Kunio Aoki

Serum concentrations of carotenoids, retinol, and α-tocopherol in healthy persons determined by high-performance liquid chromatography

Serum concentrations of alpha-carotene (AC), beta-carotene (BC), lycopene (LY), beta-cryptoxanthin (CR), zeaxanthin (including lutein. ZX), canthaxanthin (CX), retinol (RE), and alpha-tocopherol (TO) in healthy persons (618 males and 1,196 females) aged 7-86 years were determined by HPLC. Serum concentrations of BC among persons aged 20-49 years were higher with increasing age in females, but not in males. Serum CR concentrations decreased with age ranging from 7 to 39 years, while ZX concentrations rose in the age group of 20 to 59 years for both sexes. In contrast, serum RE concentrations and ratios of RE/BC and RE/CR, especially in males aged 20-49, were higher with age. Serum TO values in both sexes rose with age and were similar.

Smoking and Lung Cancer Risk in American and Japanese Men: An International Case-Control Study

Rates of lung cancer in American men have greatly exceeded those in Japanese men for several decades despite the higher smoking prevalence in Japanese men. It is not known whether the relative risk of lung cancer associated with cigarette smoking is lower in Japanese men than American men and whether these risks vary by the amount and duration of smoking. To estimate smoking-specific relative risks for lung cancer in men, a multicentric case-control study was carried out in New York City, Washington, DC, and Nagoya, Japan from 1992 to 1998. A total of 371 cases and 373 age-matched controls were interviewed in United States hospitals and 410 cases and 252 hospital controls in Japanese hospitals; 411 Japanese age-matched healthy controls were also randomly selected from electoral rolls. The odds ratio (OR) for lung cancer in current United States smokers relative to nonsmokers was 40.4 [95% confidence interval (CI) = 21.8-79.6], which was >10 times higher than the OR of 3.5 for current smokers in Japanese relative to hospital controls (95% CI = 1.6-7.5) and six times higher than in Japanese relative to community controls (OR = 6.3; 95% CI = 3.7-10.9). There were no substantial differences in the mean number of years of smoking or average daily number of cigarettes smoked between United States and Japanese cases or between United States and Japanese controls, but American cases began smoking on average 2.5 years earlier than Japanese cases. The risk of lung cancer associated with cigarette smoking was substantially higher in United States than in Japanese males, consistent with population-based statistics on smoking prevalence and lung cancer incidence. Possible explanations for this difference in risk include a more toxic cigarette formulation of American manufactured cigarettes as evidenced by higher concentrations of tobacco-specific nitrosamines in both tobacco and mainstream smoke, the much wider use of activated charcoal in the filters of Japanese than in American cigarettes, as well as documented differences in genetic susceptibility and lifestyle factors other than smoking.

Cardiovascular Disease Mortality and Serum Carotenoid Levels: a Japanese Population-based Follow-up Study

BACKGROUND Some observational epidemiologic studies suggest that dietary and serum carotenoids are associated with reduced cardiovascular disease mortality. METHODS Three thousand and sixty-one subjects (1,190 males and 1,871 females), aged 39 to 80 years, were recruited from residents of Hokkaido, Japan who had attended comprehensive health check-up programs from 1988 through 1995. Serum levels of α-carotene, β-carotene, and lycopene were separately determined by high-performance liquid chromatography. Serum levels of total carotene consisted of the sum of α-carotene, β-carotene, and lycopene levels. Each serum level of α-carotene, β-carotene, lycopene, total carotene, triglyceride, and alanine transaminase (ALT) activity was transformed logarithmically. The hazard ratios of serum α- and β-carotenes, lycopene, and total carotene values were estimated by the Cox proportional hazard model after adjusting for sex, age, and other potential confounding factors. RESULTS During the 11.9-year follow-up period, 80 deaths (49 males and 31 females) from cardiovascular disease, 40 deaths from heart disease, and 37 deaths from stroke were identified among the cohort subjects. High serum values of carotenoids such as α- and β-carotenes, and lycopene were found to be significantly associated with low hazard ratios for cardiovascular disease mortality. However, a significant inverse association between high serum lycopene value and the risk for stroke mortality was not always observed. CONCLUSIONS High serum levels of total carotene, comprising α- and β-carotenes and lycopene, may reduce the risk for cardiovascular disease mortality among the Japanese population.

