Michiko Yamada

Noncancer Disease Incidence in Atomic Bomb Survivors, 1958–1998

Abstract Yamada, M., Wong, F. L., Fujiwara, S., Akahoshi, M. and Suzuki, G. Noncancer Disease Incidence in the Atomic Bomb Survivors, 1958–1998. Radiat. Res. 161, 622–632 (2004). We examined the relationships between the incidence of noncancer diseases and atomic bomb radiation dose using the longitudinal data for about 10,000 Adult Health Study (AHS) participants during 1958–1998. The current report updates the analysis we presented in 1993 with 12 additional years of follow-up. In addition to the statistically significant positive linear dose–response relationships detected previously for the incidence of thyroid disease (P < 0.0001), chronic liver disease and cirrhosis (P = 0.001), and uterine myoma (P < 0.00001), we also found a significant positive dose response for cataract (P = 0.026), a negative linear dose–response relationship for glaucoma (P = 0.025), and significant quadratic dose–response relationships for hypertension (P = 0.028) and for myocardial infarction among survivors exposed at less than 40 years of age (P = 0.049). Significant radiation effects for calculus of the kidney and ureter were evident for men but not for women (test of heterogeneity by sex: P = 0.007). Accounting for smoking and drinking did not alter the results. Radiation effects for cataract, glaucoma, hypertension, and calculus of the kidney and ureter in men are new findings. These results attest to the need for continued follow-up of the aging A-bomb survivors to fully elucidate the effects of radiation exposure on the occurrence of noncancer diseases.

Association Between Dementia and Midlife Risk Factors: the Radiation Effects Research Foundation Adult Health Study

OBJECTIVES:  To investigate the association between midlife risk factors and the development of vascular dementia (VaD) or Alzheimers disease (AD) 25 to 30 years later.

Risk factors for hip fracture in a Japanese cohort

Risk factors for hip fracture were determined from a Japanese cohort. A cohort of 4573 people (mean age 58.5 ± 12.2) who participated in the Adult Health Study in 1978–1980 were subsequently followed by biennial examinations up to 1992. Fifty‐five incident hip fractures not due to traffic accidents were identified by medical records during the follow‐up period. Poisson regression analysis showed that baseline low body mass index (BMI), regular alcohol intake, prevalent vertebral fracture, and having five or more children significantly increased the risk of hip fracture, and low milk intake and later age at menarche were marginally associated with increased fracture risk, after multivariable adjustment. Regular alcohol intake doubled the risk of hip fracture (relative risk 1.91, 95% confidence interval 1.07–3.42). Those individuals who had a vertebral fracture had 2.6 times higher risk than those who did not. The risk was 2.5 times higher among women who had five or more children than women with one or two. Body height, health status, marital status, intake of fish, coffee, tea, Japanese tea, smoking, exposure to atomic bomb radiation, and age at menopause were not associated with hip fracture. Relative risk for hip fracture decreased with decreasing number of preventable risk factors (low BMI, low milk intake, and regular alcohol intake). We conclude that many factors, such as BMI, milk intake, alcohol intake, prevalent vertebral fracture, age at menarche, and number of children, are related to the risk of hip fracture, and prevention programs need to focus on reducing preventable risk factors.

Prevalence and risks of dementia in the Japanese population : RERF's adult health study Hiroshima subjects

OBJECTIVES: To study the prevalence rate of dementia and its subtypes in Japan and to investigate the relationship of risk factors, such as demographic features and disease history, to the prevalence of Alzheimers disease or vascular dementia.

Dementia as a Predictor of Functional Disability: A Four-Year Follow-Up Study

Background: Prospective studies have shown that cognitive impairment is a strong and consistent risk factor of physical disability. However, cognitive impairment has been based on the result of a single screening tool. Objective: To investigate the role of cognition in the subsequent incidence and decline of functional disability in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) after a full assessment of dementia. Methods: A group of 1,358 Japanese atomic bomb survivors aged 61 years or older who lived in the community or in institutions in Hiroshima City were followed for 4 years. During the baseline survey (1993–1995), subjects were administered a screening test for cognitive impairment. Those suspected of dementia underwent a series of cognitive tests (Hasegawa’s dementia scale, Clinical Dementia Rating) and a neurological examination. The diagnosis of dementia was made according to DSM-III-R criteria. Study subjects were questioned about their reported ADL and their IADL. During the follow-up period, deaths were recorded and a follow-up survey (1997–1999) used to assess ADL and IADL performance. Results: Dementia, even after adjustment for age, sex and history of stroke, was a strong predictor of functional disability, as indicated by ADL (odds ratio, OR = 14.0; confidence interval, CI = 5.4–36.3), IADL (OR = 10.1, CI = 2.2–46.4), and also by assessment of decline in ADL (OR = 9.8, CI = 4.2–22.8) or IADL status (OR = 3.9, CI = 1.8–8.3). Conclusion: Dementia is an important determinant of functional status. Deterioration in ADL is more significant than deterioration in IADL, suggesting that factors other than cognition, such as motivation or perceptual, sensory and motor abilities, may be important in IADL performance. This study confirms previous findings on risk factors that affect functional ability and extends our knowledge by examining several criteria of function that are important in the daily lives of elderly people.

