EHP LIBRARY MALARIA BULLETIN 49: NOV 11-26, 2002

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J Infect Dis 2002 Dec 1;186(11):1661-1668

Increased Efficacy of Sulfadoxine-Pyrimethamine in the Treatment of Uncomplicated Falciparum Malaria among Children with Sickle Cell Trait in Western Kenya.

Terlouw DJ, Aidoo MA, Udhayakumar V, Kolczak MS, Oloo AJ, Kager PA, Lal AA, Nahlen BL, Kuile FO.

Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; Kenya Medical Research Institute, Center for Vector Biology and Control Research, Kisumu, Kenya; and Department of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, University of Amsterdam, The Netherlands. Email: [email protected]

The role of the sickle cell hemoglobin type as a determinant of treatment outcome with sulfadoxine-pyrimethamine was retrospectively studied in young children with uncomplicated falciparum malaria who lived in an area with intense perennial malaria transmission. Between 1993 and 1997, 2795 treatments involving 813 children were monitored. Sickle cell trait (HbAS) was present in 17.7% of the children. Two-and-a-half percent of the children experienced early clinical treatment failure by day 2-3, and 17.3% of the children were parasitemic on day 7. Treatments in HbAS children were less likely than those in HbAA children to result in persistence of parasitemia by day 3 (relative risk [RR], 0.66; 95% confidence interval [CI], 0.47-0.93; P=.02) or in parasitologic treatment failure on day 7 (RR, 0.51; 95% CI, 0.36-0.71; P<.0001). These results suggest that the HbAS phenotype should be included among factors that determine sulfadoxine-pyrimethamine treatment outcome. Hematology (Am Soc Hematol Educ Program) 2002;:35-57 Malaria and the red cell. Weatherall DJ, Miller LH, Baruch DI, Marsh K, Doumbo OK, Casals-Pascual C, Roberts DJ. Because of the breakdown of malaria control programs, the constant emergence of drug resistant parasites, and, possibly, climatic changes malaria poses a major problem for the developing countries. In addition, because of the speed of international travel it is being seen with increasing frequency as an imported disease in non-tropical countries. This update explores recent information about the pathophysiology of the disease, its protean hematological manifestations, and how carrier frequencies for the common hemoglobin disorders have been maintained by relative resistance to the malarial parasite. In Section I, Dr. Louis Miller and colleagues consider recent information about the pathophysiology of malarial infection, including new information about interactions between the malarial parasite and vascular endothelium. In Section II, Dr. David Roberts discusses what is known about the complex interactions between red cell production and destruction that characterize the anemia of malaria, one of the commonest causes of anemia in tropical countries. In Section III, Dr. David Weatherall reviews recent studies on how the high gene frequencies of the thalassemias and hemoglobin variants have been maintained by heterozygote advantage against malaria and how malaria has shaped the genetic structure of human populations. Parasitol Res 2002 Dec;88(12):1040-3 The impact of malaria on common lipid parameters. Faucher JF, Ngou-Milama E, Missinou MA, Ngomo R, Kombila M, Kremsner PG. Medical Research Unit, Albert Schweitzer Hospital, Lambarene, Gabon, Email: [email protected] No data are available in the literature to indicate whether low-level Plasmodium falciparum infections induce lipid parameter changes. We hypothesized that low-level P. falciparum infections induce significant changes in common lipid parameters. We retrospectively selected samples from a malaria prophylaxis study to measure the impact of sustained parasite clearance on common lipid parameters [total cholesterol (TChol), high-density lipoprotein (HDL)-cholesterol (HDL-c), low-density lipoprotein (LDL)-cholesterol (LDL-c) and triglycerides (TG)] in 47 apparently healthy schoolchildren whose P. falciparum parasitemia was initially below 1000/ micro l. After parasite clearance, mean values were significantly increased for Tchol ( P<0.001) and HDL-c ( P<0.001), unlike LDL-c ( P=0.93); and TG were significantly decreased from the baseline ( P=0.004). No significant change was found in a control group. This is the first study showing significant lipid changes related to low-level P. falciparum infections. Further studies are needed to explore the relevance of this finding at the population level in hyperendemic malaria areas. J Immunol 2002 Dec 1;169(11):6369-6375 On the Pathogenic Role of Brain-Sequestered alphabeta CD8(+) T Cells in Experimental Cerebral Malaria. Belnoue E, Kayibanda M, Vigario AM, Deschemin JC, Rooijen Nv N, Viguier M, Snounou G, Renia L. Departement d’Immunologie, Institut Cochin, Institut National de la Sante et de la Recherche Medicale Unite 567, Centre National de la Recherche Scientifique Unite Mixte de Recherche 8104, Hopital Cochin, Universite Rene Descartes, and Unite de Parasitologie Biomedicale et Centre National de la Recherche Scientifique Unite de Recherche Associee 1960, Institut Pasteur, Paris, France. Department of Cell Biology and Immunology, Faculty of Medicine, Amsterdam, The Netherlands. Cerebral malaria (CM) develops in a small proportion of persons infected with Plasmodium falciparum and accounts for a substantial proportion of the mortality due to this parasite. The actual pathogenic mechanisms are still poorly understood, and in humans investigations of experimental CM are unethical. Using an established Plasmodium berghei-mouse CM model, we have investigated the role of host immune cells at the pathological site, the brain. We report in this study the detailed quantification and characterization of cells, which migrated and sequestered to the brain of mice with CM. We demonstrated that CD8(+) alphabeta T cells, which sequester in the brain at the time when neurological symptoms appear, were responsible for CM mortality. These observations suggest a mechanism which unifies disparate observations in humans. Acta Trop 2002 Dec;84(3):199-203

