Age-related alteration in the composition of immunocompetent blood cells in atomic bomb survivors

A total of 1328 atomic bomb survivors in Hiroshima were studied to determine alterations in the number of blood lymphocytes belonging to T-cell subpopulations, the number of CD19 antigen-positive B cells and the number of Leu 7 and CD16 antigen-positive lymphocytes. Overall, with increasing age, significant decreasing trends in the numbers of some lymphocytes in T-cell subpopulations and of B cells were observed. Furthermore, the number of blood lymphocytes positive for CD5 antigen was significantly lower in the people exposed to radiation (greater than 1 Gy) in the older age group (more than 30 years old at the time of the bombing). A similar tendency for decreases in the numbers of CD4, CD8, and CD19 antigen-positive cells was observed in these older survivors, although the differences were not statistically significant. These results suggest that aging of the T-cell related immune system is accelerated in the irradiated people of advanced age. This may be explained by the age-related decrease in thymic function in those subjects who were older at the time of the bombing resulting in a decreased functional ability of the immune system after radiation injury. On the contrary, the number of Leu 7 or CD16 antigen-positive cells was found to be increased significantly in the older age group compared to the younger group, although there was little dependence on dose.     

Hyperparathyroidism among atomic bomb survivors in Hiroshima.

To determine the effect of exposure to atomic bomb radiation on the occurrence of hyperparathyroidism, the prevalence was determined among a population of 3,948 atomic bomb survivors and their controls in Hiroshima. The diagnosis of hyperparathyroidism was based upon histopathological findings or the presence of consistent hypercalcemia and elevated levels of serum parathyroid hormone. Primary hyperparathyroidism was diagnosed in 19 persons (3 males, 16 females). Females had approximately a threefold higher overall prevalence of hyperparathyroidism than males (P less than 0.05). The prevalence rates of hyperparathyroidism increased with radiation dose (chi2(1) = 12, P less than 0.001) after adjusting for sex and age at the time of the bombing. The estimated relative risk was 4.1 at 1 Gy (95% confidence limits 1.7 to 14). There was some evidence that the effect of radiation was greater for individuals who were younger at the time of the bombing. In conclusion, exposure to atomic bomb radiation affected the occurrence of hyperparathyroidism, suggesting that doses of radiation lower than those used in radiotherapy may also induce this disorder.     

Phagocytic and bactericidal activities of leukocytes in whole blood from atomic bomb survivors

This study evaluated the phagocytic and bactericidal activities of peripheral blood leukocytes from Hiroshima and Nagasaki atomic bomb survivors for Staphylococcus aureus. The data were analyzed by multiple linear regression for age, sex, radiation exposure, city of exposure, and neutrophil counts. No significant radiation effect was observed for either blood phagocytic or bactericidal activities. The only significant variable for these functions was the neutrophil count.     

A chromosome study of 6-thioguanine-resistant mutants in T lymphocytes of Hiroshima atomic bomb survivors

Cytogenetic characterizations were made of lymphocyte colonies established from somatic mutation assays for 6-thioguanine (TG) resistance in Hiroshima atomic bomb survivors. G-banded chromosomes were analyzed in both TG-resistant (TGr) and wild-type colonies. Included were 45 TGr and 19 wild-type colonies derived from proximally exposed A-bomb survivors, as well as colonies from distally exposed control individuals who did not receive a significant amount of A-bomb radiation (18 TGr and 9-wild type colonies). Various structural and numerical chromosome abnormalities were observed in both TGr and wild-type colonies. Aberrations of the X chromosome, on which the hypoxanthine guanine phosphoribosyl transferase (HPRT) locus is present, were found in 6 colonies: 2 resistant colonies from controls (45,X/46,XX; 46,X,ins(X)), 3 resistant colonies (45,X/46,XX/46,X, + mar; 46,X,t(Xq +;14q-); 46,Y,t(Xq-;5q +)), and 1 wild-type colony (45,X/47,XXX) from proximally exposed persons. In cases with exchange aberrations, each of the break points on the X chromosome was situated proximally to band q26 where the HPRT locus is known to be assigned. DNA-replicating patterns were also studied, and it was found that abnormal X chromosomes showed early replicating patterns, while normal X chromosomes showed late replicating patterns.     

