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Preparedness for medical responses to major radiation accidents and the increasing threat of nuclear warfare worldwide necessitates an understanding of the complexity of combined radiation injury (CI) and identifying drugs to treat CI is inevitably critical. The vital sign and survival after CI were presented. The molecular mechanisms, such as microRNA pathways, NF-κB-iNOS-IL-18 pathway, C3 production, the AKT-MAPK cross-talk, and TLR/MMP increases, underlying CI in relation to organ injury and mortality were analyzed. At present, no FDA-approved drug to protect, mitigate, or treat CI is available. The development of CI-specific medical countermeasures was reviewed. Because of the worsened acute radiation syndrome resulting from CI, diagnostic triage can be problematic. Therefore, biodosimetry and CI are bundled together with the need to establish effective triage methods with CI. CI mouse model studies at AFRRI are reviewed addressing molecular responses, findings from medical countermeasures, and a proposed plasma proteomic biodosimetry approach based on a panel of radiation-responsive biomarkers (i.e., CD27, Flt-3L, GM-CSF, CD45, IL-12, TPO) negligibly influenced by wounding in an algorithm used for dose predictions is described. [ABSTRACT FROM AUTHOR]

The United States is not prepared to deal with an attack by a terrorist group using an improvised nuclear device, the author says. It should get prepared, because the risk is real even if the probability is low, and doing so could save a great many lives. The author explores the potential impact of a 10–15-kt improvised nuclear device set off in New York City. The initial blast would kill between 75,000 and 100,000 people in seconds. Another 100,000–200,000 people would be injured, many of them dying within weeks or months, some with burns, others with impact injuries, and some with acute radiation syndrome. The demands on the medical system would be vast and overwhelming, all the more so because the bomb would have destroyed much of the capacity to respond. Current planning efforts are not sufficient to manage the carnage. [ABSTRACT FROM PUBLISHER]

Animal models that accurately reflect human responses to radiation injury are needed for advanced mechanistic investigation and development of effective therapeutics. The rabbit is an established animal model accepted by the FDA for studies of cardiovascular disease, lipid metabolism, the development of anticoagulants, testing of bone implants, and the development of treatments for infectious diseases such as HIV. The purpose of this study was to investigate the New Zealand White (NZW) Rabbit model as a model of acute radiation exposure because of its established similarity to human vascular, immune, and coagulation responses. Two sequential studies were performed in a total of 81 male NZW rabbits, 16–20 weeks of age. All animals underwent clinical observations and peripheral blood analyses following a single dose of 0, 6, 7, 8, 8.5, 9, or 10 Gy of total body irradiation via a 6 MV Linear accelerator photon source on day 0. Animals were treated with timed release fentanyl patch (days 0–30), subcutaneous hydration (day 1, Study 2 only), and oral sulfamethoxazole/trimethoprim 30 mg/kg once daily (days 3–30) and were followed for 30 days or to time of mortality. Study 1 revealed the estimated LD30, −50, −70, and −90 with 95% confidence intervals (CI) at 30 days to be 6.7 (CI: 5.9–7.4), 7.3 (CI: 6.7–7.8), 7.9 (CI: 7.3–8.4), and 8.8 (CI: 7.9–9.7) Gy, respectively. In study 2, a survey of blood coagulation and biochemical parameters were performed over time and necropsy. Complete blood counts taken from animals exposed to 7, 8, or 10 Gy, demonstrated dose-dependent depletion of lymphocytes, neutrophils, and platelets. Platelet counts recovered to baseline levels in survivors by day 30, whereas lymphocyte and neutrophil counts did not. Decedent animals demonstrated grade 3 or 4 neutropenia and lymphopenia at time of death; 64% of the decedents experienced a 30% or greater drop in hematocrit. Decedent animals demonstrated more than 100% increases from serum baseline levels of blood urea nitrogen, creatinine, aspartate aminotransferase, and triglyceride levels at the time of death whereas survivors on average demonstrated modest or no elevation. This NZW rabbit model demonstrates dose-dependent depletion of hematopoietic parameters. The LD50/30 of 7.8 Gy (95% CI: 6.6–8.4) with supportive care appears to be close to the ranges reported for rhesus macaques (5.25–7.44 Gy) and humans (6–8 Gy) with supportive care. These findings support the utility of the NZW rabbit model for further mechanistic investigation of acute radiation exposure and medical countermeasure testing. [ABSTRACT FROM AUTHOR]

