Randal Dull

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Scholarly Contributions

Books

• Marcucci, C., Hutchens, M. P., Wittwer, E. D., Weingarten, T. N., Sprung, J., Nicholson, W. T., Lalwani, K., Metro, D. G., Dull, R. O., Swide, C. E., Kirsch, J. R., Sandson, N. B., & Seagull, F. J. (2015).

  A case approach to perioperative drug-drug interactions

  . Springer New York. doi:10.1007/978-1-4614-7495-1

Journals/Publications

• Dull, R. O., & Hahn, R. G. (2023). Hypovolemia with peripheral edema: What is wrong?. Critical care (London, England), 27(1), 206.
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  Fluid normally exchanges freely between the plasma and interstitial space and is returned primarily via the lymphatic system. This balance can be disturbed by diseases and medications. In inflammatory disease states, such as sepsis, the return flow of fluid from the interstitial space to the plasma seems to be very slow, which promotes the well-known triad of hypovolemia, hypoalbuminemia, and peripheral edema. Similarly, general anesthesia, for example, even without mechanical ventilation, increases accumulation of infused crystalloid fluid in a slowly equilibrating fraction of the extravascular compartment. Herein, we have combined data from fluid kinetic trials with previously unconnected mechanisms of inflammation, interstitial fluid physiology and lymphatic pathology to synthesize a novel explanation for common and clinically relevant examples of circulatory dysregulation. Experimental studies suggest that two key mechanisms contribute to the combination of hypovolemia, hypoalbuminemia and edema; (1) acute lowering of the interstitial pressure by inflammatory mediators such as TNFα, IL-1β, and IL-6 and, (2) nitric oxide-induced inhibition of intrinsic lymphatic pumping.
• Hahn, R. G., & Dull, R. O. (2023). A Slow-Exchange Interstitial Fluid Compartment in Volunteers and Anesthetized Patients: Kinetic Analysis and Physiology. Anesthesia and analgesia.
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  Physiological studies suggest that the interstitial space contains 2 fluid compartments, but no analysis has been performed to quantify their sizes and turnover rates.
• Dull, R. O., & Hahn, R. G. (2022). The glycocalyx as a permeability barrier: basic science and clinical evidence. Critical care (London, England), 26(1), 273.
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  Preclinical studies in animals and human clinical trials question whether the endothelial glycocalyx layer is a clinically important permeability barrier. Glycocalyx breakdown products in plasma mostly originate from 99.6-99.8% of the endothelial surface not involved in transendothelial passage of water and proteins. Fragment concentrations correlate poorly with in vivo imaging of glycocalyx thickness, and calculations of expected glycocalyx resistance are incompatible with measured hydraulic conductivity values. Increases in plasma breakdown products in rats did not correlate with vascular permeability. Clinically, three studies in humans show inverse correlations between glycocalyx degradation products and the capillary leakage of albumin and fluid.
• Dull, R. O., & Hahn, R. G. (2021). Transcapillary refill: The physiology underlying fluid reabsorption. The journal of trauma and acute care surgery, 90(2), e31-e39.
• Hahn, R. G., & Dull, R. O. (2021). Interstitial washdown and vascular albumin refill during fluid infusion: novel kinetic analysis from three clinical trials. Intensive care medicine experimental, 9(1), 44.
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  Increased capillary filtration may paradoxically accelerate vascular refill of both fluid and albumin from the interstitial space, which is claimed to be edema-preventing. We characterized this proposed mechanism, called "interstitial washdown", by kinetic analyses of the hemodilution induced by intravenous infusion of crystalloid fluid during 3 distinct physiological states.
• Hahn, R. G., Patel, V., & Dull, R. O. (2021). Human glycocalyx shedding: Systematic review and critical appraisal. Acta anaesthesiologica Scandinavica, 65(5), 590-606.
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  The number of studies measuring breakdown products of the glycocalyx in plasma has increased rapidly during the past decade. The purpose of the present systematic review was to assess the current knowledge concerning the association between plasma concentrations of glycocalyx components and structural assessment of the endothelium.