Systolic blood pressure and systolic hypertension in adolescence of atomic bomb survivors exposed in utero

Annual medical examinations were conducted during adolescence for the in utero clinical study sample subjects exposed prenatally to the atomic bombs in Hiroshima and Nagasaki. Systolic blood pressure and several anthropometric measurements were recorded during these examinations. For 1014 persons exposed in utero, two types of longitudinal analyses were performed, for a total of 7029 observations (6.93 observations per subject) of systolic blood pressure (continuous data) and systolic hypertension (binary data) for persons aged 9 to 19 years. Body mass index (BMI) and/or body weight were considered in the analyses as potential confounders. For the measurements of systolic blood pressure, the common dose effect was 2.09 mmHg per Gy and was significant (P = 0.017). The dose by trimester interaction was suggestive (P = 0.060). A significant radiation dose effect was found in the second trimester (P = 0.001), with an estimated 4.17 mmHg per Gy, but in the first and third trimesters, radiation dose effects were not significant (P > 0.50). For prevalence of systolic hypertension, the radiation dose effect was significant (P = 0.009); the odds ratio at 1 Gy was 2.23 [95% confidence interval (CI): 1.23, 4.04], and the dose by trimester interaction was not significant (P = 0.778). The dose response of systolic hypertension had no dose threshold, with a threshold point estimate of 0 Gy (95% CI: <0.0, 1.1 Gy). The dose response for systolic blood pressure was most pronounced in the second trimester, the most active organogenesis period for the organs relevant to blood pressure.     

In vivo mutant T cell frequency in atomic bomb survivors carrying outlying values of chromosome aberration frequencies

Frequencies of HPRT- mutant T cells were determined by means of a direct clonal assay in atomic bomb survivors who showed outlying values of chromosome aberration frequencies. The studied survivors consisted of 2 groups: those whose aberration frequency was near the higher end of the distribution (high-aberration group) and those whose aberration frequency was near the lower end of the distribution (low-aberration group). The mean radiation doses (T65D) of the high-aberration group (13 people) and low-aberration group (17 people) were 248 and 273 rad, respectively. The mean mutant frequency (Mf) of the high-aberration group was 6.7 X 10(-6), which was significantly higher than that of the low-aberration group (3.7 X 10(-6)) or that of 17 controls (3.4 X 10(-6)). When all the samples were combined, the correlation between Mf and radiation dose was not significant using either dose estimation system, T65D or DS86. However, the correlation coefficient was higher when DS86 doses were used. Mf correlated significantly with increasing aberration frequencies. The tendency that Mf correlates better with chromosome aberration frequency than with estimated radiation dose was stronger in this study than in a previous study where the samples were selected randomly.     

Malignant tumors during the first 2 decades of life in the offspring of atomic bomb survivors.

The risk of cancer (incidence) prior to age 20 years has been determined for children born to atomic bomb survivors and to a suitable comparison group. Tumor ascertainment was through death certificates and the tumor registries maintained in Hiroshima and Nagasaki. The rationale for the study stemmed from the evidence that a significant proportion of such childhood tumors as retinoblastoma and Wilms tumor arise on the basis of a mutant gene inherited from one parent plus a second somatic cell mutation involving the allele of this gene. Gonadal radiation doses were calculated by the recently established DS86 system, supplemented by an ad hoc system for those children for one or both of whose parents a DS86 dose could not be computed but for whom an ad hoc dose could be developed on the basis of the available information. The total data set consisted of (1) a cohort of 31,150 live-born children one or both of whose parents received greater than 0.01 Sv of radiation at the time of the atomic bombings (average conjoint gonad exposure 0.43 Sv) and (2) two suitable comparison groups totaling 41,066 children. Altogether, 43 malignant tumors were ascertained in the children of exposed parents, and 49 malignant tumors were ascertained in the two control groups. A multiple linear regression analysis revealed no increase in malignancy in the children of exposed parents. However, examination of the data suggested that only 3.0-5.0% of the tumors of childhood that were observed in the comparison groups are associated with an inherited genetic predisposition that would be expected to exhibit an altered frequency if the parental mutation rate were increased. There is thus far no confirmation of the positive findings that Nomura found in a mouse system.     

Multistage models and the incidence of cancer in the cohort of atomic bomb survivors

The analyses in this paper show that a number of biologically based models describe cancer incidence among the A-bomb survivors equally well. However, these different models can predict very different temporal patterns of risk after irradiation. No evidence was found to support the previous claim of Pierce and Mendelsohn that excess cancer risks for the solid tumors depend only upon attained age and not on age at exposure or time since exposure. Although the A-bomb survivor cohort is the largest epidemiological data set for the study of radiation and cancer, it is not large enough to discriminate among various possible carcinogenic mechanisms. Unfortunately for hypothesis generation, the data appear to be consistent with a number of different mechanistic interpretations of the role of radiation in carcinogenesis.     

