Naive CD4 T Cells Highly Expressing the Inflammatory Chemokine Receptor CXCR3 Increase with Age and Radiation Exposure in Atomic Bomb Survivors.

The numbers of naive T cells that react to novel pathogens not yet encountered by an immune system, decrease during aging, mainly due to age-associated involution of the thymus. CD45RA+ naive CD4 T cells consist of heterogeneous populations, including highly CXCR3-expressing cells that appear during the homeostatic proliferation of naive T cells and exhibit enhanced type-1 inflammatory phenotypes. Based on previous evidence of radiation-associated reductions in thymic function and peripheral blood naive CD4 T cells, we hypothesized that the homeostatic proliferation of naive CD4 T cells compensates for deficits in peripheral T-cell populations after radiation injury, which may increase the proportion of CXCR3high cells in naive CD4 T cells and enhance inflammation. The statistical models employed in this study revealed positive associations between the number of CXCR3high naive CD4 T cells and age as well as radiation dose among 580 Hiroshima atomic bomb survivors. In addition, the CXCR3high cells in these survivors increased not only with the levels of homeostatic cytokines, IL6 and IL7, but also with those of inflammatory indicators, CXCL10 and CRP. These results suggest that thymic T-cell production deficiency due to radiation and aging results in enhanced homeostatic proliferation that drives the appearance of CXCR3high naive CD4 T cells poised for an inflammatory response. Molecular mechanisms and clinical relevance of increasing CXCR3high cells in naive CD4 T populations should be further investigated in the context of inflammatory disease development long after radiation exposure.

Neurocognitive Function in Aged Survivors Exposed to Atomic Bomb Radiation In Utero: The Radiation Effects Research Foundation Adult Health Study.

Although some adverse effects on neurocognitive function have been reported in children and adolescents irradiated prenatally during the atomic bombings and the Chernobyl nuclear accident, little information is available for effects on the elderly. Here we evaluate the effects of prenatal exposure to atomic bomb radiation on subjective neurocognitive function in aged survivors. To evaluate neurocognitive impairment, we mailed the Neurocognitive Questionnaire (NCQ), a self-administered scale, to prenatally exposed survivors, including clinic visitors and non-visitors at the time of the 2011 and 2013 Adult Health Study (AHS) examinations. We received replies from 444 individuals (mean age, 66.9 ± 0.6 years). After adjusting for sex, city, and educational background, we found no significant effects of radiation, clinic visit, or interaction between radiation and clinic visit on the scores of the 4 NCQ factors of metacognition, emotional regulation, motivation/organization, and processing speed. Even in analyses considering gestational age at the time of the bombings, none of the 4 NCQ factor scores was related to maternal uterine dose. There remains the limitation that this study consisted of healthy survivors, but we found no significant radiation effect on late-life cognition in people prenatally exposed to atomic bomb radiation.

Female "Paradox" in Atrial Fibrillation-Role of Left Truncation Due to Competing Risks.

Female sex in patients with atrial fibrillation (AF) is a controversial and paradoxical risk factor for stroke-controversial because it increases the risk of stroke only among older women of some ethnicities and paradoxical because it appears to contradict male predominance in cardiovascular diseases. However, the underlying mechanism remains unclear. We conducted simulations to examine the hypothesis that this sex difference is generated non-causally through left truncation due to competing risks (CR) such as coronary artery diseases, which occur more frequently among men than among women and share common unobserved causes with stroke. We modeled the hazards of stroke and CR with correlated heterogeneous risk. We assumed that some people died of CR before AF diagnosis and calculated the hazard ratio of female sex in the left-truncated AF population. In this situation, female sex became a risk factor for stroke in the absence of causal roles. The hazard ratio was attenuated in young populations without left truncation and in populations with low CR and high stroke incidence, which is consistent with real-world observations. This study demonstrated that spurious risk factors can be identified through left truncation due to correlated CR. Female sex in patients with AF may be a paradoxical risk factor for stroke.

Risk Ratio and Risk Difference Estimation in Case-cohort Studies.

