Sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production.

To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2-8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G-CSF-inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario.

Acute Impacts of Ionizing Radiation Exposure on the Gastrointestinal Tract and Gut Microbiome in Mice.

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1-3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage.

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome.

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Health Effects of Ionizing Radiation on the Human Body.

Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in the form of alpha (α) and beta (ß) particles as well as the emission of gamma (γ) electromagnetic waves. People may be exposed to radiation in various forms, as casualties of nuclear accidents, workers in power plants, or while working and using different radiation sources in medicine and health care. Acute radiation syndrome (ARS) occurs in subjects exposed to a very high dose of radiation in a very short period of time. Each form of radiation has a unique pathophysiological effect. Unfortunately, higher organisms-human beings-in the course of evolution have not acquired receptors for the direct "capture" of radiation energy, which is transferred at the level of DNA, cells, tissues, and organs. Radiation in biological systems depends on the amount of absorbed energy and its spatial distribution, particularly depending on the linear energy transfer (LET). Photon radiation with low LET leads to homogeneous energy deposition in the entire tissue volume. On the other hand, radiation with a high LET produces a fast Bragg peak, which generates a low input dose, whereby the penetration depth into the tissue increases with the radiation energy. The consequences are mutations, apoptosis, the development of cancer, and cell death. The most sensitive cells are those that divide intensively-bone marrow cells, digestive tract cells, reproductive cells, and skin cells. The health care system and the public should raise awareness of the consequences of ionizing radiation. Therefore, our aim is to identify the consequences of ARS taking into account radiation damage to the respiratory system, nervous system, hematopoietic system, gastrointestinal tract, and skin.

Longitudinal multi-omic changes in the transcriptome and proteome of peripheral blood cells after a 4 Gy total body radiation dose to Rhesus macaques.

BACKGROUND: Non-human primates, such as Rhesus macaques, are a powerful model for studies of the cellular and physiological effects of radiation, development of radiation biodosimetry, and for understanding the impact of radiation on human health. Here, we study the effects of 4 Gy total body irradiation (TBI) at the molecular level out to 28 days and at the cytogenetic level out to 56 days after exposure. We combine the global transcriptomic and proteomic responses in peripheral whole blood to assess the impact of acute TBI exposure at extended times post irradiation. RESULTS: The overall mRNA response in the first week reflects a strong inflammatory reaction, infection response with neutrophil and platelet activation. At 1 week, cell cycle arrest and re-entry processes were enriched among mRNA changes, oncogene-induced senescence and MAPK signaling among the proteome changes. Influenza life cycle and infection pathways initiated earlier in mRNA and are reflected among the proteomic changes during the first week. Transcription factor proteins SRC, TGFß and NFATC2 were immediately induced at 1 day after irradiation with increased transcriptional activity as predicted by mRNA changes persisting up to 1 week. Cell counts revealed a mild / moderate hematopoietic acute radiation syndrome (H-ARS) reaction to irradiation with expected lymphopenia, neutropenia and thrombocytopenia that resolved within 30 days. Measurements of micronuclei per binucleated cell levels in cytokinesis-blocked T-lymphocytes remained high in the range 0.27-0.33 up to 28 days and declined to 0.1 by day 56. CONCLUSIONS: Overall, we show that the TBI 4 Gy dose in NHPs induces many cellular changes that persist up to 1 month after exposure, consistent with damage, death, and repopulation of blood cells.

Sex as a Factor in Murine Radiation Research: Implications for Countermeasure Development.

There is an increased threat of exposure to ionizing radiation; in the event of such exposure, the availability of medical countermeasures will be vital to ensure the protection of the population. Effective countermeasures should be efficacious across a varied population and most importantly amongst both males and females. Radiation research must be conducted in animal models which act as a surrogate for the human response. Here, we identify differences in survival in male and female C57BL/6 in both a total body irradiation (TBI) model using the Armed Forces Radiobiology Research Institute (AFRRI) 60Co source and a partial body irradiation (PBI) model using the AFRRI Linear Accelerator (LINAC) with 4 MV photons and 2.5% bone marrow shielding. In both models, we observed a higher degree of radioresistance in female animals and a corresponding radiosensitivity in males. One striking difference in male and female rodents is body size/weight and we investigated the role of pre-irradiation body weight on survivability for animals irradiated at the same dose of irradiation (8 Gy TBI, 14 Gy PBI). We found that weight does not influence survival in the TBI model and that heavier males but lighter females have increased survival in the PBI model. This incongruence in survival amongst the sexes should be taken into consideration in the course of developing radiation countermeasures for response to a mass casualty incident.

