Mortality of rheumatoid arthritis in Japan: a longitudinal cohort study.

OBJECTIVE: To determine the mortality risk of Japanese patients with rheumatoid arthritis, taking into account lifestyle and physical factors, including comorbidity. METHODS: 91 individuals with rheumatoid arthritis were identified during screening a cohort of 16 119 Japanese atomic bomb survivors in the period 1958 to 1966. These individuals and the remainder of the cohort were followed for mortality until 1999. Mortality risk of the rheumatoid patients was estimated by the Cox proportional hazards model. In addition to age and sex, lifestyle and physical factors such as smoking status, alcohol consumption, blood pressure, and comorbidity were included as adjustment factors for the analysis of total mortality and for analysis of mortality from each cause of death. RESULTS: 83 of the rheumatoid patients (91.2%) and 8527 of the non-rheumatoid controls (52.9%) died during mean follow up periods of 17.8 and 28.0 years, respectively. The age and sex adjusted hazard ratio for mortality in the rheumatoid patients was 1.60 (95% confidence interval, 1.29 to 1.99), p < 0.001. Multiple adjustments, including for lifestyle and physical factors, resulted in a similar mortality hazard ratio of 1.57 (1.25 to 1.94), p < 0.001. Although mortality risk tended to be higher in male than in female rheumatoid patients, the difference was not significant. Pneumonia, tuberculosis, and liver disease were significantly increased as causes of death in rheumatoid patients. CONCLUSIONS: Rheumatoid arthritis is an independent risk factor for mortality. Infectious events are associated with increased mortality in rheumatoid arthritis.

Prevalence of atopic dermatitis in Japanese elementary schoolchildren.

BACKGROUND: Although there have been several reports on the prevalence of atopic dermatitis (AD) in Japanese schoolchildren based on questionnaires, there has been no nation-wide study of the frequency of this condition diagnosed by dermatologists in regular health check-ups of schoolchildren. OBJECTIVES: The objective of this work was to evaluate precisely the prevalence of AD in elementary schoolchildren in Japan based on regular health check-ups by dermatologists. METHODS: In 2001/2, elementary schoolchildren: first graders (age 6-7 years) and sixth graders (age 11-12 years) were examined by dermatologists in eight prefectures of Japan (Hokkaido, Iwate, Tokyo, Gifu, Osaka, Hiroshima, Kochi and Fukuoka). In each prefecture, public elementary schools were randomly selected from urban and rural districts. We planned to examine about 700 schoolchildren in each of urban first, urban sixth, rural first and rural sixth grades from the eight areas, a total of 22 400 children (700 x 4 x 8). AD was diagnosed by the dermatologists based on the Japanese Dermatological Association criteria for the disease. RESULTS: The point prevalence of AD was 11.2% overall (2664 of 23 719) ranging from 7.4% (Iwate) to 15.0% (Fukuoka) in the eight areas. Seventy-four per cent, 24%, 1.6% and 0.3% of those afflicted were in the mild, moderate, severe and very severe groups, respectively. Overall, the prevalence of first graders was slightly higher than that of sixth graders (11.8% vs. 10.5%, P < 0.01). There was no apparent difference in prevalence between urban and rural districts, or between boys and girls. CONCLUSIONS: The prevalence of AD in Japanese elementary schoolchildren was about 10%, three-quarters of those being mildly affected. This is the first nation-wide study made of Japanese elementary schoolchildren examined by dermatologists to evaluate the frequency of AD.

Radiation dose-dependent increases in inflammatory response markers in A-bomb survivors.

