Early Intake of Radiocesium by Residents Living Near the Tepco Fukushima Dai-ichi Nuclear Power Plant After the Accident. Part 2: Relationship Between Internal Dose and Evacuation Behavior in Individuals

The Tokyo Electric Power Company's Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident exposed members of the public to radiation. This study analyses the relation between personal behavior data obtained from 112 out of 174 subjects who underwent whole-body measurements by the National Institute of Radiological Sciences (NIRS) during the period from 27 June to 28 July 2011 and their committed effective doses (CEDs) from Cs and Cs. The whereabouts of the 112 persons living in municipalities near the FDNPP (mainly, Namie town) on several days in March 2011 are graphed on maps. It was confirmed that most subjects started evacuation promptly and had left the 20-km-radius of the FDNPP by the end of 12 March. The individual CEDs were poorly correlated with the person's distances from the FDNPP at any day in March. Meanwhile, the percentage of persons remaining within the 20-km radius of the FDNPP was 100% at 16:00 on 12 March and 42.9% at 0:00 on 15 March for those with CEDs > 0.1 mSv, whereas the corresponding values were much lower for those with CEDs ≤ 0.1 mSv. This suggests that the time of evacuation would be one of the crucial factors for the early intake; however, more personal behavior data are needed to be analyzed to clarify the relevance to the individual internal dose

Catalase regulates cell growth in HL60 human promyelocytic cells: evidence for growth regulation by H2O2

Reactive oxygen species (ROS) including hydrogen peroxide (H2O2) are generated constitutively in mammalian cells. Because of its relatively long life and high permeability across membranes, H2O2 is thought to be an important second messenger. Generation of H2O2 is increased in response to external insults, including radiation. Catalase is located at the peroxisome and scavenges H2O2. In this study, we investigated the role of catalase in cell growth using the H2O2-resistant variant HP100-1 of human promyelocytic HL60 cells. HP100-1 cells had an almost 10-fold higher activity of catalase than HL60 cells without differences in levels of glutathione peroxidase, manganese superoxide dismutase (MnSOD), and copper-zinc SOD (CuZnSOD). HP100-1 cells had higher proliferative activity than HL60 cells. Treatment with catalase or the introduction of catalase cDNA into HL60 cells stimulated cell growth. Exposure of HP100-1 cells to a catalase inhibitor resulted in suppression of cell growth with concomitant increased levels of intracellular H2O2. Moreover, exogenously added H2O2 or depletion of glutathione suppressed cell growth in HL60 cells. Extracellular signal regulated kinase 1/2 (ERK1/2) was constitutively phosphorylated in HP100-1 cells but not in HL60 cells. Inhibition of the ERK1/2 pathway suppressed the growth of HP100-1 cells, but inhibition of p38 mitogen-activated protein kinase (p38MAPK) did not affect growth. Moreover, inhibition of catalase blocked the phosphorylation of ERK1/2 but not of p38MAPK in HP100-1 cells. Thus our results suggest that catalase activates the growth of HL60 cells through dismutation of H2O2, leading to activation of the ERK1/2 pathway; H2O2 is an important regulator of growth in HL60 cells

Differential expression of apoptosis-related proteins along the crypt-villus axis following radiation in mouse intestinal epithelial cells