Dose- and Segment-Dependent Disturbance of Rat Gut by Ionizing Radiation: Impact of Tight Junction Proteins.

The damaging effect of ionizing radiation (IR) exposure results in the disturbance of the gut natural barrier, followed by the development of severe gastrointestinal injury. However, the dose and application segment are known to determine the effects of IR. In this study, we demonstrated the dose- and segment-specificity of tight junction (TJ) alteration in IR-induced gastrointestinal injury in rats. Male Wistar rats were subjected to a total-body X-ray irradiation at doses of 2 or 10 Gy. Isolated jejunum and colon segments were tested in an Ussing chamber 72 h after exposure. In the jejunum, 10-Gy IR dramatically altered transepithelial resistance, short-circuit current and permeability for sodium fluorescein. These changes were accompanied by severe disturbance of histological structure and total rearrangement of TJ content (increased content of claudin-1, -2, -3 and -4; multidirectional changes in tricellulin and occludin). In the colon of 10-Gy irradiated rats, lesions of barrier and transport functions were less pronounced, with only claudin-2 and -4 altered among TJ proteins. The 2-Gy IR did not change electrophysiological characteristics or permeability in the colon or jejunum, although slight alterations in jejunum histology were noted, emphasized with claudin-3 increase. Considering that TJ proteins are critical for maintaining epithelial barrier integrity, these findings may have implications for countermeasures in gastrointestinal acute radiation injury.

Chronic Ouabain Targets Pore-Forming Claudin-2 and Ameliorates Radiation-Induced Damage to the Rat Intestinal Tissue Barrier.

Ionizing radiation (IR) causes disturbances in the functions of the gastrointestinal tract. Given the therapeutic potential of ouabain, a specific ligand of the Na,K-ATPase, we tested its ability to protect against IR-induced disturbances in the barrier and transport properties of the jejunum and colon of rats. Male Wistar rats were subjected to 6-day intraperitoneal injections of vehicle or ouabain (1 µg/kg/day). On the fourth day of injections, rats were exposed to total-body X-ray irradiation (10 Gy) or a sham irradiation. Isolated tissues were examined 72 h post-irradiation. Electrophysiological characteristics and paracellular permeability for sodium fluorescein were measured in an Ussing chamber. Histological analysis and Western blotting were also performed. In the jejunum tissue, ouabain exposure did not prevent disturbances in transepithelial resistance, paracellular permeability, histological characteristics, as well as changes in the expression of claudin-1, -3, -4, tricellulin, and caspase-3 induced by IR. However, ouabain prevented overexpression of occludin and the pore-forming claudin-2. In the colon tissue, ouabain prevented electrophysiological disturbances and claudin-2 overexpression. These observations may reveal a mechanism by which circulating ouabain maintains tight junction integrity under IR-induced intestinal dysfunction.

Humanized Mice as a Model to Assess the Response of Human Hematopoietic Stem Cells to Irradiation.

NOD SCID mice were humanized by transplanting human hematopoietic cells isolated from umbilical cord blood. A dose-dependent death of hematopoietic cells and their subsequent recovery were shown after acute external γ-irradiation in the model of humanized mice. The proposed approach can be used for preclinical studies of radioprotective agents and for assessment of the impact of adverse factors on the survival rate and functional properties of human hematopoietic stem cells in vivo.

Model for Evaluating Antimicrobial Therapy To Prevent Life-Threatening Bacterial Infections following Exposure to a Medically Significant Radiation Dose.

More evidence is needed to support recommendations for medical management of acute radiation syndrome (ARS) and associated infections resulting from a radiological/nuclear event. While current guidelines recommend the administration of antibiotics to chemotherapy patients with febrile neutropenia, the clinical benefit is unclear for acute radiation injury patients. A well-characterized nonhuman primate (NHP) model of hematopoietic ARS was developed that incorporates supportive care postirradiation. This model evaluated the efficacy of myeloid growth factors within 24 to 48 h after total body irradiation (TBI). However, in this model, NHPs continued to develop life-threatening bacterial infections, even when granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was administered in combination with antibiotic monotherapy. In this study, we evaluated the efficacy of combination antibiotic therapies administered to NHPs following 7.4-Gy TBI to understand the occurrence of bacterial infection in NHPs with hematopoietic ARS. We compared enrofloxacin-linezolid, enrofloxacin-cefepime, and enrofloxacin-ertapenem to enrofloxacin monotherapy. The primary endpoint was 60-day postirradiation mortality, with secondary endpoints of overall survival time, incidence of bacterial infection, and bacteriologic culture with antimicrobial susceptibility testing. We observed that enrofloxacin-ertapenem significantly increased survival compared to enrofloxacin monotherapy. Bacteria isolated from nonsurviving macaques with systemic bacterial infections exhibited uniform resistance to enrofloxacin and variable resistance to beta-lactam antibiotics, linezolid, gentamicin, and azithromycin. Multidrug antibiotic resistance was observed in Enterococcus spp. and Escherichia coli. We conclude that antibiotic combination therapies appear to be more effective than monotherapy alone but acknowledge that more work is needed to identify an optimal antimicrobial therapy.

