Social Sciences and Malaria

Risk factors of malaria in the fringes of an evergreen monsoon forest of Arunachal Pradesh.

Mohapatra PK, Narain K, Prakash A, Bhattacharyya DR, Mahanta J.

Regional Medical Research Centre, Northeastern Region, Indian Council of Medical Research, P.O. Box 105, Dibrugarh 786001, Assam, India.

BACKGROUND: The forested hilly and foothill regions of north-east India are highly endemic for malaria and have a distinct epidemiological pattern. Nearly half the reported cases of malaria are from these areas. A knowledge of the risk factors in this eco-geographic entity may be helpful in formulating a specific control strategy. Hence, we conducted a community-based epidemiological study in a hilly, forested terrain of Arunachal Pradesh and examined different socio-demographic factors to identify those predisposing to the occurrence of malaria, especially Plasmodium falciparum infection, in such areas. METHODS: Four epidemiological surveys were carried out during 1997 in 7 villages located at the fringes of a forest (total population: 1177) under Nompong Primary Health Centre of Changlang district, Arunachal Pradesh. Blood slides were collected randomly from the inhabitants, irrespective of their fever status, ensuring at least 50% coverage. One hundred and thirty-four microscopically confirmed Plasmodium falciparum cases were identified and 536 controls were randomly selected from the list of uninfected inhabitants. Relevant socio-demographic information was obtained from both cases and controls. The data were analysed by simple and multiple logistic regression using the unconditional maximum likelihood method. RESULTS: Factors which were found to be strongly associated with Plasmodium falciparum malaria on univariate analysis were age, ethnicity, village of residence and accessibility to the nearest health care facility. However, in multiple regression analysis, after controlling for the effects of confounding variables, the only risk factor identified was accessibility to the nearest health care facility (adjusted odds ratio: 4.5; 95% CI: 1.8-11.3; p < 0.0001 for those at a distance of 2-8 km and adjusted odds ratio: 11.1; 95% CI: 4.1-30.0; p < 0.0001 for those > 8 km away). CONCLUSION: Distance, particularly non-motorable distance, from the place of residence to the nearest health care facility was a major risk factor for malaria in this hilly forested terrain. This indicates the need for special efforts to detect cases early and institute treatment promptly in such areas of the north-eastern region, so as to reduce the morbidity and mortality of malaria.

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J Vector Ecol 2001 Jun;26(1):70-5Composition and biting activity of Anopheles (Diptera: Culicidae) attracted to human bait in a malaria endemic village in peninsular Malaysia near the Thailand border.

Hassan AA, Rahman WA, Rashid MZ, Shahrem MR, Adanan CR.

School of Biological Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.

Nine species of Anopheles mosquitoes were collected biting humans indoors and outdoors in a malaria endemic village in northern Peninsular Malaysia. Outdoor biting was higher than that observed indoors. Biting of An. maculatus was observed throughout the night. Peak indoor biting occurred at 2130 h while outdoor biting was higher after midnight. Outdoor biting of Anopheles barbirostris and An. sinensis was observed throughout the night with several peaks after the second half of the night. Outdoor biting activities of An. kochi and An. philippinensis were primarily active after dusk and steadily declined after 2130 h.

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Am J Trop Med Hyg 2001 Mar-Apr;64(3-4):178-86Cost-effectiveness of sulfadoxine-pyrimethamine for the prevention of malaria-associated low birth weight.

Wolfe EB, Parise ME, Haddix AC, Nahlen BL, Ayisi JG, Misore A, Steketee RW.

Department of International Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.

Prevention of placental malaria through administration of antimalarial medications to pregnant women in disease-endemic areas decreases the risk of delivery of low birth weight (LBW) infants. In areas of high Plasmodium falciparum transmission, two intermittent presumptive treatment doses of sulfadoxine-pyrimethamine (SP) during the second and third trimesters of pregnancy are effective in decreasing the prevalence of placental malaria in human immunodeficiency virus (HlV)-negative women, while HIV-positive women may require a monthly SP regimen to reduce their prevalence of placental parasitemia. A decision-analysis model was used to compare the cost-effectiveness of three different presumptive SP treatment regimens with febrile case management with SP in terms of incremental cost per case LBW prevented. Factors considered included HIV seroprevalence, placental malaria prevalence, LBW incidence, the cost of SP, medical care for LBW infants, and HIV testing. For a hypothetical cohort of 10,000 pregnant women, the monthly SP regimen would always be the most effective strategy for reducing LBW associated with malaria. The two-dose SP and monthly SP regimens would prevent 172 and 229 cases of LBW, respectively, compared with the case management approach. At HIV seroprevalence rates greater than 10%, the monthly SP regimen is the least expensive strategy. At HIV seroprevalence rates less than 10%, the two-dose SP regimen would be the less expensive option. When only antenatal clinic costs are considered, the two-dose and monthly SP strategies cost US $11 and $14, respectively, well within the range considered cost effective. Presumptive treatment regimens to prevent LBW associated with malaria and the subsequent increased risk of mortality during the first year of life are effective and cost effective strategies in areas with both elevated HIV prevalence and malaria transmission rates.

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PubMedJ Clin Microbiol 2001 Aug;39(8):2911-5
Molecular Cloning and Sequencing of the Circumsporozoite Protein Gene from Plasmodium falciparum Strain FCC-1/HN and Expression of the Gene in Mycobacteria.

Zheng C, Xie P, Chen Y.

Institute of Infectious and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China.

Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been used as a live bacterial vaccine to immunize more than 2 billion people against tuberculosis. In an attempt to use this vaccine strain as a vehicle for protective antigens, the Plasmodium falciparum gene from strain FCC-1/HN encoding circumsporozoite protein (CSP) was amplified from the P. falciparum genome, sequenced, and expressed in M. bovis BCG under the control of an expression cassette carrying the promoter of heat shock protein 70 (HSP70) from Mycobacterium tuberculosis. The recombinant shuttle plasmid pBCG/CSP was introduced into mycobacteria by electroporation, and the recombinant mycobacteria harboring pBCG/CSP could be induced by heating to express CSP; the molecular mass of recombinant CSP was about 42 kDa. This report of expression of the almost-full-length P. falciparum CSP gene in BCG provides scientific evidence for the application of the HSP70 promoter in expressing a foreign gene in BCG and in development of BCG as a multivalent vectoral vaccine for malaria.