NASA was recently charged with returning humans to the lunar surface within the next five years. This will require preparation for spaceflight missions of longer distance and duration than ever performed in the past. Protecting the crew and mission from the hazards associated with spaceflight will be a priority. One of the primary hazards to address is the challenging radiation environment. Space is unforgiving when it comes to radiation. There is galactic cosmic radiation (GCR) that is pervasive in space and the possibility of solar particle events (SPE) that release high energy particles from the sun that can result in high doses of radiation to the crew if unprotected. NASA has been preparing and evaluating several means of ensuring that crew health is not compromised during these missions. Physical shielding, space weather monitoring, and more recently storm shelters are all possible means of protecting crew during a SPE. Medical countermeasures have not been necessary for operations in low Earth orbit; however, future human exploration missions should consider including therapies onboard to address radiation-induced health effects. While the likelihood of experiencing a significant SPE is very low, serious adverse health effects or even death could occur if no medical countermeasures were available. Having a Food and Drug Administration (FDA) approved medical countermeasure on board that could mitigate acute radiation-induced hematopoietic syndrome due to a SPE could provide life saving measures for the crew. This paper discusses the mitigation strategies that can be implemented for Artemis missions and identifies numerous areas of research for future improvements. [ABSTRACT FROM AUTHOR]

The hemorrhagic syndrome is a major cause of morbidity and mortality associated with the acute radiation syndrome (ARS). We previously characterized the dose–response relationship for total body irradiation (TBI)-induced ARS in the New Zealand White (NZW) rabbit. Thrombocytopenia, hemorrhage, and anemia were strongly associated with morbidity/mortality during the first three weeks post-TBI. The objective of the current study was to further characterize the natural history of thrombocytopenia, hemostatic dysfunction and hemorrhage in the rabbit model at a TBI dose range to induce ARS. Fifty male NZW rabbits were randomized to receive 7.0 or 7.5 Gy of 6 MV-derived TBI. Sham-irradiated controls (n = 6) were included as a comparator. Animals were treated with minimal supportive care including pain medication, antibiotics, antipyretics for temperature >104.8 °F, and fluids for signs of dehydration. Animals were culled at pre-determined timepoints post-TBI, or for signs of imminent mortality based on pre-defined euthanasia criteria. Hematology parameters, serum chemistry, viscoelasticity of whole blood, coagulation tests, and coagulation factor activities were measured. A gross exam of vital organs was performed at necropsy. Findings in this study include severe neutropenia during the first week post-TBI followed by thrombocytopenia and severe acute anemia with petechial hemorrhages of the skin and hemorrhage of the vital organs during the second to third weeks post-TBI. Abnormalities in whole blood viscoelastometry were observed concurrent with thrombocytopenia and hemorrhage. Antithrombin activity was significantly elevated in animals after exposure to 7.5 Gy, but not 7.0 Gy TBI. The hemorrhagic syndrome in the rabbit model of TBI recapitulates the pathogenesis described in humans following accidental or deliberate exposures. The rabbit may present an alternative to the rodent model as a small animal species for characterization of the full spectrum of multiorgan injury following TBI and early testing of promising medical countermeasures. [ABSTRACT FROM AUTHOR]