BACKGROUND: In case-cohort studies with binary outcomes, ordinary logistic regression analyses have been widely used because of their computational simplicity. However, the resultant odds ratio estimates cannot be interpreted as relative risk measures unless the event rate is low. The risk ratio and risk difference are more favorable outcome measures that are directly interpreted as effect measures without the rare disease assumption. METHODS: We provide pseudo-Poisson and pseudo-normal linear regression methods for estimating risk ratios and risk differences in analyses of case-cohort studies. These multivariate regression models are fitted by weighting the inverses of sampling probabilities. Also, the precisions of the risk ratio and risk difference estimators can be improved using auxiliary variable information, specifically by adapting the calibrated or estimated weights, which are readily measured on all samples from the whole cohort. Finally, we provide computational code in R (R Foundation for Statistical Computing, Vienna, Austria) that can easily perform these methods. RESULTS: Through numerical analyses of artificially simulated data and the National Wilms Tumor Study data, accurate risk ratio and risk difference estimates were obtained using the pseudo-Poisson and pseudo-normal linear regression methods. Also, using the auxiliary variable information from the whole cohort, precisions of these estimators were markedly improved. CONCLUSION: The ordinary logistic regression analyses may provide uninterpretable effect measure estimates, and the risk ratio and risk difference estimation methods are effective alternative approaches for case-cohort studies. These methods are especially recommended under situations in which the event rate is not low.

Massive expansion of multiple clones in the mouse hematopoietic system long after whole-body X-irradiation.

Clonal hematopoiesis (CH) is prevalent in the elderly and associates with hematologic malignancy and cardiovascular disease. Although the risk of developing these diseases increases with radiation doses in atomic-bomb survivors, the causal relationship between radiation exposure and CH is unclear. This study investigated whether radiation exposure induces CH in mice 12-18 months after 3-Gy whole-body irradiation. We found radiation-associated increases in peripheral blood myeloid cells and red blood cell distribution width (RDW). Deep sequencing of bone marrow and non-hematopoietic tissue cells revealed recurrent somatic mutations specifically in the hematopoietic system in 11 of 12 irradiated mice but none in 6 non-irradiated mice. The irradiated mice possessed mutations with variant allele frequencies (VAFs) of > 0.02 on an average of 5.8 per mouse; mutations with VAFs of > 0.1 and/or deletion were prevalent. Examining hematopoietic stem/progenitor cells in two irradiated mice revealed several mutations co-existing in the same clones and multiple independent clones that deliver 60-80% of bone marrow nuclear cells. Our results indicate development of massive CH due to radiation exposure. Moreover, we have characterized mutations in radiation-induced CH.

Chromosome aberrations among atomic-bomb survivors exposed in utero: updated analysis accounting for revised radiation doses and smoking.

A previous study of peripheral blood lymphocyte translocations around age 40 among atomic-bomb survivors exposed in utero revealed no overall association with radiation dose-despite a clear association between translocations and dose among their mothers-but the data suggested an increase at doses below 100 mGy with a definite peak. That analysis of the in utero-exposed survivors did not adjust for their subsequent smoking behavior, an established cause of chromosomal aberrations, or their subsequent exposures to medical irradiation, a potential mediator. In addition, atomic-bomb survivor radiation dose estimates have subsequently been updated and refined. We therefore re-estimated the dose response using the latest DS02R1 dose estimates and adjusting for smoking as well as for city and proximal-distal location at the time of exposure to the atomic bomb. Sex of the survivor, mother's age around the time of conception, and approximate trimester of gestation at the time of exposure were also considered as explanatory variables and modifiers. Precision of the estimated dose response was slightly lower due to greater variability near zero in the updated dose estimates, but there was little change in evidence of a low-dose increase and still no suggestion of an overall increase across the entire dose range. Adjustment for smoking behavior led to a decline in background number of translocations (the dose-response intercept), but smoking did not interact with dose overall (across the entire dose range). Adjustment for medical irradiation did not alter the association between dose and translocation frequency. Sex, mother's age, and trimester were not associated with number of translocations, nor did they interact with dose overall. Interactions with dose in the low-dose range could not be evaluated because of numerical instability.