PURPOSE: The well-documented increases in malignant tumours in the A-bomb survivors have recently been supplemented by reports that non-cancer diseases, including cardiovascular disease, may also have increased in incidence with increasing radiation dose. Given that low-level inflammatory responses are widely accepted as a significant risk factor for such diseases, we undertook a detailed investigation of the long-term effects of ionizing radiation on the levels of the inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) in A-bomb survivors. MATERIALS AND METHODS: Blood samples were taken from 453 participants in a long-term epidemiological cohort of A-bomb survivors. Plasma levels of CRP and IL-6 were measured using standard antibody-mediated procedures. Relationships between CRP or IL-6 levels and radiation dose were then investigated by multivariate regression analysis. Blood lymphocytes from each individual were used for immunophenotyping by flow cytometry with murine monoclonal antibodies to CD3, CD4 and CD8. RESULTS: CRP levels were significantly increased by about 31% Gy(-1) of estimated A-bomb radiation (p=0.0001). Higher CRP levels also correlated with age, male gender, body mass index and a history of myocardial infarction. After adjustments for these factors, CRP levels still appeared to have increased significantly with increasing radiation dose (about 28% increase at 1Gy, p=0.0002). IL-6 levels also appeared to have increased with radiation dose by 9.3% at 1Gy (p=0.0003) and after multiple adjustments by 9.8% at 1Gy (p=0.0007). The elevated CRP and IL-6 levels were associated with decreases in the percentages of CD4(+) helper T-cells in peripheral blood lymphocyte populations. CONCLUSIONS: Our results appear to indicate that exposure to A-bomb radiation has caused significant increases in inflammatory activity that are still demonstrable in the blood of A-bomb survivors and which may lead to increased risks of cardiovascular disease and other non-cancer diseases.

Medical and socioenvironmental predictors of hospital readmission in patients with congestive heart failure.

BACKGROUND: Patients with chronic congestive heart failure (CHF) require frequent rehospitalization because of the exacerbation of CHF. It is of clinical importance to determine predicting factors for readmission to reduce this likelihood. Previous studies have focused primarily on the demographic and medical characteristics in selected subsets of patients. Therefore, within a broad cohort of consecutively hospitalized patients, we sought to identify not only demographic and medical predictors but also socioenvironmental factors associated with readmission. METHODS: We assessed demographic (age, sex), medical (etiology of CHF, New York Heart Association functional class, left ventricular ejection fraction, previous admission for CHF, length of hospital stay, comorbidity, and medications), and socioenvironmental variables (occupation, financial resources, living alone, and follow-up visits) in 230 patients discharged with a diagnosis of CHF and recorded hospital readmission. RESULTS: Within 1 year after discharge, 81 patients (35%) were readmitted. Five variables, including poor follow-up visits (odds ratio [OR] 4.9, 95% CI 2.0-11.8), previous admission for CHF (OR 3.3, 95% CI 1.8-6.1), no occupation (OR 2.6, 95% CI 1.2-5.5), longer hospital stay (OR 3.2, 95% CI 1.2-8.5), and hypertension (OR 2.0, 95% CI 1.1-3.7), were identified as significant independent predictors for readmission by multivariate logistic regression analysis. CONCLUSIONS: Our independent predictors of readmission support the importance of medical and socioenvironmental factors in the deterioration of CHF. Therefore interventions to decrease readmission should also target social management in all hospitalized patients.

p53 gene mutations are associated with shortened survival in patients with advanced non-small cell lung cancer: an analysis of medically managed patients.

Mutations in the p53 gene are common in many cancers. Nevertheless, the relationship between mutations of this tumor suppressor gene and patient survival in non-small cell lung cancer (NSCLC) remains unclear. Interpretation of prior studies of patient outcomes are complicated by the inclusion of both surgical and nonsurgical patients. To better isolate the potential effects of p53 gene mutations per se on tumor progression, we chose to examine patients with advanced disease in whom surgery was not performed (stages IIIA, IIIB, and IV). We have used PCR-denaturing gradient gel electrophoresis, a sensitive and specific method for the detection of a variety of p53 mutations in cytology or biopsy specimens, to evaluate the prognostic significance of p53 gene mutations in nonsurgical patients with advanced NSCLC. In 70 consecutive medical patients, p53 mutations were found in 29 cases (41%) at the time of initial diagnosis. Followed prospectively, patients with p53 mutations had a significantly reduced survival time after diagnosis than those without mutations (median survival, 17 versus 39 weeks; P = 0.0003) independent of other clinical factors. This abbreviated survival occurred in both patients who received chemotherapy (n = 39, P = 0.002) or best supportive care (n = 31, P = 0.018). These results indicate that mutations of the p53 gene in patients with NSCLC who do not undergo surgical resection portends a significantly worse prognosis.

