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At least 1,117 records · Page 62Linked to original sources
PubMed2005

Predictors of the failure of treatment with chloroquine plus chlorpheniramine, in children with acute, uncomplicated, Plasmodium falciparum malaria.

Resistance to chloroquine in Plasmodium falciparum can be reversed, both in vitro and in vivo, by chlorpheniramine, a histamine H(1) receptor antagonist. This reversal raises the possibility of using chlorpheniramine to prolong the clinical usefulness of chloroquine in resource-poor communities. The factors that identify children at risk of treatment failure after being given chloroquine plus chlorpheniramine have now been evaluated in 281 children with uncomplicated, P. falciparum malaria. The children, who had taken part in six trials of antimalarial drugs between February 1996 and September 1999, in a hyper-endemic area of south-western Nigeria, were enrolled prospectively for the present study. Following treatment with chloroquine plus chlorpheniramine, 13 (5%) of the children failed treatment by day 7 or 14. In a multivariate analysis, an age of < or =3 years (adjusted odds ratio = 11.1; 95% confidence interval = 2.2-55.3; P = 0.003) and a parasitaemia that took >3 days to clear (adjusted odds ratio=7.9; 95% confidence interval = 1.3-49.4; P = 0.027) were found to be independent predictors of treatment failure. In addition, compared with the children who had a lower axillary temperature then, the children who had an axillary temperature of > or =38 degrees C 2 days after commencing treatment were significantly more likely to be treatment failures. In resource-poor communities using chloroquine plus chlorpheniramine, the easily identifiable predictors of treatment failure might be used to identify children requiring alternative antimalarial drugs.

Acute Disease↗
PubMed2003

Integrative analysis of intraerythrocytic differentially expressed transcripts yields novel insights into the biology of Plasmodium falciparum.

BACKGROUND: The intraerythrocytic development of Plasmodium falciparum, the most virulent human malaria parasite involves asexual and gametocyte stages. There has been a significant increase in disparate datasets derived from genomic and post-genomic analysis of the parasite that necessitates delivery of integrated analysis from which biological processes important to the survival of the parasite can be determined. METHODS: In order to resolve genes associated with stage differentially expressed transcripts, we have developed and implemented an integrative approach that combines evidence from P. falciparum expressed sequence tags (ESTs), genomic, microarray, proteomic and gene ontology data. RESULTS: A total of 143 gametocyte-overexpressed and 51 asexual-overexpressed transcripts were identified. A subset of 74 genes associated with these transcripts showed evidence of stage-correlated protein expression, of which 53 have not been experimentally characterised. Our study has revealed (1) possible regulatory mechanisms in malaria parasites' gametocyte maturation, (2) correlation between EST and microarray data for a P. falciparum gene family to present unique EST-derived information, (3) candidate drug and antigenic targets on which computational and experimental studies can be performed, and (4) the need for more empirical studies on gene and protein expression in malaria parasites. CONCLUSION: Applying different domains of data to the same underlying gene set has yielded novel insights into the biology of the parasite and presents an approach to appraise critically the data quality of post-genomic datasets from malaria parasites.

Journal Article↗
PubMed1999

Low levels of fibrin-stabilizing factor (factor XIII) in human Plasmodium falciparum malaria: correlation with clinical severity.

Plasmodium falciparum malaria is associated with procoagulant activity but not with thromboembolism. We measured coagulation factor XIII, i.e., fibrin-stabilizing factor, in 45 patients with falciparum malaria over time. Of these, 22 had organ complications. The factor XIII antigen (subunits A and B) and plasma activity levels were abnormally low in those with falciparum malaria. They increased during antiparasitic therapy. In 14 of 22 patients with complications, but in no patient with mild disease (P < 0.001), subunit A and activity was < 50%. The factor X.III levels were inversely correlated with clinical severity, parasitemia, and human neutrophil elastase (HNE), but not with thrombin-antithrombin III levels. Thus, low factor XIII levels may reflect proteolysis by HNE, rather than procoagulant activity. One could speculate that factor XIII degradation in severe malaria prevents thromboembolism. On the other hand, factor XIII deficiency might reduce protection of the vascular endothelium against HNE and reactive oxygen species, which would promote organ damage.

Antithrombin III↗
PubMed1987

Expression of senescent antigen on erythrocytes infected with a knobby variant of the human malaria parasite Plasmodium falciparum.