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J Clin Microbiol 2001 Aug;39(8):2884-90Malaria rapid diagnostic devices: performance characteristics of the parasight f device determined in a multisite field study.

Forney JR, Magill AJ, Wongsrichanalai C, Sirichaisinthop J, Bautista CT, Heppner DG, Miller RS, Ockenhouse CF, Gubanov A, Shafer R, DeWitt CC, Quino-Ascurra HA, Kester KE, Kain KC, Walsh DS, Ballou WR, Gasser RA Jr.

Walter Reed Army Institute of Research, Washington.

Microscopic detection of parasites has been the reference standard for malaria diagnosis for decades. However, difficulty in maintaining required technical skills and infrastructure has spurred the development of several nonmicroscopic malaria rapid diagnostic devices based on the detection of malaria parasite antigen in whole blood. The ParaSight F test is one such device. It detects the presence of Plasmodium falciparum-specific histidine-rich protein 2 by using an antigen-capture immunochromatographic strip format. The present study was conducted at outpatient malaria clinics in Iquitos, Peru, and Maesod, Thailand. Duplicate, blinded, expert microscopy was employed as the reference standard for evaluating device performance. Of 2,988 eligible patients, microscopy showed that 547 (18%) had P. falciparum, 658 (22%) had P. vivax, 2 (0.07%) had P. malariae, and 1,750 (59%) were negative for Plasmodium. Mixed infections (P. falciparum and P. vivax) were identified in 31 patients (1%). The overall sensitivity of ParaSight F for P. falciparum was 95%. When stratified by magnitude of parasitemia (no. of asexual parasites per microliter of whole blood), sensitivities were 83% (>0 to 500 parasites/&mgr;l), 87% (501 to 1,000/&mgr;l), 98% (1,001 to 5,000/&mgr;l), and 98% (>5,000/&mgr;l). Device specificity was 86%.

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 Trop Med Int Health 2001 Jul;6(7):505-10A clinical algorithm for the diagnosis of malaria: results of an evaluation in an area of low endemicity.

Chandramohan D, Carneiro I, Kavishwar A, Brugha R, Desai V, Greenwood B.

London School of Hygiene and Tropical Medicine, London, UK; Department of Preventive and Social Medicine, Government Medical College, Surat, India.

We conducted a study of 1945 children and 2885 adults who presented with fever to a hospital outpatients clinic in an urban area of India order to develop and evaluate a clinical algorithm for the diagnosis of malaria. Only 139 (7%) children and 349 (12%) adults had microscopically confirmed malaria. None of the symptoms or signs elicited from the respondents were good predictors of clinical malaria. Simple scores were derived through combining clinical features which were associated with slide positivity or were judged by clinicians to be important. The best-performing algorithms were a score of 4 clinical features in children (sensitivity 60.0% and specificity 61.2%) and a score of 5 in adults (sensitivity 54.6% and specificity 57.5%). The clinical features differed and algorithm performances were poorer than in previous studies in highly endemic areas. The conclusion is that malaria diagnosis in areas of low endemicity requires microscopy to be accurate.

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Trop Med Int Health 2001 Jul;6(7):496-504Improving adherence to malaria treatment for children: the use of pre-packed chloroquine tablets vs. chloroquine syrup.

Ansah EK, Gyapong JO, Agyepong IA, Evans DB.

Dangme West District, Ministry of Health, Dodowa, Ghana; Health Research Unit, Ministry of Health, Accra, Ghana; Global Programme on Evidence for Health Policy (GPE), World Health Organization, Geneva, Switzerland.

Malaria is a major cause of morbidity and mortality among children under five in sub-Saharan Africa. Prompt diagnosis and adequate treatment of acute clinical episodes are essential to reduce morbidity and prevent complications and mortality. In many countries, chloroquine syrup is the mainstay of malaria treatment for children under five. Not only is syrup more expensive than tablets, adherence to the prescribed dose at home is a problem because mothers use wrongly sized measuring devices or have difficulty with the instructions. We investigated the impact of introducing pre-packed tablets for children on adherence to treatment and compared the total cost of the tablets with that of syrup. Children aged 0-5 years diagnosed with malaria at the clinic over a 6-week period received either pre-packed tablets or syrup by random assignment. The principal caregivers were interviewed at home on day 4 after attending the clinic. Of the 155 caregivers given pre-packed tablets, 91% (n=141) adhered to the recommended dosage, while only 42% (n=61) of 144 who were provided syrup did. Only 20% of caregivers who received syrup used an accurate 5 ml measure. The cost of treatment with tablets was about one-quarter that of syrup and 62% (n=96) of caregivers preferred tablets. Pre-packed chloroquine tablets are a viable alternative to syrup.

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Exp Parasitol 2001 Jun;98(2):71-82Plasmodium chabaudi chabaudi: B-1 Cell Expansion Correlates with Semiresistance in BALB/cJ Mice.

Yoder BJ, Goodrum KJ.

Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Irvine Hall, Athens, Ohio, 45701, U.S.A.

Yoder, B. J., and Goodrum, K. J. 2001. Plasmodium chabaudi chabaudi: B-1 cell expansion correlates with semiresistance in BALB/cJ mice. Experimental Parasitology 98, 71-82. The largest obstacle impeding the development of an effective malaria vaccine is the incomplete understanding of how the immune response is regulated during infection. B-1a cells, a poorly understood subcategory of B lymphocytes, produce nonpathologic autoantibodies of low affinity which have been shown to have distinct immunoregulatory capabilities. What the exact activity of B-1a cells are during the course of malaria has yet to be determined. By use of flow cytometry, it was observed that B-1a cells significantly expand by day 3 postinfection in the spleen and peritoneum of Plasmodium chabaudi chabaudi semiresistant BALB/cJ mice, but not until day 8 postinfection in the spleen of P. chabaudi chabaudi fully susceptible BALB/cByJ mice. The activation of B-1a cells was also demonstrated by the measurement of natural autoantibody IgM production from the serum and cultured peritoneal B-1a cells. Infected semiresistant BALB/cJ mice generated higher levels of anti-ssDNA IgM antibodies than infected fully susceptible BALB/cByJ mice. The preliminary data presented here suggest a possible roll of B-1 cells in contributing to the successful survival of murine malarial infection. Copyright 2001 Academic Press.