Clinical characteristics and prognosis of hospitalized patients with congestive heart failure--a study in Fukuoka, Japan.

The clinical characteristics and prognosis of patients with congestive heart failure (CHF) have been described by a number of previous studies, but very little information is available on this issue in Japan. This study aimed to delineate the clinical characteristics and prognosis of Japanese patients hospitalized with CHF. Medical records were reviewed for 230 consecutive patients at 5 teaching hospitals in Fukuoka, Japan from January to December 1997 and the survival and hospital readmission were followed through December 1999 (mean follow-up, 2.4 years). The study population had a high mean age, contained a larger population of women especially in the older ages, and had a higher incidence of overt HF (48%) despite a relatively normal ejection fraction on echocardiography. Major causes of CHF were ischemic, valvular, and hypertensive heart diseases. The 1-year mortality rate was as low as 8.3% whereas rates of hospital readmission because of an exacerbation of CHF were as high as 40% during the follow-up period. Patients hospitalized with CHF in routine clinical practice in Japan have characteristics that differ from those in the population included in community-based studies or large clinical trials.

Association of a polymorphism at the 5'-region of the angiotensin II type 1 receptor with hypertension.

Molecular variants of individual components of the renin-angiotensin system are thought to contribute to inherited predisposition towards essential hypertension. Using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and sequence analysis, we identified seven polymorphisms in the 5'-flanking region of the angiotensin II type 1 receptor (AGTR1/AT 1 ) gene. We conducted a case-control study in a sample from the Japanese population to determine whether polymorphic markers in the 5'-flanking region of the AT 1 gene were associated with essential hypertension. The study compared 149 hypertensive subjects to 156 normotensive control subjects. A significantly higher frequency of the AT 1 (-535)*T allele was observed in hypertensive subjects. Evidence was obtained that the AT 1 (-535)*T allele showed a synergistic effect on risk of hypertension with angiotensin I converting enzyme D allele (ACE*D).

Decreased proportion of CD4 T cells in the blood of atomic bomb survivors with myocardial infarction.

Epidemiological studies of the atomic bomb survivors have suggested dose-related increases in mortality from diseases other than cancer. Cardiovascular disease is one such noncancer disease for which increases in both mortality and incidence have been found to be associated with radiation dose. Immunological studies have revealed long-term impairment of T-cell-mediated immunity, especially involving deficiencies of CD4 helper T cells, in atomic bomb survivors. In the present study, we investigated whether decreases in CD4 T cells were associated with myocardial infarction in atomic bomb survivors. Of 1,006 survivors examined to determine the proportion of CD4 T cells in peripheral blood lymphocytes, 18 persons had a history of myocardial infarction. The proportion of CD4 T cells was significantly decreased with increased radiation dose [corrected]. Further, the prevalence of myocardial infarction was significantly greater in individuals with a lower proportion of CD4 T cells. These results suggest that myocardial infarction in atomic bomb survivors may be associated with defects in CD4 helper T cells.

[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.

Prevalence and risks of dementia in the Japanese population: RERF's adult health study Hiroshima subjects. Radiation Effects Research Foundation.

