Publications (71) View all
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Article: Arterial blood gases, electrolytes and metabolic indices associated with hemorrhagic shock: inter- and intra-inbred rat strain variation.
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ABSTRACT: We have previously shown inter-strain variation (indicating a genetic basis), and intra-strain variation in survival time after hemorrhage (STaH) among inbred rat strains. To assist in understanding physiological mechanisms associated with STaH, we analyzed various arterial blood measures (ABM; pH, PaCO2, oxygen content, sodium, potassium, glucose, bicarbonate, base excess, total CO2, and ionized calcium) in inbred rats. Rats from 5 inbred strains (n = 8-10/strain) were catheterized and ~24 hours later subjected to a conscious, controlled, 47% hemorrhage. ABM were measured at the start (initial) and end (final) of hemorrhage. Inter- and intra-inbred strain variations of ABM were quantified and compared, and correlations of ABM with STaH were determined. All final ABM values and some initial ABM values were different among strains. Most ABM changed () during hemorrhage and these changes differed among strains (P <0.03). Some strain-dependent correlations (r≥0.7; P≤0.05) existed between ABM and STaH (e.g., BN/Mcwi, K+, r = -0.84). Dark Agouti rats (longest STaH) had the smallest PaCO2, HCO3- and base excess, and the highest final glucose. High coefficients of variation (CVs, >10%), strain-specific CVs, and low intraclass correlation coefficients (rI <0.5) defined the large intra-strain ABM variation that exceeded inter-strain variation for most ABM. These results suggest that some ABM (K+, PaCO2, glucose, oxygen content) could predict subsequent STaH in an inbred rat strain-dependent manner. We speculate that while genetic differences may be responsible for inter-strain variation, individual-specific epigenetic processes (e.g., DNA methylation) may be partly responsible for both inter- and intra-strain ABM variation.Journal of Applied Physiology 03/2013; · 3.75 Impact Factor -
Article: Life or death? A physiogenomic approach to understand individual variation in responses to hemorrhagic shock.
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ABSTRACT: Severe hemorrhage due to trauma is a major cause of death throughout the world. It has often been observed that some victims are able to withstand hemorrhage better than others. For decades investigators have attempted to identify physiological mechanisms that distinguish survivors from nonsurvivors for the purpose of providing more informed therapies. As an alternative approach to address this issue, we have initiated a research program to identify genes and genetic mechanisms that contribute to this phenotype of survival time after controlled hemorrhage. From physiogenomic studies using inbred rat strains, we have demonstrated that this phenotype is a heritable quantitative trait, and is therefore a complex trait regulated by multiple genes. Our work continues to identify quantitative trait loci as well as potential epigenetic mechanisms that might influence survival time after severe hemorrhage. Our ultimate goal is to improve survival to traumatic hemorrhage and attendant shock via regulation of genetic mechanisms and to provide knowledge that will lead to genetically-informed personalized treatments.Current Genomics 09/2011; 12(6):428-42. · 2.41 Impact Factor -
Article: Genetic influences on survival time after severe hemorrhage in inbred rat strains.
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ABSTRACT: To find a genetic basis for differential ability to survive severe hemorrhage, we previously showed eightfold differences in survival times among inbred rat strains. We assumed that rat strains had similar normalized blood volumes (NBV; ml/100 g body wt). As NBV might vary among strains and constitute one genetic variable affecting survival time to hemorrhage, in experiment 1 of the current studies we first measured total blood volumes and calculated NBV in specific inbred rat strains (Brown Norway/Medical College of Wisconsin, BN; Dark Agouti, DA; Fawn Hooded Hypertensive, FHH; Lewis, LEW; and Dahl Salt-Sensitive, SS) previously found to be divergent in survival time. NBV differed by 20% (P < 0.01; BN > SS > FHH = LEW = DA) and had a heritability (h(2)) of 0.56. Hence, differential survival times in our previously published study might reflect strain-dependent differences in NBV. Then studies were conducted wherein rats were catheterized and, ∼24 h later, 47% of their blood volume was removed; these rats were observed for a maximum of 4 h. In experiment 2, blood volumes were measured the day prior to hemorrhage. Percent survival and survival time did not differ among strains. To obviate possible confounding effects of blood volume determination, in experiment 3 the average NBV for each strain was used to determine hemorrhage volumes. Percent survival (P < 0.01) and survival times (P < 0.001) were different with DA demonstrating the best (62.5%, 190 ± 29 min) and BN the worst (0%, 52 ± 5 min) survival responses. These data indicate that both blood volume and survival time after hemorrhage in rats are heritable quantitative traits, and continue to suggest that genetic assessment of these phenotypes might lead to novel therapeutics to improve survival to hemorrhage.Physiological Genomics 04/2011; 43(12):758-65. · 2.73 Impact Factor -
Article: Rat strains bred for low and high aerobic running capacity do not differ in their survival time to hemorrhage.