Responding to radiation accidents: what more do we need to know?

A short review of the various types of radiation incidents and accidents that have occurred is used to provide a context for discussing the findings on medical management of the victims of such incidents and accidents reported in a recent Special Issue of the Journal of Radiological Protection. The review demonstrates that accidents and incidents giving rise to high radiation doses may involve over-exposure of a single individual, a few individuals, or very large numbers. In general, these exposures will be relatively short-term, ranging from a few seconds to a few days, but chronic situations resulting in high exposures can occur. Some of these exposures may be highly localised, whereas others may result in almost uniform whole-body irradiation. This diversity of situations means that it is not feasible to have a single protocol for the diagnosis and treatment of over-exposed individuals. If the over-exposures are limited to one or a few individuals, these can be addressed on a case-by-case basis. However, where large numbers have been exposed or may have been exposed, there is a need to implement a rapid and effective system of triage. Furthermore, this system is likely to have to be implemented by individuals who have little or no direct experience of radiation-induced injuries. For those individuals who may have been significantly exposed, the key consideration is not to determine the radiation dose that they have received, but to establish their present clinical status and how it is likely to develop with time. There is at most a very limited role for bone-marrow transplantation in the treatment of acute radiation syndrome, whereas there are good arguments for administering various treatments to boost bone marrow function together with other supportive interventions, e.g. in control of infections and handling both fluid loss and bleeding. However, there is concern that the focus to date has been only on the licencing of drugs related to the management of haematopoietic effects. Although a great deal is known about the diagnosis and treatment of injuries arising from high dose exposures, this knowledge is biased towards situations in which there is relatively uniform, external whole-body exposure. More attention needs to be given to assessing the implications of various inhomogeneous exposure regimes and to developing medical countermeasures optimised for addressing the complex, multi-organ effects likely to arise from such inhomogeneous exposures.

Mitigating effects of sublethal and lethal whole-body gamma irradiation in a mouse model with soluble melanin.

The field of radiation countermeasures is growing, however, currently there are no effective and non-toxic compounds which could be administered orally to the individuals post exposure to high doses of ionising radiation. The pigment melanin is ubiquitous through all kingdoms of life and provides selective advantage under radiation stress through its role as a chemical and physical shield, and its capacity to respond and react to exposures. Soluble allomelanin was administered to mice following whole-body exposure to lethal or sublethal doses of gamma radiation to determine its capacity to mitigate the effects of acute radiation syndrome, and its utility as a radiation countermeasure. Allomelanin has shown a trend to improve survival post an 8 Gy sublethal radiation exposure when administered up to 48 h post-irradiation. Furthermore, it improved median and overall survival to a 10 Gy lethal radiation exposure, specifically when administered at 24 h post-irradiation. Histological analysis on the jejunum region of the small intestine of this treatment group indicated that alterations of the mucosal and submucosal architecture, and disruption of the lymphatic system associated with lethal radiation exposure were mitigated when allomelanin was administered at 24 h post-irradiation. Based on this work soluble allomelanin derived from a fungal source could serve as an easily sourced, cost-effective, and viable countermeasure to accidental radiation exposure and merits further investigation.

The acute radiation syndrome-need for updated medical guidelines.