Intestinal epithelium is one of the most proliferating tissues in the mammalian and these epithelial cells are thought to be sensitive to radiation. Exposure of abdominal part to high dose radiation leads to gastrointestinal tract (GIT) injury which is one of serious problems in accidental exposure and also in radiation therapy. However, the mechanism(s) is not fully understood and its treatment is unknown. Stem cells in the crypt differentiate into mature cells and migrate upward from the base of the crypt toward the villus tip. Differentiated cells rapidly lose their proliferative ability and then undergo apoptosis. Radiation breakdowns a dynamic equilibrium of cell proliferation and differentiation in the intestine. In order to study the mechanisms of GIT injury by radiation, we investigated the expression of apoptosis-related proteins in mouse intestinal epithelial cells along the crypt-villus axis following radiation. Epithelial cells were sequentially isolated cells from the villus tip to the crypts of mouse small intestine by the modified Weiser method. This method allowed us to obtain cell fractions along the crypt to villus tip. Western blot analysis showed that proteins of the proliferating cell nuclear antigen (PCNA), the Bax and the Bcl2 were constitutively expressed in the crypt and their levels were reduced toward the villus axis. On the other hand, active form of caspase 3 and cytochrome c were accumulated in the villus tip. Radiation increased levels of Bax, active form of caspase 3, and cytochrome c with concomitant reduced levels of PCNA and Bcl2 in the crypt. In contrast, radiation did not affect the caspase 3 level in the villus tip. The p53 and p21 proteins were not detected in intestinal epithelial cells without radiation. However, radiation increased the levels of these proteins toward the crypt but not in the villus. On the other hand, the p27 protein was constitutively expressed in the crypt but not in villus, and radiation decreased its level in the crypt. Immuno-histochemistry of paraffin section of the small intestine also showed that numbers of p53 and p21 positive cells were increased by radiation in the crypt. Our results suggest that the cell proliferation and response to radiation is differentially regulated in the crypt from the villus; p53 may play an important role in the crypt.ＡＡＣＲ　Ａｎｎｕａｌ　Ｍｅｅｔｉｎｇ　200

Hydrogen peroxide regulates the capacity of cell motility.

Mammalian cells constitutively generate the reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, and hydrogen peroxide through normal intracellular metabolic processes.; The generation is then increased in response to physiological stimuli including cytokines or and growth factors, the generation is increased. Recent studies have shown that ROS are important second messengers. The capacity of cell motility is important for tissue repair and cell-cell interaction in normal cells. Manganese superoxide dismutase (MnSOD) is located in mitochondria and catalyses the dismutaion of superoxide anion into hydrogen peroxide. We studied the role of ROS in cell motility modulating the cellular redox status by introducing human MnSOD cDNA into human ovarian cancer cells, SK-OV-3. Introduction of MnSOD cDNA increased the level of hydrogen peroxide in SK-OV-3 cells. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced cell motility with a concomitant increase in the level of hydrogen peroxide in these cells. Overexpression of MnSOD enhanced cell motility and generation of hydrogen peroxide induced by TPA. Treatment with TPA also induced phosphorylation of p42/44 extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cells overexpressing MnSOD. However, TPA did not affect the phosphorylation of ERK1/2 in control cells. Inhibition of the ERK1/2 pathway abrogated TPA-induced cell motility in MnSOD transfectants. Diethylmaleate (DEM) depletes glutathione and acts as a pro-oxidant, leading to the accumulation of hydrogen peroxide. Treatment with DEM activated ERK1/2 and induced cell motility in both cell lines. Further study found that introduction of oncogenic Rasv13 into SK-OV-3 cells induced cell motility with a concomitant increase in the level of intracellular hydrogen peroxide. In addition, Rasv13 -induced cell motility was inhibited by microinjection of human catalase cDNA. Thus, our results suggest that hydrogen peroxide regulates the capacity of cell motility induced by TPA through a pathway requiring ERK1/2 activation. The present study also indicates that hydrogen peroxide plays an important role in cell motility of Ras-transformed cells.95th Annual Meeting 200

Anti-cancer agent OK432 inhibits UV-induced apoptosis of human granulocytes

The acute inflammatory response is accompanied by an increased number of granulocytes. However, granulocytes are short-lived cells in the circulation; they spontaneously undergo apoptosis. The number of these cells is regulated by the balance of their production and elimination through apoptosis. Since extremely rapid changes in the number of granulocyes have to be made in response to insults, other mechanisms than an enhanced production and maturation of these cells in the bone marrow are required. OK342 is a heat- and penicillin-treated preparation of Streptococcus A3 and has anti-cancer activity; this agent is clinically used as an immuno-therapeutic agent in malignancies. We studied the effect of OK432 on the apoptosis of human granulocytes induced by ultraviolet (UV)-radiation. Flowcytometric analysis with the annexin-V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) showed that UV-radiation (0-200 mJ/cm2) induced apoptosis in a dose dependent manner. Treatment of these cells with OK432 (0-0.5 KE/ml) inhibited UV-induced apoptosis. Previous studies have shown that the extracellular signal-related protein kinase (ERK) pathway is involved in apoptosis of granulocytes. To determine whether the ERK pathway is involved in the apoptosis of these cells, we used a specific inhibitor of MAPK kinase (MEK) inhibitor, PD98059. Treatment of granulocytes with the inhibitor significantly inhibited apoptosis induced by UV-radiation. On the other hand, OK432 activated ERK and inhibition of the ERK pathway by PD98059 blocked the anti-apoptotic effect of OK432. Our findings suggest that the ERK pathway is involved in UV-induced apoptosis in granulocyes and that OK432 inhibits apoptosis by UV-radiation through a pathway requiring activation of ERK. Exposure to UV-radiation on the skin induces skin cancer and also immuno-suppression. OK432 is known to be an immuno-modulator. Regulation of granulocyte survival may be one of the important mechanisms responsible for activities of OK432 in exposure to UV-radiation