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ABSTRACT: Hemorrhagic shock reflects low tissue perfusion that is inadequate to maintain normal metabolic functions. Often associated with this condition are impairments in cellular oxygen delivery and utilization. Rat strains divergent in their running endurance have been artificially selected over 12 generations. As these rats bred for high (HCR) vs low (LCR) aerobic running capacity have greater tissue O(2) utilization capacity and improved cardiovascular function, we hypothesized that HCR would be more tolerant (i.e., have greater survivability) to the global ischemia of hemorrhagic shock than LCR. To address this hypothesis, survival time to a severe-as substantiated by dramatic changes in plasma lactate, HCO(3), and base deficit-controlled hemorrhage was measured. Male rats were catheterized and, approximately 24 h later, an estimated >35% of the calculated blood volume was removed during a 26-min period while the rats were conscious and unrestrained. Rats were observed for 6 h or until death. Contrary to our hypothesis, survival time in HCR (220 +/- 63 min; n = 6) did not differ statistically (P = 0.46) from that in LCR (279 +/- 53 min; n = 7). Similarly, there were no statistical differences (P >or= 0.08) between rat lines in blood pH, lactate, HCO(3), and base deficit pre- or post-hemorrhage. In addition, few significant differences between lines in response to hemorrhage were detected by measures of cellular antioxidant status in heart, liver, or lung. Since animals with genetically greater tissue oxygen utilization capacity failed to show longer survival times, our results suggest that other mechanisms must play a more dominant role in determining survivability to hemorrhage under conditions of this hemorrhage.Experimental Biology and Medicine 08/2009; 234(12):1503-10. · 2.64 Impact Factor -
Article: A novel swine model for evaluation of potential intravascular hemostatic agents.
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ABSTRACT: Because uncontrolled hemorrhage is a leading cause of battlefield mortality, finding an intravenous treatment that could assist endogenous clotting mechanisms is a major mission for military researchers. Evaluation of potential intravenous hemostatic agents requires both in vitro and in vivo tests. For in vivo evaluation, we have developed a novel swine model in which 1) bleeding times (BT) and coagulation function could be ascertained after multiple doses of hemostatic drug administration and 2) a subsequent exsanguinating injury could be performed in the same animal, yielding screening information regarding the effects of drug pretreatment on blood loss and survival. Transection of small mesenteric arteries and veins allowed for multiple and reproducible BT measures that correlated with coagulation function. Subsequent excision of defined areas of the liver produced bleeding predominantly from small vessels (diameter, less than 2 mm) and parenchyma while resulting in 62% mortality without the use of either heparinization or aggressive fluid infusion. This swine model allows for multiple, repeatable BT measures in the same animal in experiments already involving laparotomy. Such a model is well suited for terminal studies to test effects of multiple doses of the same drug or multiple drugs on BT and allows for multiple, easily visualized measures that permit enhanced repeatability. The liver injury provides for numerous small vessel lesions that could be amenable to closure by coagulation. Therefore, drugs or mechanisms that enhance coagulation and concomitantly decrease blood loss and increase survival time may be accurately evaluated in this new model.Comparative medicine 07/2007; 57(3):292-7. · 1.05 Impact Factor