The major immediate and severe medical consequences in man following exposure to high doses of ionising radiation can be summarised within the concept of the acute radiation syndrome (ARS). In a dose-dependent fashion, a multitude of organ systems can be affected by such irradiation, presenting considerable medical challenges to treating physicians. Accidents or malevolent events leading to ARS can provoke devastating effects, but they occur at a low frequency and in a highly varying manner and magnitude. Thus, it is difficult to make precise medical predictions and planning, or to draw conclusive evidence from occurred events. Therefore, knowledge from on-going continuous developments within related medical areas needs to be acknowledged and incorporated into the ARS setting, enabling the creation of evidence-based guidelines. In 2011 the World Health Organization published a first global consensus on the medical management of ARS among patients subjected to nontherapeutic radiation. During the recent decade the understanding of and capability to counteract organ damage related to radiation and other agents have improved considerably. Furthermore, legal and logistic hurdles in the process of formally approving appropriate medical countermeasures have been reduced. We believe the time is now ripe for developing an update of internationally consented medical guidelines on ARS.

The METREPOL criteria-are they still relevant?

The medical management of radiation accidents manual on the acute radiation syndrome proposed a successful strategic approach to diagnosing and treating acute radiation syndrome: the response category concept. Based on clinical and laboratory parameters, this approach aimed to assess damage to critical organ systems as a function of time, categorising different therapeutical approaches. After 20 years of its publication, the following paper attempts to provide a broad overview of this important document and tries to respond if proposed criteria are still relevant for the medical management of radiation-induced injuries. In addition, a critical analysis of its limitations and perspectives is proposed.

Targets for protection and mitigation of radiation injury.

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.

Training of clinical triage of acute radiation casualties: a performance comparison ofon-siteversusonlinetraining due to the covid-19 pandemic.

A collection of powerful diagnostic tools have been developed under the umbrellas of NATO for ionising radiation dose assessment (BAT, WinFRAT) and estimate of acute health effects in humans (WinFRAT, H-Module). We assembled a database of 191 ARS cases using the medical treatment protocols for radiation accident victims (n= 167) and the system for evaluation and archiving of radiation accidents based on case histories (n= 24) for training purposes of medical personnel. From 2016 to 2019, we trained 39 participants comprising MSc level radiobiology students in an on-site teaching class. Enforced by the covid-19 pandemic in 2020 for the first time, an online teaching of nine MSc radiobiology students replaced the on-site teaching. We found that: (a) limitations of correct diagnostic decision-making based on clinical signs and symptoms were experienced unrelated to the teaching format. (b) A significant performance decrease concerning online (first number in parenthesis) versus on-site teaching (reference and second number in parenthesis) was seen regarding the estimate time (31 vs 61 cases per hour, two-fold decrease,p= 0.005). Also, the accurate assessment of response categories (89.9% vs 96.9%,p= 0.001), ARS (92.4% vs 96.7%,p= 0.002) and hospitalisation (93.5% vs 97.0%,p= 0.002) decreased by around 3%-7%. The performances of the online attendees were mainly distributed within the lower quartile performance of on-site participants and the 25%-75% interquartile range increased 3-7-fold. (c) Comparison of dose estimates performed by training participants with hematologic acute radiation syndrome (HARS) severity mirrored the known limitations of dose alone as a surrogate parameter for HARS severity at doses less than 1.5 Gy, but demonstrated correct determination of HARS 2-4 and support for clinical decision making at dose estimates >1.5 Gy, regardless of teaching format. (d) Overall, one-third of the online participants showed substantial misapprehension and insecurities of elementary course content that did not occur after the on-site teaching.

Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident.

A criticality accident occurred at the uranium conversion plant in Tokaimura, Ibaraki Prefecture, Japan on 30 September 1999. When uranyl nitrate was overloaded to a critical mass level, uncontrolled fission reaction occurred. A procedure was carried out according to the JCO manual, although not an officially approved manual. Three workers were heavily exposed to neutrons andγ-rays produced by nuclear fission, and they subsequently developed acute radiation syndrome (ARS). The average doses to the whole body of the three workers were approximately 25, 9, and 3 GyEq (biologically equivalent dose ofγ-exposure), respectively; dose distribution analysis later revealed extreme heterogeneity of these doses in two workers. They were triaged according to the predicted clinical needs. Two of these workers developed severe bone marrow failure and received haematopoietic stem cell transplantation: one with peripheral stem cell transplantation from his Human Leukocyte Antigen compatible sister and the other with umbilical cord blood transplantation. The graft was initially successful in both workers; autologous haematopoietic recovery was observed after donor/recipient mixed chimerism in one of them. Despite of all medical efforts available including haematopoietic stem cell transplantation, investigational drugs, skin graft, two workers died of multiple organ involvement and failure 83 and 211 days after the accident, respectively. Clinically as well as pathologically, the direct cause of death was deemed to be intractable gastrointestinal (GI) bleeding in one, and thoraco-abdominal compartment syndrome due to dermal fibrosis/sclerosis in the other. The third worker also developed bone marrow suppression but was treated with granulocyte colony-stimulating factor. He recovered without major complications and is now under periodical medical follow-up. These experiences suggest that treatment of bone marrow is not a limiting factor for saving the life of ARS victims severely exposed. Successful treatment of other organs such as lungs, skin, and GI tract is also essential. Furthermore, the whole-body dose may not always reflect the prognosis of ARS victims because of the nature of accidental exposure, heterogenous exposure.

Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures.

Therapy of acute, high-dose whole-body exposures of humans to ionizing radiations is a complex medical challenge. Since 1944 more than 400 radiologic accidents have been registered with more than 3000 substantial radiation exposures and 127 fatalities. There are several potential interventions including supportive care, transfusions, preventative or therapeutic anti-infection drugs, molecularly-cloned myeloid growth factors and hematopoietic cell transplants. We discuss the use of the granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) to treat acute high-dose ionizing radiation exposures. Considerable data in experimental models including monkeys indicate use of these drugs accelerates bone marrow recovery and in some but not all instances increases survival. In ten accidents since 1996, 30 victims received G-CSF alone or with other growth factors. Twenty-six victims survived. In seven accidents since 1986, 28 victims received GM-CSF alone or with other growth factors; 18 victims survived. However, absent control or data from randomized trials, it is not possible to know with certainty what role, if any, receiving G-CSF or GM-CSF was of benefit. Given the favorablebenefit-to-riskratio of molecularly-cloned myeloid growth factors, their use soon after exposure to acute, high-dose whole-body ionizing radiations is reasonable.

Medical management: major lessons learned from the Chernobyl accident (the review).

Thirty-five years have passed since the moment of the disaster at the Chernobyl nuclear power plant. It is quite a sufficient period to assess the correctness of the organisation of medical care for victims, to summarise the results of monitoring the health status of various groups of persons involved in the accident, including its direct participants. Radiation from a massive source of relatively uniform gamma radiation and a heterogeneous source of beta radiation can cause affected people to develop acute radiation syndrome (ARS) of varying severity, including non-curable forms of the disease ARS developed in 134 patients; 28 patients from 134 with ARS died in a short time (100 d) after exposure. Among the patients whose disease ended in death, 2/3 of the outcome could be due to radiation skin lesions (19 people). Treatment of ARS varying severity, which was combined with common skin burns with beta radiation, requires long-term specialised treatment. The experience of treating this group of patients has demonstrated that the indications for bone marrow transplantation in the curable form of ARS are limited. The percentage of victims who have absolute indications for allogeneic bone marrow transplantation and in whom this procedure will lead to an improved prognosis for life is very small. Recovery of own myelopoiesis and survival are possible after whole-body irradiation from 6 to 8 Gy, which was found after rejection of haploidentical human leucocyte antigen transplantation, as well as in patients who did not use bone marrow transplantation due to the absence of a corresponding donor. Patients who have undergone ARS need lifelong medical supervision and the provision of necessary medical care.

Early-response multiple-parameter biodosimetry and dosimetry: risk predictions.

The accepted generic multiple-parameter and early-response biodosimetry and dosimetry assessment approach for suspected high-dose radiation (i.e. life-threatening) exposure includes measuring radioactivity associated with the exposed individual (if appropriate); observing and recording prodromal signs/symptoms; obtaining serial complete blood counts with white-blood-cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the 'gold standard' dicentric assay (premature chromosome condensation assay for exposures >5 Gy photon acute doses equivalent), measurement of proteomic biomarkers and gene expression assays for dose assessment; bioassay sampling, if appropriate, to determine radioactive internal contamination; physical dose reconstruction, and using other available opportunistic dosimetry approaches. Biodosimetry and dosimetry resources are identified and should be setup in advance along with agreements to access additional national, regional, and international resources. This multifaceted capability needs to be integrated into a biodosimetry/dosimetry 'concept of operations' for use in a radiological emergency. The combined use of traditional biological-, clinical-, and physical-dosimetry should be use in an integrated approach to provide: (a) early-phase diagnostics to guide the development of initial medical-management strategy, and (b) intermediate and definitive assessment of radiation dose and injury. Use of early-phase (a) clinical signs and symptoms, (b) blood chemistry biomarkers, and (c) triage cytogenetics shows diagnostic utility to predict acute radiation injury severity.