Different effects of blood pressure on mortality from stroke subtypes depending on BMI levels: a 19-year cohort study in the Japanese general population--NIPPON DATA80.

To evaluate the relationship between blood pressure and cerebrovascular death depending on body mass index (BMI) levels, we analysed a database of 9338 subjects from the National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged, which was originally conducted a baseline survey in 1980 and followed up in 1999. Relative risk (RR) and a 95% confidence interval (CI) of death from total stroke, cerebral infarction, and intracerebral haemorrhage after adjusting for age, sex, serum cholesterol, albumin, glucose, the use of antihypertensive agents, a past history of diabetes, BMI, smoking, and drinking were estimated with the Cox-proportional hazard model in the BMI tertile groups of a representative Japanese population. Cutoff points of BMI tertiles are 21.2 and 23.8 kg/m2. The results indicated that a 10 mmHg systolic blood pressure (SBP) increase was associated with mortality from intracerebral haemorrhage at low and middle BMI groups (RR= 1.38 and 1.23; 95% CI=1.17-1.62 and 1.03-1.47, respectively). SBP was positively associated with mortality from cerebral infarction in middle and high BMI groups (RR=1.19 and 1.21; 95% CI=1.06-1.33 and 1.06-1.38, respectively). The effects of diastolic blood pressure on intracerebral haemorrhage and infarction had the same tendency as those of SBP. These results suggested that the causal effect of blood pressure on stroke subtypes might be modified by BMI.

Correlation coefficients between the dioxin levels in mother's milk and the distances to the nearest waste incinerator which was the largest source of dioxins from each mother's place of residence in Tokyo, Japan.

BACKGROUND: To observe the relationship between the PCDD/F and Co-PCB levels in samples of human breast milk and nearby waste incinerators in Tokyo, Japan. METHODS: Breast milk was taken from 240 mothers residing in Tokyo, Japan to measure and analyze the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs; 14 congeners), polychlorinated dibenzofurans (PCDFs; 15 congeners), and coplanar polychlorinated biphenyls (Co-PCBs; 12 congeners) contained in the fat. Individual milk samples (about 50 ml) were obtained from the mothers 30 days after delivery, between the months of June and September in 1999 and 2000. A map of Tokyo was used to measure the distances between each mother's place of residence and the closest public and industrial waste incinerators. RESULTS: The distances to the nearest waste incinerators bore no apparent correlations with the congeners of PCDD/Fs and Co-PCBs. The distances were also uncorrelated with the mean toxic equivalent quantities (TEQs) of PCDD/Fs (the sum of PCDDs and PCDFs), Co-PCBs, and the total PCDD/Fs and Co-PCBs. CONCLUSIONS: Although waste incinerators were the largest source of dioxins in Japan at the time of the study, the dioxins levels of mother's milk bore no apparent relationships with the distances between the mothers' domiciles and the nearest waste incinerators. In this study, several meaningful factors were not taken into account, namely, the wind direction, the level of dioxin emitted from each incinerator, the level of environmental pollution of dioxins, and the average time the mothers stayed at home each day. A full understanding of these points awaits future studies.

Changes in epidemic patterns of Kawasaki disease in Japan.

OBJECTIVE: Clustering of cases of Kawasaki disease throughout Japan was noted three times during the period before 1986. During the ensuing 10 years, however, no nationwide epidemic has been recognized. The purpose of this study is to test the hypothesis that local outbreaks have persisted after 1987. METHOD: The data on 56 980 patients reported from 1987 through 1996 were classified according to the area of residence. The time trend of the incidence rate was compared by year and by quarter of the year (January to March, April to June, July to September and October to December) in 10 geographical areas in Japan. RESULTS: No nationwide outbreaks have been noted since 1987 in Japan, but the existence of local outbreaks of various magnitudes was recognized as occurring in different periods in certain areas. The incidence rates were continuously high in Area 1 between 1987 and 1988 and in Area 4 between 1995 and 1996. In Area 9 local outbreaks were noted on three separate occasions (from 1987 to the first half of 1988, between 1990 and 1991 and from the second half of 1992 to 1993). No clusterings were witnessed in other areas during the 10-year period. CONCLUSION: The current annual number of patients ranges from 5000 to 6000, and local epidemics occur in various areas. The current epidemiologic patterns support the infection theory for the etiology of this disease.