Animal Protein, Animal Fat, and Cholesterol Intakes and Risk of Cerebral Infarction Mortality in the Adult Health Study

Background and Purpose— A traditional diet that is poor in animal products is thought to explain the high rate of stroke in Asian populations. The purpose of the present study was to examine the effect of a diet rich in animal protein, animal fat, and cholesterol on the risk of cerebral infarction mortality in a Japanese population. Methods— A prospective study of 3731 Japanese men and women aged 35 to 89 years was conducted from 1984 to 2001. Nutrient intake was estimated at baseline from the responses to a 24-hour diary. During the follow-up period, cases of cerebral infarction deaths (as entered on death certificates) were monitored. Results— During the follow-up period, 60 deaths were attributed to cerebral infarction. A high intake of animal fat and cholesterol was significantly associated with a reduced risk of cerebral infarction death. The risk was reduced by 62% (CI, 82% to 18%) for those in the third tertile of animal fat intake, compared with those in the first tertile, with a significant linear dose-response relationship (P =0.0073). The risk of death from infarction was reduced by 63% (CI, 82% to 22%) in the high cholesterol consumption group, compared with the low consumption group. A significant linear dose–response relationship was observed. Animal protein was not significantly associated with infarction mortality after adjustment for animal fat and cholesterol. Conclusions— This study suggests that in Japan, where animal product intake is lower than in Western countries, a high consumption of animal fat and cholesterol was associated with a reduced risk of cerebral infarction death.

Noncancer disease incidence in the atomic bomb survivors : 1958-1986

Using the longitudinal data of the Adult Health Study (AHS) cohort collected during 1958-1986, we examined for the first time the relationship between exposure to ionizing radiation and the incidence of 19 nonmalignant disorders in the A-bomb survivors. Affected individuals were ascertained through the three-digit codes of the International Classification of Diseases which are encoded in the AHS database subsequent to diagnoses made on the basis of general laboratory tests, physical examinations, and history-taking conducted during biennial AHS examinations. The disease onset time was estimated using the mid-point between the AHS examination data when the disease was initially reported and the previously attended disease-free examination date. Dosimetry System 86 organ doses judged to be most appropriate were used. Tests of dose effects were performed assuming a linear relative risk model with stratified background incidence. For the entire study period, significant excess risk was detected for uterine myoma (P < 0.001), chronic liver disease and cirrhosis (P = 0.006), and thyroid disease (P < 0.0001), defined broadly as the presence of one or more of certain noncancerous thyroid conditions. The incidence of myocardial infarction was shown to be increased (P = 0.03) in later years (1968-1986) among the younger heavily exposed AHS subjects, confirming the results of the recent Life Span Study (LSS) noncancer mortality report on coronary heart disease. The findings for uterine myoma may serve as additional evidence indicating benign tumor growth as a possible consequence of radiation exposure. Our results indicating the involvement of radiation in the development of liver diseases are consistent with the report of increased mortality from liver cirrhosis with radiation dose in the LSS cohort. An effect of age at exposure was detected for nonmalignant thyroid disease (P = 0.02), with an increased risk for those exposed who were under 20 years of age, but not for older survivors. Thus the AHS data suggest that thyroid glands in the young are more radiosensitive not only to the development of malignancies, but also to the development of nonmalignant disorders as well. The findings hold independently of the dose effects observed for thyroid cancer. This study also shows that for the period 1958-1986 new occurrences of lens opacity are not increased with radiation dose (P = 0.39) in the AHS subjects.