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Exp Parasitol 2001 Jun;98(2):59-70Plasmodium falciparum: Gene Mutations and Amplification of Dihydrofolate Reductase Genes in Parasites Grown in Vitro in Presence of Pyrimethamine.

Thaithong S, Ranford-Cartwright LC, Siripoon N, Harnyuttanakorn P, Kanchanakhan NS, Seugorn A, Rungsihirunrat K, Cravo PV, Beale GH.

Department of Biology

Thaithong, S., Ranford-Cartwright, L. C., Siripoon, N., Harnyuttanakorn, P., Kanchanakhan, N. S., Seugorn, A., Rungsihirunrat, K., Cravo, P. V. L., and Beale, G. H. 2001. Plasmodium falciparum: Gene mutations and amplification of dihydrofolate reductase genes in parasites grown in vitro in presence of pyrimethamine. Experimental Parasitology 98, 59-70. Samples of three pyrimethamine-sensitive clones of Plasmodium falciparum were grown for periods of 22-46 weeks in media containing stepwise increases in pyrimethamine concentrations and were seen to develop up to 1000-fold increases in resistance to the drug. With clone T9/94RC17, the dihydrofolate reductase (DHFR) gene was sequenced from 10 uncloned populations and 29 pure clones, all having increased resistance to pyrimethamine, and these sequences were compared with the sequence of the original pyrimethamine-sensitive clone. No changes in amino acid sequence were found to have occurred. Some resistant clones obtained by this method were then examined by pulsed-field gel electrophoresis, and the results indicated that there had been an increase in the size of chromosome 4. This was confirmed by hybridization of Southern blots with a chromosome 4-specific probe, the vacuolar ATPase subunit B gene, and a probe to DHFR. Dot-blotting with an oligonucleotide probe to DHFR confirmed that there had been increases up to 44-fold in copy number of the DHFR gene in the resistant strains. Resistant clones obtained by this procedure were then grown in medium lacking pyrimethamine for a period of nearly 2 years, and reversion nearly to the level of pyrimethamine sensitivity of the original clone T9/94RC17 was found to occur after about 16 months. Correspondingly, the chromosome 4 of the reverted population reverted to a size like that of the original sensitive clone T9/94RC17. The procedure of growing parasites in stepwise increases of pyrimethamine concentration was repeated with two other pyrimethamine-sensitive clones: TM4CB8-2.2.3 and G112CB1.1. (The DHFR gene of these clones encodes serine at position 108, in place of threonine as in clone T9/94RC17, and it was thought that this difference might conceivably affect the rate of mutation to asparagine at this position). Clones TM4CB8-2.2.3 and G112CB1.1 also responded by developing gradually increased resistance to pyrimethamine. However, in clone TM4CB8-2.2.3 a single mutation from Ile to Met at position 164 in the DHFR gene sequence was identified, and in clone G112CB1.1 there was a single mutation from Ala to Ser at position 16, but no mutations at position 108 were obtained in any of the clones studied here. In addition, chromosome 4 of clone TM4CB8-2.2.3 increased in size, presumably due to amplification of the DHFR gene. No increase in size was seen in clone G112CB1.1. We conclude that whereas some mutations producing changes in the amino acid sequence of the DHFR molecule may occur occasionally in clones or populations of P. falciparum grown in vitro in the presence of pyrimethamine, amplification of the DHFR gene following adaptation to growth in medium containing pyrimethamine occurs as a regular feature. The bearing of these findings on the development of pyrimethamine-resistant forms of malaria parasites in endemic areas is discussed. Copyright 2001 Academic Press.

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Science 2001 Jul 20;293(5529):482-4Comment in: Science. 2001 Jul 20;293(5529):416-7

Recent origin of Plasmodium falciparum from a single progenitor.

Volkman SK, Barry AE, Lyons EJ, Nielsen KM, Thomas SM, Choi M, Thakore SS, Day KP, Wirth DF, Hartl DL.

The Harvard-Oxford Malaria Genome Diversity Project, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Genetic variability of Plasmodium falciparum underlies its transmission success and thwarts efforts to control disease caused by this parasite. Genetic variation in antigenic, drug resistance, and pathogenesis determinants is abundant, consistent with an ancient origin of P. falciparum, whereas DNA variation at silent (synonymous) sites in coding sequences appears virtually absent, consistent with a recent origin of the parasite. To resolve this paradox, we analyzed introns and demonstrated that these are deficient in single-nucleotide polymorphisms, as are synonymous sites in coding regions. These data establish the recent origin of P. falciparum and further provide an explanation for the abundant diversity observed in antigen and other selected genes.

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Mol Biochem Parasitol 2001 Aug;116(1):73-9Molecular characterization of a 2-Cys peroxiredoxin from the human malaria parasite Plasmodium falciparum.

Kawazu S, Komaki K, Tsuji N, Kawai S, Ikenoue N, Hatabu T, Ishikawa H, Matsumoto Y, Himeno K, Kano S.

Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, 162-8655, Tokyo, Japan

We have identified the 2-Cys peroxiredoxin (PfPrx-1) from the human malaria parasite Plasmodium falciparum. The PfPrx-1 showed the highest identity at amino acid level to the type II Prx among the currently known six subfamilies of mammalian Prx. The sequence identity between the PfPrx-1 and the previously reported 1-Cys Prx of P. falciparum (PfPrx-2), which corresponded to mammalian type VI Prx, was 25%. This suggests that the parasite possesses two Prx subfamilies. The PfPrx-1 showed significant sequence similarities with those of 2-Cys peroxiredoxins of plants in the BLASTX search. This may reflect the consequences of a genetic transfer from an algal endosymbiont to the parasite nucleus during evolution. The recombinant PfPrx-1 protein (rPfPrx-1) was expressed as a histidine fusion protein in Escherichia coli and purified with Ni chromatography. The rPfPrx-1 existed as dimers under non-reducing conditions and dissociated into monomers in the presence of dithiothreitol. The PfPrx-1 protein also exists as a dimer in the parasites themselves. The reduction of the oxidized enzyme by the donation of electrons from E. coli thioredoxin (Trx)/Trx reductase system was demonstrated in its reaction with H(2)O(2), using the rPfPrx-1 protein. These results suggested that the PfPrx-1 can act as a terminal peroxidase of the parasite Trx system. An elevated expression of the PfPrx-1 protein seen in the trophozoite, the stage with active metabolism, suggests an association of the parasite Trx system with its intracellular redox control.

