Early inflammatory mediator gene expression in two models of traumatic brain injury: ex vivo cortical slice in mice and in vivo cortical impact in piglets

Background: The immunological response during the first 24 hours after traumatic brain injury (TBI) may be a critical therapeutic interval for limiting the secondary neuronal damage that is influenced by enhanced inflammatory mediator expression. Methods: To gain further insight of the early injury response, we examined the expression of several inflammatory genes by real-time qPCR as a function of time or distance from injury in two distinct mammalian models: an ex vivo mouse cortical slice injury system and an in vivo piglet model of brain injury. Results: Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), chemokine ligands 2 (CCL2), 3 (CCL3), 4 (CCL4), and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNAs increased within 5 h after injury in mouse cortical slices. Chemokine and PTGS2 mRNAs remained elevated in slices at 24 h, whereas IL-1β and TNF-α expressions decreased from earlier peak levels. At 24 h after cortical injury in 1-month-old piglets, the expression of CCL2 mRNA was significantly increased in the lesion core and in the penumbra region. The expression of PTGS2, IL-1β, and TNF-α was variable among the piglets. Conclusions: These in vitro and large animal models of cortical injury expand our understanding of the early timing and spread of the immunological response and can serve as preclinical systems to facilitate the discovery of therapeutic agents for TBI aimed at regulating inflammatory mediator expression

Establishing a Clinically Relevant Large Animal Model Platform for TBI Therapy Development: Using Cyclosporin A as a Case Study

We have developed the first immature large animal translational treatment trial of a pharmacologic intervention for traumatic brain injury (TBI) in children. The preclinical trial design includes multiple doses of the intervention in two different injury types (focal and diffuse) to bracket the range seen in clinical injury and uses two post-TBI delays to drug administration. Cyclosporin A (CsA) was used as a case study in our first implementation of the platform because of its success in multiple preclinical adult rodent TBI models and its current use in children for other indications. Tier 1 of the therapy development platform assessed the short-term treatment efficacy after 24 h of agent administration. Positive responses to treatment were compared with injured controls using an objective effect threshold established prior to the study. Effective CsA doses were identified to study in Tier 2. In the Tier 2 paradigm, agent is administered in a porcine intensive care unit utilizing neurological monitoring and clinically relevant management strategies, and intervention efficacy is defined as improvement in longer term behavioral endpoints above untreated injured animals. In summary, this innovative large animal preclinical study design can be applied to future evaluations of other agents that promote recovery or repair after TBI

Insights into the catalytic production of hydrogen from propane in the presence of oxygen: cooperative presence of vanadium and gold catalysts

[EN] H-2 and propylene can be obtained from propane and oxygen in defect using appropriate catalysts. Meanwhile propylene is formed from propane via oxidative or non-oxidative dehydrogenation, molecular hydrogen can be obtained from several reactions such as propane dehydrogenation, coke formation and water gas shift. It has been observed that a gold catalyst hardly activates propane and no H-2 was detected, whereas using vanadium oxide a relatively high concentration of propylene and H-2 was obtained. Interestingly, the simultaneous use of vanadium oxide and gold has meant a higher hydrogen production, higher in a 40% than that of the catalyst containing only vanadium oxide. This performance has been. related to the capacity of gold to activate CO in the water gas shift reaction. (C) 2015 Elsevier B.V. All rights reserved.The authors would like to acknowledge the DGICYT in Spain (CTQ2012-37925-C03-1, CTQ2012-37925-C03-2 and CTQ2012-37984-C02-01) for financial support We also thank the University of Valencia and SCSIE-UV for assistance. J.M. Lopez would also like to thank Spanish MICINN and CSIC for funding his Ramon y Cajal contract (RYC-2009-04483).Garcia, T.; Lopez, JM.; López Nieto, JM.; Sanchis, R.; Dejoz, A.; Vazquez, MI.; Solsona, B. (2015). Insights into the catalytic production of hydrogen from propane in the presence of oxygen: cooperative presence of vanadium and gold catalysts. Fuel Processing Technology. 134:290-296. https://doi.org/10.1016/j.fuproc.2015.02.012S29029613

The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth

Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming

Developmental programming: the role of growth hormone

Developmental programming of the fetus has consequences for physiologic responses in the offspring as an adult and, more recently, is implicated in the expression of altered phenotypes of future generations. Some phenotypes, such as fertility, bone strength, and adiposity are highly relevant to food animal production and in utero factors that impinge on those traits are vital to understand. A key systemic regulatory hormone is growth hormone (GH), which has a developmental role in virtually all tissues and organs. This review catalogs the impact of GH on tissue programming and how perturbations early in development influence GH function

Mechanisms of reduced luteal sensitivity to PGF2alpha in ruminants.

The corpus luteum (CL) of ruminants exhibits periods of reduced sensitivity to the luteolysin prostaglandin F2α (PGF2α). The CL has reduced sensitivity to PGF2α early in the luteal phase. Mechanisms of reduced luteal sensitivity to PGF2α during the early portion of the luteal phase have been widely studied, with a focus on regulation of cyclooxygenase-2 and components of the endothelin system. The first ovulation in postpartum cows results in a CL that regresses during transition from a period of reduced sensitivity to susceptibility to PGF2α, and there is evidence that the first CL in the postpartum cow is more sensitive to PGF2α. Corpora lutea are less sensitive to PGF2α during the maternal recognition of pregnancy. In the ewe, studies were performed to quantify mRNA for prostaglandin metabolic enzymes and components of the endothelin system, as well as catabolism of PGF2α to inactive PGFM in CL expected to regress early in postpartum cows and in pregnant ewes expected to have CL that do not regress after an injection of PGF2α. In both experiments, transcription of enzymes involved in prostaglandin anabolism were regulated by the abundance of PGE synthase and PGF synthase mRNA instead of cyclooxygenase-2 mRNA. Catabolism of PGF2α to PGFM was regulated post-transcriptionally. It was also demonstrated that the endothelin system may contribute to reduced luteal sensitivity to PGF2α through alterations in the endothelin converting enzyme-1 mRNA instead of alterations in the abundance of preproendothelin-1 or endothelin receptor type A mRNA. In conclusion, the early regressing CL in the postpartum cow did not appear to differ from non-regressing CL with respect to PGE synthesis or PGF2α catabolism. Nevertheless, premature uterine secretion of PGF2α activates mediators of regression. In pregnant ewes, the conceptus, which alters uterine secretion of prostaglandins to a greater ratio of PGE2: PGF2α, may cause a similar shift in prostaglandin production in the CL to a greater ratio of PGE2: PGF2α, a reduction of endothelin converting enzyme-1, and greater catabolism of PGF2α to the inactive metabolite PGFM