Delayed effects of acute radiation exposure (DEARE) in a murine model of the hematopoietic acute radiation syndrome: Multiple-organ injury consequent to total body irradiation

Introduction. Victims of radiation exposure from terrorist activity, radiation accidents or radiologic warfare will face a variety of acute and chronic organ injuries requiring multi-faceted approaches to treatment. The hematopoietic system is the most sensitive tissue to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) after exposures of 2-10 Gy in mice. If untreated, H-ARS results in death within weeks from opportunistic infection and/or hemorrhage due to loss of neutrophils and platelets, respectively. However, survivors of ARS are plagued months to years later in life by delayed effects of acute radiation exposure (DEARE), a myriad of chronic illnesses affecting multiple organ systems believed to be due to persistent systemic oxidative stress, inflammation, fibrosis and loss of stem cell self-renewal. Fibrosis and collagen deposition disrupt both normal tissue structure and function and are common to organs with late radiation injury including the kidney and heart after radiation doses >15Gy, but have not been shown to exist after doses as low as those used in the H-ARS model (8Gy). The goal of this study was to determine the extent, if any, of heart and kidney DEARE in survivors of H-ARS. Methods. Mice (male and female C57BL/6) received total body irradiation (TBI; LD50/30 to LD70/30) and kidney and heart were harvested at 9 and 21 months from the H-ARS survivor mice. Tissues were fixed in neutral buffered formalin, paraffin embedded and sectioned, then stained with hematoxylin/eosin (H&E), trichrome, or picosirius red. Serum was collected at 4.3, 9, and 21 months post-TBI and analyzed for blood urea nitrogen (BUN) as an indicator of kidney function. Total RNA was purified from heart and relative changes in NADPH oxidase 2 (Nox2) mRNA expression were assessed by quantitative real-time PCR. Results/Significance. Compared to age-matched non-irradiated controls (NI), renal pathology at 9 months post-TBI was manifest primarily as enlargement of Bowman’s capsule and glomerosclerosis along with limited interstitial fibrosis. By 21 months there was progression of these pathologies as well as extensive interstitial fibrosis, tubular atrophy, cysts, and atubular glomeruli, all of which were more pronounced in TBI mice compared to NI. Consistent with the renal pathology, BUN in TBI mice was significantly increased at 9 and 21 months post-TBI vs. 4.3 months, but normal in NI mice at all time points. In the heart, pericardial, perivascular and interstitial fibrosis were observed at 9 months with increased severity at 21 months post-TBI compared to NI. The perivascular fibrosis was associated with increased medial layer collagen and apparent loss of vascular smooth muscle cells. Nox2 mRNA in heart was increased at 9 and 21 months post-TBI, indicating an increase in oxidant stress. To our knowledge, such striking heart and kidney damage has not been documented after radiation doses as low as those in our H-ARS model (~8Gy) and indicate that DEARE is a concern for individuals exposed to radiation doses previously thought to not elicit late effects

Nox2 and p47phox modulate compensatory growth of primary collateral arteries

The role of NADPH oxidase (Nox) in both the promotion and impairment of compensatory collateral growth remains controversial because the specific Nox and reactive oxygen species involved are unclear. The aim of this study was to identify the primary Nox and reactive oxygen species associated with early stage compensatory collateral growth in young, healthy animals. Ligation of the feed arteries that form primary collateral pathways in rat mesentery and mouse hindlimb was used to assess the role of Nox during collateral growth. Changes in mesenteric collateral artery Nox mRNA expression determined by real-time PCR at 1, 3, and 7 days relative to same-animal control arteries suggested a role for Nox subunits Nox2 and p47phox. Administration of apocynin or Nox2ds-tat suppressed collateral growth in both rat and mouse models, suggesting the Nox2/p47phox interaction was involved. Functional significance of p47phox expression was assessed by evaluation of collateral growth in rats administered p47phox small interfering RNA and in p47phox−/− mice. Diameter measurements of collateral mesenteric and gracilis arteries at 7 and 14 days, respectively, indicated no significant collateral growth compared with control rats or C57BL/6 mice. Chronic polyethylene glycol-conjugated catalase administration significantly suppressed collateral development in rats and mice, implying a requirement for H2O2. Taken together, these results suggest that Nox2, modulated at least in part by p47phox, mediates early stage compensatory collateral development via a process dependent upon peroxide generation. These results have important implications for the use of antioxidants and the development of therapies for peripheral arterial disease