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Mol Biochem Parasitol 2001 Aug;116(1):65-72von Willebrand Factor A Domain-related Protein, a novel microneme protein of the malaria ookinete highly conserved throughout Plasmodium parasites.

Yuda M, Yano K, Tsuboi T, Torii M, Chinzei Y.

Department of Medical Zoology, Mie University School of Medicine, Tsu, 514-0001, Edobashi, Japan

The mosquito-invasive form of the malarial parasite, the ookinete, develops numerous secretory organelles, called micronemes, in the apical cytoplasm. Micronemal proteins are thought to be secreted during midgut invasion and to play a crucial role in attachment and motility of the ookinete. We found a novel ookinete micronemal protein of rodent malarial parasite Plasmodium berghei, named P. berghei von Willebrand factor A domain-related protein (PbWARP), and report it here as a putative soluble adhesive protein of the ookinete. The PbWARP gene contained a single open reading frame encoding a putative secretory protein of 303 amino acids, with a von Willebrand factor type A module-like domain as a main component. Western blot analysis demonstrated that PbWARP was firstly produced 12 h after fertilization by maturing ookinetes as SDS-resistant complexes. Recombinant PbWARP produced with a baculovirus system also formed SDS-resistant high-order oligomers. Immuno-electron microscopic studies showed that PbWARP was randomly distributed in the micronemes. PbWARP homologues also exist in human malarial parasites, Plasmodium falciparum and Plasmodium vivax. Highly conserved primary structures of PbWARP homologues among these phylogenetically distant Plasmodium species suggest their functional significance and the presence of a common invasion mechanism widely utilized throughout Plasmodium parasites.

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Lancet 2001 Jul 14;358(9276):110-4Association between maternal serum concentration of the DDT metabolite DDE and preterm and small-for-gestational-age babies at birth.

Longnecker MP, Klebanoff MA, Zhou H, Brock JW.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, PO Box 12233 MD A3-05, NC 27709, USA. [email protected]
BACKGROUND: DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) is highly effective against most malaria-transmitting mosquitoes and is being widely used in malaria-endemic areas. The metabolite, DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), has been linked to preterm birth in small studies, but these findings are inconclusive. Our aim was to investigate the association between DDE exposure and preterm birth. METHODS: Our study was based on the US Collaborative Perinatal Project (CPP). From this study we selected a subset of more than 44000 eligible children born between 1959 and 1966 and measured the DDE concentration in their mothers’ serum samples stored during pregnancy. Complete data were available for 2380 children, of whom 361 were born preterm and 221 were small-for-gestational age. FINDINGS: The median maternal DDE concentration was 25 mg/L (range 3-178)-several fold higher than current US concentrations. The adjusted odds ratios (OR) of preterm birth increased steadily with increasing concentrations of serum DDE (ORs=1, 1.5, 1.6, 2.5, 3.1; trend p<0.0001). Adjusted odds of small-for-gestational-age also increased, but less consistently (ORs=1, 1.9, 1.7, 1.6, 2.6; trend p=0.04). After excluding preterm births, the association of DDE with small-for-gestational-age remained. INTERPRETATION: The findings strongly suggest that DDT use increases preterm births, which is a major contributor to infant mortality. If this association is causal, it should be included in any assessment of the costs and benefits of vector control with DDT.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):303-9Increased multiplicity of Plasmodium falciparum infections and skewed distribution of individual msp1 and msp2 alleles during pregnancy in Ndiop, a Senegalese village with seasonal, mesoendemic malaria.

Schleiermacher D, Rogier C, Spiegel A, Tall A, Trape JF, Mercereau-Puijalon O.

Unite Immunologie Moleculaire des Parasites, Centre National de la Recherche Scientifique Unite de Recherche Associee 1960, Institut Pasteur, Paris, France.

Pregnancy is associated with a greater susceptibility to Plasmodium falciparum infections, which may result in serious complications affecting both the mother and the fetus. To compare allelic diversity and multiplicity of infection in the same women during and outside pregnancy, we conducted a retrospective analysis of the monthly fingerprick blood samples collected during a longitudinal survey conducted in Ndiop, a Senegalese village with mesoendemic malaria. Merozoite surface protein-1 (msp1) block 2 and merozoite surface protein-2 (msp2) genotypes were determined for 308 blood samples collected from 20 women. Pregnancy was associated with a significantly higher prevalence of P. falciparum infection, higher parasite densities, and a higher multiplicity of infection. The highest multiplicity of infection was observed in the youngest pregnant women. Because of co-linearity, it was not possible to dissociate the impact of age from that of parity on multiplicity of infection. Some individual msp1 and msp2 alleles showed a highly skewed pregnancy-associated distribution. These results indicate that pregnancy is associated with increased permissiveness to a large number of clones, as well as with infection by specific genotypes.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):290-2Automated detection of malaria pigment in white blood cells for the diagnosis of malaria in Portugal.

Hanscheid T, Melo-Cristino J, Pinto BG.

Department of Clinical Pathology, Hospital Santa Maria, Lisbon, Portugal. [email protected]
A novel automated method (Cell-Dyn 3500) allows malaria diagnosis by detecting malaria pigment in white blood cells during routine full blood counts. In Portugal, 174 samples from 148 patients who presented to the emergency department were analyzed. Compared with microscopy the sensitivity was 95% and the specificity was 88%. In 5 cases, false-positive Cell-Dyn 3500 results were from patients who had a recent history of treated malaria, indicating that the method may remain positive during convalescence. Six patients were diagnosed due to the changes observed with the automated method only, because clinicians had not requested malaria smears. This instrument appears to provide a promising method for the diagnosis of malaria, especially where automated full blood counts are routine in the work-up of febrile patients.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):262-7Prospective risk of morbidity in relation to malaria infection in an area of high endemicity of multiple species of Plasmodium.