The purpose if this study was to develop a rabbit model of total body irradiation (TBI) -induced thrombocytopenia and coagulopathy across the dose-range which induces the hematopoietic subsyndrome of the acute radiation syndrome (H-ARS). Twenty male New Zealand White rabbits were assigned to arms to receive 6-MV of TBI at a dose of 6.5, 7.5, 8.5 or 9.5 Gy. Animals were treated with moderate levels of supportive care including buprenorphine for pain management, antibiotics, antipyretics for rectal body temperature >104.8 °F, and fluids for signs of dehydration. Animals were closelyfollowed for up to 45 days after TBI for signs of major morbidity/mortality. Hematology and serum chemistry parameters were routinely monitored. Hemostasis parameters were analyzed prior to TBI, 2 and 6 hours post-TBI, and at the time of euthanasia. Animals developed the characteristic signs and symptoms of H-ARS during the first-week post TBI. Animals became thrombocytopenic with signs of severe acute anemia during the second week post TBI. Moribund animals presented with petechia and ecchymosis of the skin and generalized internal hemorrhage. Multiorgan dysfunction characterized by bone marrow failure, gastric ileus, acute renal toxicity, and liver abnormalities were common. Severe abnormalities in coagulation parameters were observed. The presentation of bone marrow failure and multiorogan injury associated with ARS in the New Zealand White rabbit model is consistent with that described in the canine, swine, non-human primate, and in humans. The hemorrhagic syndrome associated with the ARS in rabbits is characterized by thrombocytopenia and hemostasis dysfunction, which appear to underlie the development of multiorgan dysfunction following TBI to rabbits. Taken together, the rabbit recapitulates the pathogenesis of ARS in humans, and may present an alternative small animal model for medical countermeasure pilot efficacy screening, dose-finding and schedule optimization studies prior to moving into large animal models of TBI-induced ARS. [ABSTRACT FROM AUTHOR]

Purpose: G€ottingen minipig (G-MP) displays classic gastrointestinal acute radiation syndrome (GIARS) following total body irradiation (TBI) at GI doses which are lethal by 10-14 days. In collaboration with BARDA, we are developing a hemi-body/partial body irradiation (PBI) model by exposing only the abdomen and lower extremities to study GI structure/function impairment, natural history of injury and recovery, as well as correlative biomarkers out to 30 days. Materials and methods: Twenty-four G-MP were exposed to either 12 or 16 Gy (LINAC Elekta); head, forelimbs, and thorax were outside the irradiation field, sparing -50% of the bone marrow. Animals were followed for 30 days with euthanasia scheduled at pre-set intervals to study the time course of GI injury and recovery. Hematological profiles, clinical symptoms, gross- and histopathology including markers of proliferation and apoptosis in the small intestines, gut function parameters (food tolerance, digestion, absorption, citrulline production), and levels of two biomarkers, CRP and IGF-1, were evaluated. Results: PBI at 16Gy yielded higher lethality than 12 Gy. Unlike TBI, PBI did not cause severe pancytopenia or external hemorrhage, as expected, and allowed to focus the injury on GI organs while sparing the radiation sensitive heart and lung. Compromised animals showed inactivity, anorexia, vomiting, diarrhea, and weight loss. Histology revealed that in 12Gy irradiated animals, lesions recovered overtime. In 16Gy irradiated animals, lesions were more pronounced and persistent. BrdU and Ki67 labelling demonstrated dose-dependent loss of crypts and subsequent mucosal ulceration which recovered over time. Minimal apoptosis was observed at both doses. Reductions in food tolerance, digestion, absorption, and citrulline production were time and dose-dependent. Loss of citrulline reached a nadir between 6-12 days and then recovered partially. CRP and IGF-1 were upregulated following PBI at GI doses. Conclusions: This lower hemi-body irradiation model allowed for extended survival at GI-specific ARS doses and development of a well-controlled GI syndrome with minimal hematopoietic injury or confounding mortality from cardiopulmonary damage. A dose-dependent impairment in the intestinal structure resulted in overall decreased gut functionality followed by a partial recovery. However, while the structure appeared to be recovered, not all functionality was attained. PBI induced systemic inflammation and altered the IGF-1 hormone indicating that these can be used as biomarkers in the minipig even under partial body conditions. This PBI model aligns with other minipig models under BARDA's large animal consortium to test medical countermeasure efficacy against a less complex GI-specific ARS injury. [ABSTRACT FROM AUTHOR]