ŒSTROGEN PROFILES OF ASIAN AND NORTH AMERICAN WOMEN

Abstract Œstrone, œstradiol, and œstriol were measured in 24—hour urine collections from 30 women in two cities of North America where breast-cancer rates are high, and 29 women from three areas of Asia where rates are low. The proportion of œstriol among the three œstrogens was considerably higher for Asian than for North American women, both in follicular and luteal phase specimens. Two age-groups were studied—15-19 and 35-39. The difference in œstriol ratio was distinct among the younger women and slight among the older. These findings support the hypothesis that the oestrogen profile of women during the reproductive years is associated with subsequent breast-cancer risk.

Risk modification in lung cancer by a dietary intake of preserved foods and soyfoods: findings from a case-control study in Okinawa, Japan

To disclose the association of dietary intake of preserved foods and soyfoods with lung cancer risk, we analyzed the data from a case-control study conducted in Okinawa, Japan, from 1988 to 1991. The analysis, based on 333 cases and 666 age-, sex- and residence-matched population controls, provided the following major findings. (1) The more the miso soup intake, the higher the risk (test for trend: P = 0.001 for males; P = 0.043 for females). (2) Frequent intake of pickles (excluding salted fish) tended to be linked with an elevated risk in males. The adjusted odds ratio (OR) for once or twice per week or more, relative to less than once a month was 1.88 (95% confidence interval (CI): 1.26-2.81). (3) Frequent intake of soybeans was associated with a decreased risk in men (OR: 0.63, 95% CI: 0.40-0.98 for once or twice per week or more, relative to less than once a month). (4) Daily consumers of tofu were at a decreased risk, particularly for squamous cell carcinoma; the OR (95% CI) being 0.55 (0.34-0.89) in males and 0.14 (0.02-0.89) in females. These findings suggested deleterious effects of preserved foods and protective ones of soyfoods rich in isoflavones.

Prognostic Significance of Selected Lifestyle Factors in Urinary Bladder Cancer

To examine the prognostic significance of lifestyle factors in urinary bladder cancer, we conducted a follow‐up study of 258 incident bladder cancer patients, who were originally recruited in a case‐control study in metropolitan Nagoya. Information on individual survivals was obtained from the computer data‐file of the tumor registry of the Nagoya Bladder Cancer Research Group. Univariate analyses revealed significant associations of 5‐year survivorship with educational attainment, marital status, drinking habits and consumption of green tea in males, and age at first consultation, histological type and grade of tumor, stage and distant metastasis in both sexes. After adjustment for age, stage, histology (histological type and grade) and distant metastasis by means of a proportional hazards model, drinking of alcoholic beverages was significantly associated with the prognosis of bladder cancer in males. Its adjusted hazard ratio was 0.46 (95% confidence interval: 0.26–0.79), favoring patients who had taken alcoholic beverages. In detailed analysis, ex‐drinkers and all levels of current drinkers demonstrated hazard ratios smaller than unity, although no clear dose‐response relationship was detected. No prognostic significance was found for such lifestyle factors as smoking habit, uses of artificial sweeteners and hairdye, and consumption of coffee, black tea, matcha (powdered green tea) and cola.

Activation of Protein Kinase C by Mycobacterial Cord Factor, Trehalose 6-Monomycolate, Resulting in Tumor Necrosis Factor-α Release in Mouse Lung Tissues

Cord factors are mycoloyl glycolipids in cell walls of bacteria belonging to Actinomycetales, such as Mycobacterium, Nocardia and Rhodococcus. They induce granuloma formation in the lung and interstitial pneumonitis, associated with production of macrophage‐derived cytokines. We studied how cord factors induce biological activities in the cells. Cord factors isolated from M. tuberculosis, trehalose 6‐monomycolate (mTMM) and trehalose 6,6′‐dimycolate (mTDM), enhanced protein kinase C (PKC) activation in the presence of phosphatidylserine (PtdSer), diacylglycerol and Ca2+, and mTMM activated PKCα more strongly than PKCβ or γ under the same assay conditions. Kinetic studies of mTMM in response to PKC activation revealed that mTMM increased the apparent affinity of PKC to Ca2+ in the presence of both PtdSer and diolein. Although this is similar to observations with unsaturated fatty acids, such as arachidonic acid, mTMM was synergistic with PtdSer for PKC activation, but arachidonic acid was not. mTMM was also different as regards PKC activation, as phorbol ester was. A single i.p. administration of mTMM to mouse induced tumor necrosis factor‐α (TNF‐α) in serum and in the lung, which is a unique target tissue of cord factors. Based on our recent finding that TNF‐α is an endogenous tumor promoter, the correlation between lung cancer and pulmonary tuberculosis is discussed.