Smith T, Genton B, Baea K, Gibson N, Narara A, Alpers MP.

Swiss Tropical Institute, Basel.

In an area of Papua New Guinea with high prevalence of Plasmodium falciparum (39.6%), Plasmodium vivax (18.3%), and Plasmodium malariae (13.8%), cross-sectional analysis found P. falciparum infection to be independent of the other species despite heterogeneities in transmission. Plasmodium vivax and P. malariae infections were negatively correlated. Plasmodium malariae infection was positively associated with homologous infection four months previously and with prior P. falciparum, but not P. vivax infection. There were no other indications that any Plasmodium species protected against heterologous infection. Prospective analysis of health-center morbidity supported the idea that P. malariae infection protects against disease, but indicated greater protection against non-malaria than P. falciparum-associated fevers. Plasmodium vivax appeared to protect against P. falciparum disease but not against other forms of morbidity. Covariate adjustment had considerable effects on estimated relationships between species, and confounding variables may account for many differences among reports of inter-species interactions in human malaria.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):257-61A field study on malaria prevalence in southeastern Laos by polymerase chain reaction assay.

Toma H, Kobayashi J, Vannachone B, Arakawa T, Sato Y, Nambanya S, Manivong K, Inthakone S.

Department of Parasitology, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.

A detection survey for malaria infection by routine microscopy and polymerase chain reaction (PCR) assay was conducted on 336 inhabitants of two villages in Khammouane Province, Lao People’s Democratic Republic (Lao PDR), in July 1997. Malaria infection was demonstrated in 58 (17.3%) subjects by microscopy and in 117 (34.8%) by PCR assay. Specimens positive by both methods were frequent in young villagers, suggesting the presence of many subclinical infections in older persons. The most common species of malaria parasite was Plasmodium falciparum (82.9%). Polymerase chain reaction assay detected mixed infections with 2-4 species in 27 specimens (23.1%). The results demonstrate that there are many subclinical malaria infections with low parasite level and infection with all four human malaria species in Lao PDR.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):247-56A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand.

Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann I, Mull R, Bakshi R.

Novartis Pharma, International Clinical Development, Basel, Switzerland.

The efficacy-safety and pharmacokinetics of the six-dose regimen of artemether-lumefantrine (Coartem/Riamet; Novartis Pharma AG, Basel, Switzerland) were assessed in a randomized trial in 219 patients (> or = 12 years old) with acute, uncomplicated Plasmodium falciparum malaria in Thailand. One hundred and sixty-four patients received artemether-lumefantrine and 55 received the standard treatment combination of mefloquine-artesunate. Both drugs induced rapid clearance of parasites and malaria symptoms. The 28-day cure rates were 95.5% (90% confidence interval [CI] = 91.7, 97.9%) for artemether-lumefantrine and 100% (90% CI = 94.5, 100%) for mefloquine-artesunate. This high-dose regimen of artemether-lumefantrine was very well tolerated, with very good compliance. The most frequent adverse events were headache, dizziness, nausea, abdominal pain, dyspepsia, vomiting, and skin rash. Overall, only 2% of patients in both groups showed QTc prolongations but without any cardiac complication, and no differences were seen between patients with and without measurable baseline plasma levels of quinine or mefloquine. Plasma levels of artemether, dihydroartemisinin, and lumefantrine were consistent with historical data for the same dose regimen, and were higher, particularly for lumefantrine, than those previously observed with the four-dose regimen, explaining the greater efficacy of the six-dose regimen in a drug-resistant setting. These results confirm the excellent safety and efficacy of the six-dose regimen of artemether-lumefantrine in the treatment of multidrug-resistant P. falciparum malaria.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):242-6Chloroquine treatment of uncomplicated Plasmodium falciparum malaria in Mali: parasitologic resistance versus therapeutic efficacy.

Plowe CV, Doumbo OK, Djimde A, Kayentao K, Diourte Y, Doumbo SN, Coulibaly D, Thera M, Wellems TE, Diallo DA.

Center for Vaccine Development, Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA. 
[email protected]
Whether and when to replace chloroquine with other antimalarial drugs is an urgent public health question in much of Africa, where Plasmodium falciparum, which is increasingly resistant to chloroquine, continues to kill millions each year. Antimalarial drug efficacy has traditionally been measured as parasitologic resistance, but recent guidelines use both clinical and parasitologic criteria to monitor therapeutic efficacy. To assess the new efficacy protocol, we measured parasitologic and therapeutic outcomes in 514 patients treated with chloroquine for uncomplicated P. falciparum malaria in Mali. There was a general agreement between parasitologic and therapeutic outcomes at two sites, with 13-17% parasitologic resistance rates and 10-15% treatment failure rates. However, the new protocol overestimated early treatment failure rates (21-71% of cases classified as early treatment failure had sensitive or RI parasitologic responses), particularly where resistance was rare, and missed low-level parasitologic resistance. Modifications of the protocol for monitoring antimalarial therapeutic efficacy are recommended.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):229-32Clinical trial of beta-arteether versus quinine for the treatment of cerebral malaria in children in Yaounde, Cameroon.

Moyou-Somo R, Tietche F, Ondoa M, Kouemeni LE, Ekoe T, Mbonda E, Nsangou C, Jemea B, Guemkam G.

