To investigate the host genetic factors affecting the clinical course of falciparum malaria, polymorphism of the tumor necrosis factor-alpha (TNF-alpha) promoter region was analyzed in patients with cerebral malaria. Two hundred and forty-three Myanmar patients with falciparum malaria at Mae Sot Malaria clinic and Mae Sot General Hospital located at the border between Thailand and Myanmar, were included in this study. Among the patients (128 from Karen, 115 from Burma), 200 were uncomplicated and 43 had cerebral malaria. The TNF-alpha 5'- flanking region showed biallelic polymorphic sites at -238, -308, -857, -863, -1031, and there were 7 alleles (TNFP-A, B, C, D, M1, M4, M7) found in the patients from Myanmar. We found that the TNFP-D allele was significantly associated with cerebral malaria in the populations from Karen (Pc<0.0001, OR=124.86) and Burma (Pc<0.0001, OR=34.50). TNFP-D showed no significant linkage disequilibrium with any alleles of HLA-B or HLA-DRB1, suggesting that TNFP-D was primarily associated with cerebral malaria in Myanmar.
This study was conducted during 2002-2004 at Mae Sot District, on the Thai-Myanmar border, an area of multidrug-resistant Plasmodium falciparum malaria. Sixty-two patients with P. vivax malaria were included in the study. All were randomized into two groups to receive a 3-day regimen of chloroquine or a 3-day regimen of quinine. Primaquine was given to patients in both groups for the elimination of hepatic stages. Results from the present study suggest that the standard regimen of chloroquine and a 3-day course of quinine at the dose regimens under investigation were very effective and well tolerated for the treatment of P. vivax malaria in this area. All patients responded well to both drug regimens; the cure rates with chloroquine or quinine, when given concurrently with the tissue schizontocidal drug primaquine, were virtually 100% within 28 days of follow-up. No significant correlations between parasite clearance time (PCT) or fever clearance time (FCT) and inhibitory concentration 50 (IC50) were found. Patients who had PCT < or = 24 h and those with PCT >24 h had comparable IC50 to chloroquine (alone and plus primaquine) and quinine, as well as similar concentrations of chloroquine/desethylchloroquine (in blood) or quinine (in plasma) at the investigated time points.
The ParaSight-F test for the detection of Plasmodium falciparum was evaluated for its accuracy and usefulness in predicting treatment outcome in 75 patients (70 males, 5 females) with acute uncomplicated malaria who attended a malaria clinic in Mae Sot, Tak province, on the Thai-Myanmar border. All patients were admitted to the clinic for 28 d to exclude reinfection. The test was performed using blood samples collected into ethylenediaminetetraacetic acid from the patients on admission, and on days 1, 2, 7, and 14. The presence of microscopically detectable parasitaemia was used as the reference for sensitivity and specificity of the test. The reappearance of parasites on day 28 was used to determine the accuracy of predicting the outcome of artemether treatment on day 14. The sensitivity of the ParaSight-F test on admission, and on days 1, 2, 7, and 14, was 98.7%, 96.7%, 100%, 100% and 100%, respectively, with corresponding specificities of 50%, 24.2%, 47.1% and 72.9%. The sensitivity for predicting recrudescence by using the test on day 14 was 100%, with 97.7% specificity, and the sensitivity of predicting a sensitive response on day 14 was 97.7%, with 100% specificity. The test seems to permit more precise detection of treatment failure under 'field' conditions if used on day 14 after the start of treatment.
Human amoebiasis caused by Entamoeba histolytica is widely distributed in the tropics and subtropics, but also occurring in neighbouring parts of the temperate zones. Invasive amoebiasis causes dysentery and, by haematogenous spread, also extra-intestinal hepatic, pulmonary or cerebral abscesses, not rarely fatal conditions. The available anti-amoebic drugs have shortcomings regarding tolerability and efficacy. To facilitate the screening of candidate material, an in vitro system has been developed that permits the determination of specific anti-amoebic activity. PYE medium, supplemented with bovine serum, proved to be suitable for the maintenance of the stock cultures of Entamoeba histolytica strain HM1:1MSS. For sensitivity testing, Waymouth medium and cultivation under aerobic conditions were most reliable. After adapting the system to the use of 96-well (8 x 12) tissue culture plates, sensitivity tests were carried out with metronidazole, dehydroemetine and dihydroartemisinin as active control drugs, and seven extracts from Stemona tuberosa, Aglaia edulis, Aglaia elaeagnoidea and Aglaia odorata. Stem bark extract from Aglaia elaeagnoidea was the most active material with an IC(99) of 496 ng/ml and a slope S of 1.1325, followed by leaf extract from Stemona tuberosa with an IC(99) of 638 ng/ml and a slope S of 1.5648. All seven extracts showed full activity at concentrations <4000 ng/ml and qualified for further investigation.
The possibility of short-term in vitro cultivation, i.e. growth of asexual erythrocytic stages up to the stage of mature schizonts, permits in principle the development of drug sensitivity tests also for Plasmodium vivax. In the absence of a sequestration of erythrocytes carrying the advanced stages of schizogony, asexual parasites of all stages may be seen in the peripheral blood of patients infected with P. vivax. This precludes schizont maturation tests since schizont development will be unduly influenced by the number of advanced trophozoites. A test system reflecting the age composition of the parasite population and its progression without and under the influence of inhibitors was found to yield precise results also in the higher IC ranges. The population-based test procedure would also permit the identification of any stage-specific impact of antimalarial agents.
The genus Crithidia is a member of the family Trypanosomatidae and is related to the genera Leishmania and Trypanosoma with which it shares a variety of biochemical mechanisms, such as polyamine synthesis and methionin salvage. In consequence, a screening system for antiparasitic candidate material has been developed with Crithidia fasciculata, a parasite naturally occurring in insects and amphibians, but devoid of pathogenicity for humans. Initially a variety of culture media were evaluated of which TPS was best suited for the maintenance of stock cultures, and E-medium - a newly developed formula - for sensitivity testing. Optimal growth of C. fasciculata was observed under microaerophilic conditions. A system for sensitivity testing was developed and applied to the investigation of extracts from higher tropical plants of the genera Stemona and Aglaia for anticrithidial activity. Extracts with significant anti-crithidial activity were scheduled for chromatographic fractionation and the subsequent isolation, purification and structural identification of individual compounds for further sensitivity testing. Encouraging results were obtained with extracts from Aglaia odorata leaves, A. elaeagnoidea stem bark and A. edulis leaves, with EC(90) values of 1213 ng/ml, 1606 ng/ml, and 1462 ng/ml, respectively.
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