• Potje, S. R., Isbatan, A., Tostes, R. C., Bendhack, L. M., Dull, R. O., Carvalho-de-Souza, J. L., & Chignalia, A. Z. (2021). Glypican 1 and syndecan 1 differently regulate noradrenergic hypertension development: Focus on IP3R and calcium. Pharmacological research, 172, 105813.
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  Vascular dysfunction is a checkpoint to the development of hypertension. Heparan sulfate proteoglycans (HSPG) participate in nitric oxide (NO) and calcium signaling, key regulators of vascular function. The relationship between HSPG-mediated NO and calcium signaling and vascular dysfunction has not been explored. Likewise, the role of HSPG on the control of systemic blood arterial pressure is unknown. Herein, we sought to determine if the HSPG syndecan 1 and glypican 1 control systemic blood pressure and the progression of hypertension.
• Chignalia, A. Z., Weinberg, G., & Dull, R. O. (2020). Norepinephrine Induces Lung Microvascular Endothelial Cell Death by NADPH Oxidase-Dependent Activation of Caspase-3. Oxidative medicine and cellular longevity, 2020, 2563764.
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  Norepinephrine (NE) is the naturally occurring adrenergic agonist that is released in response to hypotension, and it is routinely administered in clinical settings to treat moderate to severe hypotension that may occur during general anesthesia and shock states. Although NE has incontestable beneficial effects on blood pressure maintenance during hypotensive conditions, deleterious effects of NE on endothelial cell function may occur. In particular, the role of reactive oxygen species (ROS) and NADPH oxidase (Nox) on the deleterious effects of NE on endothelial cell function have not been fully elucidated. Therefore, we investigated the effects of NE on ROS production in rat lung microvascular endothelial cells (RLMEC) and its contribution to cell death. RLMEC were treated with NE (5 ng/mL) for 24 hours and ROS production was assessed by CellROX and DCFDA fluorescence. Nox activity was assessed by NADPH-stimulated ROS production in isolated membranes and phosphorylation of p47phox; cell death was assessed by flow cytometry and DNA fragmentation. Caspase activation was assessed by fluorescent microscopy. Nox1, Nox2, and Nox4 mRNA expression was assessed by real-time PCR. NE increased ROS production, Nox activity, p47phox phosphorylation, Nox2 and Nox4 mRNA content, caspase-3 activation, and RLMEC death. Phentolamine, an -adrenoreceptor antagonist, inhibited NE-induced ROS production and Nox activity and partly inhibited cell death while -blockade had no effect. Apocynin and PEGSOD inhibited NE-induced caspase-3 activation and cell death while direct inhibition of caspase-3 abrogated NE-induced cell death. PEG-CAT inhibited NE-induced cell death but not caspase-3 activation. Collectively, these results indicate that NE induces RLMEC death via activation of Nox by -adrenergic signaling and caspase-3-dependent pathways. NE has deleterious effects on RLMECs that may be important to its long-term therapeutic use.
• Fancher, I. S., Le Master, E., Ahn, S. J., Adamos, C., Lee, J. C., Berdyshev, E., Dull, R. O., Phillips, S. A., & Levitan, I. (2020). Impairment of Flow-Sensitive Inwardly Rectifying K Channels via Disruption of Glycocalyx Mediates Obesity-Induced Endothelial Dysfunction. Arteriosclerosis, thrombosis, and vascular biology, 40(9), e240-e255.
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  To determine if endothelial dysfunction in a mouse model of diet-induced obesity and in obese humans is mediated by the suppression of endothelial Kir (inwardly rectifying K) channels. Approach and Results: Endothelial dysfunction, observed as reduced dilations to flow, occurred after feeding mice a high-fat, Western diet for 8 weeks. The functional downregulation of endothelial Kir2.1 using dominant-negative Kir2.1 construct resulted in substantial reductions in the response to flow in mesenteric arteries of lean mice, whereas no effect was observed in arteries of obese mice. Overexpressing wild-type-Kir2.1 in endothelium of arteries from obese mice resulted in full recovery of the flow response. Exposing freshly isolated endothelial cells to fluid shear during patch-clamp electrophysiology revealed that the flow-sensitivity of Kir was virtually abolished in cells from obese mice. Atomic force microscopy revealed that the endothelial glycocalyx was stiffer and the thickness of the glycocalyx layer reduced in arteries from obese mice. We also identified that the length of the glycocalyx is critical to the flow-activation of Kir. Overexpressing Kir2.1 in endothelium of arteries from obese mice restored flow- and heparanase-sensitivity, indicating an important role for heparan sulfates in the flow-activation of Kir. Furthermore, the Kir2.1-dependent component of flow-induced vasodilation was lost in the endothelium of resistance arteries of obese humans obtained from biopsies collected during bariatric surgery.