Institute of Medical Research and Study of Medicinal Plants/Medical Research Center, Yaounde, Cameroon, West Africa. [email protected]
One hundred and two children aged 0-10 years with cerebral malaria (Blantyre coma score of 2 or less) were randomly treated either with intramuscular arteether (3.2 mg/kg on Day 0, followed by 1.6 mg/kg on Days 1 to 4) or intravenous (i.v.) quinine dihydrochloride (20 mg of the salt/kg, followed by 10 mg of the salt/kg every 8 hr up to Day 6). Treatment with oral quinine sulfate (10 mg/kg every 8 hr) was substituted for i.v. quinine when the patient was able to take oral medicine. All patients were followed up in the hospital for 7 days; thereafter, they were treated as outpatients on Days 14, 21, and 28. Mortality rate, the main efficacy parameter, was 11.8% lower in the arteether treatment group than in the quinine group (15.7% versus 27.4%); however, the difference was not significant (P = 0.25). Means for fever clearance time, coma resolution time, and parasite clearance time were similar in the 2 treatment groups (42.2 +/- 34.9 hr; 34.8 +/- 18.8 hr, and 46.3 +/- 28.5 hr, respectively for arteether, versus 45.0 +/- 26.7 hr; 30.3 +/- 18.9 hr, and 40.7 +/- 18.9 hr, respectively, for quinine). At 28 days, the cure rates were 73.2% and 64.9% for the arteether and quinine treatment groups, respectively. Arteether is safe and therapeutically at least as effective as quinine for the treatment of cerebral malaria in children in Cameroon. Because of its ease of administration, arteether appears to be suited for use in the rural zones where monitoring facilities do not exist.

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Am J Trop Med Hyg 2001 May-Jun;64(5-6):223-8Chloroquine/doxycycline combination versus chloroquine alone, and doxycycline alone for the treatment of Plasmodium falciparum and Plasmodium vivax malaria in northeastern Irian Jaya, Indonesia.

Taylor WR, Widjaja H, Richie TL, Basri H, Ohrt C, Tjitra, Taufik E, Jones TR, Kain KC, Hoffman SL.

United States Naval Medical Research Unit Number 2, Jakarta, Indonesia.

Combination therapy is one method of overcoming the global challenge of drug-resistant Plasmodium falciparum malaria. We conducted a hospital-based 28-day in vivo test comparing chloroquine/doxycycline to chloroquine or doxycycline alone for treating P. falciparum and Plasmodium vivax malaria in Irian Jaya, Indonesia. Eighty-nine patients with uncomplicated falciparum malaria were randomized to standard dose chloroquine (n = 30), doxycycline (100 mg every 12 hours [7 days], n = 20), or chloroquine with doxycycline (n = 39); corresponding numbers for vivax malaria (n = 63) were 23, 16, 24. Endpoints were parasite sensitivity (S) or resistance (RI/RII/RIII). Of the 105 evaluable patients, chloroquine/doxycycline cured (S) 20/22 (90.9% [95% CI 78.9-100%]) patients with P. falciparum malaria; 2/22 (9.1% [0-21%]) were RIII resistant. Doxycycline cured 11/17 (64.7% [42.0-87.4%]) patients, and chloroquine 4/20 (20% [2.5-37.5%]). Against P. vivax, chloroquine/doxycycline cured (S) 12/17 (70.6% [48.9-92.2%]) patients, doxycycline 4/12 (33.3% [6.6-59.9%]), and chloroquine 5/17 (29.4% [7.7-51.1%]). Chloroquine/doxycycline was effective against P. falciparum but only modestly effective against P. vivax. These findings support the use of chloroquine/doxycycline as an inexpensive alternative to mefloquine for treating chloroquine-resistant P. falciparum but not chloroquine-resistant P. vivax in this setting.

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J Med Assoc Thai 2001 Mar;84(3):357-63Comparison of the OptiMAL rapid test with routine microscopic examination of Giemsa-Stained Thick Blood Film for diagnosis of malaria.

Congpuong K, Bualombai P, Jitchamroen S, Konchom S.

Department of Communicable Disease Control, Ministry of Public Health, Nonthaburi, Thailand.

The OptiMAL is a rapid immunodiagnostic test developed by Flow Inc., Portland, Oreg. for diagnosis and differentiation of P. falciparum and non P. falciparum malaria infection. It has been based on detection of circulating parasite lactate dehydrogenase enzyme (pLDH), produced by live Plasmodium parasites. The purpose of this study was to compare the efficacy of the OptiMAL test with routine microscopic examination of Giemsa-Stained Thick Blood Film (routine GS-TBF) for the diagnosis of malaria at a local malaria clinic in a hyperendemic area of Thailand by using a standard GS-TBF (standard GS-TBF) as reference. One hundred and seventy five patients attending the clinic were recruited; 50, 42 and 83 were falciparum malaria, vivax malaria and non-malaria patients, respectively. Compared with the reference, the OptiMAL test had sensitivities of 92 per cent and 97.6 per cent, whereas, the routine GS-TBF had sensitivities of 81.3 per cent and 81 per cent for the detection of P. falciparum and P. vivax, respectively. Both tests showed no false positive resulting in 100 per cent specificities. However, the OptiMAL test was able to detect only 20 per cent of infection with less than 200 parasitaemia/microlitre. It was also shown in our study that the OptiMAL test was advantageous in follow-up of the treatment outcome. No false positive occurred among 40 follow-up cases. The OptiMAL test detected malaria infection more accurately than the routine GS-TBF (p < 0.05) and was simple, easy to perform and rapid. It is an alternative tool for the diagnosis of malaria in a hyperendemic area where experienced microscopists are not available.

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J Exp Med 2001 Jul 16;194(2):173-80Swift development of protective effector functions in naive cd8(+) t cells against malaria liver stages.

Sano Gi, Hafalla JC, Morrot A, Abe R, Lafaille JJ, Zavala F.

Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10010.

We generated T cell receptor transgenic mice specific for the liver stages of the rodent malaria parasite Plasmodium yoelii and studied the early events in the development of in vivo effector functions in antigen-specific CD8(+) T cells. Differently to activated/memory cells, naive CD8(+) T cells are not capable of exerting antiparasitic activity unless previously primed by parasite immunization. While naive cells need to differentiate before achieving effector status, the time required for this process is very short. Indeed, interferon (IFN)-gamma and perforin mRNA are detectable 24 h after immunization and IFN-gamma secretion and cytotoxic activity are detected ex vivo 24 and 48 h after immunization, respectively. In contrast, the proliferation of CD8(+) T cells begins after 24 h and an increase in the total number of antigen-specific cells is detected only after 48 h. Remarkably, a strong CD8(+) T cell-mediated inhibition of parasite development is observed in mice challenged with viable parasites only 24 h after immunization with attenuated parasites. These results indicate that differentiation of naive CD8(+) T cells does not begin only after extensive cell division, rather this process precedes or occurs simultaneously with proliferation.