Purpose: There remains an unmet medical need for radioprotective and mitigative agents. BP-C2 is a novel lignin-derived polyphenolic composition with ammonium molybdate, developed as radioprotector/radiomitigator. Objectives: The present study evaluated BP-C2 for the mitigation of acute radiation syndrome (ARS). Methods: A total-body irradiation mouse model (TBI, 4.0-8.0 Gy) was used in the study. Results: In a 30-day survival study, performed in CBA mice, BP-C2, at a dosage of 81.0mg/kg, improved survival (dose reduction factor (DRF)=1.1) and increased the formation of endogenous spleen colony-forming units (CFU). In C57BL/6 mice, BP-C2, when administered daily for 7 days, starting 24 hours after TBI, also improved survival. In animals irradiated with 5.0 Gy, BP-C2 increased the number of CFUs (6.7 ± 5.1) compared to the 5.0 Gy placebo group (2.3± 2.3, p=.0245). The number of surviving intestinal crypts was maintained in the 5.0 Gy BP-C2 group (133.7 ± 13.9), in contrast to the 5.0 Gy placebo group (124.2 ± 10.5, p<.0023). BP-C2 also increased the number of LGR5þpositive cells in intestinal crypts. Conclusion: BP-C2 mitigates radiation-induced damage in mid-lethal range of radiation doses. Effects are mediated by enhancement of extramedullar hematopoiesis in the spleen and a protective effect on the intestinal epithelium. [ABSTRACT FROM AUTHOR]

Intestinal injury is inevitable during exposure to high radiation doses and is a common side effect observed during abdominal/pelvic radiotherapy. Yet, no radiation countermeasures are available for gastrointestine (GI) injury management. The aim of this study is to determine the effects of podophyllotoxin and rutin in combination (G-003M) on ionising radiation induced GI injury. We prophylactically administered G-003M to C57BL/6J mice exposed to 9 Gy total body radiation (TBI) and assessed for morphological changes, loss in absorption, fluid retention, biochemical alterations, immunohistochemical analysis to study cPARP, caspase-3, PCNA expression, and TUNEL staining. The irradiated intestine demonstrated extensive loss in crypts and villi, disrupted mucosal lining with reduced xylose uptake and enhanced fluid level post 7-day radiation. Mice receiving G-003M before radiation showed significant protection to intestinal epithelium, better allocation of secretory goblet cells, recovery in absorption, and reduced intestinal oedema. Additionally, G-003M administration also prevented radiation induced ROS generation, lipid peroxidation (MDA levels) and maintained the intestinal glutathione pool compared to the irradiated animals. G-003M supplementation also resulted in restoration of intestinal mitochondrial membrane potential, which was otherwise depolarised by radiation treatment. Immunohistochemical analysis demonstrated decrease in c-PARP and caspase-3 expression in jejuna cross sections and upregulation of PCNA in G-003M treated crypt cells as compared to 9 Gy irradiated mice. Our findings show that G-003M augment survival of mice against lethal radiation by promoting structural and functional regeneration in intestinal tissue. This combination therefore can be effectively explored for preventing radiation induced GI toxicity. [ABSTRACT FROM PUBLISHER]

Autophagy is an evolutionary conserved, indispensable, lysosome-mediated degradation process, which helps in maintaining homeostasis during various cellular traumas. During stress, a context-dependent role of autophagy has been observed which drives the cell towards survival or death depending upon the type, time, and extent of the damage. The process of autophagy is stimulated during various cellular insults, e.g. oxidative stress, endoplasmic reticulum stress, imbalances in calcium homeostasis, and altered mitochondrial potential. Ionizing radiation causes ROS-dependent as well as ROS-independent damage in cells that involve macromolecular (mainly DNA) damage, as well as ER stress induction, both capable of inducing autophagy. This review summarizes the current understanding on the roles of oxidative stress, ER stress, DNA damage, altered mitochondrial potential, and calcium imbalance in radiation-induced autophagy as well as the merits and limitations of targeting autophagy as an approach for radioprotection and radiosensitization. [ABSTRACT FROM PUBLISHER]

Several candidate drugs for acute radiation syndrome (ARS) have been identified that have low toxicity and significant radioprotective and radiomitigative efficacy. Inasmuch as exposing healthy human volunteers to injurious levels of radiation is unethical, development and approval of new radiation countermeasures for ARS are therefore presently based on animal studies and Phase I safety study in healthy volunteers. The Animal Efficacy Rule, which underlies the Food and Drug Administration approval pathway, requires a sound understanding of the mechanisms of injury, drug efficacy, and efficacy biomarkers. In this context, it is important to identify biomarkers for radiation injury and drug efficacy that can extrapolate animal efficacy results, and can be used to convert drug doses deduced from animal studies to those that can be efficacious when used in humans. Here, we summarize the progress of studies to identify candidate biomarkers for the extent of radiation injury and for evaluation of countermeasure efficacy. [ABSTRACT FROM PUBLISHER]