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 Alzheimer's disease or vascular dementia. DESIGN: A prevalence study within a longitudinal cohort study. SETTING: The original Adult Health Study (AHS) cohort consisted of atomic-bomb survivors and their controls selected from residents in Hiroshima and Nagasaki using the 1950 national census supplementary schedules and the Atomic Bomb Survivors Survey. Since 1958, the AHS subjects have been followed through biennial medical examinations. PARTICIPANTS: Subjects were 637 men and 1585 women aged 60 years or older in the AHS cohort. Forty-eight subjects resided in hospitals and institutions. MEASUREMENTS: In addition to the biennial medical examinations ongoing since 1958, a screening test for cognitive impairment (CASI) was conducted by trained nurses between September 1992 and September 1996. The prevalence of dementia and its subtypes was assessed in 343 subjects suspected to have dementia and in 272 subjects with high CASI scores who were selected randomly. RESULTS: The prevalence of dementia based on DSM III/R criteria, using neurological examination, the IQCODE, and CDR > or = 1, was 7.2%. The prevalence of Alzheimer's disease was 2.0% in men and 3.8% in women, and the prevalence of vascular dementia was 2.0% in men and 1.8% in women. The relationship of risk factors to Alzheimer's disease or vascular dementia was investigated by the multivariate logistic linear regression analysis. Odds ratios of Alzheimer's disease for age (in 10-year increments), attained education (in 3-year increments), history of head trauma, and history of cancer are 6.3, 0.6, 7.4, and 0.3, respectively. Odds ratios of vascular dementia for age, history of stroke, and history of hypertension are 2.0, 35.7, and 4.0, respectively. Neither type of dementia showed any significant effect of sex or radiation exposure. CONCLUSION: This study is the first study of Japanese dementia rates carried out with a protocol similar enough to that of a US study to allow meaningful comparisons. The prevalence rates demonstrated are more similar to US rates than were found in many previous reports in Japan.

Life-style related factors and idiopathic dilated cardiomyopathy--a case-control study using pooled controls.

A case-control study was conducted to investigate how basic habits of life including dietary habit, physical activity, cigarette smoking, and drinking, are involved in the development of idiopathic dilated cardiomyopathy (DCM). Collection of cases was entrusted to the clinical research group of DCM, and national pooled controls established by sex and age category by the epidemiological research group of intractable diseases were used to ensure representativeness of the controls. Fifty-eight cases of DCM which developed in and after January 1991 were collected, and 5,912 controls matched with the cases by residential area, sex, and age were selected. Analysis of the results of the study showed that items in the questionnaire suggestive of viral infection, such as "susceptibility to common cold" and "susceptibility to diarrhea", items concerning dietary habit, including "taking no breakfast", "ingestion of salty food", and "ingestion of fatty food", and such items as "cigarette smoking" and "lack of sleep" tended to be observed in the case group at significantly higher frequencies. Since viral infection has been suspected as a causative factor of DCM, further research of this area is thought to be of particular importance for determining the etiology of DCM.

Rates of change in spinal bone density among Japanese women.

To determine the rates of change in bone mineral density (BMD) at the spine in healthy Japanese women, longitudinal measurements of spinal BMD using dual X-ray absorptiometry were collected from 984 women over 17 years of age (mean age 51.6) at eight medical research centers. They were followed up for 20.9 months on average without any treatment influencing bone and calcium metabolism. Measurements of BMD obtained by two different scanners were converted into standardized BMD (sBMD) values. The multiple linear regression model predicts that spinal sBMD increases up to about 23 years of age: the estimated average rates of increases were 0.13%/year for women aged 20 years. After the age of 23, the sBMD began decreasing: the rates of loss increased by 0.045%/year for each year increase in age among premenopausal women. In perimenopausal women, the rate of loss was 2. 1%/year. In postnatural menopausal women, the rates of loss decreased exponentially with increasing years since menopause. The rates of loss increased by 0.04%/year for 1 kg decrease in body weight or by 0.1%/year for 1 kg/m2 decrease in body mass index. No significant differences in changes in sBMD were found between scanners and between centers after multiple adjustment. We conclude that the rates of change in spinal sBMD are associated with age in premenopausal women, and with years since menopause and weight or BMI in postmenopausal women. Caution is needed, however, when using data from different densitometers to evaluate rates in bone loss in multicenter trials.