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Vaccine 2001 Jul 20;19(30):4153-61Potentiation by a novel alkaloid glycoside adjuvant of a protective cytotoxic T cell immune response specific for a preerythrocytic malaria vaccine candidate antigen.

Heal KG, Sheikh NA, Hollingdale MR, Morrow WJ, Taylor-Robinson AW.

School of Biology, University of Leeds, Clarendon Way, LS2 9JT, Leeds, UK

We have recently demonstrated that the novel glycoalkaloid tomatine, derived from leaves of the wild tomato Lycopersicon pimpinellifolium, can act as a powerful adjuvant for the elicitation of antigen-specific CD8(+) T cell responses. Here, we have extended our previous investigation with the model antigen ovalbumin to an established malaria infection system in mice and evaluated the cellular immune response to a major preerythrocytic stage malaria vaccine candidate antigen when administered with tomatine. The defined MHC H-2k(d) class I-binding 9-mer peptide (amino acids 252-260) from Plasmodium berghei circumsporozoite (CS) protein was prepared with tomatine to form a molecular aggregate formulation and this used to immunise BALB/c (H-2k(d)) mice. Antigen-specific IFN-gamma secretion and cytotoxic T lymphocyte activity in vitro were both significantly enhanced compared to responses detected from similarly stimulated splenocytes from naive and tomatine-saline-immunised control mice. Moreover, when challenged with P. berghei sporozoites, mice immunised with the CS 9-mer-tomatine preparation had a significantly delayed onset of erythrocytic infection compared to controls. The data presented validate the use of tomatine to potentiate a cellular immune response to antigenic stimulus by testing in an important biologically relevant system. Specifically, the processing of the P. berghei CS 9-mer as an exogenous antigen and its presentation via MHC class I molecules to CD8(+) T cells led to an immune response that is an in vitro correlate of protection against preerythrocytic malaria. This was confirmed by the protective capacity of the 9-mer-tomatine combination upon in vivo immunisation. These findings merit further work to optimise the use of tomatine as an adjuvant in malaria vaccine development.

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Ann Trop Med Parasitol 2001 Jun;95(4):325-30The rise and fall of malarial sporozoite rates in Anopheles gambiae s.l. and An. funestus in north-eastern Tanzania, between 1934 and 1999.

Mboera LE, Magesa SM.

National Institute for Medical Research, Ubwari Field Station, P.O. Box 81, Muheza, Tanzania. 

[email protected]

The proportion of Anopheles mosquitoes found to be carrying Plasmodium sporozoites, usually called the ‘malarial sporozoite rate’, has often been used as a measure of mosquito infectivity. Although the sporozoite rates found in Anopheles gambiae and An. funestus in Muheza, north-eastern Tanzania, showed a marked decline between the mid-1930s and the mid-1970s, they then began to rise again. This fall and rise in mosquito infectivity is attributed to the widespread use of antimalarial drugs, which initially tended to reduce the infectivity of patients for mosquitoes, and the subsequent development of resistance to these drugs in the malarial parasites. The rise observed in the sporozoite rates in Muheza in the 1980s-1990s may be attributed to widespread resistance of P. falciparum to chloroquine, until recently the drug of choice for the treatment of malaria in Tanzania. Changes in the survival rates, abundance, or predominant species of the mosquito vectors are unlikely to have influenced the pattern observed. The role of antimalarial drugs in malaria transmission risk is discussed.

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Eur J Immunol 2001 Jul;31(7):1989-98A synthetic malaria vaccine elicits a potent CD8(+) and CD4(+) T lymphocyte immune response in humans. Implications for vaccination strategies.

Lopez JA, Weilenman C, Audran R, Roggero MA, Bonelo A, Tiercy JM, Spertini F, Corradin G.

Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.

We report the first synthetic peptide vaccine eliciting strong CD8(+) and CD4(+) T lymphocyte responses in humans. The vaccine, representing the C-terminal region of the circumsporozoite protein of Plasmodium falciparum (amino acids 282-383) was well tolerated and strong sporozoite-specific antibodies were elicited. In addition, robust lymphocyte proliferation responses were equally elicited with concomitant in vitro production of IFN-gamma, crucial in the elimination of the parasite. Most importantly, we also observed the development of CD8(+) T lymphocyte responses decisive in the immunity to malaria. The latter finding opens new, possibly safer, avenues for vaccination strategies when a CD8(+) T cell response is needed.

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Proc Natl Acad Sci U S A 2001 Jul 17;98(15):8750-5

Full-text article at: http://www.pnas.orgA role for CD36 in the regulation of dendritic cell function.

Urban BC, Willcox N, Roberts DJ.

Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; and National Blood Service, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.

Dendritic cells (DC) are crucial for the induction of immune responses and thus an inviting target for modulation by pathogens. We have previously shown that Plasmodium falciparum-infected erythrocytes inhibit the maturation of DCs. Intact P. falciparum-infected erythrocytes can bind directly to CD36 and indirectly to CD51. It is striking that these receptors, at least in part, also mediate the phagocytosis of apoptotic cells. Here we show that antibodies against CD36 or CD51, as well as exposure to early apoptotic cells, profoundly modulate DC maturation and function in response to inflammatory signals. Although modulated DCs still secrete tumor necrosis factor-alpha, they fail to activate T cells and now secrete IL-10. We therefore propose that intact P. falciparum-infected erythrocytes and apoptotic cells engage similar pathways regulating DC function. These findings may have important consequences for the treatment of malaria and may suggest strategies for modulating pathological immune responses in autoimmune diseases.

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J Infect Dis 2001 Aug 1;184(3):330-6Nitric Oxide Synthase 2Lambarene (G-954C), Increased Nitric Oxide Production, and Protection against Malaria.

Kun JF, Mordmuller B, Perkins DJ, May J, Mercereau-Puijalon O, Alpers M, Weinberg JB, Kremsner PG.

