% Cl 0.53-0.99). No association was observed with intake of several antioxidants. These results suggest that in addition to well-established determinants, such as cigarette smoking and occupational exposure, dietary factors may play a role in the onset of chronic nonspecific lung diseases.

The impact of glucose tolerance, measured repeatedly, on the mortality from ischemic heart disease (IHD) was assessed in a cohort of 202 elderly patients, aged 64 to 84 years in 1971, from a general practice. During the period from 1971 to 1975 the participants were examined annually. The area under the glucose tolerance curve (AUC) was used as a summary index, and for every subject the mean AUC over the 5-year period was calculated. This index was most strongly correlated with the mean 60-minute glucose level (r = 0.96). Between 1975 and 1987, 125 participants died, 28.8% of whom died from IHD. No association between a single measurement of glucose tolerance and IHD mortality was observed. However, using the mean AUC over the 5-year period, a positive association was observed, independent of age, sex, and other potential confounders (P = 0.04). These results indicate that glucose tolerance independently predicts mortality from coronary heart disease in an elderly cohort, provided that information on repeated measurements is taken into account. A continuous risk gradient is suggested.

Chronic diseases such as coronary heart disease and diabetes mellitus are uncommon in Eskimos. Total cholesterol levels are generally low, whereas HDL cholesterol levels are higher than those in an age- and sex-matched Danish population. It is frequently assumed that this is mainly due to their dietary pattern, especially with its high content of n-3 polyunsaturated fatty acids, derived from fish and other seafoods. Dietary surveys have shown that the intake of n-3 polyunsaturated fatty acids in Eskimos is about 14 g/day, whereas it is 3 g/day in Denmark and about 0.2 g/day in the United States. However, the Eskimo diet also differs from the Western diet in other aspects, especially in the intake of saturated fatty acids which is low (9 energy-%). The intake of dietary cholesterol is rather high because of the large consumption of seafood. Individually based studies are better suited to disentangle the health effects of different nutrients, inasmuch as confounding factors can be taken into account. Several cohort studies have now shown that the consumption of 1-2 fish meals per week is associated with a reduction in the risk of coronary heart disease. Recently, similar results concerning glucose intolerance and stroke were also reported. These combined data suggest that a diet low in saturated fatty acids, in combination with a low or moderate level of fish consumption, may be of importance in the prevention of diseases such as coronary heart disease, ischemic stroke, and diabetes mellitus.

Repeated risk factor measurements reduce the amount of random error due to intraindividual variation. Annual measurements of serum cholesterol and systolic blood pressure were done in a cohort of 878 men, aged 40-59 years, between 1960 and 1970. This study examined for both risk factors the association with the incidence of myocardial infarction (MI) during follow-up till 1985. Mean values from repeated measurements yielded stronger statistical associations with MI incidence than single observations. However, when measurements were extended over too many years in this middle-aged cohort, a bias occurred due to selective loss of high-risk individuals as early cases. This was especially the case of serum cholesterol. Taking account of trends in regression analysis did not show any advantage over the use of mean values.

The impact of glucose tolerance on the incidence of ischemic heart disease (IHD), cerebrovascular disease (CVA), and peripheral arterial disease (PAD) was investigated in the Zutphen Study. In 1970 a complete oral glucose tolerance test (GTT) was carried out on 400 normoglycemic men aged 50-70 yr. A morbidity follow-up was completed in 1985. With GTT classified as the dichotomous variable using the median value of the area under the curve, elevated risks for IHD (RR = 1.6, p < 0.05), fatal IHD (RR = 2.3, p < 0.01), and CVA (RR = 1.9, p < 0.10) were observed, adjusted for potential confounders. No association with PAD was found. Also the risk among non-insulin-dependent diabetics (n = 46) was assessed. These men were clinically diagnosed between 1960 and 1985, median year of diagnosis being 1973, at age 61 yr. Compared with 230 matched non-diabetics increased risks were observed for fatal IHD (p = 0.05), CVA (p = 0.10) as well as PAD (p = 0.05). Thus an elevated risk for IHD, and possibly CVA, may have been found with lower levels of glucose than assumed previously, suggesting a continuous risk gradient. For PAD the relations with glucose tolerance are more complex.

