Abstract. We present a mathematical model of the blood-stage dynamics of mixed Plasmodium vivax-Plasmodium falciparum malaria infections in humans. The model reproduces features of such infections found in nature and suggests several phenomena that may merit clinical attention, including the potential recrudescence of a long-standing, low-level P. falciparum infection following a P. vivax infection or relapse and the capacity of an existing P. vivax infection to reduce the peak parasitemia of a P. falciparum superinfection. We simulate the administration of antimalarial drugs, and illustrate some potential complications in treating mixed-species malaria infections. Notably, our model indicates that when a mixed-species infection is misdiagnosed as a single-species P. vivax infection, treatment for P. vivax can lead to a surge in P. falciparum parasitemia.Plasmodium vivax and P. falciparum are the most widespread and commonly studied of the four species that cause human malaria. Dual infections are common and frequently recorded in field surveys, but there has been little research on the within-host interactions or clinical impacts of coinfecting species. Cohen 1 reviewed prevalence surveys and concluded that in general, fewer mixed-species infections are observed than would be expected from the prevalences of the constituent species. Richie 2 reviewed prevalence surveys and concluded that there is no general pattern in the frequencies of mixed-species infections in humans. Our reviews of more recent cross-sectional studies 3,4 found that lower-than-expected frequencies of dual P. vivax-P. falciparum infections correspond to higher overall malaria prevalence, and, in general, that the frequencies of mixed-species Plasmodium infections detected in humans may depend upon the particular combinations of Plasmodium species present. We have also found mixed-species Plasmodium infections common in vector Anopheles species. 5Longitudinal studies of mixed-species infections are extremely rare. Several neurosyphilis malariatherapy charts published by Boyd and Kitchen 6,7 suggest that P. falciparum suppressed P. vivax parasitemia in these patients. Interspecies inhibition was also suggested by other such studies. [8][9][10][11] Shute 12 reported that P. vivax often failed to thrive if inoculated simultaneously with P. falciparum, but could reach patent levels if inoculated a few days before P. falciparum. More recently, clinical studies 13,14 have found high rates of P. vivax infection following treatment of patients previously assumed to be infected only with P. falciparum. Studies with non-human malarias have also suggested interspecific suppression. [15][16][17][18][19] The pathologic consequences of mixed-species infections are of particular interest to clinicians. Jeffrey 20 noted that prior infection with P. ovale could alter the clinical course of subsequent P. falciparum infection. Other studies have noted relationships between mixed-species infections and enlarged spleen size, 10 decreased spleen size, 1 and depres...
A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
During malaria surveys in Myanmar, 2 peculiar forms of Plasmodium malariae-like parasites were found. The morphologies of their early trophozoite stages were distinct from that of the typical P. malariae, resembling instead that of Plasmodium vivax, var. minuta, reported by Emin, and Plasmodium tenue, reported by Stephens, both in 1914. Two polymerase chain reaction (PCR)-based diagnoses, which target the same regions in the small subunit ribosomal RNA (SSUrRNA) genes, indicated that these parasites were new variant forms of P. malariae and that they could be separated into 2 genetic types that correlated with the 2 morphological types. Sequence analysis of the SSUrRNA and the circumsporozoite protein genes revealed that they were distinct both from each other and from other known P. malariae isolates and that the P. tenue-like type was closer to a monkey quartan malaria parasite, Plasmodium brasilianum. These results illustrate that the microscopic appearance of human P. malariae parasites may be more varied than previously assumed and suggest the value of molecular tools in the evaluation of malaria morphological variants.
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