Molecular typing of Plasmodium falciparum from Giemsa-stained blood smears confirms nosocomial malaria transmission.

Kirchgatter K, Wunderlich G, Branquinho MS, Salles TM, Lian YC, Carneiro-Junior RA, Di Santi SM. Nucleo de Estudos em Malaria, Superintendencia de Controle de Endemias (SUCEN), Av. Dr. Eneas de Carvalho Aguiar 470, Cerqueira Cesar, SP 05403-000, Sao Paulo, Brazil.

In this report, we describe the partial molecular characterisation of Plasmodium falciparum isolates obtained from two individuals who were involved in a probable case of accidental malaria transmission after admission to a hospital in the metropolitan area of Sao Paulo, Brazil. Molecular analysis of polymorphic stretches of the merozoite surface protein 1 and 2 genes using PCR-typing and nucleotide sequencing revealed that the two isolates were identical and that the identified msp-1 gene was different from all others published to date. Additional anamnestic data supported our findings and made all other possible routes of infection unlikely. The methodology used here is simple to perform and needs as little as one Giemsa-stained blood smear as starting material. Mol Cells 2002 Oct 31;14(2):198-204

Intraspecific hybridization of Anopheles sinensis (Diptera: Culicidae) strains from Thailand and Korea.

Min GS, Choochote W, Jitpakdi A, Kim SJ, Kim W, Jung J, Junkum A. Email: [email protected]

Anopheles (Anopheles) sinensis [Wiedemann (1828)] is a member of the hyrcanus species group, and it has been incriminated as the natural or experimental malaria vectors in the Republic of Korea, Japan, China, and Indonesia. In Thailand, however, An. sinensis seems to be of little medical importance. Hybridization tests among the three iso-female lines (isolines) of An. sinensis [i.e., Form A (X, Y1) and Form B (X, Y2) (Thailand strain), and Form B (X, Y2) (Korean strain)] were established based on two distinct types of metaphase chromosomes and geographical differences The chromosomal form of the Korean strain was first identified from this study. Results of reciprocal and back crosses indicated that both karyotypic forms of theAn. sinensis Thailand and Korean strains were genetically compatible, and provided viable progenies and completely synaptic polytene chromosomes. The sequences of the rDNA internal-transcribed spacer 2 (ITS2) and mitochondrial cytochrome c oxidase subunit II (COII) among the An. sinensis strains were nearly identical to each other, and the intraspecific sequence variability was very low (0.0-0.6%). Sequence comparisons among the cryptic inter-species (i.e., An. sinensis, An. lesteri, and An. yatsushiroensis), however, revealed extensive divergence, and the intraspecific variability ranged from 12.2 to 34.6%. Therefore, it is concluded from these results and previous vector ability studies that the An. sinensis Forms A and B exhibit cytological polymorphic races that have different vector abilities in their transmission of malaria, depending on their geographical locations. Genome Biol 2002 Oct 25;3(11):REVIEWS1031 Plasmodium falciparum virulence determinants unveiled. Crabb BS, Cowman AF. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia. Email: [email protected] The human malaria parasite Plasmodium falciparum, one of the world’s most devastating pathogens, has an astonishing array of sequences and genes that play key roles in pathogenesis and immune evasion. We must understand the functions of these elements if the chronicity and unpredictable virulence of Plasmodium is to be explained. Infect Immun 2002 Dec;70(12):7013-21

Recognition of Variant Rifin Antigens by Human Antibodies Induced during Natural Plasmodium falciparum Infections.