Harman and norharman induce SOS responses and frameshift mutations in bacteria.

Norharman and harman, beta-carboline derivatives with comutagenic activity in Salmonella typhimurium, were examined for their activity to induce SOS responses in S. typhimurium using the umu-test and mutations in Escherichia coli. The inducibility of the umuC gene by norharman and harman was assayed by measuring the levels of beta-galactosidase activity in tester cells harbouring the umuC'-'lacZ fusion gene on a plasmid. In the umu-test, both norharman and harman weakly induced umuC gene expression at 25-100 and 50-150 micrograms/ml, respectively. In the mutation test using reversion from trpE9777 to Trp+, harman was relatively more potent than norharman in inducing the mutations. These results indicate that norharman and harman induce SOS responses as well as reversion of trpE9777 frameshift mutation in bacteria.

Evaluation of the new system (umu-test) for the detection of environmental mutagens and carcinogens.

The umu operon in Escherichia coli is responsible for chemical and radiation mutagenesis, and the expression of the operon itself is inducible by these DNA-damaging agents. The principle of the umu-test is based on the ability of the DNA-damaging agents, most of which are potential carcinogens, to induce the umu operon. A plasmid (pSK1002) carrying a fused gene umuC'-'lacZ was introduced into Salmonella typhimurium TA1535. The strain TA1535/pSK1002 enabled us to monitor the levels of umu operon expression by measuring the beta-galactosidase activity in the cells produced by the fusion gene. Using this strain, a simple, inexpensive, and sensitive system, the umu-test, for the screening of environmental mutagens and carcinogens was developed. 38 chemicals with different structures and modes of action, including 31 known animal carcinogens, were examined by the test to evaluate the system. The threshold sensitivity of the umu-test was approximately equal to that of the Ames test for chemicals genotoxic in both tests. By the umu-test, using the single tester strain, we detect many types of DNA-damaging agents for which the Ames test requires several tester strains. Furthermore, the umu-test provides a potential practical advantage for the screening of various environmental samples containing amino acids and nutrients such as urine, serum and foods.

SOS-inducing activity of chemical carcinogens and mutagens in Salmonella typhimurium TA1535/pSK1002: examination with 151 chemicals.

The umu test system is a newly developed method to evaluate genotoxic activities of a wide variety of environmental carcinogens and mutagens (Oda et al., 1985). In the present study, we further examined the abilities of 151 chemicals to induce umu gene expression in Salmonella typhimurium TA1535/pSK1002. Among the chemicals examined, 72 compounds induced umu gene expression, which could be defined on a basis of increased beta-galactosidase activity by 2-fold over the background level. The potent genotoxic compounds without metabolic activation were adriamycin, bleomycin, daunorubicin, 1,3-dinitropyrene, 1,6-dinitropyrene, 1,8-dinitropyrene, N-ethyl-N'-nitro-N-nitrosoguanidine, furylfuramide, methyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, mitomycin C, 1-nitropyrene and 4-nitroquino-line-1-oxide. In the presence of S9, aflatoxin B1, 2-aminoanthracene, Glu-P-1, IQ, MeIQ, MeIQx, Trp-P-1 and Trp-P-2 also induced umu gene expression markedly. Several chemicals such as 2-acetylaminofluorene, 9-aminoacridine, azobenzene, benzanthracene, benzidine, diethyl nitrosamine, 1-nitronaphthalene, paraquat, potassium dichromate and sodium nitrite were weakly genotoxic and the induction by these compounds could be detected only when the incubation time was prolonged from 2 h to 5 h. Data are also presented that some of the chemicals such as dimethyl sulfoxide, m-dioxan, 5-fluorouracil and paraquat, which have been reported to be non-mutagenic in Ames/Salmonella assay, were found to be active in inducing umu gene expression, while the known mutagenic compounds including acrylonitrile, 4,4'-dinitrobiphenyl, furfural, methylene chloride, 1-naphthylamine, sodium azide, o-tolidine and o-toluidine were non-genotoxic in the present assay system.

Temporal changes of plasma erythropoietin level in hypobaric hypoxic mice and the influence of an altered blood oxygen affinity.