Purpose: We examined the effect of epidermal growth factor (EGF) and bone marrow transplantation (BMT) on gastrointestinal damage after high-dose irradiation of mice. Material and methods:C57Black/6 mice were used. Two survival experiments were performed (12 and 13 Gy;60Co, 0.59–0.57 Gy/min). To evaluate BMT and EGF action, five groups were established – 0 Gy, 13 Gy, 13 Gy + EGF (at 2 mg/kg, first dose 24 h after irradiation and then every 48 h), 13 Gy + BMT (5 × 106cells from green fluorescent protein [GFP] syngenic mice, 4 h after irradiation), and 13 Gy + BMT + EGF. Survival data, blood cell counts, gastrointestine and liver parameters and GFP positive cell migration were measured. Results:BMT and EGF (three doses, at 2 mg/kg, administered 1, 3 and 5 days after irradiation) significantly increased survival (13 Gy). In blood, progressive cytopenia was observed with BMT, EGF or their combination having no improving effect early after irradiation. In gastrointestinal system, BMT, EGF and their combination attenuated radiation-induced atrophy and increased regeneration during first week after irradiation with the combination being most effective. Signs of systemic inflammatory reaction were observed 30 days after irradiation. Conclusions:Our data indicate that BMT together with EGF is a promising strategy in the treatment of high-dose whole-body irradiation damage. [ABSTRACT FROM PUBLISHER]

Purpose: The effects of radiation exposure are long-lasting. Long-term monitoring is imperative to diagnose late effects and improve our far-sightedness about possible events in the future. A radiation accident occurred in Istanbul in 1998 that resulted in mild to moderate acute radiation syndrome (ARS). In this study we aimed to investigate the changes in hematological parameters at the long-term follow-up of ARS patients. Methods: Ten adults were hospitalized after exposure to a 60Co source. Seven were diagnosed as having ARS and had severe and symptomatic pancytopenia. All of the exposed people recovered following intensive treatment. Treatment was supportive with transfusion, granulocyte-colony stimulating factor, and anti- infective management covering antifungal agents. Patients were closely monitored. Nine years after the accident, the initial and follow-up complete blood count examinations and peripheral blood smears (PBS) were comparatively evaluated by an experienced hematologist. The hematological laboratory values of the patients on admission, after treatment, and nine years after the accident were documented and compared. Results: Biodosimetric analysis revealed that whole-body doses ranged from 1–1.9 Gy. All subjects have shown complete recovery of the hematological laboratory values after treatment. All but one of the subjects showed complete blood cell recovery. The improvement of the blood cell count of the excepted patient stalled at a mildly reduced level and his bone marrow was still hypocellular nine years after the accident; however, no malignant changes were detected. Values at admission were significantly different compared with post treatment and present values of all patients. Post treatment and follow-up values were similar. One of the patients died of lung cancer. None of the patients developed hematological malignancy. Conclusions: In this study, the recovery from ARS was complete after treatment. The small population, short follow-up period, and the relatively small doses resulted in no long-term adverse effects, as would be predicted. [ABSTRACT FROM PUBLISHER]

Purpose: To characterize acute radiation syndrome (ARS) sequelae at doses intermediate between the bone marrow (H-ARS) and full gastrointestinal (GI-ARS) syndrome. Methods: Male minipigs, approximately 5 months old, 9-12 kg in weight, were irradiated with Cobalt-60 (total body, bilateral gamma irradiation, 0.6 Gy/min). Endpoints were 10-day survival, gastrointestinal histology, plasma citrulline, bacterial translocation, vomiting, diarrhea, vital signs, systemic inflammatory response syndrome (SIRS), febrile neutropenia (FN). Results: We exposed animals to doses (2.2-5.0 Gy) above those causing H-ARS (1.6-2.0 Gy), and evaluated development of ARS. Compared to what was observed during H-ARS (historical data: Moroni et al. 2011a, 2011c), doses above 2 Gy produced signs of increasingly severe pulmonary damage, faster deterioration of clinical conditions, and faster increases in levels of C-reactive protein (CRP). In the range of 4.6-5.0 Gy, animals died by day 9-10; signs of the classic GI syndrome, as measured by diarrhea, vomiting and bacterial translocation, did not occur. At doses above 2 Gy we observed transient reduction in circulating citrulline levels, and animals exhibited earlier depletion of blood elements and faster onset of SIRS and FN. Conclusions: An accelerated hematopoietic subsyndrome (AH-ARS) is observed at radiation doses between those producing H-ARS and GI-ARS. It is characterized by early onset of SIRS and FN, and greater lung damage, compared to H-ARS. [ABSTRACT FROM AUTHOR]