Department of Parasitology, Institute for Tropical Medicine, University of Tubingen, D-72074 Tubingen, Germany. [email protected]
A point mutation in the promoter of the nitric oxide synthase 2 gene (NOS2), termed NOS2(Lambarene) (NOS2-G954C), protects heterozygous carriers against severe malaria as effectively as the sickle cell trait. In a prospective longitudinal study, 841 individual infections of initially 200 children (151 wild-type vs. 49 NOS2(Lambarene) carriers) were monitored for 4 years, to assess the rates of malarial attacks in the 2 groups; carriers of the NOS2(Lambarene) polymorphism were significantly less likely to experience malarial attacks than were others (P=.002). The distribution of the NOS2(Lambarene) polymorphism was investigated in malaria-endemic areas. It was found to be present with the highest frequency in Africa and at a lower frequency in Asia. Ex vivo studies showed that cells isolated from people with this polymorphism have a 7-fold higher baseline NOS activity, compared with the levels detected in cells from subjects with the wild-type gene (P=.003).

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Am J Trop Med Hyg 2001 Mar-Apr;64(3-4):207-13Blood-brain barrier function in cerebral malaria in Malawian children.

Brown H, Rogerson S, Taylor T, Tembo M, Mwenechanya J, Molyneux M, Turner G.

Nuffield Department of Clinical Laboratory Sciences, The John Radcliffe Hospital, Oxford, United Kingdom.

Cerebral malaria (CM) is a serious complication of Plasmodium falciparum infection. Binding of parasitized erythrocytes to cerebral endothelium plays a key role in disease pathogenesis. Central nervous system signs and symptoms (coma, seizures, raised intracranial pressure) predominate in African children, whereas in adults, multiorgan system failure is more common. In this study we investigated whether changes in blood-brain barrier (BBB) structure and function are compatible with the signs and symptoms observed in Malawian children with CM. Immunohistochemistry on autopsy brain tissues from eight cases of CM showed activation of endothelial cells and macrophages, and disruption of endothelial intercellular junctions in vessels containing sequestered parasitized erythrocytes, but no gross leakage of plasma proteins. Examination of the partition of albumin between circulating plasma and the cerebrospinal fluid from 72 cases of CM showed subtle but measurable changes compatible with impaired BBB function in malaria. These findings suggest that BBB breakdown occurs in areas of parasite sequestration in CM in African children.

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Am J Trop Med Hyg 2001 Mar-Apr;64(3-4):194-203Identification of frequently recognized dimorphic T-cell epitopes in plasmodium falciparum merozoite surface protein-1 in West and East Africans: lack of correlation of immune recognition and allelic prevalence.

Lee EA, Flanagan KL, Odhiambo K, Reece WH, Potter C, Bailey R, Marsh K, Pinder M, Hill AV, Plebanski M.

Institute of Molecular Medicine, Nuffield Department Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom. [email protected] The merozoite surface protein-1 (MSP1) is the most studied malaria blood-stage vaccine candidate. Lymphokines such as interferon gamma (IFN-gamma) and interleukin 4 (IL-4) may mediate blood-stage specific protection. Here we identify Plasmodiumfalciparum MSP1 T-cell epitopes capable of rapid induction of IFN-gamma and/or IL-4 from peripheral blood mononuclear cells of East and West African donors. Both allelic forms of these novel MSP1 T-cell epitopes were stimulatory. An unusually high numbers of Gambian responders (> 80%) to these epitopes were observed, suggesting that MSPI reactivity may have been underestimated previously in this population. Surprisingly, IFN-gamma responses to allelic T-cell epitopes failed to correlate with differential antigenic exposure in The Gambia compared to Kenya. These results suggest an unexpected level of immunoregulation of IFN-gamma response with variable allelic T-cell reactivity independent of the level of antigenic exposure. Further analysis of the mechanisms determining this response pattern may be required if vaccines are to overcome this allelic reactivity bias in malaria-exposed populations.

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Clin Biochem 2001 Jun;34(4):341-4Oxidative stress of platelets and thrombocytopenia in patients with vivax malaria.

Erel O, Vural H, Aksoy N, Aslan G, Ulukanligil M.

Department of Clinical Biochemistry, Medical Faculty of Harran University, 63200, Sanliurfa, Turkey

Oxidative stress and antioxidative capacity of platelets and the relationship with thrombocytopenia were determined in patients with vivax malaria and compared with those of healthy subjects. Whole blood thrombocyte count, platelet superoxide dismutase and glutathione peroxidase activities of patients with vivax malaria were lower and platelet lipid peroxidation levels were higher in patients than those of healthy subjects. There was an important negative correlation between whole blood thrombocyte count and platelet lipid peroxidation level. The antioxidative mechanisms of thrombocytes were insufficient in malaria patients and caused oxidative stress. The oxidative damage of thrombocytes might be important in the ethiopathogenesis of thrombocytopenia occurring in malaria.

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Placenta 2001 Jul;22(6):573-9Expression of Intercellular Adhesion Molecule 1 (ICAM-1) in Plasmodium falciparum -infected Placenta.

Sugiyama T, Cuevas LE, Bailey W, Makunde R, Kawamura K, Kobayashi M, Masuda H, Hommel M.

Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK

We investigated the expression of intercellular adhesion molecule 1 (ICAM-1) in malarial placenta and related histological changes. Thirty-two malarial and 40 control term placentae were collected at Tanga, Tanzania and examined histologically and immunohistochemically. Malaria infected placentae were further divided into acute (15) and chronic (17) cases according to the presence of malarial pigment. The expression of ICAM-1 on monocyte, syncytio- and cytotrophoblasts, endothelial and stromal cells was assessed. Birthweight was lower and leukocyte counts higher in placentae with chronic infection. Many monocytes were present within the intervillous spaces, especially in placentae with chronic infection, and aggregated with parasitized erythrocytes. Some monocytes were adhesive to the surface of fibrinoid deposits. ICAM-1 expression on monocytes of malarial placentae was significantly conspicuous and correlated to the degree of intervillous leukocyte infiltration. Syncytiotrophoblasts often did not show ICAM-1, even though ICAM-1 was expressed by endothelium and weakly by cytotrophoblasts and stromal cells in both infected and control placentae. These results suggest that the expression of ICAM-1 on monocytes contributes to sequestration of infected erythrocytes within the intervillous spaces and their adhesion to fibrin masses and that ICAM-1 is unlikely to be associated with the direct adhesion of infected erythrocytes to the syncytiotrophoblasts. Copyright 2001 Harcourt Publishers Ltd.