• Gerber, T. J., Fehr, V. C., Oliveira, S. D., Hu, G., Dull, R., Bonini, M. G., Beck-Schimmer, B., & Minshall, R. D. (2019). Sevoflurane Promotes Bactericidal Properties of Macrophages through Enhanced Inducible Nitric Oxide Synthase Expression in Male Mice. Anesthesiology, 131(6), 1301-1315.
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  Sevoflurane with its antiinflammatory properties has shown to decrease mortality in animal models of sepsis. However, the underlying mechanism of its beneficial effect in this inflammatory scenario remains poorly understood. Macrophages play an important role in the early stage of sepsis as they are tasked with eliminating invading microbes and also attracting other immune cells by the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Thus, the authors hypothesized that sevoflurane mitigates the proinflammatory response of macrophages, while maintaining their bactericidal properties.
• Patel, M., Chignalia, A. Z., Isbatan, A., Bommakanti, N., & Dull, R. O. (2019). Ropivacaine inhibits pressure-induced lung endothelial hyperpermeability in models of acute hypertension. Life sciences, 222, 22-28.
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  Increases in hydrostatic pressure results in endothelial hyperpermeability via eNOS-dependent pathways. Ropivacaine is known to inhibit eNOS activation and to attenuate lung injury. Herein, we sought to determine if ropivacaine regulates pressure-induced lung endothelial hyperpermeability.
• Wagener, B. M., Hu, P. J., Oh, J. Y., Evans, C. A., Richter, J. R., Honavar, J., Brandon, A. P., Creighton, J., Stephens, S. W., Morgan, C., Dull, R. O., Marques, M. B., Kerby, J. D., Pittet, J. F., & Patel, R. P. (2019). Correction: Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study. PLoS medicine, 16(11), e1002991.
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  [This corrects the article DOI: 10.1371/journal.pmed.1002522.].
• Zhang, Y., Wang, L., Lv, Y., Jiang, C., Wu, G., Dull, R. O., Minshall, R. D., Malik, A. B., & Hu, G. (2019). The GTPase Rab1 Is Required for NLRP3 Inflammasome Activation and Inflammatory Lung Injury. Journal of immunology (Baltimore, Md. : 1950), 202(1), 194-206.
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  Uncontrolled inflammatory response during sepsis predominantly contributes to the development of multiorgan failure and lethality. However, the cellular and molecular mechanisms for excessive production and release of proinflammatory cytokines are not clearly defined. In this study, we show the crucial role of the GTPase Ras-related protein in brain (Rab)1a in regulating the nucleotide binding domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and lung inflammatory injury. Expression of dominant negative Rab1 N124I plasmid in bone marrow-derived macrophages prevented the release of IL-1β and IL-18, NLRP3 inflammasome activation, production of pro-IL-1β and pro-IL-18, and attenuated TLR4 surface expression and NF-кB activation induced by bacterial LPS and ATP compared with control cells. In alveolar macrophage-depleted mice challenged with cecal ligation and puncture, pulmonary transplantation of Rab1a-inactivated macrophages by expression of Rab1 N124I plasmid dramatically reduced the release of IL-1β and IL-18, neutrophil count in bronchoalveolar lavage fluid, and inflammatory lung injury. Rab1a activity was elevated in alveolar macrophages from septic patients and positively associated with severity of sepsis and respiratory dysfunction. Thus, inhibition of Rab1a activity in macrophages resulting in the suppression of NLRP3 inflammasome activation may be a promising target for the treatment of patients with sepsis.
• Bloomstone, J. A., Dull, R. O., Eckhardt, W. F., & McGee, W. T. (2018). Emergency Intubation: Early Identification and Strategic Management (Can) Save Lives. Critical care medicine, 46(6), e619-e620.
• Chignalia, A. Z., Dull, R. O., Fancher, I. S., Isbatan, A., Levitan, I., & Phillips, S. A. (2018).