Abdel-Latif MS, Khattab A, Lindenthal C, Kremsner PG, Klinkert MQ.

Department of Parasitology, Institute for Tropical Medicine, University of Tubingen, Germany. Medical Research Unit, Albert-Schweitzer Hospital, Lambarene, Gabon.

Antibodies from individuals living in areas where malaria is endemic are known to react with parasite-derived erythrocyte surface proteins. The major immunogenic and clonally variant surface antigen described to date is Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1), which is encoded by members of the multicopy var gene family. We report here that rifin proteins (RIF proteins), belonging to the largest known family of variable infected erythrocyte surface-expressed proteins, are also naturally immunogenic. Recombinant RIF proteins were used to analyze the antibody responses of individuals living in an area of intense malaria transmission. Elevated anti-rifin antibody levels were detected in the majority of the adult population tested, whereas the prevalence of such antibodies was much lower in malaria-exposed children. Despite the high degree of diversity between rif sequences and the high gene copy number, it appears that P. falciparum infections can induce antibodies that cross-react with several variant rifin molecules in many parasite isolates in a given community, and the immune response is most likely to be stable over time in a hyperendemic area. The protein was localized by fluorescence microscopy on the membrane of ring and young trophozoite-infected erythrocytes with antibodies from human immune sera with specificities for recombinant RIF protein. Infect Immun 2002 Dec;70(12):6961-7

Vaccination of Monkeys with Recombinant Plasmodium falciparum Apical Membrane Antigen 1 Confers Protection against Blood-Stage Malaria.

Stowers AW, Kennedy MC, Keegan BP, Saul A, Long CA, Miller LH.

Malaria Vaccine Development Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852.

A major challenge facing malaria vaccine development programs is identifying efficacious combinations of antigens. To date, merozoite surface protein 1 (MSP1) is regarded as the leading asexual vaccine candidate. Apical membrane antigen 1 (AMA1) has been identified as another leading candidate for an asexual malaria vaccine, but without any direct in vivo evidence that a recombinant form of Plasmodium falciparum AMA1 would have efficacy. We evaluated the efficacy of a form of P. falciparum AMA1, produced in Pichia pastoris, by vaccinating Aotus vociferans monkeys and then challenging them with P. falciparum parasites. Significant protection from this otherwise lethal challenge with P. falciparum was observed. Five of six animals had delayed patency; two of these remained subpatent for the course of the infection, and two controlled parasite growth at <0.75% of red blood cells parasitized. The protection induced by AMA1 was superior to that obtained with a form of MSP1 used in the same trial. The protection induced by a combination vaccine of AMA1 and MSP1 was not superior to the protection obtained with AMA1 alone, although the immunity generated appeared to operate against both vaccine components. Infect Immun 2002 Dec;70(12):6948-60

In Vitro Studies with Recombinant Plasmodium falciparum Apical Membrane Antigen 1 (AMA1): Production and Activity of an AMA1 Vaccine and Generation of a Multiallelic Response.

Kennedy MC, Wang J, Zhang Y, Miles AP, Chitsaz F, Saul A, Long CA, Miller LH, Stowers AW.

Malaria Vaccine Development Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852.

Apical membrane antigen 1 (AMA1) is regarded as a leading malaria blood-stage vaccine candidate. While the overall structure of AMA1 is conserved in Plasmodium spp., numerous AMA1 allelic variants of P. falciparum have been described. The effect of AMA1 allelic diversity on the ability of a recombinant AMA1 vaccine to protect against human infection by different P. falciparum strains is unknown. We characterize two allelic forms of AMA1 that were both produced in Pichia pastoris at a sufficient economy of scale to be usable for clinical vaccine studies. Both proteins were used to immunize rabbits, singly and in combination, in order to evaluate their immunogenicity and the ability of elicited antibodies to block the growth of different P. falciparum clones. Both antigens, when used alone, elicited high homologous anti-AMA1 titers, with reduced strain cross-reactivity. Similarly, sera from rabbits immunized with a single antigen were capable of blocking the growth of homologous parasite strains at levels theoretically sufficient to clear parasite infections. However, heterologous inhibition was significantly reduced, providing experimental evidence that AMA1 allelic diversity is a result of immune pressure. Encouragingly, rabbits immunized with a combination of both antigens exhibited titers and levels of parasite inhibition as good as those of the single-antigen-immunized rabbits for each of the homologous parasite lines, and consequently exhibited a broadening of allelic diversity coverage. Infect Immun 2002 Dec;70(12):6860-70

A Modified Hepatitis B Virus Core Particle Containing Multiple Epitopes of the Plasmodium falciparum Circumsporozoite Protein Provides a Highly Immunogenic Malaria Vaccine in Preclinical Analyses in Rodent and Primate Hosts.

