A comparative assessment of major international disasters: the need for exposure assessment, systematic emergency preparedness, and lifetime health care.

BACKGROUND: The disasters at Seveso, Three Mile Island, Bhopal, Chernobyl, the World Trade Center (WTC) and Fukushima had historic health and economic sequelae for large populations of workers, responders and community members. METHODS: Comparative data from these events were collected to derive indications for future preparedness. Information from the primary sources and a literature review addressed: i) exposure assessment; ii) exposed populations; iii) health surveillance; iv) follow-up and research outputs; v) observed physical and mental health effects; vi) treatment and benefits; and vii) outreach activities. RESULTS: Exposure assessment was conducted in Seveso, Chernobyl and Fukushima, although none benefited from a timely or systematic strategy, yielding immediate and sequential measurements after the disaster. Identification of exposed subjects was overall underestimated. Health surveillance, treatment and follow-up research were implemented in Seveso, Chernobyl, Fukushima, and at the WTC, mostly focusing on the workers and responders, and to a lesser extent on residents. Exposure-related physical and mental health consequences were identified, indicating the need for a long-term health care of the affected populations. Fukushima has generated the largest scientific output so far, followed by the WTCHP and Chernobyl. Benefits programs and active outreach figured prominently in only the WTC Health Program. The analysis of these programs yielded the following lessons: 1) Know who was there; 2) Have public health input to the disaster response; 3) Collect health and needs data rapidly; 4) Take care of the affected; 5) Emergency preparedness; 6) Data driven, needs assessment, advocacy. CONCLUSIONS: Given the long-lasting health consequences of natural and man-made disasters, health surveillance and treatment programs are critical for management of health conditions, and emergency preparedness plans are needed to prevent or minimize the impact of future threats.

Changes in the number of double-strand DNA breaks in Chinese hamster V79 cells exposed to γ-radiation with different dose rates.

A comparative investigation of the induction of double-strand DNA breaks (DSBs) in the Chinese hamster V79 cells by γ-radiation at dose rates of 1, 10 and 400 mGy/min (doses ranged from 0.36 to 4.32 Gy) was performed. The acute radiation exposure at a dose rate of 400 mGy/min resulted in the linear dose-dependent increase of the γ-H2AX foci formation. The dose-response curve for the acute exposure was well described by a linear function y = 1.22 + 19.7x, where "y" is an average number of γ-H2AX foci per a cell and "x" is the absorbed dose (Gy). The dose rate reduction down to 10 mGy/min lead to a decreased number of γ-H2AX foci, as well as to a change of the dose-response relationship. Thus, the foci number up to 1.44 Gy increased and reached the "plateau" area between 1.44 and 4.32 Gy. There was only a slight increase of the γ-H2AX foci number (up to 7) in cells after the protracted exposure (up to 72 h) to ionizing radiation at a dose rate of 1 mGy/min. Similar effects of the varying dose rates were obtained when DNA damage was assessed using the comet assay. In general, our results show that the reduction of the radiation dose rate resulted in a significant decrease of DSBs per cell per an absorbed dose.

Clonal chromosomal and genomic instability during human multipotent mesenchymal stromal cells long-term culture.

BACKGROUND AIMS: Spontaneous mutagenesis often leads to appearance of genetic changes in cells. Although human multipotent mesenchymal stromal cells (hMSC) are considered as genetically stable, there is a risk of genomic and structural chromosome instability and, therefore, side effects of cell therapy associated with long-term effects. In this study, the karyotype, genetic variability and clone formation analyses have been carried out in the long-term culture MSC from human gingival mucosa. METHODS: The immunophenotype of MSC has been examined using flow cytofluorometry and short tandem repeat (STR) analysis has been carried out for authentication. The karyotype has been examined using GTG staining and mFISH, while the assessment of the aneuploidy 8 frequency has been performed using centromere specific chromosome FISH probes in interphase cells. RESULTS: The immunophenotype and STR loci combination did not change during the process of cultivation. From passage 23 the proliferative activity of cultured MSCs was significantly reduced. From passage 12 of cultivation, clones of cells with stable chromosome aberrations have been identified and the biggest of these (12%) are tetrasomy of chromosome 8. The random genetic and structural chromosomal aberrations and the spontaneous level of chromosomal aberrations in the hMSC long-term cultures were also described. CONCLUSIONS: The spectrum of spontaneous chromosomal aberrations in MSC long-term cultivation has been described. Clonal chromosomal aberrations have been identified. A clone of cells with tetrasomy 8 has been detected in passage 12 and has reached the maximum size by passage 18 before and decreased along with the reduction of proliferative activity of cell line by passage 26. At later passages, the MSC line exhibited a set of cells with structural variants of the karyotype with a preponderance of normal diploid cells. The results of our study strongly suggest a need for rigorous genetic analyses of the clone formation in cultured MSCs before use in medicine.

Use of paracrine factors from stem cells to treat local radiation burns in rats.