Changes in Serum Concentrations of β‐Carotene and Changes in the Dietary Intake Frequency of Green‐Yellow Vegetables among Healthy Male Inhabitants of Japan

Serum levels of β‐carotene among 147 healthy male inhabitants were measured twice with an interval of one year in order to determine the relationship between changes in serum β‐carotene levels and changes in the dietary intake of green‐yellow vegetables. A positive association was found to exist between changes in the intake frequency of green‐yellow vegetables and changes in serum β‐carotene levels, whereas changes in alcohol intake and smoking were discovered to be negatively associated with changes in serum β‐carotene levels. The positive association between changes in the intake frequency of green‐yellow vegetables and changes in serum β‐carotene levels was preserved after adjustment for these negative factors.

Serum antioxidants and subsequent mortality rates of all causes or cancer among rural Japanese inhabitants.

The purpose of this study was to investigate whether a relationship exists between mortality rates and serum antioxidant levels among Japanese inhabitants. The follow-up subjects, who participated in comprehensive health examinations, consisted of 2444 inhabitants (949 males and 1495 females) of a rural area in Hokkaido, Japan. Between 1991 and December 2000, 146 subjects (94 males and 52 females) died, with cancer accounting for 76 of these deaths (48 males and 28 females). Serum samples at fasting were collected at entry into the study, and serum levels of beta- and alpha-carotenes, lycopene, beta-cryptoxanthin, canthaxanthin, zeaxanthin/lutein, tocopherols, and retinol were measured separately by high-performance liquid chromatography (HPLC). The statistical analyses were conducted using the Cox proportional hazard model. Age- and gender-adjusted hazard ratios of the groups with high serum levels of lycopene, beta-carotene, zeaxanthin/lutein, and total carotenoids compared to those with low serum levels were 0.36 (95% C.I: 0.19-0.69), 0.53 (0.29-0.95), 0.73 (0.43-1.25), and 0.52 (0.30-0.92) for cancers of all sites, and 0.44 (95% C.I: 0.28-0.69), 0.59 (0.39-0.90), 0.61 (0.40-0.93), and 0.50 (0.33-0.76) for all causes, respectively. Similar results were found after adjusting for gender, age, smoking habits, alcohol consumption, and serum levels of total cholesterol and glutamic pyruvic transaminase (GPT) activity. Moreover, after excluding mortality within the first three years of follow-up, the hazard ratios of subjects with high serum levels of lycopene, total carotenes, and total carotenoids were significantly and inversely associated with subsequent mortality from all causes and cancers of all sites after adjusting for gender, age, and serum levels of total cholesterol, alpha-tocopherol, and retinol. These results suggest that high serum levels of antioxidants, such as lycopene, beta-carotene and zeaxanthin/lutein, play roles in preventing death from cancer and from all causes. However, high serum levels of tocopherols and retinol did not demonstrate clear associations with either low mortality rates from all causes or cancer of all sites.

Cancer deaths by city and county in Japan (1969–1971): A test of significance for geographic clusters of disease

Abstract In geographic epidemiology, distribution of the categorized mortality or morbidity rates are visualized on a map. either based on actual land area or adjusted for the population density. Irrespective of the map used, visual study per se by no means indicates the statistical significance of the observed clusters, i.e. whether the geographic aggregations could occur by chance alone. We have developed an approach for assessing the deviation from chance expectation of the geographic pattern actually observed on a map and have described it in this paper. A simple chi-square test is proposed, and the parameters required for the test are (1) total number of areas. (2) numbers of subareas for each mortality or morbidity category. (3) total number of geographically adjacent areas, and (4) observed numbers of adjacent areas having concordant category pairs. When the test was applied to the geographic distribution of esophageal cancer mortality by city and county in Japan (1969–1971). the areas with high mortality were significantly clustered in both sexes, and those with low mortality in males. There were no significant aggregations for breast cancer, though the areas with high mortality seemed distributed mainly in the northern half of the mainland. Japan. For uterus cancer low mortality showed significant clusters, and total geographic pattern was highly significant. The validity of the proposed simple chi-square test of significance was substantiated by a Monte Carlo approach, which was derived analytically as a special case of Knoxs test for space-time clustering.