Birkett A, Lyons K, Schmidt A, Boyd D, Oliveira GA, Siddique A, Nussenzweig R, Calvo-Calle JM, Nardin E. Apovia Inc., San Diego, California 92121.

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

Despite extensive public health efforts, there are presently 200 to 400 million malaria infections and 1 to 2 million deaths each year due to the Plasmodium parasite. A prime target for malaria vaccine development is the circumsporozoite (CS) protein, which is expressed on the extracellular sporozoite and the intracellular hepatic stages of the parasite. Previous studies in rodent malaria models have shown that CS repeat B-cell epitopes expressed in a recombinant hepatitis B virus core (HBc) protein can elicit protective immunity. To design a vaccine for human use, a series of recombinant HBc proteins containing epitopes of Plasmodium falciparum CS protein were assayed for immunogenicity in mice [A. Birkett, B. Thornton, D. Milich, G. A. Oliveira, A. Siddique, R. Nussenzweig, J. M. Calvo-Calle, and E. H. Nardin, abstract from the 50th Annual Meeting of the American Society of Tropical Medicine and Hygiene 2001, Am. J. Trop. Med. Hyg. 65(Suppl. 3):258, 2001; D. R. Milich, J. Hughes, J. Jones, M. Sallberg, and T. R. Phillips, Vaccine 20:771-788, 2001]. The present paper summarizes preclinical analyses of the optimal P. falciparum HBc vaccine candidate, termed ICC-1132, which contains T- and B-cell epitopes from the repeat region and a universal T-cell epitope from the C terminus of the CS protein. The vaccine was highly immunogenic in mice and in Macaca fascicularis (cynomolgus) monkeys. When formulated in adjuvants suitable for human use, the vaccine elicited antisporozoite antibody titers that were logs higher than those obtained in previous studies. Human malaria-specific CD4(+)-T-cell clones and T cells of ICC-1132-immunized mice specifically recognized malaria T-cell epitopes contained in the vaccine. In addition to inducing strong malaria-specific immune responses in naive hosts, ICC-1132 elicited potent anamnestic antibody responses in mice primed with P. falciparum sporozoites, suggesting potential efficacy in enhancing the sporozoite-primed immune responses of individuals living in areas where malaria is endemic. Infect Immun 2002 Dec;70(12):6606-6613 Immunization with a Combination of Merozoite Surface Proteins 4/5 and 1 Enhances Protection against Lethal Challenge with Plasmodium yoelii. Kedzierski L, Black CG, Goschnick MW, Stowers AW, Coppel RL. Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia. Malaria Vaccine Development Unit, The Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852. It is widely believed that subunit vaccines composed of multiple components will offer greater protection against challenge by malaria, and yet there is little experimental evidence to support this view. We set out to test this proposition in the Plasmodium yoelii challenge system in rodents by comparing the degree of protection conferred by immunization with a mixture of merozoite surface proteins to that conferred by single proteins. We therefore examined a defined protein mixture made of the epidermal growth factor-like domains of P. yoelli merozoite surface protein 1 (MSP1) and MSP4/5, the homologue of P. falciparum MSP4 and MSP5. In the present study we demonstrate that this combination of recombinant proteins dramatically enhances protection against lethal malaria challenge compared to either protein administered alone. Many mice immunized with the MSP4/5 plus MSP1(19) combination did not develop detectable parasitemia after challenge. Combined immunization with MSP1(19) and yMSP4/5, a product characterized by lower protective efficacy, also greatly enhanced protection by reducing peak parasitemias and increasing the numbers of survivors. In some combination trials, levels of antibodies to MSP1(19) were elevated compared to the MSP1(19) alone group; however, improved protection occurred regardless of whether boosting of the anti-MSP1(19) response was observed. Boosting of anti-MSP1(19) did not appear to be due to contaminating endotoxin in the EcMSP4/5 material since enhanced protection was observed in C3H/HeJ mice, which are endotoxin insensitive. Collectively, these experiments show that multiantigen combinations offer enhanced levels of protection against asexual stage infection and suggest that combinations of MSP1, MSP4, and MSP5 should be evaluated further for use in humans. Br J Haematol 2002 Dec;119(3):839-847

Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome.

Ladhani S, Lowe B, Cole AO, Kowuondo K, Newton CR.

Centre for Geographical Medicine Research (Coast), Kenya Medical Research Institute, Kilifi, Kenya, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University, UK, Department of Genome Sciences, University of Washington, Seattle, USA, and Neurosciences Unit, Institute of Child Health, London, UK.

