Malignant breast tumors among atomic bomb survivors, Hiroshima and Nagasaki, 1950-74.

For 1950-74, 360 cases of malignant breast tumors were identified among the 63,000 females of the Radiation Effects Research Foundation's (Hiroshima and Nagasaki) Extended Life-Span Study sample of survivors of the 1945 atomic bombings of Hiroshima and Nagasaki; 288 of these females were residing in one of these two cities at the time of bombing (ATB). Two-thirds of all cases were classified as breast cancers on the basis of microscopic review of slides, and 108 cases received an estimated breast tissue dose of at least 10 rads. The number of cases of radiogenic breast cancer could be well estimated by a linear function of radiation dose for tissue doses below 200 rads. Excess risk estimates, based on this function, for women 10-19, 20-29, 30-39, and 50 years old or older ATB were 7.3, 4.2, 2.6, and 4.7 cases per million women per year per rad, respectively. Women irradiated in their forties showed no dose effect. Among all women who received at least 10 rads, those irradiated before age 20 years will have experienced the highest rates of breast cancer throughout their lifetimes. Separate excess risk estimates for Hiroshima and Nagasaki did not differ significantly, which indicates that for radiogenic breast cancer the effects of neutrons (emitted only in the Hiroshima explosion) and gamma radiation were about equal. Radiation did not reduce the latency period for the development of breast cancer, which was at least 10 years. The distribution of histologic types of cancers did not vary significantly with radiation dose. The data suggested that irradiation prior to menarche conferred a greater risk than irradiation after menarche.

Isolation of urinary trypsin inhibitor-like inhibitor from human lung cancer tissue.

In the present study, a trypsin inhibitor was first extracted from lung cancer tissue and purified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A final yield of 20 to 60 micrograms of inhibitor with a specific activity of 2040 units/mg of protein was obtained from 1 g of original lung cancer tissue. This inhibitor inhibited trypsin strongly, plasma kallikrein weakly, and plasmin more weakly, and its molecular weight was approximately 43,000 to 45,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its antigenicity was confirmed to be quite the same as that of human urinary trypsin inhibitor by double immunodiffusion, immunoelectrophoresis, and neutralization with anti-urinary trypsin inhibitor rabbit immunoglobulin.

Radiosensitivity of skin fibroblasts from atomic bomb survivors with and without breast cancer.

Fibroblasts were established in vitro from skin biopsies obtained from 55 women and 1 man with or without breast cancer and with or without exposure to radiation from the atomic bomb explosion in Hiroshima. The radiosensitivity of these cells was evaluated by clonogenic assays after exposure to X-rays or to fission neutrons from a 252Cf source. Data were fitted to a multitarget model, S/S0 = A [1 - (1 - ekD)N], for both X-ray and neutron dose-survival curves. A single hit model, S/S0 = AekD, fits the neutron dose-survival responses as well. There were no differences in the means or variances of radiosensitivity between exposed and nonexposed groups or between patients with or without breast cancer. Hence, although the sample is not large, it provides no support for the hypothesis that atomic bomb radiation preferentially induces breast cancer in women whose cells in vitro are sensitive to cell killing by radiation.

Cytomegalovirus-associated hemophagocytic syndrome in a patient with adult onset Still's disease.

Reactive hemophagocytic syndrome (HPS) is characterized by hemophagocytosis by activated histiocytes, resulting in pancytopenia and liver dysfunction. We describe a patient with adult onset Still's disease (AOSD) in whom HPS developed. An 80-year-old Japanese woman with high fever, arthralgia, skin rash, and pleuritis was admitted to our hospital for further examination. She was diagnosed with AOSD and steroid therapy was initiated. During the course of steroid therapy, a re-elevation of serum ferritin levels and a marked increase in serum transaminase were observed. Bone marrow aspiration revealed an increase in the number of histiocytes with hemophagocytosis and cytomegalovirus (CMV)-positive leukocytes were detected. At this time we diagnosed the patient as having virus-associated hemophagocytic syndrome (VAHS) and elevated levels of trasaminase and ferritin were normalized by ganciclovir treatment. Reactive HPS occurs in cases of active AOSD. However, it should be noted that HPS may be accompanied by opportunistic infections during immunosuppressive therapy requiring prompt antibiotic therapy.

Zinc, copper, manganese, and selenium metabolism in thyroid disease.