Radiation Effects on Late-life Neurocognitive Function in Childhood Atomic Bomb Survivors: A Radiation Effects Research Foundation Adult Health Study.

High-dose radiation in childhood such as is used in radiation therapy causes cognitive decline, but there is insufficient research on the cognitive effects of low- to medium-dose radiation. We aimed to reveal the association between atomic bomb radiation exposure in childhood and late-life neurocognitive function. In 2011 and 2013, we mailed the Neurocognitive Questionnaire (NCQ) to subjects who were 12 years old or younger at the time of the atomic bombing. We converted the four NCQ subscales (metacognition, emotional regulation, motivation/organization, and processing speed) to T scores and defined the highest 10% of the controls (exposure dose < 5 mGy) as impaired. We used a generalized linear mixed model to evaluate the effect of radiation exposure on T scores and percentage impaired. We enrolled 859 participants. At the time of the bombing, the mean (SD) age was 6.7 (3.8) years for the control (N = 390) and 6.1 (3.8) years for the exposed (N = 469). At the time of replying to the questionnaire, the mean age of all the participants was 73.7 (3.8) years of age. After adjusting for cofactors, older age was related to the decline of all neurocognitive subscales. Sex and education level had relevance to some of the subscales. For neurocognitive function, exposure dose was not related except to percentage impaired, motivation/organization. Late-life neurocognitive function in atomic bomb survivors exposed as children was associated with age, but not clearly with radiation dose. More studies are needed to evaluate the effect of low-dose radiation during childhood on long-term neurocognitive function.

Radiation effects on atherosclerosis in atomic bomb survivors: a cross-sectional study using structural equation modeling.

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [- 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

Mortality among individuals exposed to atomic bomb radiation in utero: 1950-2012.

We examined the mortality risks among 2463 individuals who were exposed in utero to atomic bomb radiation in Hiroshima or Nagasaki in August 1945 and were followed from October 1950 through 2012. Individual estimates of mother's weighted absorbed uterine dose (DS02R1) were used. Poisson regression method was used to estimate the radiation-associated excess relative risk per Gy (ERR/Gy) and 95% confidence intervals (CI) for cause-specific mortality. Head size, birth weight, and parents' survival status were evaluated as potential mediators of radiation effect. There were 339 deaths (216 males and 123 females) including deaths from solid cancer (n = 137), lymphohematopoietic cancer (n = 8), noncancer disease (n = 134), external cause (n = 56), and unknown cause (n = 4). Among males, the unadjusted ERR/Gy (95% CI) was increased for noncancer disease mortality (1.22, 0.10-3.14), but not for solid cancer mortality (- 0.18, < - 0.77-0.95); the unadjusted ERR/Gy for external cause mortality was not statistically significant (0.28, < - 0.60-2.36). Among females, the unadjusted ERRs/Gy were increased for solid cancer (2.24, 0.44-5.58), noncancer (2.86, 0.56-7.64), and external cause mortality (2.57, 0.20-9.19). The ERRs/Gy adjusted for potential mediators did not change appreciably for solid cancer mortality, but decreased notably for noncancer mortality (0.39, < - 0.43-1.91 for males; 1.48, - 0.046-4.55 for females) and external cause mortality (0.10, < - 0.57-1.96 for males; 1.38, < - 0.46-5.95 for females). In conclusion, antenatal radiation exposure is a consistent risk factor for increased solid cancer mortality among females, but not among males. The effect of exposure to atomic bomb radiation on noncancer disease and external cause mortality among individuals exposed in utero was mediated through small head size, low birth weight, and parental loss.

Biologically-based modeling of radiation risk and biomarker prevalence for papillary thyroid cancer in Japanese a-bomb survivors 1958-2005.

PURPOSE: Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC). MATERIALS AND METHODS: The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology (n = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models. RESULTS: Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses <0.015 Gy typical for the Fukushima accident. CONCLUSIONS: Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation.

Longitudinal changes in red blood cell distribution width decades after radiation exposure in atomic-bomb survivors.