Little is known about the changes in white blood cells and platelets in children with falciparum malaria in endemic areas. We measured the white cell count (WCC) and platelets of 230 healthy children from the community, 1369 children admitted to hospital with symptomatic malaria, and 1461 children with other medical conditions. Children with malaria had a higher WCC compared with community controls, and leucocytosis was strongly associated with younger age, deep breathing, severe anaemia, thrombocytopenia and death. The WCC was not associated with a positive blood culture. In children with malaria, high lymphocyte and low monocyte counts were independently associated with mortality. A platelet count of less than 150 x 109/l was found in 56.7% of children with malaria, and was associated with age, prostration and parasite density, but not with bleeding problems or mortality. The mean platelet volume was also higher in children with malaria compared with other medical conditions. This may reflect early release from the bone marrow in response to peripheral platelet destruction. Thus, leucocytosis was associated with both severity and mortality in children with falciparum malaria, irrespective of bacteraemia, whereas thrombocytopenia, although very common, was not associated with adverse outcome. Rev Inst Med Trop Sao Paulo 2002 Sep-Oct;44(5):293-6 Evaluation of a rapid dipstick test, Malar-Check, for the diagnosis of Plasmodium falciparum malaria in Brazil. Avila PE, Kirchgatter K, Brunialti KC, Oliveira AM, Siciliano RF, Di Santi SM. Nucleo de Estudos em Malaria, Superintendencia de Controle de Endemias, Sao Paulo, Brasil. 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. Antimicrob Agents Chemother 2002 Dec;46(12):3947-3953

Therapeutic Efficacies of Artesunate-Sulfadoxine-Pyrimethamine and Chloroquine-Sulfadoxine-Pyrimethamine in Vivax Malaria Pilot Studies: Relationship to Plasmodium vivax dhfr Mutations.

Tjitra E, Baker J, Suprianto S, Cheng Q, Anstey NM.

National Institute of Health Research and Development, Ministry of Health. Directorate-General of Communicable Disease Control and Environmental Health, Ministry of Health, Jakarta, Indonesia. International Health Program, Division of Infectious Diseases, Menzies School of Health Research. Division of Medicine, Flinders University Northern Territory Clinical School, Darwin, Northern Territory. Australian Army Malaria Institute, Enoggera, Queensland, Australia.

Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T–>M mutation at residue 61 linked to an S–>T (but not an S–>N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination. Antimicrob Agents Chemother 2002 Dec;46(12):3933-3939

Intramuscular Bioavailability and Clinical Efficacy of Artesunate in Gabonese Children with Severe Malaria.

Nealon C, Dzeing A, Muller-Romer U, Planche T, Sinou V, Kombila M, Kremsner PG, Parzy D, Krishna S.

Department of Infectious Diseases, St. George’s Hospital Medical School, London SW17 ORE, United Kingdom. Department of Parasitology, Mycology and Tropical Medicine, Faculty of Medicine, University of Libreville, Libreville. Medical Research Unit, Albert Schweitzer Hospital, Lambarene, Gabon. Department of Parasitology, Eberhard Karls Universitat, Tubingen, Germany. Parasitology Department, Institut de Medecine Tropicale du Service de Sante des Armees, 13998, Marseille Armees, France.

