Reactive oxygen species (ROS) are important second messengers generated in response to many types of environmental stress. In this setting, changes in intracellular ROS can activate signal transduction pathways that influence how cells react to their environment. In sepsis, a dynamic proinflammatory cellular response to bacterial toxins (e.g. lipopolysaccharide or LPS) leads to widespread organ damage and death. The present study demonstrates for the first time that the activation of Rac1 (a GTP-binding protein), and the subsequent production of ROS, constitutes a major pathway involved in NFkappaB-mediated tumor necrosis factor-alpha (TNFalpha) secretion following LPS challenge in macrophages. Expression of a dominant negative mutant of Rac1 (N17Rac1) reduced Rac1 activation, ROS formation, NFkappaB activation, and TNFalpha secretion following LPS stimulation. In contrast, expression of a dominant active form of Rac1 (V12Rac1) mimicked these effects in the absence of LPS stimulation. IKKalpha and IKKbeta were both required downstream modulators of LPS-activated Rac1, since the expression of either of the IKK dominant mutants (IKKalphaKM or IKKbetaKA) drastically reduced NFkappaB-dependent TNFalpha secretion. Moreover, studies using CD14 blocking antibodies suggest that Rac1 induces TNFalpha secretion through a pathway independent of CD14. However, a maximum therapeutic inhibition of LPS-induced TNFalpha secretion occurred when both CD14 and Rac1 pathways were inhibited. Our results suggest that targeting both Rac1- and CD14-dependent pathways could be a useful therapeutic strategy for attenuating the proinflammatory cytokine response during the course of sepsis.

Oxygen free radicals have been implicated as a causal factor in posttraumatic neuronal cell loss following cerebral ischemia and head injury. The conversion of salicylate to dihydroxybenzoic acid (DHBA) in vivo was employed to study the formation of hydroxyl radical (.OH) following central nervous system (CNS) injury. Bilateral carotid occlusion (BCO) in gerbils and concussive head trauma in mice were selected as models of brain injury. The lipid peroxidation inhibitor, tirilazad mesylate (U-74006F), was tested for its ability to attenuate hydroxyl radical formation in these models. In addition, U-74006F was studied as a scavenger of hydroxyl radical in an in vitro assay based on the Fenton reaction. For in vivo experimentation, hydroxyl radical formation was expressed as the ratio of DHBA to salicylate (DHBA/SAL) measured in brain. In the BCO model, hydroxyl radical formation increased in whole brain with 10 min of occlusion followed by 1 min of reperfusion. DHBA/SAL was also found to increase in the mouse head injury model at 1 h postinjury. In both models, U-74006F (1 or 10 mg/kg) blocked the increase in DHBA/SAL following injury. In vitro, reaction of U-74006F with hydroxyl radical gave a product with a mol wt that was 16 greater than U-74006F, indicative of hydroxyl radical scavenging. We speculate that U-74006F may function by blocking oxyradical-dependent cell damage, and thereby maintaining free iron (which catalyzes hydroxyl radical formation) concentrations at normal levels.

During the 1980s and 1990s, Jamaican posses captured the imagination of the press corps, film makers, and numerous of criminal justice scholars in the United States. However, except for a few historical references, their virtual disappearance from the contemporary criminal justice literature leaves many unanswered questions. In updating the literature, this paper examines the main factors contributing to the decline of Jamaican posses in the United States and explains how their criminal activities were displaced to Jamaica through aggressive U.S. anti drug and anti-gang operations and immigration policies.

The exportation of the US war on drugs to the international arena has relied on the deployment of various strategies designed to reduce the supply of illegal drugs to the American market, and to hold perpetrators in foreign countries accountable. This paper focuses on the use of extradition in facilitating the prosecution of foreign nationals, and, through a case study of Jamaica, examines some of the problems inherent in the process of arresting and transferring drug offenders from countries within Latin America and the Caribbean to "face justice" in American courts.

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