Red blood cell distribution width (RDW), which generally increases with age, is a risk marker for morbidity and mortality in various diseases. We investigated the association between elevated RDW and prior radiation exposure by examining longitudinal RDW changes in 4204 atomic-bomb survivors over 15 years. A positive association was found between RDW and radiation dose, wherein RDW increased by 0·18%/Gy. This radiation-associated effect increased as the participants aged. Elevated RDW was also associated with higher all-cause mortality. The biological mechanisms underlying these observed associations merit further investigation.

Lifetime Mortality Risk from Cancer and Circulatory Disease Predicted from the Japanese Atomic Bomb Survivor Life Span Study Data Taking Account of Dose Measurement Error.

Dosimetric measurement error is known to potentially bias the magnitude of the dose response, and can also affect the shape of dose response. In this report, generalized relative and absolute rate models are fitted to the latest Japanese atomic bomb survivor solid cancer, leukemia and circulatory disease mortality data (followed from 1950 through 2003), with the latest (DS02R1) dosimetry, using Bayesian techniques to adjust for errors in dose estimates and assessing other model uncertainties. Linear-quadratic models are fitted and used to assess lifetime mortality risks for contemporary UK, USA, French, Russian, Japanese and Chinese populations. For a test dose of 0.1 Gy absorbed dose weighted by neutron relative biological effectiveness, solid cancer, leukemia and circulatory disease mortality risks for a UK population using a generalized linear-quadratic relative rate model were estimated to be 3.88% Gy-1 [95% Bayesian credible interval (BCI): 1.17, 6.97], 0.35% Gy-1 (95% BCI: -0.03, 0.78) and 2.24% Gy-1 (95% BCI: -0.17, 13.76), respectively. Using a generalized absolute rate linear-quadratic model at 0.1 Gy, the lifetime risks for these three end points were estimated to be 3.56% Gy-1 (95% BCI: 0.54, 6.78), 0.41% Gy-1 (95% BCI: 0.01, 0.86) and 1.56% Gy-1 (95% BCI: -1.10, 7.21), respectively. There was substantial evidence of curvature for solid cancer (in particular, the group of solid cancers excluding lung, breast and stomach cancers) and leukemia, so that for solid cancer and leukemia, estimates of excess risk per unit dose were nearly doubled by increasing the dose from 0.01 to 1.0 Gy, with most of the increase occurring in the interval from 0.1 to 1.0 Gy. For circulatory disease, the dose-response curvature was inverse, so that risk per unit dose was nearly halved by going from 0.01 t o 1.0 Gy weighted absorbed dose, although there were substantial uncertainties. In general, there were higher radiation risks for females compared to males. This was true for solid cancer and circulatory disease overall, as well as for lung, breast, stomach and the group of other solid cancers, and was the case whether relative or absolute rate projection models were employed; however, for leukemia this pattern was reversed. Risk estimates varied somewhat between populations, with lower cancer risks in aggregate for China and Russia, but higher circulatory disease risks for Russia, particularly using the relative rate model. There was more pronounced variation for certain cancer sites and certain types of projection models, so that breast cancer risk was markedly lower in China and Japan using a relative rate model, but the opposite was the case for stomach cancer. There was less variation between countries using the absolute rate models for stomach cancer and breast cancer, but this was not the case for lung cancer and the group of other solid cancers, or for circulatory disease.

Association between a biomarker of glucose spikes, 1,5-anhydroglucitol, and cancer mortality.

INTRODUCTION: 1,5-Anhydroglucitol (1,5-AG) is a biomarker of glucose spikes. To evaluate the effect of acute glucose excursions on cancer death, we clarified the association between 1,5-AG and cancer mortality among Japanese individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS: We measured 1,5-AG in 6783 (2842 men, 3941 women) individuals with normal fasting and 2-hour plasma glucose who received a 75 g oral glucose tolerance test between 1994 and 2012. They were followed for mortality until August 2013. A systematic review of death certificates was used to confirm the cause of death. We divided the participants into four groups according to the quartile of 1,5-AG level at registration. We used Cox regression to clarify the association between 1,5-AG levels and cancer mortality with multivariate adjustment for possible confounders. RESULTS: During the follow-up period (median, 10.0 years), 140 men and 109 women died of cancer. The HR for cancer mortality of the lowest quartile group was higher than that of the highest quartile group in men (HR, 2.62; 95% CI, 1.60 to 4.41) and in women (HR, 1.47; 95% CI, 0.88 to 2.47). These associations were not attenuated with further adjustment for HbA1c. CONCLUSIONS: 1,5-AG was associated with high risk of cancer mortality in Japanese men after adjustment for HbA1c.

Increased cancer mortality among Japanese individuals with hyperinsulinemia.

AIMS: To evaluate the effect of hyperinsulinemia on cancer death, we clarified the association between hyperinsulinemia and cancer mortality among Japanese individuals. METHODS: All the participants (5586 men and 6652 women) lived in Hiroshima City, underwent a 75 g oral glucose tolerance test between 1994 and 2012, and were followed for mortality until August 2013. A systematic review of death certificates was used to confirm the cause of death. RESULTS: During the follow-up period (median, 10.0 years), 587 participants died of cancer. Lung cancer was the most common cause of organ-specific death. We divided the participants into 3 groups according to the tertiles of fasting immunoreactive insulin (FIRI) levels (low, middle, and high groups). The high group had the highest mortality rate (5.5 per 1000 person-years). The hazard ratio (HR) for cancer mortality of the high group after adjustment for possible confounders, such as age, sex, body mass index, smoking status, alcohol intake, and radiation effects (model 1), was significantly higher than that of the low group (HR, 1.55; 95% confidence interval (CI), 1.23-1.95). In model 2 (model 1 plus fasting plasma glucose) and model 3 (model 1 plus HbA1c), the multivariate HRs for cancer mortality were 1.46 (95% CI, 1.15-1.85) and 1.48 (95% CI, 1.17-1.87), respectively.The HR for cancer death at high FIRI levels (per 1 µU/mL) was 1.04 (95% CI, 1.02-1.05) in all participants after adjusting for fasting plasma glucose level and other confounders. In the subgroup analysis, the HRs were 1.03 (95% CI, 0.98-1.09), 1.05 (95% CI, 1.02-1.08), and 1.04 (95% CI, 1.02-1.06) in the normal, prediabetes, and diabetes group, respectively. CONCLUSIONS: Hyperinsulinemia was associated with a high risk of cancer mortality and may be an important link between cancer mortality and diabetes or prediabetes.

Association between low doses of ionizing radiation, administered acutely or chronically, and time to onset of stroke in a rat model.

Exposure to high-doses of ionizing radiation has been reported to be associated with the risk of stroke. However, risks associated with lower dose exposures remain unclear, and there is little information available for the risk modification according to the dose-rate. There are few studies using animal models which might be able to provide complementary information on this association. In this study, the male stroke-prone spontaneously hypertensive rat (SHRSP) was used as a model animal. The rats were acutely irradiated with doses between 0 and 1.0 Gy or chronically irradiated with a cumulative dose of 0.5 or 1.0 Gy (at a dose rate of 0.05 or 0.1 Gy/day, respectively). The onset time of stroke related symptoms in SHRSP was used as an endpoint for evaluating the effects of low dose and the low dose-rate gamma-ray exposures. With respect to acute exposure, the time to the onset of stroke in the irradiated rats suggested the presence of a threshold around 0.1 Gy. For the low dose-rate chronically exposed, no significant increase in stroke symptom was observed. These findings are novel and demonstrate that the SHRSP system can be used to determine the association between the risk of stroke and radiation exposure with high sensitivity. Moreover, these studies provide important information regarding the association between the low dose and low dose-rate radiation exposure and circulatory diseases, especially stroke.

Effects of Radiation on Blood Pressure and Body Weight in the Spontaneously Hypertensive Rat Model. Are Radiation Effects on Blood Pressure Affected by Genetic Background?