Amino-diol borate complexation for controlling transport phenomena of penetrant molecules into polymeric matrices

The development of new high performance materials, coatings, composites and adhesives relies on insight into the origin of material performance on a molecular level. This paper explores a new type of epoxy-amine-borate (EAB) hybrid material for control of penetrant solvent molecules into cross-linked thermoset polymer networks

Amino-borate complexation for controlling transport phenomena of penetrant molecules into polymeric matrices

The development of new high performance materials, coatings, composites and adhesives relies on insight into the origin of performance on a molecular level. This research explores a new type of epoxy-amine-borate (EAB) hybrid material for control of penetrant solvent molecules into cross-linked thermoset polymer networks. The properties of these materials are explored through material and mechanical testing and model studies are used to probe the mode-of-action through which EAB materials deliver their improved performance properties

The Effect of Short and Long Recovery Periods on the Contribution of Oxidative Processes to Energy Expenditure During Multiple Bouts of Supramaximal Exercise

The Effect of Short and Long Recovery Periods on the Contribution of Oxidative Processes to Energy Expenditure During Multiple Bouts of Supramaximal Exercise Olson, E. (undergraduate), Christensen, K., Jajtner, A., Copeland, J., Unthank, M., and Mitchell, J. Exercise Physiology Lab, Texas Christian University, Ft. Worth, TX. The contribution of oxidative energy production to multiple sprint exercises is of interest due to implications for the training needs of people engaging in anaerobic activities. PURPOSE: The purpose of this study was to examine the effect of short and long active recovery durations on oxidative and anaerobic contributions to energy output during maximal intensity cycle ergometry. METHODS: Six male subjects, including well-trained endurance athletes and well-trained strength athletes, completed the study. After a VO2max test on the bicycle ergometer, each subject completed two conditions: a short recovery condition (SRC) and a long recovery condition (LRC). The SRC consisted of 10, 10-sec. supramaximal sprints with 30-sec. recovery periods. The LRC consisted of 10, 10-sec supramaximal sprints with 3-min. recovery periods. The load applied to the ergometer was 1.2 g/kg and the RPM during the sprints varied based on the maximal output. During recovery, no load was applied and subjects maintained a cadence of 80 RPM. Oxygen uptake was measured during the entirety of both conditions and peak power and total work were calculated from two, 5-sec RPM averages generated during the sprints. Blood samples were taken pre-exercise, after sprints 4, 7, and 10, and 3 minutes post-exercise. RESULTS: Peak power and total work were significantly greater (p \u3c 0.05) in the LRC (1091.3 + 88.7 W and 1363.6 + 34.6 kg-m) compared to the SRC (915.3 + 109.2 W and 1161.6 + 33.9 kg-m). In addition, peak power decayed by 21.7% over the 10 sprints in the SRC compared to no decay in the LRC. Oxygen uptake averaged 28.3 + 0.9 ml/kg/min for the entirety of the LRC; whereas, in the SRC there was a large increase in oxygen uptake during the second sprint that remained elevated and averaged 47 + 1.5 ml/kg/min for the remaining 8 sprints. There was no difference in blood lactate concentrations between conditions. CONCLUSION: The heightened aerobic response and the lower work and power outputs seen in the SRC are suggestive of a decrement in both anaerobic glycolysis and phosphocreatine (PCr) activity as successive sprints were completed. After repeated bouts of explosive exercise with short rest periods, oxidative processes play a more important role in energy production, most likely due to fatigue occurring in the anaerobic energy producing systems. These findings point to the need for enhancing the aerobic capacity of athletes engaging in consecutive high intensity bouts of exercise when rest intervals are short

Delayed effects of acute radiation exposure on the cardiovascular system using a murine model of the hematopoietic acute radiation syndrome