Nanostructure and force spectroscopy analysis of human peripheral blood CD4+ T cells using atomic force microscopy

To date, nanoscale imaging of the morphological changes and adhesion force of CD4⁺ T cells during in vitro activation remains largely unreported. In this study, we used atomic force microscopy (AFM) to study the morphological changes and specific binding forces in resting and activated human peripheral blood CD4⁺ T cells. The AFM images revealed that the volume of activated CD4⁺ T cells increased and the ultrastructure of these cells also became complex. Using a functionalized AFM tip, the strength of the specific binding force of the CD4 antigen-antibody interaction was found to be approximately three times that of the unspecific force. The adhesion forces were not randomly distributed over the surface of a single activated CD4⁺ T cell, indicated that the CD4 molecules concentrated into nanodomains. The magnitude of the adhesion force of the CD4 antigen-antibody interaction did not change markedly with the activation time. Multiple bonds involved in the CD4 antigen-antibody interaction were measured at different activation times. These results suggest that the adhesion force involved in the CD4 antigen-antibody interaction is highly selective and of high affinity.     

Effects of radiation on incidence of primary liver cancer among atomic bomb survivors.

We describe the radiation risk for primary liver cancers between 1958 and 1987 in a cohort of atomic bomb survivors in Hiroshima and Nagasaki, Japan. The analysis is based on a comprehensive pathology review of known or suspected liver neoplasms that generated 518 incident, first primary cases, mostly hepatocellular carcinoma. Excess relative risk from atomic bomb radiation was linear: 0.81 per sievert weighted liver dose (95% CI [0.32, 1.43]; P < 0.001). Males and females had similar relative risk so that, given a threefold higher background incidence in males, the radiation-related excess incidence was substantially higher in males. Excess risk peaked for those with age at exposure in the early 20s; there was essentially no excess risk in those exposed before age 10 or after age 45. Whether this was due to a difference in sensitivity or possible confounding by other factors could not be addressed retrospectively in the full cohort. A paucity of cholangiocarcinoma and hemangiosarcoma cases suggested that they are not significantly associated with whole-body radiation exposure, as they are with the internal alpha-particle-emitting radiological contrast medium Thorotrast. Because most of the radiation-related excess cases occurred among males, it is important to ascertain what factors put men at greater risk of radiation-related liver cancer.     

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.     

Fully functional memory CD8 T cells in the absence of CD4 T cells

The role of CD4 T cells in providing help to CD8 T cells in primary and secondary responses to infection remains controversial. Using recombinant strains of virus and bacteria expressing the same Ag, we determined the requirement for CD4 T cells in endogenous CD8 T cell responses to infection with vesicular stomatitis virus and Listeria monocytogenes (LM). Depletion of CD4 T cells had no effect on the frequency of primary or secondary vesicular stomatitis virus-specific CD8 T cells in either lymphoid or nonlymphoid tissues. In contrast, the primary LM-specific CD8 T cell response was CD4 T cell dependent. Surprisingly, the LM-specific CD8 T cell recall response was also CD4 T cell dependent, which correlated with a requirement for CD40/CD40L interactions. However, concomitant inhibition of CD40L and CD4 T cell removal revealed that these pathways may be operating independently. Importantly, despite the absence of CD4 T cells during the recall response or throughout the entire response, CD8 memory T cells were functional effectors and proliferated equivalently to their "helped" counterparts. These data call into question the contention that CD4 T cells condition memory CD8 T cells during the primary response and indicate that the principal role of CD4 T cells in generating CD8 memory cells after infection is augmentation of proliferation or survival through costimulatory signals.     

Temporal analysis of a dose-response relationship: leukemia mortality in atomic bomb survivors

A data analysis that incorporates time dependencies is demonstrated for the dose response of leukemia mortality in the atomic bomb survivors. The time dependencies are initially left unspecified and the data on leukemia mortality--up to the end of 1978--are used to infer them. Several findings based on T65 revised doses (T65DR) are obtained. First, it is shown that the fits to the data of time-dependent L (linear in gamma dose)-Q (quadratic in gamma dose)-L (linear in neutron dose), L-L, and Q-L dose-response models are significantly improved (P less than 0.001) by using the corresponding time-dependent dose-response models. Second, it is shown that the increased risk of leukemia mortality due to gamma irradiation decreases in time while the increased risk due to neutron exposure decreases more slowly, if at all, in time. Consequently, relative biological effectiveness (RBE) of neutrons is shown to increase in time (P = 0.002) and the current definition of RBE as a time-independent quantity is therefore challenged. It is demonstrated with time-dependent models that the L-L model has a poor fit (P = 0.01) to the data for the first 7 years of study, but has an adequate fit for the remaining 21 years. In contrast the Q-L model has an adequate fit for the entire follow-up period (P greater than 0.30).