Erythrocytes infected with a knobby variant of Plasmodium falciparum selectively bind IgG autoantibodies in normal human serum. Quantification of membrane-bound IgG, by use of 125I-labeled protein A, revealed that erythrocytes infected with the knobby variant bound 30 times more protein A than did noninfected erythrocytes; infection with a knobless variant resulted in less than a 2-fold difference compared with noninfected erythrocytes. IgG binding to knobby erythrocytes appeared to be related to parasite development, since binding of 125I-labeled protein A to cells bearing young trophozoites (less than 20 hr after parasite invasion) was similar to binding to uninfected erythrocytes. By immunoelectron microscopy, the membrane-bound IgG on erythrocytes infected with the knobby variant was found to be preferentially associated with the protuberances (knobs) of the plasma membrane. The removal of aged or senescent erythrocytes from the peripheral circulation is reported to involve the binding of specific antibodies to an antigen (senescent antigen) related to the major erythrocyte membrane protein band 3. Since affinity-purified autoantibodies against band 3 specifically bound to the plasma membrane of erythrocytes infected with the knobby variant of P. falciparum, it is clear that the malaria parasite induces expression of senescent antigen.

Animals↗
PubMed2006

The 10 kDa domain of human erythrocyte protein 4.1 binds the Plasmodium falciparum EBA-181 protein.

BACKGROUND: Erythrocyte invasion by Plasmodium falciparum parasites represents a key mechanism during malaria pathogenesis. Erythrocyte binding antigen-181 (EBA-181) is an important invasion protein, which mediates a unique host cell entry pathway. A novel interaction between EBA-181 and human erythrocyte membrane protein 4.1 (4.1R) was recently demonstrated using phage display technology. In the current study, recombinant proteins were utilized to define and characterize the precise molecular interaction between the two proteins. METHODS: 4.1R structural domains (30, 16, 10 and 22 kDa domain) and the 4.1R binding region in EBA-181 were synthesized in specific Escherichia coli strains as recombinant proteins and purified using magnetic bead technology. Recombinant proteins were subsequently used in blot-overlay and histidine pull-down assays to determine the binding domain in 4.1R. RESULTS: Blot overlay and histidine pull-down experiments revealed specific interaction between the 10 kDa domain of 4.1R and EBA-181. Binding was concentration dependent as well as saturable and was abolished by heat denaturation of 4.1R. CONCLUSION: The interaction of EBA-181 with the highly conserved 10 kDa domain of 4.1R provides new insight into the molecular mechanisms utilized by P. falciparum during erythrocyte entry. The results highlight the potential multifunctional role of malaria invasion proteins, which may contribute to the success of the pathogenic stage of the parasite's life cycle.

Animals↗
PubMed2002

The influence of the genetic complexity of Plasmodium falciparum infections on the epidemiology of malaria.

Genetic characterization of malaria parasites in human blood stage infections has provided important insights into the genetics of Plasmodium falciparum populations and given rise to a field frequently referred to as 'molecular epidemiology'. This might be defined as the combination of parasite population genetic analysis with clinical and epidemiological analysis of a study population in order to achieve a better understanding of infection and immunity and long-term patterns of disease incidence and severity. Longitudinal studies on infection and clinical disease incidence, combined with improvements in the sensitivity of detection of low level, normally asymptomatic, parasite infections have formed an important part of this effort. Two molecular epidemiological studies of malaria under low and moderate intensity transmission, in Sudan and Ghana respectively, are reviewed here to illustrate how the parasite genotyping approaches based on deoxyribonucleic acid which Douglas Barker pioneered in the study of Leishmania have developed after their application to malaria research.

Animals↗
PubMed2001

Molecules on the surface of the Plasmodium falciparum infected erythrocyte and their role in malaria pathogenesis and immune evasion.

The surface of the erythrocyte undergoes a number of modifications during infection by Plasmodium falciparum. These modifications are critical for pathogenesis of severe disease and the acquisition of host immunity through their role in interactions between the host and the parasite and in antigenic variation. Our knowledge of the molecular basis for these processes has increased dramatically over the last few years, through a combination of genomic and biochemical studies. This review provides a summary of the molecules involved in cytoadherence and antigenic variation in P. falciparum.

Animals↗
PubMed1998

Development and comparison of quantitative assays for the dihydropteroate synthetase codon 540 mutation associated with sulfadoxine resistance in Plasmodium falciparum.