Artesunate (ARS) is a water-soluble artemisinin derivative that is a potential alternative to quinine for the treatment of severe childhood malaria. We studied the pharmacokinetics and bioavailability of ARS given by the intramuscular (i.m.) route in an open crossover study design. Fourteen children were randomized to receive intravenous (i.v.) ARS in a loading dose (2.4 mg/kg of body weight) followed 12 h later by an i.m. dose (1.2 mg/kg) (group I), and 14 children were randomized to receive i.m. ARS (2.4 mg/kg) followed by an i.v. dose of ARS (1.2 mg/kg) (group II). We carried out a two-compartment analysis of ARS and dihydroartemisinin (DHA; the principal antimalarial metabolite) levels in 21 children (groups I and II combined). Absorption of i.m. ARS was rapid, with the maximum concentration of DHA in serum being achieved in less than 1 h in most children (median time to the maximum concentration of drug in serum, 35.1 min; range, 10.8 to 71.9 min). The absolute bioavailability of DHA was a median of 86.4% (range, 11.4 to 462.1%), the median steady-state volume of distribution was 1.3 liters/kg (range, 0.5 to 7.9 liters/kg), and the median clearance was 0.028 liters/kg/min (range, 0.001 to 1.58 liters/kg/min). There were no major adverse events attributable to ARS. Parasite clearance kinetics were comparable between the two treatment groups. These results support the use of i.m. ARS in children with severe malaria. Int J Parasitol 2002 Dec;32(13):1669-76 The integration of genomic and structural information in the development of high affinity plasmepsin inhibitors. Nezami A, Freire E. Department of Biology and The Johns Hopkins Malaria Research Institute, The Johns Hopkins University, 21218, Baltimore, MD, USA The plasmepsins are key enzymes in the life cycle of the Plasmodium parasites responsible for malaria. Since plasmepsin inhibition leads to parasite death, these enzymes have been acknowledged to be important targets for the development of new antimalarial drugs. The development of effective plasmepsin inhibitors, however, is compounded by their genomic diversity which gives rise not to a unique target for drug development but to a family of closely related targets. Successful drugs will have to inhibit not one but several related enzymes with high affinity. Structure-based drug design against heterogeneous targets requires a departure from the classic ‘lock-and-key’ paradigm that leads to the development of conformationally constrained molecules aimed at a single target. Drug molecules designed along those principles are usually rigid and unable to adapt to target variations arising from naturally occurring genetic polymorphisms or drug-induced resistant mutations. Heterogeneous targets need adaptive drug molecules, characterised by the presence of flexible elements at specific locations that sustain a viable binding affinity against existing or expected polymorphisms. Adaptive ligands have characteristic thermodynamic signatures that distinguish them from their rigid counterparts. This realisation has led to the development of rigorous thermodynamic design guidelines that take advantage of correlations between the structure of lead compounds and the enthalpic and entropic components of the binding affinity. In this paper, we discuss the application of the thermodynamic approach to the development of high affinity (K(i) approximately pM) plasmepsin inhibitors. In particular, a family of allophenylnorstatine-based compounds is evaluated for their potential to inhibit a wide spectrum of plasmepsins. Int J Parasitol 2002 Dec;32(13):1661-7

Antimalarial chemotherapeutic peroxides: artemisinin, yingzhaosu A and related compounds.

Borstnik K, Paik I, Shapiro TA, Posner GH.

Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218-2685, USA.

Mechanism-based rational design and gram-scale chemical synthesis have produced some new trioxane and endoperoxide antimalarial drug candidates that are efficacious and safe. This review summarises recent achievements in this area of peroxide drug development for malaria chemotherapy. Int J Parasitol 2002 Dec;32(13):1655-60 Artemisinin: mechanisms of action, resistance and toxicity. Meshnick SR. Department of Epidemiology, University of North Carolina, School of Public Health, Chapel Hill, 27599-7435, NC, USA Artemisinin and its derivatives are widely used throughout the world. The mechanism of action of these compounds appears to involve the heme-mediated decomposition of the endoperoxide bridge to produce carbon-centred free radicals. The involvement of heme explains why the drugs are selectively toxic to malaria parasites. The resulting carbon-centred free radicals are alkylate heme and proteins, one of which is the translationally controlled tumour protein. Clinically relevant artemisinin resistance has not been demonstrated, but it is likely to occur since artemisinin resistance has been obtained in laboratory models. At high doses, artemisinin can be neurotoxic but toxicity has not been found in clinical studies. The mechanism of neurotoxicity may be similar to the mechanism of action. Int J Parasitol 2002 Dec;32(13):1645-53

Theories on malarial pigment formation and quinoline action.

Sullivan DJ.

The Malaria Research Institute, W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe St., 21205, Baltimore, MD, USA.

Haeme metabolism remains a vulnerable problem for the intraerythrocytic Plasmodium which catabolises haemoglobin as a source of amino acids in an acidic, oxygen-rich lysosome-like digestive vacuole. Haeme monomer, capable of generating oxygen radicals, transforms into an inert crystal named malarial pigment or haemozoin by forming unique dimers that then crystalise. Laveran first described pigmented bodies in humans to define a protozoan as the aetiologic agent of malaria. The trail of malaria pigment enabled Ross to implicate the mosquito in the life cycle of Plasmodium. In 1991, Slater and Cerami postulated a unique iron-carboxylate bond between two haemes in haemozoin crystals based on infrared and X-ray spectroscopy data. Additionally, parasite extracts were shown to possess a ‘haeme polymerase’ enzymatic activity as the process of crystal formation was then termed. Importantly, the quinolines, such as choloroquine, inhibit haemozoin formation. A Plasmodium falciparum derived histidine-rich protein II, which binds haeme and initiates haemozoin formation, is present in the digestive vacuole. Pfhistidine-rich protein II and Pfhistidine-rich protein III are sufficient, but not necessary for haemozoin formation as a laboratory clone lacking both still makes the haeme crystals. The reduvid bug, and the Schistosoma and Haemoproteus genera also make haemozoin. Recently, Bohle and coworkers used X-ray diffraction to document the iron-carboxylate bond in intact desiccated parasites and to show that a Fe1-O41 head to tail haeme dimer is the unit building block of haemozoin. The role of the Plasmodium histidine-rich protein family members, lipids or potential novel proteins in the exact molecular assembly of the large molecular weight haeme crystals in the protein rich digestive vacuole needs to be solved. Accurate experimental determination of the role of haemozoin formation and inhibition as the target of chloroquine is fundamental to determination of the mechanism of quinoline drug action and resistance. The enhanced understanding of the biosynthetic pathway leading to haemozoin formation using functional proteomic tools and the mechanisms through which existing antimalarial drugs affect Plasmodium haeme chemistry will help design improved chaemotherapeutic agents. Int J Parasitol 2002 Dec;32(13):1637-43