  Abstract 16551: Shear-Induced Kir2.1 Channel Activation is Mediated Through Interactions With Syndecan-1

  . Circulation.
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  Inwardly rectifying K+ (Kir) channels are known to be sensitive to flow and proposed to play a major role in endothelial mechanotransduction. We recently identified a critical role for endothelial ...
• Chignalia, A. Z., Isbatan, A., Patel, M., Ripper, R., Sharlin, J., Shosfy, J., Borlaug, B. A., & Dull, R. O. (2018). Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure. Bioscience reports, 38(6).
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  Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension. Male Sprague-Dawley rats were anesthetized and mechanically ventilated. Acute hypertension was induced by norepinephrine (NE) infusion and resulted in an increase in LVEDP and pulmonary artery pressure (P) that were associated with a rapid fall in PO, and increases in lung wet/dry ratio and injury scores. Heart failure (HF) lungs showed increased nitrotyrosine content and ROS levels. L-NAME pretreatment mitigated the development of PE and reduced lung ROS concentrations to sham levels. Apocynin (Apo) pretreatment inhibited PE. Addition of tetrahydrobiopterin (BH4) to AHF rats lung lysates and pretreatment of AHF rats with folic acid (FA) prevented ROS production indicating endothelial NOS (eNOS) uncoupling. Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF. Acute increases in pulmonary vascular pressure, without NOS activation, was insufficient to cause significant PE. These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targetting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF.
• Wagener, B. M., Hu, P. J., Oh, J. Y., Evans, C. A., Richter, J. R., Honavar, J., Brandon, A. P., Creighton, J., Stephens, S. W., Morgan, C., Dull, R. O., Marques, M. B., Kerby, J. D., Pittet, J. F., & Patel, R. P. (2018). Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study. PLoS medicine, 15(3), e1002522.
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  Trauma is the leading cause of death and disability in patients aged 1-46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood.
• Bloomstone, J. A., Dull, R. O., & Navarro, L. H. (2017). Goal-Directed Fluid Therapy: What the Mind Does Not Know, the Eye Cannot See. Turkish journal of anaesthesiology and reanimation, 45(1), 56-58.
• Bommakanti, N., Isbatan, A., Bavishi, A., Dharmavaram, G., Chignalia, A. Z., & Dull, R. O. (2017). Hypercapnic acidosis attenuates pressure-dependent increase in whole-lung filtration coefficient (K). Pulmonary circulation, 7(3), 719-726.
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  Hypercapnic acidosis (HCA) has beneficial effects in experimental models of lung injury by attenuating inflammation and decreasing pulmonary edema. However, HCA increases pulmonary vascular pressure that will increase fluid filtration and worsen edema development. To reconcile these disparate effects, we tested the hypothesis that HCA inhibits endothelial mechanotransduction and protects against pressure-dependent increases in the whole lung filtration coefficient (K). Isolated perfused rat lung preparation was used to measure whole lung filtration coefficient (K) at two levels of left atrial pressure (P = 7.5 versus 15 cm HO) and at low tidal volume (LV) versus standard tidal volume (STV) ventilation. The ratio of K/K was used as the index of whole lung permeability. Double occlusion pressure, pulmonary artery pressure, pulmonary capillary pressures, and zonal characteristics (ZC) were measured to assess effects of HCA on hemodynamics and their relationship to K/K. An increase in P from 7.5 to 15 cm HO resulted in a 4.9-fold increase in K/K during LV and a 4.8-fold increase during STV. During LV, HCA reduced K/K by 2.7-fold and reduced STV K/K by 5.2-fold. Analysis of pulmonary hemodynamics revealed no significant differences in filtration forces in response to HCA. HCA interferes with lung vascular mechanotransduction and prevents pressure-dependent increases in whole lung filtration coefficient. These results contribute to a further understanding of the lung protective effects of HCA.
• Changyaleket, B., Chong, Z. Z., Dull, R. O., Nanegrungsunk, D., & Xu, H. (2017). Heparanase promotes neuroinflammatory response during subarachnoid hemorrhage in rats. Journal of neuroinflammation, 14(1), 137.
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  Heparanase, a mammalian endo-β-D-glucoronidase that specifically degrades heparan sulfate, has been implicated in inflammation and ischemic stroke. However, the role of heparanase in neuroinflammatory response in subarachnoid hemorrhage (SAH) has not yet been investigated. This study was designed to examine the association between heparanase expression and neuroinflammation during subarachnoid hemorrhage.