BACKGROUND: Mesenchymal stem cells based paracrine bioactive factors that deploy their task as an essential mechanism, but their efficiency for skin regeneration still requires clarification. METHODS: The mesenchymal stem cell-based paracrine factors were administered by subcutaneous injection of 0.5 mL peptides (general protein 8 mg/mL). These were performed after radiation on different days like the first, third, sixth, eighth, and 10th. To determine the consequences, we performed photography, planimetry, and preclinical test each week after 15 days of radiation. MSC-based peptides were injected into a rat that had radiation burns, and its observation encouraged cell-free therapeutic remedies to regenerate skin. Both control and experimental groups were exposed to 110 Gy of X-rays, which resulted in the formation of localized radiation burns on the skin (S=6 cm2) 15 days later. Thirty days after radiation, the wound stabilized (surface of the wound was S=2.2±0.2 cm2) and fluctuated throughout the course of the pathological process. RESULTS: The wounded area on the skin from the 15th to the 29th day after radiation was practically the same in both groups. The wounded area gradually reduced by 6.1±0.4 cm2 (experimental group) and 5.9±0.6 cm2 (control group) 15 days after radiation up to 2.2±0.3 cm2 (in both control and experimental groups) on the 29th day after radiation. However, starting from the 36th day, there was a constant reduction in the burn area in the experimental group up to 0.2±0.1 cm2 till the 71st day after radiation. CONCLUSION: In the control group, the area of the lesion ranged from 1.4±0.6 cm2 on the 50th day to 1.9±0.8 cm2 on the 71st day. During the 57th to the 71st day, the difference between the affected area in the experimental and control groups was 1:8. The experimental group has a significantly higher level of skin regeneration and significant decrease in the level of leukocyte infiltration, thereby reducing necrosis.

Residual γH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells.

Mechanisms underlying the effects of low-dose ionizing radiation (IR) exposure (10-100 mGy) remain unknown. Here we present a comparative study of early (less than 24h) and delayed (up to 11 post-irradiation passages) radiation effects caused by low (80 mGy) vs intermediate (1000 mGy) dose X-ray exposure in cultured human bone marrow mesenchymal stem cells (MSCs). We show that γН2АХ foci induced by an intermediate dose returned back to the control value by 24 h post-irradiation. In contrast, low-dose irradiation resulted in residual γН2АХ foci still present at 24 h. Notably, these low dose induced residual γН2АХ foci were not co-localized with рАТМ foci and were observed predominantly in the proliferating Кi67 positive (Кi67+) cells. The number of γН2АХ foci and the fraction of nonproliferating (Кi67-) and senescent (SA-ß-gal+) cells measured at passage 11 were increased in cultures exposed to an intermediate dose compared to unirradiated controls. These delayed effects were not seen in the progeny of cells that were irradiated with low-dose X-rays, although such exposure resulted in residual γН2АХ foci in directly irradiated cells. Taken together, our results support the hypothesis that the low-dose IR induced residual γH2AÐ¥ foci do not play a role in delayed irradiation consequences, associated with cellular senescence in cultured MSCs.

Accumulation of spontaneous γH2AX foci in long-term cultured mesenchymal stromal cells.

Expansion of mesenchymal stromal/stem cells (MSCs) used in clinical practices may be associated with accumulation of genetic instability. Understanding temporal and mechanistic aspects of this process is important for improving stem cell therapy protocols. We used γH2AX foci as a marker of a genetic instability event and quantified it in MSCs that undergone various numbers of passage (3-22). We found that γH2AX foci numbers increased in cells of late passages, with a sharp increase at passage 16-18. By measuring in parallel foci of ATM phosphorylated at Ser-1981 and their co-localization with γaH2AX foci, along with differentiating cells into proliferating and resting by using a Ki67 marker, we conclude that the sharp increase in γH2AX foci numbers was ATM-independent and happened predominantly in proliferating cells. At the same time, gradual and moderate increase in γH2AX foci with passage number seen in both resting and proliferating cells may represent a slow, DNA double-strand break related component of the accumulation of genetic instability in MSCs. Our results provide important information on selecting appropriate passage numbers exceeding which would be associated with substantial risks to a patient-recipient, both with respect to therapeutic efficiency and side-effects related to potential neoplastic transformations due to genetic instability acquired by MSCs during expansion.

Current Status and Prospects of Occupational Medicine in the Russian Federation.

An in-depth analysis conducted on the historical background and current status of occupational medicine in Russia is presented. Scientific and practical bases of occupational medicine in the Russian Federation were based on 2 of the most important principles of health service: free medical care and its preventive orientation. Our analysis of the current situation in occupational medicine in modern Russia shows a transition from the vision of zero occupation-related harm to the strategy of recognizing, assessing, and managing occupational exposures. The system of workplace monitoring is developing successfully, with the creation of a federal database for the state of working conditions and the implementation of mechanisms for occupational risk assessment and management. However, at the same time, the system of medical surveillance for workers needs substantial reform. Over the past few years, the professional community of specialists in occupational medicine has taken several steps to improve the quality of its work. Understanding of the need for reforming the system of occupational medicine has continued to grow, which will improve the quality of medical monitoring for workers and extend professional longevity. Current challenges and prospects of occupational medicine in the Russian Federation are discussed.

Dose-dependent analysis of acute medical effects of mixed neutron-gamma radiation from selected severe 235U or 239Pu criticality accidents in USSR, United States, and Argentina.

Eight of the most severe cases of acute radiation disease (ARS) known to have occurred in humans (as the result of criticality accidents) had survival times less than 120 h (herein defined as "early death"). These accidents were analyzed and are discussed with respect to the specific accident scenarios and the resulting accident-specific, mixed neutron-gamma radiation clinical dose distributions. This analysis concludes that the cardiovascular system appears to be the most critical organ system failure for causing "early death" following approximate total body, mixed gamma-neutron radiation doses greater than 40-50 Gy. The clinical data also suggest that there was definite chest dose dependence in the resulting survival times for these eight workers, who unfortunately suffered profound radiation injury and unusual clinical effects from such high dose radiation exposures. In addition, "toxemic syndrome" is correlated with the irradiation of large volumes of soft tissues. Doses to the hands or legs greater than 80-100 Gy or radiation lung injury also play significant but secondary roles in causing "early death" in accidents delivering chest doses greater than 50 Gy.