This study was designed to evaluate trace metal metabolism in adults with thyroid diseases. Erythrocyte zinc values were significantly lower than normal in hyperthyroidism and higher in hypothyroidism. A significantly higher than normal urinary excretion of zinc was observed in hyperthyroidism. The mean concentrations of plasma and erythrocyte copper were significantly above normal in hyperthyroidism. Plasma selenium levels were significantly lower than normal in hyperthyroidism. No statistically significant difference was found in plasma zinc, erythrocyte manganese, or urine copper values between patients with thyroid diseases and healthy controls. The erythrocyte manganese content correlated well with thyroxine and triiodothyronine levels. Plasma prealbumin and retinol-binding protein correlated well with the erythrocyte zinc content but not with plasma zinc levels. There was no correlation between erythrocyte superoxide dismutase activity and erythrocyte copper or zinc concentrations. The results of this study suggest that the metabolism of zinc, copper, manganese, and selenium is abnormal in thyroid diseases.

Adenine nucleotide metabolism during hepatic ischemia and subsequent blood reflow periods and its relation to organ viability.

In an experimental model system for liver transplantation, the ability of the rat liver to synthesize ATP and to maintain adequate energy charge and total adenine nucleotides during restoration of hepatic blood flow following warm ischemia was found to determine tissue viability and survival of the animal. A portafemoral shunt prepared to relieve portal congestion enhanced the rate and extent of ATP resynthesis by the reflow following hepatic ischemia and this was accompanied by an increase in the survival rate of the rat.

Protective effects of alpha-tocopherol and coenzyme Q10 on warm ischemic damages of the rat kidney.

Studies were done on the protective effects of alpha-tocopherol and coenzyme Q10 (CoQ10) on warm ischemic damage to the rat kidney. Administration of alpha-tocopherol (10 mg/kg body wt/day) for 7 days or a single i.p. injection of CoQ10 (6 mg/kg body wt) increased the survival rate from 0 to 46.7% of the rats subjected to warm ischemia for 120 min. The administration of alpha-tocopherol and CoQ10 increased adenosine triphosphate (ATP) in the renal tissue from 0.53 +/- 0.18 to 0.92 +/- 0.29, and from 0.64 +/- 0.26 to 1.00 +/- 0.54 mumol/g wet weight, respectively, 4-hr reperfusion after 120 min of warm ischemia. Serum creatinine levels of the surviving rats after 120 min of warm ischemia was 9.98 +/- 0.19 mg/100 ml in the control group and 5.84 +/- 0.95 and 7.27 +/- 1.62 mg/100 ml, respectively, in alpha-tocopherol and CoQ10 administered group, when determined 2 days after the operation. These results indicate that alpha-tocopherol and CoQ10 have a protective effect on warm ischemic damage to the rat kidney, demonstrated by an increase in ATP resynthesis after reflow following warm ischemia and by the maintenance of a lower serum creatinine level. This effect was accompanied by an increase in the survival rate of ischemic rats.

Clinical evaluation of the plasma levels of immunoreactive atrial natriuretic peptide in elderly patients with heart diseases.

Plasma levels of immunoreactive atrial natriuretic peptide (ANP) were estimated in 69 elderly patients over 60 years of age (mean 76.4 years) with or without heart diseases and in ten young, healthy volunteers (mean 33.0 years) to evaluate the clinical significance of ANP in the elderly. Plasma ANP levels in nine patients without heart diseases were significantly (P less than .01) higher than in the ten young, healthy subjects (mean +/- SD, 46.0 +/- 22.0 vs 22.1 +/- 6.3 pg/mL) and a significant positive correlation was observed between ANP level and age in these subjects (r = 0.60, P less than 0.01). Plasma ANP levels in 60 patients with heart diseases (158.4 +/- 158.5 pg/mL) were significantly (P less than 0.05) greater than in nine patients without heart diseases. Plasma ANP levels in patients with congestive heart failure or atrial fibrillation were 285.8 +/- 185.2 or 223.0 +/- 185.9 pg/mL, respectively; each of these values was significantly (P less than 0.01) higher than in patients without heart diseases. In three patients with paroxysmal atrial fibrillation, plasma ANP levels during atrial fibrillation were three times greater than when atrial fibrillation returned to normal sinus rhythm (377.3 +/- 78.5 vs 101.1 +/- 68.5 pg/mL). These results indicate that plasma ANP levels increase with advancing age, and that increased ANP levels are associated with various heart diseases in elderly subjects, possibly through stretch of the atrial wall.

Prevalence rate of thyroid diseases among autopsy cases of the atomic bomb survivors in Hiroshima, 1951-1985.

