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.

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.

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.

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.

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.

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.

[Trends, risk factors, and prevention of ischemic heart disease in Japan].

The mortality from ischemic heart disease has increased steadily in most industrialized countries from the 19th century up to 1970. In some developed countries, such as the U.S.A. and Australia, it started to decrease in the nineteen seventies and accelerated recently. However, it has increased in some East European countries, such as Rumania, Poland and Hungary. The mortality had been extraordinarily low and the age standardized rate declined since the nineteen seventies in our country as in the U.S.A. These finding strongly suggests the possibility of prevention of ischemic heart disease worldwide. Among the risk factors, hypertension has gradually decreased due to treatment and lower intake salt in Japan. However, the compliance of antihypertensive treatment could be improved and the average intake of salt further decreased. The frequency of hypercholesterolemia was quite low for many years, but increased recently in Japan. However, the national average level of serum cholesterol is probably close to 200 mg/dl, and the new cholesterol level data will be revealed by the national survey in 1990. The world-famous high figure of smoking among Japanese men has been declining for these 20 years down to 61.2% in 1988, along with an exceptionally low rate for women in industrialized countries. The average figure of body weight by stature was in line with the desirable body weight for Japanese and the average intake of lipids has leveled off recently according to the National Nutrition Survey. After all it can be concluded that incidence of ischemic heart disease could be reduced further, even in Japan.

[Left high R wave amplitude and blood pressure levels before and after 5 minutes' rest in a mass screening program].

In order to evaluate the implication of blood pressures measured without 5 minutes' rest in mass screening programs, blood pressures were measured before and after 5 minutes' rest on 820 subjects in a rural community, aged 35 to 65 years and not receiving hypertensive treatment. Although the systolic blood pressure showed a significant drop of an average of 3 mmHg among males and 4 mmHg among females after rest, 23.3% of 820 subjects had higher systolic blood pressure reading after rest than before. The relationship between left high R (LHR) in electrocardiograms and blood pressure (BP) before and after rest was studied. The presence of LHR was significantly related to BP both before and after rest among males, but more strongly associated to BP before rest. The relationship of the difference between BP before and after rest to the prevalence of LHR was analyzed by multiple logistic method. A significantly higher prevalence of LHR with greater difference between systolic BP before and after rest was observed among males, even with age and systolic BP level after rest taken into account. These findings suggest the potential significance of blood pressure readings before 5 minutes' rest which may be a response to mental stress of having the initial blood pressure reading taken by the observer. It would seem worthy to obtain blood pressure before rest as well as after rest in detecting blood pressure abnormalities.

A method for estimating incidence rates of onchocerciasis from skin-snip biopsies with consideration of false negatives.

The aim of this study is to estimate incidence rates of onchocerciasis from skin-snip biopsies, based on incomplete data obtained in field surveys, with consideration of false negatives. The method of maximum likelihood is employed and the effect of false negatives on the incidence rates is discussed.