Temporal changes of plasma erythropoietin (Epo) in mice exposed to hypobaric hypoxia were studied by a fetal mouse liver cell culture method. Since a colony formation inhibitory activity was found in the mouse plasma, thirteen pretreatment procedures for bioassay were compared and the procedure of shaking with chloroform followed by dialysis was concluded to be the best. When normal mice (P50 = 40.4 +/- 2.2 Torr) were exposed to hypoxia of 350 Torr, the plasma Epo level was elevated, with peak at the 2nd to 3rd day, and afterwards declined gradually. On the contrary, cyanated mice (P50 = 30.1 +/- 1.5 Torr) showed much less of the Epo response when exposed to 350 Torr. Under 200 Torr hypoxia, both mice exhibited a similar and remarkable extent of the response. These results suggest that the renal Epo-producing tissue or its oxygen-sensing system is less hypoxic in cyanated mice than in normal mice under 350 Torr, and that the physiologically optimal oxygen affinity of blood is variable depending on hypoxic degrees. The fact that the inhibitory activity showed an inverse temporal change to that of Epo, suggested a possible important role of this activity in the regulation of erythropoiesis under hypoxia.

[Estimation of the future numbers of patients with diabetes mellitus in Japan based on the results of national patient surveys].

The projected numbers of patients with diabetes mellitus (ICD 9th; 250) 15 years from now were estimated. First, the numbers of patients with the disease in 1984, 1987, 1990, and 1993 were calculated by age and sex using data from the National Patient Surveys conducted by the Ministry of Health and Welfare. Then, population prevalence for calendar years 1996, 1999, 2002, 2005, and 2008 were estimated based on the past data using linear regression models. Finally, the total numbers of patients were calculated from the estimated prevalence multiplied by the estimated population figure of the national government. The prevalence and the numbers of patients are estimated to increase, and the numbers will be 1.7 million among males and 1.5 million among females in 2008. Besides, because of the increases of both the aged population and the disease prevalence, the proportion of patients aged 65 years or over will become as large as 40% of total male patients and 60% of females.

[Chronological trend of the incidence rate of Creutzfeldt-Jakob disease in Japan].

OBJECTIVE: The purpose of this study was to find whether the number of incidents of Creutzfeldt-Jakob disease has increased during the last decade in Japan. METHODS: The chronological trend was observed by examining the data from a nationwide epidemiologic survey conducted by a special committee sponsored by the Ministry of Health and Welfare of Japan in May 1996. The subjects of the survey were patients with Creutzfeldt-Jakob disease who had been diagnosed between January 1985 and May 1996. Although the number of patients reported each year increased continually during the 11-year 5-month period, there were two issues that remained to cast doubt on the accuracy of this apparently obvious chronological trend: (1) the existence of hospitals that did not respond to the survey, and (2) the existence of hospitals where no information was available before a specific time during the observation period. To make up for the incomplete data, the following two methods were proposed: (1) for those hospitals where the precise annual incidence was not known, the average annual incidence for those years when the information was available should be used to make up for the missing data and (2) when a hospital did not have the information for certain years, it would be considered to be a nonrespondent for those years; the response rate should be calculated year-by-year; then the total number of patients should be obtained by the reported number of patients divided by the response rate. The first method underestimates the annual trend if a trend does exist. To evaluate the trend mathematically, linear regression and quadratic regression models were used, in which the independent variable was the calendar year, the dependent variable, the number of patients. RESULTS: With either method, a trend for increases in incidence was noted. Statistical significance was obtained for the increasing trend in each model. It was found that the quadratic regression model was a better fit than the linear model. CONCLUSION: The incidence of Creutzfeldt-Jakob disease in Japan has increased during the last decade.

[Building aging level indices based on ability to perform personal care and household management activities].

Defining aging as deterioration of the ability required for the activities of daily living with increasing age, we developed a formula for estimating the age of aging. In 1994 and 1995, a questionnaire survey was conducted for 11,592 individuals (4,885 men, mean age 61.6, standard deviation 14.6; and 6,677 women, mean age 63.2, standard deviation 14.8) who were members of 7 cohorts (5 community-based cohorts and 2 cohorts of examiners at a health-promotion center). The questionnaire included three groups of questions related to medical treatment, aging-related symptoms, and personal care (ADL; Activities of Daily Living) and household management (IADL: Instrumental ADL). Multiple regression analysis was made by sex and age group (over 65 years old, under 65 years old) using age as a dependent variable and the three question categories as explanatory variables. Using multiple regression analysis by question category, five items were abstracted from each of the three groups, so that a total of 15 items were abstracted from all questions. Five items were then abstracted from the 15 by multiple regression analysis, and the predicted aging age for an individual is estimated using this statistical model from the results of the questionnaire survey. The predicted aging age is significantly associated with age (r = 0.40-0.49, p = 0.0001). The difference between the predicted aging age and age is greater among the older or younger people. The expected predicted aging age is estimated using regression analysis of the predicted aging age on age. Aging level indices by sex and age groups were determined by the difference between the expected predicted aging age and age. We are planning to carry out an epidemiological study on the risk factor for aging using the aging level indices in seven cohorts.