From 1971 until 1975, 204 patients from a general practice, aged 64-87 at entry, were examined annually. At every examination body weight, serum lipids, and systolic blood pressure were measured, and a complete glucose tolerance test was carried out. Clinically diagnosed diabetics were excluded. Adjusted for age and sex, the annual change in the area under the glucose curve (AUC) was significantly associated with body weight change. Changes in serum total cholesterol, serum triglycerides, and systolic blood pressure were also associated with body weight change. The results were independent of potential confounders such as alcohol use, smoking habits, presence of cardiovascular disease, and baseline levels of the different risk factors. The change in AUC was also associated with changes in serum total cholesterol, independent of confounders such as body weight. Changes in AUC were not related to changes in systolic blood pressure and serum triglycerides. The results of this study suggest that changes in glucose tolerance are not only related to changes in body weight, but also to changes in serum cholesterol.

Objective: To examine the association of fish intake with the subsequent risk of impaired glucose tolerance and diabetes mellitus (glucose intolerance)., Research Design and Methods: In 1971, information about food intake was obtained by the cross-check dietary history method on 175 men and women aged 64-87 yr who were normoglycemic and free of clinical diabetes. During the follow-up period from 1972 to 1975, an oral glucose tolerance test was performed annually, and in 59 of 175 elderly people a diagnosis of glucose intolerance was made at least once., Results: In 1971, approximately 60% of the subjects usually ate fish, with a mean daily intake of 24.2 g. In fish eaters, the incidence of glucose intolerance was significantly lower compared with nonfish eaters (odds ratio [OR] 0.40, 95% confidence interval [CI] 0.21-0.77). With logistic regression analysis, this inverse association could not be explained by taking into account age and sex or possible confounding baseline characteristics, such as the prevalence of myocardial infarction, body mass index, energy intake per kilogram body weight, or intake of carbohydrates (OR 0.47, 95% CI 0.23-0.93). Baseline characteristics of the oral glucose tolerance test and serum triglyceride levels could also not account for this result., Conclusions: These results suggest that, in an elderly population, the habitual consumption of a small amount of fish may protect against the development of impaired glucose tolerance and diabetes mellitus.

The association between the intake of carbohydrates, body mass index (BMI), and the 4-y incidence of impaired glucose tolerance and diabetes mellitus (glucose intolerance) was investigated in elderly men and women aged 64-87 y. In 1971 the baseline population consisted of 175 normoglycemic subjects. During the follow-up period (1972-1975) an oral glucose-tolerance test (OGTT) was carried out annually. In univariate analyses, baseline BMI and the habitual intake of carbohydrates and pastries, as determined from a cross-check dietary history, were positively associated with the incidence of glucose intolerance. The habitual intake of legumes was inversely related to the incidence of glucose intolerance. These results could not be explained by potential confounding factors such as age, gender, alcohol use, energy intake, prescribed diet, medication use, and comorbidity. These results suggest that energy balance and the use of carbohydrate-rich foods are related to the development of glucose intolerance in an elderly population.

The intra- and interindividual variability of the oral glucose tolerance test (OGTT) and other risk factors was investigated in 237 subjects, aged 64-87, examined annually in the period 1971-1975. Coefficients of intraindividual variation (CVa) were calculated from individual regressions on time. The lowest CVa was found for the summary index including fasting glucose (area under the curve, AUC): 10.0 +/- 4.9%. For fasting and 30, 60, and 120 min glucose the values ranged from 12 to 18%. The CVa's were not associated with age, gender, drug use, and disease prevalence, and may also be applied to other populations. The reliability coefficient depended on the prevalence of diabetes in the population and was higher than observed in younger populations. The highest reliability coefficient was observed for AUC: 0.81. For the combined information of OGTT, reflected by AUC or by classification according to WHO criteria, the variability was comparable to that of other cardiovascular risk factors such as serum total cholesterol.

