Life or Death? A Physiogenomic Approach to Understand Individual Variation in Responses to Hemorrhagic Shock

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

Dehydrogenase and Oxoreductase Activities of Porcine Placental 11β-Hydroxysteroid Dehydrogenase

Dehydrogenase (cortisol to cortisone) and oxoreductase (cortisone to cortisol) activities of porcine placental 11β-hydroxysteroid dehydrogenase ( 11β-HSD) were measured in tissue fragment cultures on day 75 of gestation. Dehydrogenase activity was over fivefold greater than oxoreductase activity (p \u3c .001). There were positive linear associations (p \u3c .01) between net dehydrogenase activity (dehydrogenase minus oxoreductase) and fetal weight, fetal length, and placental weight. These data indicate a predominance of placental 11β-HSD dehydrogenase activity at this gestational stage that would insure a net conversion of cortisol to cortisone as it traverses the placenta. The data further suggest that 11β-HSD activities may provide an optimal glucocorticoid environment that is supportive of enhanced fetal and placental growth

Prolonged Suppression of Plasma LH Levels in Male Rats after a Single Injection of an LH‐RH Agonist in Poly(DL‐Lactide‐Co‐Glycolide) Microcapsules

The authors have examined the effects of a subcutaneous injection of the LH‐RH agonist D‐Trp6‐LH‐RH formulated in biodegradable poly(DL‐lactide‐co‐glycolide) microcapsules on plasma levels of D‐Trp6LH‐RH, LH, and PRL in adult, gonadectomized male rats. Immunoreactive D‐Trp6‐LH‐RH was detectable in the plasma of these animals at 1, 2, 3, and 4 weeks after injection. LH concentrations were greatly reduced 1 week after administering the D‐Trp6‐LH‐RH microcapsule, continued to decrease during the following week, and remained suppressed until the end of the study, 6 weeks after the injection. Plasma PRL levels appeared elevated 1 to 2 weeks after the injection and suppressed thereafter, but these effects were significant only in animals rendered hyperprolactinemic by transplantation of an isologous pituitary under the renal capsule. These results demonstrate that an LH‐RH agonist formulated in biodegradable microcapsules and administered as a subcutaneous injection can exert marked biologic effects in rats for at least 6 weeks. These findings also suggest that prolonged exposure to an LH‐RH agonist may first produce stimulation, followed by an inhibition of PRL release from both in situ and ectopic pituitaries