To examine the radiogenic risk of latent thyroid cancer, thyroid adenoma, colloid/adenomatous goiter and chronic thyroiditis, the data for 3821 subjects collected in the course of autopsies of atomic bomb survivors in Hiroshima from 1951 to 1985 by the Radiation Effects Research Foundation (RERF) were analyzed using a logistic model. About 80% of the autopsies were performed at RERF and the remainder at local hospitals. The frequencies of the above diseases were not associated with whether the underlying cause of death was cancer. However, note that our results may be influenced by potentially biasing factors associated with autopsy selection. The relative frequency of latent thyroid cancer (greatest dimension < or = 1.5 cm but detectable on a routine microscopic slide of the thyroid gland) increased as the radiation dose increased and was about 1.4-fold greater at 1 Gy than in the 0-Gy dose group. The relative occurrence of thyroid adenoma also increased as radiation dose increased, and was about 1.5-fold greater at 1 Gy than in the 0-Gy dose group. Sex, age at the time of the bombing or period of observation did not significantly modify the radiogenic risks for thyroid adenoma or latent thyroid cancer. No statistically significant association was found between radiation exposure and the rates of colloid/adenomatous goiter and chronic thyroiditis. The possible late effect of atomic bomb radiation on the frequency of benign thyroid diseases is discussed on the basis of these data.

Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1980.

Ascertainment of breast cancer incidence among the cohort of the RERF Life Span Study extended sample identified 574 breast cancers among 564 cases diagnosed during 1950-1980 of which 412 cancers were reviewed microscopically. There were no dose-dependent differences with respect to diagnostic certainty or histological type. As in previous studies, the dose response appeared to be roughly linear and did not differ between the two cities. The most remarkable new finding was the emergence of a radiation-related excess among women under 10 years of age at exposure. The risk of radiogenic breast cancer appears to decrease with increasing age at exposure, whether expressed in relative or absolute terms. These results suggest that exposure of female breast tissue to ionizing radiation at any time during the first four decades of life, even during the premature stage, can cause breast cancer later in life, and that the length of time that tumor promoters such as endogenous hormones operate following exposure has an important influence on the development of radiation-induced breast cancer. An unresolved question is whether breast cancer risk is increased by radiation exposure at ages older than 40.

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.

Preservation of ischemic rat liver mitochondrial functions and liver viability with CoQ10.

The present study was undertaken to determine whether CoQ10 administration to rats can protect hepatic mitochondrial functions, improve energy metabolism during hepatic ischemia and subsequent reperfusion, and prolong the viability of the organ. Although ischemia of the liver for 90 minutes did not permit survival of the animals, CoQ10 administration (6 mg/kg of body weight) increased the survival rate to 60%. The period of ischemia was accompanied by decreases in hepatic adenosine triphosphate (ATP) level and respiratory control index without significant increases in mitochondrial calcium content and lipid peroxide formation. The subsequent restoration of blood flow resulted in a low recovery of ATP level, recovery of respiratory control and ADP:O ratio to levels significantly lower than normal, and on the contrary, marked increases in mitochondrial calcium and lipid peroxide levels. However, in CoQ10-treated animals mitochondrial functions were all completely reversible, and resynthesis of ATP was accelerated even after 90 minutes of ischemia. The pretreatment also completely suppressed the elevation of mitochondrial calcium and lipid peroxide levels. These results suggest that preservation with CoQ10 of cellular damages caused by hepatic ischemia is probably due to protection of cellular and subcellular membranes from lipid peroxidation, so that mitochondrial functions are restored and cellular calcium homeostasis is maintained.

Comparison of radiosensitivities of human autologous normal and neoplastic thyroid epithelial cells.

Studies were conducted to examine differences between the radiosensitivities of normal and neoplastic epithelial cells of the human thyroid. Freshly excised thyroid tissues from the tumours of eight patients with papillary carcinoma (PC) and five with follicular adenoma (FA) were cultured in vitro separately from normal thyroid tissue obtained from the surgical margins of the same patients. Plating efficiency of unirradiated control tissue was lower, on average for tumour tissue compared with normal tissue. Radiosensitivity, measured by the 37% inactivation dose D0, was greater for carcinoma tissue than for normal tissue in seven out of eight PC cases. Adenomatous tissue was less radiosensitive than normal tissue in four out of five FA cases. This is the first report comparing the radiosensitivity of autologous normal and abnormal epithelial tissue from the human thyroid.

A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Thyroid cancer: reports up to date and a review.

Evidence to date from a number of studies, indicates that there is an increased incidence of thyroid cancer among A-bomb survivors, and that the incidence rises with increase of dose and is especially predominant in females exposed at younger ages. Although 45 years have elapsed since A-bomb exposure, there are still some questions about the development of thyroid cancer: 1) Is the incidence now decreasing? 2) What factors, other than radiation exposure, are involved? 3) What is the incidence of multiple cancer, including thyroid cancer? With these questions in mind, it is apparent that studies in this field must continue for some time to come.

Thyroid cancer: epidemiological study of thyroid cancer in A-bomb survivors from extended life span study cohort in Hiroshima.