Relationships between specific dietary factors and aspects of glucose tolerance were examined using data from the Zutphen Study. In 1970, an oral glucose tolerance test was carried out in 394 non-diabetic men aged 50-70. Habitual dietary intake was assessed using the cross-check dietary history method. In univariate analyses, positive associations were observed between fasting glucose and the intake of saturated fat (correlation coefficient (r) = 0.13, p less than 0.01) and dietary cholesterol (r = 0.16, p less than 0.01), and also reflected by an association with egg consumption. These results were confirmed in multivariate analyses, taking into account total energy intake, subscapular skinfold thickness and age. In univariate analyses, significant inverse associations were found between the incremental area under the curve (IAUC) and the intake of mono- and disaccharides (r = -0.22, p less than 0.001) and pectin (r = -0.15, p less than 0.01), as well as the consumption of sugar products. Similar results were obtained in multivariate analyses. The change in saturated fat intake in the period 1960-1970 was positively associated with IAUC, independent of concurrent intake in 1970, age, subscapular skinfold and change in energy intake. In a similar model the change in pectin intake was inversely associated with IAUC. These findings suggest that the intake of saturated fat and dietary cholesterol may be detrimental to glucose tolerance, in contrast to the intake of pectin and mono- and disaccharides.

Risk factors for coronary heart disease were studied in healthy middle-aged Cretan men in order to compare them with the middle-aged men of a previous generation studied in 1960 as the Cretan cohort of the Seven Countries Study (1960). In the present cohort mean values for total cholesterol were 5.48 mmol/L, for HDL-cholesterol 1.26 mmol/L, for triglycerides 1.41 mmol/L, for systolic blood pressure 128 mmHg, and for diastolic blood pressure 77 mmHg. Serum cholesterol was higher and blood pressure slightly lower than the values observed in 1960. However, it is uncertain whether these changes were real or caused by changes in methodology. The mean body mass index has increased from 22.6 in 1960 to 26.9 kg/m2 in 1982, due to an increase in fatness. The percentage of smokers had increased from 57.4% to 74.1%. Upon multiple regression analysis the body mass index, the subscapular to triceps skinfold ratio and smoking were negatively and independently related with HDL-cholesterol. Body mass index correlated positively with serum triglycerides. Although the incidence of coronary heart disease is still low in Crete, it is concluded that there is nothing in the risk profile of these middle-aged men to suggest that they are at a low risk for coronary heart disease.

The association between classical cardiovascular risk factors, including diet, and the 25-year incidence of non-insulin-dependent diabetes mellitus was examined in 841 middle-aged men within the Zutphen Study. The incidence rate was 3.8/1,000 person-years. In univariate analyses, baseline measurements of subscapular and tricipital skinfold thicknesses, body mass index (weight (kg)/height (m)2), cigarette use, resting heart rate, and systolic blood pressure were significantly associated with diabetes incidence. In multivariate survival analyses also taking age, energy intake, and alcohol consumption into account, subscapular skinfold thickness, resting heart rate, and cigarette use were independently related to diabetes incidence. The effect of subscapular skinfold thickness was shown among subjects free of cardiovascular disease at baseline and during follow-up and among cases who developed cardiovascular disease. Cigarette smoking was an independent risk factor only in men who remained free of cardiovascular disease, while the effect of resting heart rate was stronger within incident cases of cardiovascular disease. No associations were found between dietary factors and diabetes incidence.

The relationship between body fat and different aspects of glucose tolerance was examined within the Zutphen Study. In 1970 an oral glucose tolerance test (OGTT) was carried out in 404 non-diabetic men aged 50-70. None of the subjects could be classified as having impaired glucose tolerance. Body mass index (BMI), subscapular and triceps skinfold were positively related with fasting and 60 min serum glucose. Weak positive associations were found between 30 min glucose, BMI, and subscapular skinfold. For 120 min glucose, only the relationship with subscapular skinfold was significant. After adjustment for age and the other body fat indicators, the positive associations between body fat and fasting, 60 min and 120 min glucose were confirmed for subscapular skinfold only. Correlations between these glucose measurements and measurements of subscapular skinfold in the years between 1960 and 1970 were also significant and increased with time. Independent from subscapular skinfold in 1970 and age, changes in skinfold during the period 1960-70 were in general not significantly associated with glucose levels, except for 30 min glucose. The findings could to a large extent be explained by current knowledge of glucose metabolism.