Effects of pyruvate administration on infarct volume and neurological deficits following permanent focal cerebral ischemia in rats

Recent experimental evidences indicate that pyruvate, the final metabolite of glycolysis, has a remarkable protective effect against different types of brain injury. The purpose of this study was to assess the neuroprotective effect and the neurological outcome after pyruvate administration in a model of ischemic stroke induced by permanent middle cerebral artery occlusion (pMCAO) in rats. Three doses of pyruvate (250, 500 and 1000 mg/kg, i.p.) or vehicle were administered intraperitoneally 30 min after pMCAO. In other set of experiments, pyruvate was given either before, immediately after ischemia or in a long-term administration paradigm. Functional outcome, mortality and infarct volume were determined 24 h after stroke. Even when the lowest doses of pyruvate reduced mortality and neurological deficits, no concomitant reduction in infarct volume was observed. The highest dose of pyruvate increased cortical infarction by 27% when administered 30 min after pMCAO. In addition, when pyruvate was given before pMCAO, a significant increase in neurological deficits was noticed. Surprisingly, on the contrary of what was found in the case of transient global ischemia, present findings do not support a great neuroprotective role for pyruvate in permanent focal cerebral ischemia, suggesting two distinct mechanisms involved in the effects of this glycolytic metabolite in the ischemic brain

Bargaining with intertemporal maximin payoffs

We present a new class of dynamic bargaining problems, called "bargaining problems with intertemporal maximin payoffs," that may reflect sustainability problems having to encompass conflicting issues in the long-run. Each bargainer (or stake-holder) has a representative indicator, namely a function of the state and decisions, and aims at maximizing its minimal value over time. Bargaining on sustainability issues consists in defining the vector of stake-holder's payoffs. We are interested in defining the set of feasible outcomes of such problems. This set is interpreted as a support for a social choice of sustainability objectives. We introduce a MONDAI condition – Monotonicity of Dynamics And Indicators – consistent with many economic problems and, in particular, "environmental economic" sustainability issues. We characterize the set of feasible outcomes for problems satisfying these monotonicity properties, and the bargaining solutions under the axioms of Pareto efficiency and Independence of Irrelevant Alternatives. We also provide a "satisficing" common decision rule to achieve any given solution. We then examine the time-consistency of the solution under the axioms of Veto Power and Individual Rationality.bargaining theory, dynamics, maximin, monotonicity, feasibility set, sustainability

Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats

Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/kg) on prostaglandin E2 (PGE2) levels, myeloperoxidase (MPO) activity, Evans Blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischemia in the rat. Postischemic treatment with nimesulide markedly reduced the increase in PGE2 levels in the ischemic cerebral cortex 24 h after stroke and diminished infarct size by 48 % with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the other hand, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition

Reactor Neutrino Flux Uncertainty Suppression on Multiple Detector Experiments

This publication provides a coherent treatment for the reactor neutrino flux uncertainties suppression, specially focussed on the latest $\theta_{13}$ measurement. The treatment starts with single detector in single reactor site, most relevant for all reactor experiments beyond $\theta_{13}$. We demonstrate there is no trivial error cancellation, thus the flux systematic error can remain dominant even after the adoption of multi-detector configurations. However, three mechanisms for flux error suppression have been identified and calculated in the context of Double Chooz, Daya Bay and RENO sites. Our analysis computes the error {\it suppression fraction} using simplified scenarios to maximise relative comparison among experiments. We have validated the only mechanism exploited so far by experiments to improve the precision of the published $\theta_{13}$. The other two newly identified mechanisms could lead to total error flux cancellation under specific conditions and are expected to have major implications on the global $\theta_{13}$ knowledge today. First, Double Chooz, in its final configuration, is the only experiment benefiting from a negligible reactor flux error due to a $\sim$90\% geometrical suppression. Second, Daya Bay and RENO could benefit from their partial geometrical cancellation, yielding a potential $\sim$50\% error suppression, thus significantly improving the global $\theta_{13}$ precision today. And third, we illustrate the rationale behind further error suppression upon the exploitation of the inter-reactor error correlations, so far neglected. So, our publication is a key step forward in the context of high precision neutrino reactor experiments providing insight on the suppression of their intrinsic flux error uncertainty, thus affecting past and current experimental results, as well as the design of future experiments

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3 to 24 h after ischemia. Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia. The effect of nimesulide on prostaglandin E2 (PGE2) levels in the injured brain was also investigated. Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE2 accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage