BackgroundWounding following whole-body γ-irradiation (radiation combined injury, RCI) increases mortality. Wounding-induced increases in radiation mortality are triggered by sustained activation of inducible nitric oxide synthase pathways, persistent alteration of cytokine homeostasis, and increased susceptibility to bacterial infection. Among these factors, cytokines along with other biomarkers have been adopted for biodosimetric evaluation and assessment of radiation dose and injury. Therefore, wounding could complicate biodosimetric assessments.ResultsIn this report, such confounding effects were addressed. Mice were given 60Co γ-photon radiation followed by skin wounding. Wound trauma exacerbated radiation-induced mortality, body-weight loss, and wound healing. Analyses of DNA damage in bone-marrow cells and peripheral blood mononuclear cells (PBMCs), changes in hematology and cytokine profiles, and fundamental clinical signs were evaluated. Early biomarkers (1 d after RCI) vs. irradiation alone included significant decreases in survivin expression in bone marrow cells, enhanced increases in γ-H2AX formation in Lin+ bone marrow cells, enhanced increases in IL-1β, IL-6, IL-8, and G-CSF concentrations in blood, and concomitant decreases in γ-H2AX formation in PBMCs and decreases in numbers of splenocytes, lymphocytes, and neutrophils. Intermediate biomarkers (7 – 10 d after RCI) included continuously decreased γ-H2AX formation in PBMC and enhanced increases in IL-1β, IL-6, IL-8, and G-CSF concentrations in blood. The clinical signs evaluated after RCI were increased water consumption, decreased body weight, and decreased wound healing rate and survival rate. Late clinical signs (30 d after RCI) included poor survival and wound healing.ConclusionResults suggest that confounding factors such as wounding alters ionizing radiation dose assessment and agents inhibiting these responses may prove therapeutic for radiation combined injury and reduce related mortality.
New, safe antimicrobial agents are needed to prevent and overcome severe bacterial, viral, and fungal infections. Based on our previous experience and that of others, we postulated that herbal essential oils, such as those of origanum, and monolaurin offer such possibilities. We examined in vitro the cidal and/or static effects of oil of origanum, several other essential oils, and monolaurin on Staphylococcus aureus, Bacillus anthracis Sterne, Escherichia coli, Klebsiella pneumoniae, Helicobacter pylori, and Mycobacterium terrae. Origanum proved cidal to all tested organisms with the exception of B. anthracis Sterne in which it was static. Monolaurin was cidal to S. aureus and M. terrae but not to E. coli and K. pneumoniae. Unlike the other two gram-negative organisms, H. pylori were extremely sensitive to monolaurin. Similar to origanum, monolaurin was static to B. anthracis Sterne. Because of their longstanding safety record, origanum and/or monolaurin, alone or combined with antibiotics, might prove useful in the prevention and treatment of severe bacterial infections, especially those that are difficult to treat and/or are antibiotic resistant.
Combined injuries, which are expected after a radiation dispersal device release or nuclear weapon detonation, are the combination of radiation exposure and tissue injuries from blast and thermal energy. To determine the impact of such trauma, mice were used to (1) evaluate the consequences of skin tissue injuries after various qualities and doses of radiation and (2) document substances that increase survival from radiation injury. Female 12- to 20-wk-old mice weighing 23 +/- 3 g received dorsal skin burns or wounds (15% total body skin surface) under methoxyflurane anesthesia before or after irradiation in this study approved by the Armed Forces Radiobiology Research Institute (AFRRI) Institutional Animal Care and Use Committee. Methoxyflurane is analgesic up to 48 h after injury. The radiations used in these studies included Co gamma photons (1.25 MeV) and research-reactor-produced neutrons with an average energy of 0.96 MeV in either an enriched-field [n/(n + gamma) = 0.95] configuration at 4.2 kW or a mixed-field [n/(n + gamma) = 0.67] configuration operated at 45 kW. Dose rates averaged 0.4 Gy/min. Endpoints included survival, LD50/30s (lethal dose to produce 50% mortality in 30 d), dose modifying factors, relative biological effectiveness values, tissue alterations, susceptibility to bacterial challenge, and countermeasure efficacies. Countermeasures evaluated included S-3-(3-methylaminopropylamino) propylthiophosphorothioic acid (WR-151327), antibiotics, immune modulators, and bone marrow transplantation. Of these treatments, survival was improved by WR-151327, antibiotics, synthetic trehalose discorynomycolate, and bone marrow transplantation. Because trauma to irradiated personnel and medical countermeasures may affect biodosimetric measurements, it will be necessary to quickly determine radiation dose in order to implement appropriate therapy.
Exposure to ionizing radiation alone (radiation injury, RI) or combined with traumatic tissue injury (radiation combined injury, CI) is a crucial life-threatening factor in nuclear and radiological accidents. As demonstrated in animal models, CI results in greater mortality than RI. In our laboratory, we found that B6D2F1/J female mice exposed to 60Co-γ-photon radiation followed by 15% total-body-surface-area skin burns experienced an increment of 18% higher mortality over a 30-day observation period compared to irradiation alone; that was accompanied by severe cytopenia, thrombopenia, erythropenia, and anemia. At the 30th day after injury, neutrophils, lymphocytes, and platelets still remained very low in surviving RI and CI mice. In contrast, their RBC, hemoglobin, and hematocrit were similar to basal levels. Comparing CI and RI mice, only RI induced splenomegaly. Both RI and CI resulted in bone marrow cell depletion. It was observed that only the RI mice treated with pegylated G-CSF after RI resulted in 100% survival over the 30-day period, and pegylated G-CSF mitigated RI-induced body-weight loss and depletion of WBC and platelets. Peg-G-CSF treatment sustained RBC balance, hemoglobin levels, and hematocrits and inhibited splenomegaly after RI. The results suggest that pegylated G-CSF effectively sustained animal survival by mitigating radiation-induced cytopenia, thrombopenia, erythropenia, and anemia.
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