Factors influencing lumbar spine bone mineral density assessment by dual-energy X-ray absorptiometry: comparison with lumbar spinal radiogram.

A study was conducted to determine the effect of radiographic findings of lumbar spinal changes upon bone mineral density measurements obtained by dual energy X-ray absorptiometry (DXA). Four hundred subjects were chosen from among 1543 community residents, aged 40-79 years. Study groups of 50 subjects each were selected by sex and 10-year age groups. This study investigated 390 of the 400 subjects who agreed to the conduct of spine bone mineral density measurement and spinal radiography. Lumbar spine radiograms were examined for findings of osteophyte formation, facet joint osteoarthritis, vertebral fracture, and aortic calcification. The prevalence of osteophyte formation, facet joint osteoarthritis, vertebral fracture, and aortic calcification increased with age in both men and women. On multiple regression analysis, bone mineral density was significantly higher (P < 0.001) in subjects with osteophyte formation or facet joint osteoarthritis than in those without these conditions, while bone mineral density was significantly lower in subjects with vertebral fracture. This study demonstrated that osteophyte formation, facet joint osteoarthritis, and vertebral fracture should be taken into account in the evaluation of bone mineral density by DXA in people in older age groups, since these conditions occur at a considerable rate in such subjects.

Relationship between the level of activities of daily living and chronic medical conditions among the elderly.

The purpose of this study is to observe the disease-disability association through a cross-sectional study. Between 1994 and 1995, we conducted a questionnaire survey in 5 towns in Japan. Among the items included in the questionnaire, 5 related to ADL (bathing, feeding, dressing/undressing, toileting, and going out socially) were treated as purpose variables; and 5 related to the history of medical treatment received over the past year (diabetes, heart disease, cerebrovascular disease, neuralgia, and bone fractures) were used as explanatory variables. Multiple logistic models were applied to observe the relationship. The history of medical treatment for cerebrovascular disease greatly and unavoidably affects disability related to ADL. Bone fractures, diabetes, and heart diseases contributed to specific ADL disabilities.

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 of uterine myoma detected by ultrasound examination in the atomic bomb survivors.

Benign tumors of several organs have been demonstrated to occur as late effects of atomic bomb exposure, and a recent addition to the list of affected organs is the uterus. The increased incidence of uterine myoma noted in Radiation Effects Research Foundation (RERF) Adult Health Study Report 7 (Wong et al., Radiat, Res. 135, 418-430, 1993), however, was based on self-reported information, optional gynecological examination and patient-requested ultrasound examination. Thus the possibility of dose-related bias in case detection was a serious concern. Therefore, the relationship between the prevalence of uterine myoma and dose to the uterus was examined after excluding as much bias as possible by asking all women who had undergone biennial examinations from December 1991 through December 1993 to undergo ultrasound examinations. Among 2506 female participants in Hiroshima, the uterus was visualized by ultrasound examination in 1190, and 238 were found to have uterine nodules. Multiple logistic analysis using Dosimetry System 1986 uterine doses revealed a significant dose response for the prevalence of uterine nodules. The odds ratio at 1 Gy was 1.61 (95% confidence interval: 1.12-2.31). It is unlikely that the observed relationship after adjusting for bladder filling, volume of the uterus, age and menopause status was the result of dose-related bias. These results support previous findings at RERF and provide further evidence that radiation exposure is one of the factors associated with uterine myoma.

Analysis of cancer mortality among atomic bomb survivors registered at Hiroshima University.