In this work, we utilized spontaneously hypertensive rats (SHR) and Wister Kyoto rats (WKY), from which the SHR was established, to evaluate the effects of whole-body acute radiation on the cardiovascular system at doses from 0 to 4 Gy. In the irradiated SHR, the systolic blood pressure (SBP) increased with increasing dose, while body weight gain decreased with increasing radiation dose. Furthermore, pathological observations of SHR demonstrated that the number of rats with cystic degeneration in the liver increased with increasing dose. The effects observed among SHR, such as increased SBP and retardation of body weight gain, appear very similar to those observed in Japanese atomic bomb survivors. In contrast, the SBP among WKY did not change relative to dose; the body weight, however, did change, as in the SHR. Therefore, the association between radiation exposure and SBP, but not between radiation exposure and retardation of body weight gain, may be affected by genetic background, as evident from strain difference. These results suggest that the SHR and WKY animal models may be useful for studying radiation effects on non-cancer diseases including circulatory diseases, chronic liver disease and developmental retardation.

Longitudinal examination of pancreatic ß-cell function in Japanese individuals.

AIMS/INTRODUCTION: We carried out a retrospective, longitudinal analysis of ß-cell function between a diabetes mellitus group, including those that progressed to diabetes mellitus during the follow-up period, and a diabetic type with glycated hemoglobin (HbA1c) <6.5 group, including those that progressed to a diabetic type during the follow-up period. ß-Cell function was assessed using homeostasis model of assessment of ß-cell function. MATERIALS AND METHODS: The relationship between the duration of diabetes mellitus or the diabetic type and pancreatic ß-cell function was compared between the diabetes mellitus group (1,817) and diabetic type with HbA1c <6.5 group (1,843) using results from an oral glucose tolerance test. Linear mixed effects models were used to analyze repeated measurements of oral glucose tolerance tests. RESULTS: The slope of the regression line of ß-cell function for the duration of the diabetes mellitus group was -2.2%/year before the diagnosis. The slope differed after the diagnosis, and the difference was 1.3. The slope of the diabetic type group was -1.2%/year, and no significant difference was observed in the slope before and after the diagnosis. ß-Cell function at the onset was 54.3% in the diabetic type group and 40.6% in the diabetes mellitus group, and the slope of the regression line was significantly higher in the diabetes mellitus group. We divided the diabetes mellitus and diabetic type with HbA1c <6.5 groups into obese and non-obese participants. ß-Cell function declined more with obesity. CONCLUSIONS: Subsequent declines in ß-cell function were faster in the diabetes mellitus group than that in the diabetic type with HbA1c <6.5 group, and increased with obesity.

Radiation risk of incident colorectal cancer by anatomical site among atomic bomb survivors: 1958-2009.

Radiation effects on colorectal cancer rates, adjusted for smoking, alcohol intake and frequency of meat consumption and body mass index (BMI) by anatomical subsite (proximal colon, distal colon and rectum) were examined in a cohort of 105,444 atomic bomb survivors. Poisson regression methods were used to describe radiation-associated excess relative risks (ERR) and excess absolute rates (EAR) for the 1958-2009 period. There were 2,960 first primary colorectal cancers including 894 proximal, 871 distal and 1,046 rectal cancers. Smoking, alcohol intake and BMI were associated with subsite-specific cancer background rates. Significant linear dose-responses were found for total colon (sex-averaged ERR/Gy for 70 years old exposed at age 30 = 0.63, 95% confidence interval [CI]: 0.34; 0.98), proximal [ERR = 0.80, 95% CI: 0.32; 1.44] and distal colon cancers [ERR = 0.50, 95% CI: 0.04; 0.97], but not for rectal cancer [ERR = 0.023, 95% CI: -0.081; 0.13]. The ERRs for proximal and distal colon cancers were not significantly different (p = 0.41). The ERR decreased with attained age for total colon, but not for proximal colon cancer, and with calendar year for distal colon cancer. The ERRs and EARs did not vary by age at exposure, except for decreasing trend in EAR for proximal colon cancer. In conclusion, ionizing radiation is associated with increased risk of proximal and distal colon cancers. The ERR for proximal cancer persists over time, but that for distal colon cancer decreases. There continues to be no indication of radiation effects on rectal cancer incidence in this population.