We analysed thyroid cancers which were diagnosed clinically or detected at autopsy during 22 years (1958 to 1979) in a sample of 75,493 study subjects exposed in Hiroshima belonging to the extended LSS sample of the Radiation Effects Research Foundation. One hundred and twenty-five cases of clinical thyroid cancer (15 in males and 110 in females) were confirmed, giving a crude incidence rate per 100,000 person-years of 2.7 for males, 12.4 for females and 8.6 for both sexes combined. There was a significant increase of thyroid cancer with increase of atomic bomb radiation dose (thyroid tissue dose based on T65D) in females and in the sexes combined. This tendency was predominant in those exposed at less than 19 years of age. Compared to the control group, the relative risk in the greater than or equal to 0.50 Gy group was higher at 4.0 for males (not significant) and at 4.3 for females (p less than 0.01). Latent thyroid cancer was detected in 155 cases or 3.5% (2.5% for males and 4.5% for females) of the 4,425 cases that came to autopsy during the same period. Compared to the control group, the relative risk in the 50+ rad group was 1.7 for males (not significant), 2.0 for females (p less than 0.05) and 1.9 for both sexes combined (p less than 0.05). New data obtained from autopsy cases between 1950 and 1985 have been added.

X-ray sensitivity of fibroblast cell strains derived from atomic bomb survivors with and without breast cancer.

Fibroblasts were established in vitro from skin biopsies obtained from 55 women and 1 man with or without breast cancer and with or without exposure to radiations from the atomic bomb (A-bomb) explosion in Hiroshima. The radiosensitivity of these cells was evaluated by clonogenic assays after exposure to X-rays. Dose-response curves were fitted to a multitarget model, S/S0 = A[1-(1-e-D/D0)N]. There was no difference in the means or variances of radiosensitivity between exposed and nonexposed groups, or between groups with and without breast cancer.

Colorectal cancer incidence among atomic bomb survivors, 1950-80.

Colorectal cancer incidence in the LSS sample during 1950-80 was investigated. A total of 730 incidence cases of colorectal cancer were confirmed from a variety of sources. Sixty-two percent of the cancers were microscopically verified and 12% were ascertained through death certificate only. The risk of colon cancer increased significantly with intestinal dose, but no definite increase of risk was observed for rectal cancer. Relative risk at 1 Sv and excess risk per 10(4) PY-Sv for colon cancer are 1.80 (90% confidence internal 1.37-2.36) and 0.36 (90% confidence interval 0.06-0.77) respectively. City and sex did not significantly modify the dose-response of colon cancer, but the risk decreased with age at the time of bombings (ATB). The relative risk of colon cancer does not vary substantially over time following exposure. A non-linear dose response did not significantly improve the fit. Further, the anatomic location of the tumors indicate that the cecum and ascending, transverse and descending, and sigmoid colon seem equally sensitive to radiation. No difference in the distribution of tumor histological types could be observed by radiation dose.

[Teratological study on ranitidine hydrochloride in rabbits].

Ranitidine hydrochloride, a histamine H2-receptor antagonist, was orally given to pregnant rabbits of Japanese White strain from day 6 to 18 of gestation at doses of 25, 100 and 400 mg/kg/day, as ranitidine base, and teratogenicity of the drug was studied. The results were as follows: (1) At dose of 400 mg/kg/day, ranitidine hydrochloride showed no effects on dams, excepting slight suppression in body weight gain in early period of administration. (2) In fetuses, no effects of ranitidine hydrochloride on fetal growth, sex ratio, viability and degree of ossification were observed. (3) External and visceral abnormalities were observed 5, 3, 3 and 4 fetuses in control, 25, 100 and 400 mg/kg/day groups, respectively, but there was no significant difference of the incidence ratio in the treated groups from control, and was no increase in the same type of abnormality. Ranitidine hydrochloride induced no increase in incidence of visceral and skeletal variations. Therefore it was concluded that ranitidine hydrochloride had no teratogenic effect on rabbits at dose of 400 mg/kg/day or lower than that.

[Studies on toxicity of clobetasone-17-butyrate (II)--chronic toxicity in rats (author's transl)].

Chronic toxicity of clobetasone-17-butyrate, an anti-inflammatory corticosteroid, was investigated in rats. Subcutaneous administration with the drug at dose of 0.003, 0.01 and 0.03 mg/kg/day for three and six months induced no significant changes in the rats. At 0.1 and 0.3 mg/kg/day, however, some dose-dependent symptoms such as suppression of body weight gain, emaciation, regressive changes in adrenals, lymphatic and hematopoietic tissues, decrease in circulating white blood cell and lymphocyte counts, which have been known as toxic effects of synthetic corticosteroids, were induced. The results indicates that the maximum no-toxic dose of clobetasone-17 butyrate was 0.03 mg/kg/day on this experimental condition. In the recovery test for two months no significant differences in the treated rats from controls were found, suggesting that the toxic effects were reversible in the animals treated at 0.3 mg/kg/day and lower than that.