[Case-control study of risk factors for cedar pollinosis among parents of 3-year-old children].

PURPOSE: To identify risk factors associated with cedar pollinosis among parents of three-year-old children. METHODS: The subjects were parents whose children underwent health examination at the age of three years in September and October 1997 in Tochigi prefecture. We distributed questionnaires to the examinees beforehand with the request that they be filled in and brought to the examination site. Information on parents' environmental factors (place of residence, type and structure of housing, and distance from roads with heavy traffic), and mothers' past history and family history of allergic diseases was obtained. We defined cedar pollinosis in terms of three symptoms, sneezing, nasal discharge, and nasal obstruction, between February and May. Controls were those who did not have any of the three symptoms. Environmental factors were assessed with univariate and multivariate analyses using unconditional logistic models. Maternal genetic factors were also analyzed with odds ratios and 95% confidence intervals calculated for each. We also compared odds ratios of environmental factors between groups with and without genetic factors. RESULTS: Of the parents of children taking the health examination, 90.2% took part (2,968 of 3,291 couples). Information was obtained from 2,846 mothers and 2,905 fathers. Mother and father cases were 312 and 229, and controls were 1,857 and 1,934, respectively. For the univariate analysis of environmental factors, place of residence (residential area/agricultural area), type of housing (apartment complex/solitary house), structure (reinforced concrete building/wooden house), and distance from heavy traffic (< 100 m/100 m+) were positively related to cedar pollinosis. For the multivariate analysis using unconditional logistic models, the odds ratio was significantly high for distance from heavy traffic (< 100 m/100 m+) among fathers. Mothers' past history and family history of allergic diseases showed high odds ratios for cedar pollinosis. We classified groups with and without past and family histories of allergic diseases (group with and without genetic factors) for assessment with multivariate analyses. Odds ratios for the group with an allergic history were higher than for those without such a history, but difference for factors such as, distance from heavy traffic type of housing, and structure were not statistically significant. CONCLUSION: Risk of cedar pollinosis increases with distance from heavy traffic among fathers. Mothers with histories of allergy show slightly elevated odds ratios for environmental factors, but without statistic significance.

[Relationship between breast milk and atopic dermatitis in children].

OBJECTIVE: To determine whether or not dioxins and furans in breast milk have a role in the prevalence of atopic dermatitis among children. METHODS: The target population of the study was all children participating in health check-up program for 3-year-old children in Tochigi Prefecture in September and October 1997. Using a questionnaire, information on nutrition in infants (breast milk only, bottled milk only, or mixed), parity, mothers' age at birth, and a history of atopic dermatitis was obtained. Besides, data on potential confounding factors were obtained. RESULTS: Questionnaires from 2,968 children (85.3% of those who were to participate in the programs, and 90.2% of children who participated them) were analyzed. The risk of atopic dermatitis was higher among children with breast milk (odds ratio [OR] = 1.37 with 95% confidence interval [CI] 1.02-1.83) and those with mixed nutrition (OR = 1.21, 95% CI: 0.94-1.57) in comparison with children with only bottled milk. Mothers' age at birth (OR for those who were more than 30 years or older in comparison with those who were younger than 30 years = 1.27; 95% CI, 1.01-1.62) and those with second or later parity orders (OR = 1.32, 95% CI; 1.04-1.67) were also risk factors of the dermatitis after the adjustment for some potential confounding factors. CONCLUSION: Breast milk elevates the risk of atopic dermatitis slightly; the risk is, however, higher in children in second or later parity orders. If the PCDDs and PCDFs in breast milk cause the dermatitis, this would contradict the assumed metabolism of these chemicals in human bodies.