A point mutation in codon 540 of the dihydropteroate synthetase (dhps) gene affecting sulfadoxine resistance has previously been found in parasites from patients with Plasmodium falciparum infection. Here, we investigated 4 methods of identifying this mutation in clinical specimens and established a reliable quantitative assay to estimate the percentage of resistant type in mixed infections. A diagnostic PCR assay based on allele-specific amplification was developed, which clearly typed the clinical specimens examined. The mutation in codon 540 introduces an additional FokI cleavage site which provided a second method to differentiate mutant from wild type, where the former gives rise to 2 characteristic fragments of 538 and 326 bp that are absent from the latter. To calibrate quantitatively the ratio of alleles in mixed samples, we constructed artificial mixes containing 2 plasmid DNAs, one carrying the mutation and the other a wild-type insert. When 32P-labelling was employed, the allele-specific PCR assay could detect the level of resistant type in a mixture down to 0.1-1%, while for the restriction enzyme/PCR analysis, the figure was approximately 10%. Furthermore, neither fluorescent dye-labelled terminator nor dye-labelled primer cycle sequencing was able to detect the mutant allele if it was present at less than 20-30%. We conclude that the allele-specific PCR assay is the most sensitive method of detecting the codon 540 mutation in P. falciparum dhps, and the method of choice for estimating the composition of mixed samples.

Animals↗
PubMed1994

Parasite virulence and disease patterns in Plasmodium falciparum malaria.

Heterogeneity in parasite virulence is one of several factors that have been proposed to contribute to the wide spectrum of disease severity in Plasmodium falciparum malaria. We used observed age-structured patterns of disease to define a population structure of P. falciparum, where the latter contains several independently transmitted antigenic types or "strains" that each induce some degree of strain-specific antidisease immunity upon infection. Patterns of incidence of severe and mild disease may be explained by assuming that a majority of these strains are associated with mild disease and that although severe malarial anemia is a complication occurring in a certain proportion of early infections with "mild" parasites, cerebral malaria is caused by a few distinct highly virulent strains. Considerable variation in parasite virulence, as a major factor of disease severity in malaria, is made possible by the absence of competition between the various parasite strains, arising from weak shared immune responses. The theoretical framework presented in this paper can explain other epidemiological observations, such as the results of interventions with insecticide-impregnated bednets.

Age Factors↗
PubMed1999

Infection rates in, and the number of Plasmodium falciparum genotypes carried by Anopheles mosquitoes in Tanzania.

Naturally fed mosquitoes were collected from houses in a rural village in northern Tanzania. The number of Plasmodium falciparum oocysts which developed in each was counted, and the number of parasite genotypes carried by a subset was determined by PCR-based techniques. A higher proportion of Anopheles gambiae s.l. mosquitoes developed oocysts than of An. funestus but, on average, both species carried similar numbers of parasite genotypes. Overall, 68% of the sampled mosquitoes carried more than one genotype.

Animals↗
PubMedDate not supplied

Evaluation of a rapid dipstick test, Malar-Check, for the diagnosis of Plasmodium falciparum malaria in Brazil.

The present study was carried out to evaluate the Malar-Check trade mark Pf test, an immunochromatographic assay that detects Plasmodium falciparum Histidine Rich Protein II, does not require equipment, and is easy and rapid to perform. In dilution assays performed to test sensitivity against known parasite density, Malar-Check were compared with thick blood smear (TBS), the gold standard for diagnosis. Palo Alto isolate or P. falciparum blood from patients with different parasitemias was used. The average cut-off points for each technique in three independent experiments were 12 and 71 parasites/mm3 (TBS and Malar-Check, respectively). In the field assays, samples were collected from patients with fever who visited endemic regions. Compared to TBS, Malar-Check yielded true-positive results in 38 patients, false-positive results in 3, true-negative results in 23, and false-negative result in 1. Malar-Check performed with samples from falciparum-infected patients after treatment showed persistence of antigen up to 30 days. Malar-Check should aid the diagnosis of P. falciparum in remote areas and improve routine diagnosis even when microscopy is available. Previous P. falciparum infection, which can determine a false-positive test in cured individuals, should be considered. The prompt results obtained with the Malar-Check for early diagnosis could avoid disease evolution to severe cases.

Animals↗
PubMed2002

A new method for culturing Plasmodium falciparum shows replication at the highest erythrocyte densities.