Malaria associated anaemia, drug resistance and antimalarial combination therapy.

Bjorkman A.

Division of Infectious Diseases, Department of Medicine, Karolinska Hospital, SE-17176, Stockholm, Sweden.

Malaria associated anaemia represents a major cause of childhood mortality in sub-Saharan Africa. Prevention of severe anaemia necessitates rapid treatment of symptomatic high density parasitaemia, as well as reduction of asymptomatic parasite prevalence to provide recovery period to restore production of erythrocytes. Both interventions are being increasingly impaired by reduced efficacy of antimalarial treatment due to parasite drug resistance. A new treatment strategy, including combinations of antimalarial drugs with optimal pharmacodynamic and kinetic properties may respond to the need of rapid and radical parasite clearance, temporary protection to re-infection, and prevention of drug resistance. Int J Parasitol 2002 Dec;32(13):1617-24

Spatial simulation of malaria transmission and its control by malaria transmission blocking vaccination.

Carter R.

Division of Biological Sciences, ICAPB, University of Edinburgh, West Mains Road, EH9 3JT, Edinburgh, UK.

A simple, visual representation of spatial aspects of malaria transmission in successive snap-shots in time, is presented. The spatial components of the simulation involve (i) the identification of mosquito vector breeding sites of defined shape and area, (ii) the identification of a zone of malaria transmission determined by the shapes and areas of the vector breeding sites and the distance from these sites that the mosquitoes disperse, (iii) a human population dispersed in relation to the malaria transmission zone, (iv) perimeters around each individual human within which his or her infection can be transmitted by the local vector mosquitoes. The intensity of transmission within a malaria transmission zone is given by a number which is the number of new cases of malaria that each existing case will distribute through the human population within the duration of an infection. The simulation has been used here to examine the effects of vaccination against malaria transmission. Different levels of vaccine coverage are represented under endemic and epidemic malaria. The consequences of full or partial coverage of a zone of malaria transmission are also examined. The results are numerically compatible with the predictions of previous simple mathematical simulations of malaria transmission and interventions. The present simulation allows the nature of malaria transmission and the effects of interventions to be communicated easily and directly to an audience. It could have practical value in discussions of malaria control strategies with health planners. Int J Parasitol 2002 Dec;32(13):1607-15

Genetic markers for study of the anopheline vectors of human malaria.

Norris DE. W. Harry Feinstone.

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Malaria Research Institute, 615 North Wolfe Street, Room E5008, 21205, Baltimore, MD, USA Human malaria is truly a disease of global proportions and is one of the most broadly distributed vector-borne infections. Anopheline mosquitoes are the exclusive vectors of human malaria. A handful of species predominate as the most notorious malaria vectors, but the species and forms involved in the transmission of human malaria world-wide are incredibly diverse. Many of the anophelines that vector malaria exist as members of species complexes that often contain vector and non-vector species. Additionally, single anopheline species often exhibit significant heterogeneity across the species’ range. This phenotypic and genotypic plasticity exacerbates the difficulties in identification of vector populations and implementation of effective surveillance and control strategies. Polytene chromosome investigations were among the first to provide researchers with tangible genetic markers that could be used to differentiate between what are now recognised as species and chromosomal forms of anopheline mosquitoes. The advent of the polymerase chain reaction gave access to the molecular genetics of genomes and the techniques that followed have facilitated investigation of the genetics of individual specimens or population size samples. The variety and number of genetic markers available for the study of malaria vectors has literally exploded in the last 10 years. Markers have expanded from the ‘traditional tools’ to include a vast array of molecular markers. Contemporary markers range from what are now referred to as ‘classical genetic markers’ to methods used to detect and identify single nucleotide polymorphisms and finally to highly polymorphic markers. One of the greatest advantages of this wide variety of genetic markers is that researchers may choose to utilise any combination of markers or techniques to address multifaceted questions relating to malaria transmission. These molecular markers have proven useful in a wide variety of applications including molecular taxonomy, evolutionary systematics, population genetics, genetic mapping, and investigation of defined phenotypes. Int J Parasitol 2002 Dec;32(13):1599-605

Genetic transformation of mosquitoes: a quest for malaria control.