poster abstractIntroduction. Exposure to high level radiation from accidents or belligerent activities results in acute and chronic organ damage. The hematopoietic system is the most sensitive organ to radiation damage (2-10 Gy) and results in the hematopoietic acute radiation syndrome (H-ARS). Survivors of H-ARS are plagued months to years later with delayed effects of acute radiation exposure (DEARE), characterized by chronic illnesses affecting multiple organ systems. Previous results using the murine H-ARS model showed numerous kidney and heart DEARErelated pathologies similar to humans, including tissue fibrosis and elevated blood urea nitrogen. The goal of this study was to utilize the murine H-ARS model to determine possible roles for abnormal iron metabolism, inflammation, oxidant stress, and senescence in the development of cardiac DEARE. Methods. Mice (C57BL/6; 12 week-old) received total body irradiation (TBI: ~8.5-8.7 Gy, 137Cs, LD50to LD70) and hearts were harvested at various times post-TBI from H-ARS survivors. Paraffin tissue sections were stained with hematoxylin/eosin or Perls Prussian Blue, or reacted with a macrophage-specific antibody (F4/80). Total RNA was purified from fresh tissue and changes in mRNA expression were assessed by real-time PCR for the senescence marker p16 and NADPH oxidase subunits Nox2, Nox4, or p47phox. Results/Significance. Compared to age-matched non-irradiated controls (NI), tissue iron deposits were increased in irradiated (IR) hearts at 4 months, and progressively declined with time post-TBI. Numbers of macrophages were greater in IR vs. NI sections at all time points and decreased with time post-TBI. Nox2 and Nox4 mRNA expression was increased at both 9 and 21 months post-TBI, but p47phox increased only at 21 months. Expression of p16 in IR heart was increased at 7, but not at 22 months post-TBI. Taken together, the results indicate abnormal iron metabolism, inflammation, oxidant stress, and early senescence may contribute to development of cardiac DEARE

A highly diastereoselective chloride-mediated dynamic kinetic resolution at phosphorus on-route to a key intermediate in the synthesis of GSK2248761A

A highly diastereoselective chloride-mediated dynamic kinetic resolution at phosphorus has been developed to access a key intermediate in the synthesis of GSK2248761A. This procedure utilises a soluble chloride source and a cheap readily available chiral auxiliary. The practicality of this transformation is demonstrated on a multi-gram scale

Novel Method to Assess Arterial Insufficiency in Rodent Hindlimb

BACKGROUND: Lack of techniques to assess maximal blood flow capacity thwarts the use of rodent models of arterial insufficiency to evaluate therapies for intermittent claudication. We evaluated femoral vein outflow (VO) in combination with stimulated muscle contraction as a potential method to assess functional hind limb arterial reserve and therapeutic efficacy in a rodent model of subcritical limb ischemia. MATERIALS AND METHODS: VO was measured with perivascular flow probes at rest and during stimulated calf muscle contraction in young, healthy rats (Wistar Kyoto, WKY; lean Zucker rats, LZR) and rats with cardiovascular risk factors (spontaneously hypertensive [SHR]; obese Zucker rats [OZR]) with acute and/or chronic femoral arterial occlusion. Therapeutic efficacy was assessed by administration of Ramipril or Losartan to SHR after femoral artery excision. RESULTS: VO measurement in WKY demonstrated the utility of this method to assess hind limb perfusion at rest and during calf muscle contraction. Although application to diseased models (OZR and SHR) demonstrated normal resting perfusion compared with contralateral limbs, a significant reduction in reserve capacity was uncovered with muscle stimulation. Administration of Ramipril and Losartan demonstrated significant improvement in functional arterial reserve. CONCLUSIONS: The results demonstrate that this novel method to assess distal limb perfusion in small rodents with subcritical limb ischemia is sufficient to unmask perfusion deficits not apparent at rest, detect impaired compensation in diseased animal models with risk factors, and assess therapeutic efficacy. The approach provides a significant advance in methods to investigate potential mechanisms and novel therapies for subcritical limb ischemia in preclinical rodent models

Design and Optimisation of a Microwave Reactor for Kilo-Scale Polymer Synthesis

Current industrial production of polymer resins is generally undertaken in large multi-tonne stirred tank reactors. These are characterised by relatively slow heating and cooling cycles, resulting in long vessel cycle times and extended production campaigns. In this work we present a design for a hybrid microwave/oil jacket proof of concept system capable of producing up to 4.1 kg of polymer resin per batch. By exploiting rapid volumetric heating effects of microwave energy at 2.45GHz, we have optimised the synthetic regime, such that a 3.7 kg batch of polyester resin pre-polymer can be made in only 8 hours 20 minutes, with higher molecular weight (Mn 2,100) compared to the conventional process taking 22 hours 15 minutes (Mn 1,200), yielding an increase in synthesis rate of at least 265. The increase in polymer molecular weight also suggests a higher conversion was achieved over a shorter time scale