Plasmodium falciparum replicates poorly in erythrocyte densities greater than a hematocrit of 20%. A new method to culture the major malaria parasite was developed by using a hollow fiber bioreactor that preserves healthy erythrocytes at hematocrit up to 100%. P. falciparum replicated equally well at all densities studied. This method proved advantageous for large-scale preparation of parasitized erythrocytes (and potentially immunogens thereof), because high yields ( approximately 10(10) in 4 days) could be prepared with less cost and labor. Concomitantly, secreted proteins were concentrated by molecular sieving during culture, perhaps contributing to the parasitemic limit of 8%-12% with the 3D7 strain. The finding that P. falciparum can replicate at packed erythrocyte densities suggests that this system may be useful for study of the pathogenesis of fatal cerebral malaria, of which one feature is densely packed blood cells in brain microvasculature.

Animals↗
PubMed2001

[In vitro susceptibility of 232 isolates of Plasmodium falciparum to antimalarials in Burkina Faso (West Africa)].

Plasmodium falciparum in vitro susceptibility to chloroquine, quinine, mefloquine and halofantrine was investigated in patients living in Bobo-Dioulasso (Burkina Faso, West Africa). Our study was carried out from July to November 1997 at the Malaria Chemoresistance Reference Centre, Centre MurazIOCCGE. Inclusion criteria were: presence of a single infection by R falciparum with a parasite count > or =4000 infected red cells/mm3. The susceptibility to drugs was measured after an incubation period of 48 hours at 37 degrees C, under 5% CO2. (3H) Hypoxanthine was added to the medium to monitor parasite growth. 134 isolates of P. falciparum were tested against chloroquine; 24.6% (33/134) were resistant. We have also documented 11.2% (15/133) of resistant isolates to halofantrine. All the tested isolates were susceptible to quinine (n=135) and mefloquine (n=136). A significant positive correlation was found between the following IC50 values: chloroquine-quinine, quinine-mefloquine and mefloquine-halofantrine. Our study shows no significant increase of the prevalence of chloroquine-resistant strains of P. falciparum in our study area; as well as the persistence of resistance to halofantrine with regard to previous publications in the subject.

Adolescent↗
PubMed1997

Plasmodium falciparum antigenic diversity: evidence of clonal population structure.

Plasmodium falciparum, the agent of malignant malaria, is one of mankind's most severe scourges. Efforts to develop preventive vaccines or remedial drugs are handicapped by the parasite's rapid evolution of drug resistance and protective antigens. We examine 25 DNA sequences of the gene coding for the highly polymorphic antigenic circumsporozoite protein. We observe total absence of silent nucleotide variation in the two nonrepeated regions of the gene. We propose that this absence reflects a recent origin (within several thousand years) of the world populations of P. falciparum from a single individual; the amino acid polymorphisms observed in these nonrepeat regions would result from strong natural selection. Analysis of these polymorphisms indicates that: (i) the incidence of recombination events does not increase with nucleotide distance; (ii) the strength of linkage disequilibrium between nucleotides is also independent of distance; and (iii) haplotypes in the two nonrepeat regions are correlated with one another, but not with the central repeat region they span. We propose two hypotheses: (i) variation in the highly polymorphic central repeat region arises by mitotic intragenic recombination, and (ii) the population structure of P. falciparum is clonal--a state of affairs that persists in spite of the necessary stage of physiological sexuality that the parasite must sustain in the mosquito vector to complete its life cycle.

Amino Acid Sequence↗
PubMed1985

Structural alteration of the membrane of erythrocytes infected with Plasmodium falciparum.

Human erythrocytes infected with five strains of Plasmodium falciparum and Aotus erythrocytes infected with three strains of P. falciparum were studied by thin-section and freeze-fracture electron microscopy. All strains of P. falciparum we studied induced electron-dense conical knobs, measuring 30-40 nm in height and 90-100 nm in diameter on erythrocyte membranes. Freeze-fracture demonstrated that the knobs were distributed over the membrane of both human and Aotus erythrocytes. A distinct difference was seen between the intramembrane particle (IMP) distribution over the knobs of human and Aotus erythrocyte membranes. There was no change in IMP distribution in infected human erythrocyte membranes, but infected Aotus erythrocytes showed an aggregation of IMP over the P face of the knobs with a clear zone at the base. This difference in IMP distribution was related only to the host species and not to parasite strains. Biochemical analysis demonstrated that a higher proportion of band 3 was bound to the cytoskeleton of uninfected Aotus erythrocytes than uninfected human erythrocytes after Triton X-100 extraction. This may account for the different effects of P. falciparum infection on IMP distribution in the two different cell types.