The aim of this study was to investigate the late effect on cancer mortality risk of the radiation exposure of atomic bomb survivors who comprised a study population different from that previously studied by the Radiation Effects Research Foundation (RERF). We examined survivors residing in Hiroshima Prefecture, who were followed up between 1968 and 1989 by the Research Institute for Radiation Biology and Medicine (RIRBM) at Hiroshima University. We used the dose-evaluation system known as Atomic Bomb Survivors 1993 Dose (ABS93D), which was based on the Dosimetry System 1986 for the survivors registered with RERF. The dose estimation was applied in a total of 35,123 subjects. Among survivors who had been alive for > 20 years after the bombing, the relative mortality risk of leukaemia at 1 Gy of organ dose was 2.37 (90% confidence interval: 1.36-3.39), which was significantly higher than the zero dose control group. Similarly, significantly higher risks were observed for all cancers except leukaemia, including cancers of the lung, colon and female breast. Comparison is made with RERF results regarding temporal changes in the relative risk. Although we observed slightly lower relative risks than RERF values for the cancer of the stomach and lung, and for all cancer except leukaemia, no marked trends for any cancer were observed in this study. Though there were some differences in population between RERF and RIRBM, no marked discrepancies were observed.

Profiles of non-cancer diseases in atomic bomb survivors.

This article summarizes the results of a recent study of atomic bomb radiation and non-cancer diseases in the AHS (Adult Health Study) population by the RERF (Radiation Effects Research Foundation) along with a general discussion of previous studies. The association of atomic bomb radiation and CVD was examined by incidence studies and prevalence studies of various endpoints of atherosclerosis, such as MI, stroke, aortic arch calcification, isolated systolic hypertension, and pulse wave velocity, and, although the excess was small, all endpoints indicated an increase of CVD in the heavily exposed group. Because of the consistency of the results, it is almost certain that CVD is higher among atomic bomb survivors. However, all CVD risk factors associated with lifestyle had not necessarily been adjusted for in studies to date, and it is difficult at present to conclude that the increase in CVD among survivors was a direct effect of radiation. Recent studies have demonstrated almost certainly that uterine myoma is more frequent among atomic bomb survivors. It cannot, at present, be concluded that uterine myoma is caused by radiation, because there are no reported studies of other exposed populations. Further analyses including the role of confounding factors as well as molecular approaches are needed to verify this radiation effect. The relationship between atomic bomb radiation exposure and hyperparathyroidism can now be said to have been established in view of the strong dose response, the agreement with results of studies of other populations, the high risk in the younger survivors, and the biological plausibility. Future studies by molecular approaches, etc., are needed to determine the pathogenic mechanism. Among other benign tumours, a dose response has been demonstrated for tumours of the thyroid, stomach and ovary. Although fewer studies have been conducted than for cancer, a clear association between radiation and various benign tumours is emerging. Concerning the association between atomic bomb radiation exposure and chronic liver diseases, the recent incidence study of members of the AHS population demonstrated a significant dose response. Both chronic hepatitis and cirrhosis were suggested as being associated with exposure. The possibility that the increased occurrence of chronic liver diseases among the survivors may be due to hepatitis virus infection cannot be excluded, and the results of the ongoing hepatitis C virus antibody titre studies are awaited.

Relation between cold pressor test and development of hypertension based on 28-year follow-up.

The present study examined the relation between blood pressure reactivity to cold stimulus and the subsequent development of hypertension based on a follow-up study from 1960 through 1988 of 824 normotensive participants (mean age, 35.8 +/- 10.8 years) in the Adult Health Study in Nagasaki, Japan. Hypertension developed in 343 individuals during the 28 years of follow-up, with a mean incidence rate of 24.6 per 10(3) person-years. Confounding variables, including attained age, resting systolic and diastolic blood pressures, and body mass index at baseline, were adjusted using a Poisson regression model. Systolic response was found to be an independent and significant predictor. The relative risk of hypertension for systolic hyperreactors was 1.37, with a 95% confidence interval of 1.10 to 1.71. Diastolic response was significant only when resting diastolic blood pressure was also considered. The cold pressor test appears to be useful if performed on middle-aged subjects older than 40 years at the time of examination, when hypertension is more prevalent. The current results support the hypothesis that hyperreactivity is a predictor of the development of hypertension.