• Danilov, S. M., Tovsky, S. I., Schwartz, D. E., & Dull, R. O. (2017). ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors. Journal of cardiovascular pharmacology and therapeutics, 22(4), 374-386.
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  Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response.
• Du, X., Jiang, C., Lv, Y., Dull, R. O., Zhao, Y. Y., Schwartz, D. E., & Hu, G. (2017). Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling. PloS one, 12(7), e0180213.
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  A patient's recovery from lung inflammatory injury or development of multi-system organ failure is determined by the host's ability to resolve inflammation and repair tissue damage, both of which require the clearance of apoptotic neutrophils by macrophages (efferocytosis). Here, we investigated the effects of isoflurane on macrophage efferocytosis and resolution of lung inflammatory injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic neutrophils. Isoflurane significantly increased the surface expression of the receptor tyrosine kinase Mer in macrophages, but markedly decreased the levels of a soluble form of Mer protein in the medium. Isoflurane treatment also caused a decrease in a disintegrin and metalloproteinase 17 (ADAM17) on the cell surface and a concomitant increase in its cytoplasmic fraction. These responses induced by isoflurane were completely reversed by a pharmacological inhibitor or genetic deletion of AMP-activated protein kinase (AMPK). In a mouse model of lipopolysaccharide-induced lung injury, isoflurane accelerated the recovery of lung inflammation and injury that was coupled with an increase in the number of alveolar macrophages containing apoptotic bodies. In alveolar macrophage-depleted mice, administration of isoflurane-pretreated BMDMs facilitated resolution of lung inflammation following lipopolysaccharide challenge. Thus, isoflurane promoted resolution of lipopolysaccharide-induced lung inflammatory injury via enhancement of macrophage efferocytosis. Increased macrophage efferocytosis following isoflurane treatment correlates with upregulation of Mer surface expression through AMPK-mediated blockade of ADAM17 trafficking to the cell membrane.
• Xu, H., Changyaleket, B., Valyi-Nagy, T., Dull, R. O., Pelligrino, D. A., Schwartz, D. E., & Chong, Z. Z. (2016). The Role of HMGB1 in Pial Arteriole Dilating Reactivity following Subarachnoid Hemorrhage in Rats. Journal of vascular research, 53(5-6), 349-357.
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  High-mobility group box 1 protein (HMGB1) has been implicated in inflammatory responses, and is also associated with cerebral vasospasm after subarachnoid hemorrhage (SAH). However, there are no direct evident links between HMGB1 and cerebral vasospasm. We therefore investigated the effects of HMGB1 on pial arteriole reactivity following SAH in rats. We initially found that SAH induced a significant decrease in pial arteriole dilating responses to sciatic nerve stimulation (SNS), hypercapnia (CO2), and the topical suffusion of acetylcholine (ACh), adenosine (ADO), and s-nitroso-N-acetylpenicillamine (SNAP) over a 7-day period after SAH. The percent change of arteriolar diameter was decreased to the lowest point at 48 h after SAH, in response to dilating stimuli (i.e., it decreased from 41.0 ± 19.0% in the sham group to 11.00 ± 0.70% after SNS) (n = 5, p < 0.01). HMGB1 infusion in the lateral ventricle in normal rats for 48 h did not change the pial arteriole dilating response. In addition, inhibitors of HMGB1-receptor for advanced glycation end-product or HMGB1-toll-like receptor 2/4 interaction, or the HMBG1 antagonist did not improve pial arteriole reactivity 48 h after SAH. These findings suggest that HMGB1 may not be a major player in cerebral vascular dilating dysfunction after SAH.

Poster Presentations

• Chignalia, A. Z., De Souza, J. L., & Dull, R. (2020, April/Spring). Glypican‐1 Plays a Cardiac Protective Effect During Heart Failure Induced by Pressure Overload. Experimental Biology.
• Dull, R., De Souza, J. L., & Chignalia, A. Z. (2020, April/Spring). Glypican‐1 and Remodeling Cardiac Hypertrophy.. Experimental Biology.
• Chignalia, A. Z., De Souza, J. L., Dull, R., Tostes, R., Bendhack, L. M., Potje, S. R., Potje, S. R., Bendhack, L. M., Tostes, R., Dull, R., De Souza, J. L., & Chignalia, A. Z. (2019, Fall). Heparan sulfate proteoglycans modulate calcium storage and mobility in aortic rings. Society for Free Radicals Biology and Medicine. Las Vegas: Society for Free Radicals Biology and Medicine.