Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma

<p>Abstract</p> <p>Background</p> <p>Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen) has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil) into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix.</p> <p>Methods</p> <p>One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO) treatment (2 bar, pO₂= 2 bar, 4 exposures à 90 min), whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO₂= 0.2 bar) served as controls. Three doses of 5FU were tested for dose response. Uptake of [³H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (P_if), collagen content, oxygen stress (measured as malondialdehyd levels), lymphatics and transcapillary transport in the tumors.</p> <p>Results</p> <p>The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%), but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor P_ifand collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake.</p> <p>Conclusion</p> <p>We showed that hyperoxia increases the uptake of [³H]-5FU in DMBA-induced mammary tumors <it>per se</it>, independently of changes in P_if, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO₂.</p

Records Review of Musculoskeletal Injuries in Aeromedical Evacuation Personnel

Background: Aeromedical evacuation providers care for patients during air transport. By applying standard medical practices, oftentimes developed for ground care, these practitioners perform their mission duties under additional physical stress in this unique medical environment. Awkward postures and excessive forces are common occurrences among personnel operating in this domain. Additionally, anecdotal reports highlight the risk of developing musculoskeletal injuries for these providers. Currently, there is limited research focusing on musculoskeletal injuries in aeromedical evacuation providers. Purpose: To determine the prevalence of musculoskeletal injuries and associated symptoms in aeromedical evacuation providers to understand the risk and burden of these injuries to military personnel. Methods: This study utilized a retrospective review of military medical records containing ICD-9 codes to investigate the incidence of musculoskeletal injuries within flight nurses and medical technicians compared to their non-flying counterparts from 2006 through 2011. Data were analyzed from 2013 through 2014. Results: Although musculoskeletal injuries were identified within the test populations, results showed fewer injuries for aeromedical evacuation populations compared to non–aeromedical evacuation counterparts. Conclusions: One contributing factor may be a potential under-reporting of musculoskeletal injuries resulting from the fear of being placed on limited flying status. As flyers, aeromedical evacuation personnel must undergo yearly medical examinations and complete training courses that emphasize proper lifting techniques and physical requirements necessary for the safe and efficient transport of patients on various platforms. These additional requirements may create a healthy worker effect, likely contributing to lower musculoskeletal injuries

Efficient growth inhibition of Bacillus anthracis by knocking out the ribonucleotide reductase tyrosyl radical

Bacillus anthracis, the causative agent of anthrax, is a worldwide problem because of the need for effective treatment of respiratory infections shortly after exposure. One potential key enzyme of B. anthracis to be targeted by antiproliferative drugs is ribonucleotide reductase. It provides deoxyribonucleotides for DNA synthesis needed for spore germination and growth of the pathogen. We have cloned, purified, and characterized the tyrosyl radical-carrying NrdF component of B. anthracis class Ib ribonucleotide reductase. Its EPR spectrum points to a hitherto unknown three-dimensional geometry of the radical side chain with a 60° rotational angle of C(α)-(C(β)-C(1))-plane of the aromatic ring. The unusual relaxation behavior of the radical signal and its apparent lack of line broadening at room temperature suggest a weak interaction with the nearby diiron site and the presence of a water molecule plausibly bridging the phenolic oxygen of the radical to a ligand of the diiron site. We show that B. anthracis cells are surprisingly resistant to the radical scavenger hydroxyurea in current use as an antiproliferative drug, even though its NrdF radical is efficiently scavenged in vitro. Importantly, the antioxidants hydroxylamine and N-methyl hydroxylamine scavenge the radical several orders of magnitude faster and prevent B. anthracis growth at several hundred-fold lower concentrations compared with hydroxyurea. Phylogenetically, the B. anthracis NrdF protein clusters together with NrdFs from the pathogens Bacillus cereus, Bacillus thuringiensis, Staphylococcus aureus, and Staphylococcus epidermidis. We suggest the potential use of N-hydroxylamines in combination therapies against infections by B. anthracis and closely related pathogens