No abstract

Sepsis-induced multiple organ failure is the major cause of mortality in critically ill patients, and its incidence is rising [1]. The heart and cardiovascular systems are seriously affected during sepsis [2]. Although myocardial impairment in sepsis has been extensively studied, its etiology remains unclear [3]. Some reports The existence of an inducible mitochondrial nitric oxide synthase has been recently related to the nitrosative ⁄ oxidative damage and mitochondrial dysfunction that occurs during endotoxemia. Melatonin inhibits both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase activities, a finding related to the antiseptic properties of the indoleamine. Hence, we examined the changes in inducible nitric oxide synthase ⁄ inducible mitochondrial nitric oxide synthase expression and activity, bioenergetics and oxidative stress in heart mitochondria following cecal ligation and puncture-induced sepsis in wild-type (iNOS + ⁄ + ) and inducible nitric oxide synthase-deficient (iNOS -⁄ -) mice. We also evaluated whether melatonin reduces the expression of inducible nitric oxide synthase ⁄ inducible mitochondrial nitric oxide synthase, and whether this inhibition improves mitochondrial function in this experimental paradigm. The results show that cecal ligation and puncture induced an increase of inducible mitochondrial nitric oxide synthase in iNOS + ⁄ + mice that was accompanied by oxidative stress, respiratory chain impairment, and reduced ATP production, although the ATPase activity remained unchanged. Real-time PCR analysis showed that induction of inducible nitric oxide synthase during sepsis was related to the increase of inducible mitochondrial nitric oxide synthase activity, as both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase were absent in iNOS -⁄ -mice. The induction of inducible mitochondrial nitric oxide synthase was associated with mitochondrial dysfunction, because heart mitochondria from iNOS -⁄ -mice were unaffected during sepsis. Melatonin treatment blunted sepsis-induced inducible nitric oxide synthase ⁄ inducible mitochondrial nitric oxide synthase isoforms, prevented the impairment of mitochondrial homeostasis under sepsis, and restored ATP production. These properties of melatonin should be considered in clinical sepsis.

No abstract

Nearly all neuronal information processing and interneuronal communication in the brain involves action potentials, or spikes, which drive the short-term synaptic dynamics of neurons, but also their long-term dynamics, via synaptic plasticity. In many brain structures, action potential activity is considered to be sparse. This sparseness of activity has been exploited to reduce the computational cost of large-scale network simulations, through the development of event-driven simulation schemes. However, existing event-driven simulations schemes use extremely simplified neuronal models. Here, we implement and evaluate critically an event-driven algorithm (ED-LUT) that uses precalculated look-up tables to characterize synaptic and neuronal dynamics. This approach enables the use of more complex (and realistic) neuronal models or data in representing the neurons, while retaining the advantage of high-speed simulation. We demonstrate the method's application for neurons containing exponential synaptic conductances, thereby implementing shunting inhibition, a phenomenon that is critical to cellular computation. We also introduce an improved two-stage event-queue algorithm, which allows E. Ros, R. Carrillo, E. Ortigosa, B. Barbour, and R. Agís the simulations to scale efficiently to highly connected networks with arbitrary propagation delays. Finally, the scheme readily accommodates implementation of synaptic plasticity mechanisms that depend on spike timing, enabling future simulations to explore issues of long-term learning and adaptation in large-scale networks.