Pneumocystis carinii pneumonia remains one of the most serious complications of immunosuppressed patients. In this study, the in vitro pharmacodynamic parameters of four sordarin derivatives (GM 191519, GM 237354, GM 193663, and GM 219771) have been evaluated by a new quantitative approach and compared with the commercially available drugs pentamidine, atovaquone, and trimethoprim-sulfamethoxazole (TMP-SMX). In vitro activities and in vivo therapeutic efficacies of sordarin derivatives against P. carinii were also evaluated. In vitro activity was determined by the broth microdilution technique, comparing the total number of microorganisms in treated and drug-free cultures by using Giemsa staining. The in vitro maximum effect (E max ), the drug concentrations to reach 50% of E max (EC 50 ), and the slope of the dose-response curve were then estimated by the Hill equation (
Many in vitro systems have been used to cultivate Pneumocystis, but only limited parasite growth has been obtained by different authors. A reliable in vitro system enabling a sustained propagation of Pneumocystis appears to be an important condition for a better definition of the transmission of P. carinii pneumonia. In this work, Pneumocystis in vitro culture was performed on monolayers of L2 rat lung epithelial-like cells. Ultrastructural assessment revealed that culture parasites were structurally intact. Pneumocystis culture samples were intratracheally inoculated into corticosteroid-treated nude rats (nonlatently infected by P. carinii), which developed P. carinii pneumonia at 40 days postinoculation. The infectious power of parasites obtained in vitro was 7-10 times higher than that of parasites freshly extracted from parasitized rat lung. In summary, the present results show that it is possible to obtain in vitro highly infectious Pneumocystis forms, and this study provides a promising infectivity test for use by investigators working on Pneumocystis in vitro systems.
SummaryA kindred is described with a probably new inherited syndrome, involving bilateral congenital hip dysplasia with coxa vara, patella aplasia and tarsal synostosis. This association is probably inherited as an incomplete dominant trait, apparently as a result of a new mutation.In this case a single pleiotropic gene might be held responsible for the multiple skeletal defects.From a bibliographical review, it may be concluded that the nosological association of these multiple defects has never been published so far.
The role of the erythrocyte skeleton in the invasion process of Plasmodium falciparum was evaluated using genetically variant erythrocytes containing well-defined molecular defects in alpha spectrin (alpha Sp) or protein 4.1 from eight unrelated families. Invasion into red cells from subjects of three black families with hereditary pyropoikilocytosis (HPP) due to inheritance of alpha I/74 mutant spectrin was significantly reduced in cells both from the patients and from the relatives of these who carried asymptomatic hereditary elliptocytosis (HE). Likewise, reduced invasion was also seen in red cells from two families with HE in which the alpha I/65 variant spectrin was present. Resistance to invasion was not absolute in any sample and varied between 38% and 71% of that seen in normal cells. The decreased invasion correlated with the percentage of spectrin dimers present within the membrane of variant cells. In contrast, invasion into elliptocytes from three families that had a partial deficiency in protein 4.1 (HE/4.1+) but a normal percentage of spectrin dimers was either unchanged or increased. The precise mechanism and molecular basis behind the reduced invasion into HPP and HE red cells bearing Sp alpha I domain variants remains to be elucidated but might relate to alterations in merozoite/red cell-receptor interactions and/or merozoite endocytosis. The occurrence of elliptocytosis with spectrin defects (in particular, Sp alpha I/65 and Sp alpha I/46 variants in West Africa) suggests that these mutations of the alpha Sp gene could be related to some protection against malaria.
In the blood of a Cercocebus albigena and of a C. galeritus agilis monkey, the infection with Plasmodium gonderi was found to follow its well-known chronic course; P. georgesi seemed to occur as a relapsing type of malaria parasite; P. petersi was found for only a few days and at a low level in C. albigena (end of an attack?). As shown by using polarized light, the pigment granules appeared mostly as fine dots in P. georgesi, short rods in P. gonderi and long needles in P. petersi. The three species can be distinguished by the morphological appearance of the nucleus of the young trophozoites, and also by the measurement of its surface area (Sa): small round nucleus (Sa = 0.81 +/- 0.06 microns 2) in P. gonderi, large 2-coloured nucleus (Sa = 1.43 +/- 0.21 microns 2) in P. petersi, and long crescent-shaped nucleus (Sa = 2.18 +/- 0.25 microns 2) in P. georgesi. The first colour illustrations of the blood-stages of P. georgesi are presented. The dynamics of single and mixed blood infections in primate malaria parasites are discussed, with a proposal to classify them into 3 types.
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