Hydrogen peroxide regulates the capacity of cell motility.

Mammalian cells constitutively generate the reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, and hydrogen peroxide through normal intracellular metabolic processes.; The generation is then increased in response to physiological stimuli including cytokines or and growth factors, the generation is increased. Recent studies have shown that ROS are important second messengers. The capacity of cell motility is important for tissue repair and cell-cell interaction in normal cells. Manganese superoxide dismutase (MnSOD) is located in mitochondria and catalyses the dismutaion of superoxide anion into hydrogen peroxide. We studied the role of ROS in cell motility modulating the cellular redox status by introducing human MnSOD cDNA into human ovarian cancer cells, SK-OV-3. Introduction of MnSOD cDNA increased the level of hydrogen peroxide in SK-OV-3 cells. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced cell motility with a concomitant increase in the level of hydrogen peroxide in these cells. Overexpression of MnSOD enhanced cell motility and generation of hydrogen peroxide induced by TPA. Treatment with TPA also induced phosphorylation of p42/44 extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cells overexpressing MnSOD. However, TPA did not affect the phosphorylation of ERK1/2 in control cells. Inhibition of the ERK1/2 pathway abrogated TPA-induced cell motility in MnSOD transfectants. Diethylmaleate (DEM) depletes glutathione and acts as a pro-oxidant, leading to the accumulation of hydrogen peroxide. Treatment with DEM activated ERK1/2 and induced cell motility in both cell lines. Further study found that introduction of oncogenic Rasv13 into SK-OV-3 cells induced cell motility with a concomitant increase in the level of intracellular hydrogen peroxide. In addition, Rasv13 -induced cell motility was inhibited by microinjection of human catalase cDNA. Thus, our results suggest that hydrogen peroxide regulates the capacity of cell motility induced by TPA through a pathway requiring ERK1/2 activation. The present study also indicates that hydrogen peroxide plays an important role in cell motility of Ras-transformed cells.95th Annual Meeting 200

A mechanism for increased levels of -amylase in blood of irradiated mice

96th Annual Meetin

Lessons Learned from Response to the Accident at the TEPCO Fukushima Daiichi Nuclear Power Plant: from the Viewpoint of Radiation Emergency Medicine and Combined Disaster

Since the JCO criticality accident in 1999, it has been thought to be prudent to prepare a system for radiation emergency medicine. The Great East Japan Earthquake measuring 9.0 on the Richter scale occurred in Japan on March 11, 2011, and this earthquake and tsunami caused serious damage to the Fukushima Daiichi Nuclear Power Plant (NPP) of Tokyo Electric Power Co.(TEPCO). Hospitals that had been designated as radiation emergency facilities lost their function because they were located in the evacuation areas, and community lifelines such as water supply and electricity were severely damaged. However, hospitals not thusly designated could not receive patients from NPP because of concerns about the health effects of radiation from patients. InJapan, local governments with nuclear facilities such as NPPs run the training system of radiation emergency for medical professionals. However, those without nuclear facilities do not have the system. Therefore, education and training were restricted to related organizations and agencies.From the response to this accident, we learned that all hospitals, their staffs and first responders need knowledge about radiation and the basics of radiation emergency medicine. The response to this accident has also highlighted the challenges of a radiation emergency medical response system for a combined disaster. In our efforts for recovery from the damages, reconstruction of the medical system for radiation emergency in the affected areas has to be accelerated, since reactors have not been stabilized and many workers are still involved in recovery work, with high risks of radiation exposure at the NPP site. From our response to this combined disaster ofearthquake, tsunami, and radiation, we also learned that there is an urgent need for an all-hazards approach