Association of Weight Fluctuation With Mortality in Japanese Adults.

Importance: Weight cycling is associated with the risk of mortality from heart disease, but many studies have not distinguished between simple nonlinear (monotone) weight changes and more complex changes that reflect fluctuations. Objective: To assess whether extreme body weight variation is associated with mortality after controlling for nonlinear weight changes. Design, Setting, and Participants: In this prospective clinical cohort study, 4796 Japanese atomic bomb survivors were examined in the clinic as part of a biennial health examination and research program. The study consisted of a 20-year longitudinal baseline period (July 1, 1958, to June 30, 1978) and subsequent mortality follow-up of 27 years (July 1, 1978, to June 30, 2005) Participants were initially between the ages of 20 and 49 years during the baseline period and, throughout the baseline period, had no diagnoses of cardiovascular disease (CVD) or cancer and attended at least 7 of 10 scheduled examinations. Data analysis was performed from October 16, 2015, to May 13, 2016. Exposures: Residual variability in body mass index (BMI) during the baseline period. Main Outcomes and Measures: Outcomes were mortality from ischemic heart disease, cerebrovascular disease, other CVDs combined, other causes (except cancer), and cancer. Root mean squared error was calculated to capture individual residual variation in BMI after adjustment for baseline BMI trends, and the association of magnitude of residual variation with mortality was calculated as relative risk. Results: In total, 4796 persons (mean [SD] age, 35.0 [7.3] years at first baseline examination; 3252 [67.8%] female; mean [SD] BMI, 21.2 [2.8] at first baseline visit [20.6 (2.4) among men and 21.5 (2.9) among women]) participated in the study. During follow-up, 1550 participants died: 82 (5.3% of all deaths) of ischemic heart disease, 181 (11.7%) of cerebrovascular disease, 186 (12.0%) of other CVDs, 615 (39.7%) of cancer, and 486 (31.3%) of other causes. Magnitude of residual variation in weight was associated with all-cause mortality (relative risk, 1.25 for 1 U of additional variation; 95% CI, 1.06-1.47) and ischemic heart disease mortality (relative risk, 2.49; 95% CI, 1.41-4.38). Conclusions and Relevance: The findings suggest that an association exists between weight variation and heart disease mortality and that weight loss interventions, if deemed to be necessary, should be considered carefully.

Association Between Prevalence of Peripheral Artery Disease and Radiation Exposure in the Atomic Bomb Survivors.

Background Past reports suggested that total-body irradiation at 0.5 to 1.0 Gy could be responsible for atherosclerosis. Peripheral artery disease ( PAD ) is a manifestation of systematic atherosclerosis. Whether the consequences of a low-to-moderate dose of radiation include increased risk of PAD remains to be determined. The purpose of this study was to examine the association between radiation exposure and prevalence of PAD among Japanese atomic bomb survivors. Methods and Results Radiation exposure from the atomic bombing was assessed in 3476 participants (41.1% men, mean age 74.8 years with SD 6.4 years) with a cross-sectional survey in 2010 to 2014. Left- and right-side ankle-brachial indexes and upstroke time ( UT ) were obtained using oscillometric VP -2000. PAD was defined as an ankle-brachial index of 1.0 or less or a prior history related to revascularization. UT was considered a sensitive marker of early-stage PAD . Association between radiation exposure and PAD or UT was assessed using multivariable regression analyses with adjustment for potential confounding factors. Of 3476 participants, 79 (2.3%) were identified as having prevalent PAD . Multivariate logistic regression analysis indicated that radiation dose was unrelated to PAD prevalence (odds ratio, 0.83; 95% confidence interval [0.57-1.21]). UT appeared to increase with radiation dose, but the increase was not statistically significant (1.09 ms/Gy; 95% confidence interval [-0.17 to 2.36]). Conclusions We found no clear association of radiation dose with PAD , but it remains to be determined whether UT is associated with radiation dose.