The adaptive potential of a survival artist: characterization of the in vitro interactions of Toxoplasma gondii tachyzoites with di-cationic compounds in human fibroblast cell cultures

The impact of di-cationic pentamidine-analogues against Toxoplama gondii (Rh- and Me49-background) was investigated. The 72 h-growth assays showed that the arylimidamide DB750 inhibited the proliferation of tachyzoites of T. gondii Rh and T. gondii Me49 with an IC(50) of 0.11 and 0.13 muM, respectively. Pre-incubation of fibroblast monolayers with 1 muM DB750 for 12 h and subsequent culture in the absence of the drug also resulted in a pronounced inhibiton of parasite proliferation. However, upon 5-6 days of drug exposure, T. gondii tachyzoites adapted to the compound and resumed proliferation up to a concentration of 1.2 muM. Out of a set of 32 di-cationic compounds screened for in vitro activity against T. gondii, the arylimidamide DB745, exhibiting an IC(50) of 0.03 muM and favourable selective toxicity was chosen for further studies. DB745 also inhibited the proliferation of DB750-adapted T. gondii (IC(50)=0.07 muM). In contrast to DB750, DB745 also had a profound negative impact on extracellular non-adapted T. gondii tachyzoites, but not on DB750-adapted T. gondii. Adaptation of T. gondii to DB745 (up to a concentration of 0.46 muM) was much more difficult to achieve and feasible only over a period of 110 days. In cultures infected with DB750-adapted T. gondii seemingly intact parasites could occasionally be detected by TEM. This illustrates the astonishing capacity of T. gondii tachyzoites to adapt to environmental changes, at least under in vitro conditions, and suggests that DB745 could be an interesting drug candidate for further assessments in appropriate in vivo models.

God: Savior, Butcher, Or Oblivious Artist? The Theodicy Of Alfred North Whitehead

This paper is a critical examination of Alfred North Whitehead's attempt to solve the traditional problem of evil. Whitehead's conception of evil is crucial to his process cosmology because it is integral to his process cosmology because it is integral to his notion of creation in which evil is understood in relationship to the larger dynamic of God’s creative activity. While Whitehead’s process theodicy is interesting, he fails to successfully escape between the horns of the traditional dilemma. Whitehead is often criticized for treating evil as merely apparent. While some process philosophers, notably Maurice Barineau, have defended Whitehead from this charge, it can be shown that this is an implication of Whitehead’s approach. Moreover, Whitehead’s theodicy fails to address radical moral evil in its concrete dimension in respect to real human suffering. As a result, Whitehead’s theodicy is not relevant to Christian theology. My paper is divided into two parts. I will first briefly discuss the traditional problem of evil and some of the traditional problem of evil and some of the traditional solutions proposed to resolve it. The reminder of the paper will demonstrate why Whitehead’s theodicy addresses the traditional problem of evil only at the expense of theological irrelevancy.