Effects of Radiation on the Longitudinal Trends of Total Serum Cholesterol Levels in the Atomic Bomb Survivors

The effects of radiation on the long-term trends of the total serum cholesterol levels of the Hiroshima and Nagasaki atomic bomb survivors were examined using data collected in the Adult Health Study over a 28-year period (1958-1986). The growth-curve method was used to model the longitudinal age-dependent changes in cholesterol levels. For each sex, temporal trends of cholesterol levels were characterized with respect to age, body mass index, city and birth year. We then examined whether the temporal trends differed by radiation dose. We showed that the mean growth curve of cholesterol levels for the irradiated subjects were significantly higher than that for the unirradiated subjects, and that the increase was greater for women than for men. No difference in dose response was detected between Hiroshima and Nagasaki. An increased mean level of cholesterol was evident for irradiated women in general, but a notable increase was apparent in males only for the youngest birth cohort of 1935-1945. The difference in the mean cholesterol levels between the irradiated and unirradiated subjects diminished past 70 years of age. It is not known whether this is due to natural progression or is an artifact of nonrandom variation in the rate of participation in the examinations. The maximum predicted increase at 1 Gy for women occurred at age 52 years for the 1930 cohort: 2.5 mg/dl (95% CI 1.6-3.3 mg/dl) for Hiroshima and 2.3 mg/dl (95% CI 1.5-3.1 mg/dl) for Nagasaki. The corresponding increase for men occurred at age 29 years for the 1940 cohort: 1.6 mg/dl (95% CI 0.4-2.8) for Hiroshima and 1.4 mg/dl (95% CI 0.3-2.6) for Nagasaki. Controlling for cigarette smoking did not alter the dose-response relationship. Although the difference in the mean growth curves of the irradiated and unirradiated groups was statistically significant, there was a considerable overlap in the individual growth curves of the two groups. The significant sex difference and the greater magnitude of radiation effects in women suggest that hormonal changes resulting from radiation exposure, such as accelerated menopause, is an area worth investigating to delineate the mechanisms underlying the increased cholesterol levels of the irradiated female subjects. This increase may also partially explain the increased rate of coronary heart disease seen in the atomic bomb survivors.

Mutation of the Follicle-Stimulating Hormone Receptor Gene 5'-Untranslated Region Associated With Female Hypertension

Inactivating mutations in the follicle-stimulating hormone receptor (FSHR) gene have been reported to cause hereditary hypergonadotropic ovarian failure. It has been found recently that the FSHR knockout mouse exhibits hypertension. The aim of the present study was to investigate the association between polymorphisms in the human FSHR gene and essential hypertension (EH) by using single nucleotide polymorphisms (SNPs). We selected 5 SNPs in the gene (rs1394205, rs2055571, rs11692782, rs1007541, and rs2268361) and performed 2 genetic case–control studies in different populations. A confirmative case–control study was performed using 1035 EH patients and 1058 age-matched controls. Transcriptional activities were measured with a luciferase assay system. The first case–control study found that the A allele of rs1394205 was significantly higher in EH females (P=0.010). In addition, in the confirmative case–control study, there was a significant difference for this SNP between female normotensive subjects (44.5%) and EH patients (50.7%) (P=0.043). Multiple logistic regression analysis in female subjects also revealed a significant association of subjects with the A allele of rs1394205 with EH (P=0.033), with the odds ratio calculated as 1.68 (95% CI: 1.04 to 2.73). Transcriptional activity of the A allele was 56±8% (mean±SD) of that observed for the G-type allele (P=0.001). Serum estradiol levels were significantly lower in patients with the A/A genotype than in patients without the A/A genotype (P=0.004). The SNP in the 5′-untranslated region of the FSHR gene affects levels of transcriptional activity and is a susceptibility mutation of EH in women.

Relationship between HbA1c and mortality in a Japanese population

Aim/hypothesisHbA1c concentrations are known to be associated with all-cause excess mortality risk in Caucasians. However, the relationship has not been clarified well in the Japanese. In addition, studies of the relationship between HbA1c and mortality from malignant neoplasms are scarce.MethodsHbA1c was measured for 3,710 people of a cohort composed of A-bomb survivors and controls. At baseline they were divided into five groups: a normal HbA1c group of 1,143 individuals with HbA1c of <5.5%, a slightly high but normal HbA1c group of 1,341 individuals with HbA1c ≥5.5% to <6.0%, a slightly high HbA1c group of 589 individuals with HbA1c ≥6.0% to <6.5%, a high HbA1c group of 259 individuals with HbA1c ≥6.5%, and a group of 378 individuals known to have type 2 diabetes. Using a Cox proportional hazards model, hazard ratios based on comparisons with the normal HbA1c group were obtained.ResultsDuring the observation period there were 754 deaths. For all-cause and cardiovascular disease mortality, a significant increase of the hazard ratio was observed for the slightly high HbA1c group. A similar increase in malignant neoplasm-related mortality was observed for both the high HbA1c group and the diabetes group.Conclusions/interpretationOur results suggest that individuals in the Japanese population with HbA1c levels of 6% or more might have increased mortality risk. The results indicate that HbA1c measurements should be sought even for people who have not been diagnosed with diabetes.