Animals↗
PubMed2000

Hyperexpression of ICAM-1 and CD36 in placentas infected with Plasmodium falciparum: a possible role of these molecules in sequestration of infected red blood cells in placentas.

AIMS: During pregnancy, Plasmodium falciparum malaria is frequent and associated with maternofetal complications. This could be the consequence of sequestration by several adhesion molecules of parasite-infected red blood cells in syncytiotrophoblast. To investigate the expression of ICAM-1 and CD36, two of the adhesion molecules for Plasmodium falciparum, an immunohistochemical study was carried out in malaria-infected placentas. METHODS AND RESULTS: Thirty-five infected and 35 noninfected samples were chosen randomly. According to the histological classification of Bulmer, the infected placentas were separated in three groups: active, active chronic and past-chronic infection. CD36 was localized in the cytoplasm of stromal cells of terminal villi of infected or noninfected placentas, but not in syncytiotrophoblast. ICAM-1 was detected in the cytoplasm of stromal and endothelial villous cells in both infected and noninfected placentas and in syncytiotrophoblast of eight infected placentas showing more frequently active than active chronic or past-chronic infection (P < 0.001). The percentage of cells immunostained for CD36 or ICAM-1 was evaluated in the terminal villi. The proportion of villous cells, with ICAM-1 and CD36 immunostaining, was significantly higher in infected vs. noninfected placentas (P < 0.0001) and CD36 was detected more in acute inflammatory vs. past-chronic inflammatory placentas (P < 0.05). CONCLUSIONS: The higher expression of ICAM-1 in infected placentas and its localization in syncytiotrophoblast particularly during acute infection, suggest ICAM-1 can act directly in the sequestration of parasite-infected red blood cells (IRBCs). On the other hand, the expression of CD36 is influenced by the presence of IRBCs without being directly implicated in sequestration of IRBCs. The hyperexpression of these two molecules could explain the high frequency of malaria during pregnancy.

Adult↗
PubMed2002

Rapid genotyping of loci involved in antifolate drug resistance in Plasmodium falciparum by primer extension.

Current methods used to genotype point mutations in Plasmodium falciparum genes involved in resistance to antifolate drugs include restriction digestion of PCR products, allele-specific amplification or sequencing. Here we demonstrate that known point mutations in dihydrofolate reductase and dihydropteroate synthase can be scored quickly and accurately by single-nucleotide primer extension and detection of florescent products on a capillary sequencer. We use this method to genotype parasites in natural infections from the Thai-Myanmar border. This approach could greatly simplify large-scale screening of resistance mutations of the type required for evaluating and updating antimalarial drug treatment policies. The method can be easily adapted to other P. falciparum genes and will greatly simplify scoring of point mutations in this and other parasitic organisms.

Animals↗
PubMed2003

Trans stimulation provides evidence for a drug efflux carrier as the mechanism of chloroquine resistance in Plasmodium falciparum.

The mechanism underpinning chloroquine drug resistance in the human malarial parasite Plasmodium falciparum has remained controversial. Currently considered models to explain the resistance phenotype include acquisition of a chloroquine efflux pump, changes in intracellular chloroquine partitioning, diminished binding affinity of chloroquine to its intracellular target, heme, and changes in heme crystallization. To challenge these different models, we have investigated chloroquine accumulation under trans-stimulation conditions and in the presence and absence of glucose. We show that, in chloroquine-sensitive strains, labeled chloroquine accumulation is steadily reduced as the pre-equilibrated chloroquine concentration is raised. In the resistant cells, the extent of accumulation is, strikingly, raised at the lower levels of preloading, in comparison with resistant controls in the absence of chloroquine. The trans-stimulation effect observed in chloroquine-resistant cells is strictly energy-dependent. The data are interpreted in terms of a model in which chloroquine is bound to intracellular binding sites, not different as between sensitive and resistant cells, but where, in resistant cells, there exists an energy-dependent carrier that moves chloroquine out of this intracellular compartment. A mathematical model describing the kinetics of these processes is presented.

Adenosine Triphosphate↗