Acute radiation dermatitis (ARD) is a common side effect of radiation therapy and is characterized by erythema, dry desquamation or moist desquamation. This wet desquamation is a very painful condition for the patient and often leads to interruption of radiotherapy. The objective of this article is to assess the efficacy of topical corticosteroids in the prevention of ARD compared with placebo, other topical medication or no treatment. The prophylactic application of topical corticosteroid among patients undergoing radiotherapy appears to significantly reduce the incidence of ARD, specifically moist desquamation, compared with other treatments. Future trials with a more standardized measure of radiation dermatitis grading are recommended. Further research may also be conducted to determine if a mildly potent, midpotent or super potent topical steroid will be more effective in preventing ARD. [ABSTRACT FROM AUTHOR]

KZ-41, a quinic acid derivative, significantly reduces mortality in a murine model of hematopoietic acute radiation syndrome. The purpose of this study was to evaluate the systemic pharmacokinetics, elimination, and oral bioavailability of KZ-41 in rats. Male Sprague-Dawley rats (n == 6 per group) received a single dose (10 mg/kg) of KZ-41 administered either intravenously via the jugular vein or orally via gavage. In vitro stability was determined using both rat liver microsomes and the bacteria Gluconobacter oxydans. KZ-41 concentrations were determined using LC-MS/MS (liquid chromatography tandom mass spectrometry). Half-life of KZ-41 was ≈≈3 hr after either intravenous or oral administration. Mean volume of distribution was 3.3 L/kg. Extent of absorption (F) after oral administration was estimated to be ~100%, which was consistent with the finding that KZ-41 was stable to liver microsomal and bacterial degradation. Following intravenous administration, KZ-41 demonstrated a medium clearance and volume of distribution with a terminal half-life of ≈≈3 hr. KZ-41 was rapidly and completely absorbed (F ≅ 1), which was consistent with the findings that KZ-41 is resistant to presystemic elimination mechanisms (i.e. enteric bacterial degradation and hepatic metabolism). Thus, KZ-41 represents an excellent candidate for further development as an orally available agent for the mitigation of radiation injury. [ABSTRACT FROM AUTHOR]

Planning for and exercising the medical response to potential chemical, biological, radiological, nuclear, and explosive (CBRNE) terrorist events are new responsibilities for most health care providers. Among potential CBRNE events, radiological and/or nuclear (rad/nuc) events are thought to have received the least attention from health care providers and planners. To assist clinicians, the U.S. Department of Health and Human Services (HHS) has created a new, innovative tool kit, the Radiation Event Medical Management (REMM) web portal (http://remm.nlm.gov). Goals of REMM include providing (1) algorithm-style, evidence-based, guidance about clinical diagnosis and treatment during mass casualty rad/nuc events; (2) just-in-time, peer-reviewed, usable information supported by sufficient background material and context to make complex diagnosis and management issues understandable to those without formal radiation medicine expertise; (3) a zip-file of complete web portal files downloadable in advance so the site would be available offline without an Internet connection; (4) a concise collection of the printable, key documents that can be taken into the field during an event; (5) a framework for medical teams and individuals to initiate rad/nuc planning and training; and (6) an extensive bibliography of key, peer-reviewed, and official guidance documents relevant to rad/nuc responses. Since its launch, REMM has been well received by individual responders and teams across the country and internationally. It has been accessed extensively, particularly during training exercises. Regular content updates and addition of new features are ongoing. The article reviews the development of REMM and some of its key content areas, features, and plans for future development. [ABSTRACT FROM AUTHOR]