DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis

Background: Chemotherapy remains the primary tool for treatment and control of human leishmaniasis. However, currently available drugs present serious problems regarding side-effects, variable efficacy, and cost. Affordable and less toxic drugs are urgently needed for leishmaniasis. Methodology/Principal Findings: We demonstrate, by microscopy and viability assays, that superoxide dismutase inhibitor diethyldithiocarbamate (DETC) dose-dependently induces parasite killing (p,0.001) and is able to ??????sterilize?????? Leishmania amazonensis infection at 2 mM in human macrophages in vitro. We also show that DETC-induced superoxide production (p,0.001) and parasite destruction (p,0.05) were reverted by the addition of the antioxidant N-acetylcysteine, indicating that DETC-induced killing occurs through oxidative damage. Furthermore, ultrastructural analysis by electron microscopy demonstrates a rapid and highly selective destruction of amastigotes in the phagosome upon DETC treatment, without any apparent damage to the host cell, including its mitochondria. In addition, DETC significantly induced parasite killing in Leishmania promastigotes in axenic culture. In murine macrophages infected with Leishmania braziliensis, DETC significantly induced in vitro superoxide production (p = 0.0049) and parasite killing (p = 0.0043). In vivo treatment with DETC in BALB/C mice infected with Leishmania braziliensis caused a significant decrease in lesion size (p,0.0001), paralleled by a 100-fold decrease (p = 0.0087) in parasite burden. Conclusions/Significance: Due to its strong leishmanicidal effect in human macrophages in vitro, its in vivo effectiveness in a murine model, and its previously demonstrated in vivo safety profile in HIV treatment, DETC treatment might be considered as a valuable therapeutic option in human leishmaniasis, including HIV/Leishmania co-infection

Elites and the Diffusion of Foreign Models in Russia

Globalization has sparked renewed interest in the diffusion of ideas and norms across boundaries. Although much work has focused on diffusion at the macro-level and on the groups that transmit ideas, few researchers have studied the cognitive processes of political elites as they weigh the merits of various foreign-inspired models. Drawing on a series of original, in-depth interviews with Russian parliamentarians and high-ranking bureaucrats conducted in 1996, this paper makes two contributions to the study of individual-level borrowing in the Russian context. First, the openness of Russian elites to foreign borrowing is investigated; despite the public rhetoric about Russia\u27s uniqueness, a substantial number of Russian elites are willing to borrow from foreign experience – particularly from models of European welfare capitalism. Second, three explanations of why policy-makers prefer to emulate some countries rather than others are tested – because they are similar to their own country either geographically, historically or culturally (comparability); because they have geostrategic prominence (prestige); or because they excel economically and/or politically (performance). Comparability and prestige are found to be of lesser importance than performance to Russian elites when considering the merits of various foreign models. Given that Russia closely approximates a most-likely case for validating explanations stressing comparability, this suggests that the array of foreign ideas that could become part and parcel of Russia\u27s transition process is probably wider than is usually assumed. It also implies that, in general, the regional dimension of diffusion plays a smaller role than previously theorized