Moreira LA, Ghosh AK, Abraham EG, Jacobs-Lorena M.

Case Western Reserve University, Department of Genetics, 10900 Euclid Avenue, 44106-4955, Cleveland, OH, USA.

Malaria inflicts an enormous toll in human lives and this burden is increasing. Present means to fight the disease, such as drugs and insecticides, are insufficient. Moreover, an effective vaccine has not yet been developed. This review examines an alternative strategy for malaria control, namely the genetic modification of mosquitoes to make them inefficient vectors for the parasite. The article summarises progress made toward the development of transposable element vectors for germ line transformation and the search for mosquito markers of transformation. Also reviewed is the search for anti-malarial effector genes whose products can inhibit development of the parasite in the mosquito with minimal fitness burden. While much progress has been made, much work remains to be done. Future research directions are discussed. Int J Parasitol 2002 Dec;32(13):1587-98

Malaria pathogenesis: a jigsaw with an increasing number of pieces.

Heddini A.

Microbiology and Tumor Biology Center, Karolinska Institutet and Swedish Institute for Infectious Disease Control, Box 280, S-171 77, Stockholm, Sweden.

Plasmodium falciparum malaria remains as one of the most devastating global health problems of today. It is estimated that around 150 million individuals get the disease every year and of these 2-3 million die from it. Our knowledge of the mechanisms underlying the pathology has expanded greatly over the last decades, but many aspects of the molecular biology, immunology and epidemiology that govern the pathogenesis and spread of this parasite are still unclear. As new insights are gained we are also revealing a challenging biological complexity. Piecing this information together is the key to vaccine development and production of new antimalarial drugs. Int J Parasitol 2002 Dec;32(13):1559-66 Functional characterisation of sexual stage specific proteins in Plasmodium falciparum. Kongkasuriyachai D, Kumar N. Johns Hopkins Malaria Research Institute, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 21205, Baltimore, MD, USA The various stages of the malaria parasites in the vertebrate host and in the mosquito vector offer numerous candidates for vaccine and drug development. However, the biological complexity of the parasites and the interaction with the immune system of the host continue to frustrate all such efforts thus far. While most of the targets for drug and vaccine design have focused on the asexual stages, the sexual stages of the parasite are critical for transmission and maintenance of parasites among susceptible vertebrate hosts. Sexual stage parasites undergo a series of morphological and biochemical changes during their development, accompanied by a co-ordinated cascade of a distinct expression pattern of sexual stage specific proteins. Mechanisms underlying the developmental switch from asexual parasite to sexual parasite still remain elusive. Methods that can break the malaria transmission cycle thus occupy a central place in the overall malaria control strategies. This paper provides a review of genes expressed in sexually differentiated Plasmodium. In the past few years, a molecular approach based on targeted gene disruption has revealed fascinating biological roles for many of the sexual stage gene products. In addition, we will briefly discuss other functional genomic approaches employed to study not only sexual but also other aspects of host-parasite biology. Int J Parasitol 2002 Dec;32(13):1551-7

Gene expression analysis during liver stage development of Plasmodium.

Sacci JB, Azad AF.

Department of Microbiology and Immunology, University of Maryland School of Medicine, 655 W. Baltimore Street, 21201, Baltimore, MD, USA.

The complex life cycle of malaria parasites requires significant changes in gene expression as the parasites move from vector to host and back to the vector. Although recognised as an important vaccine and drug target, the liver stage parasite has remained difficult to study. One of the major impediments in identifying parasite gene expression at the liver stage has remained the large number of uninfected hepatocytes relative to the number of infected hepatocytes in the liver after sporozoite inoculation. This article describes several of the approaches that have been utilised to overcome this difficulty in rodent models of malaria. While significant progress has been made to identify genes that are expressed during liver stage parasite development, a great deal more work remains to be done. Int J Parasitol 2002 Dec;32(13):1543-50

Stochastic versus stable transcriptional differences on Plasmodium falciparum DNA microarrays.

Ganesan K, Jiang L, Rathod PK. Department of Chemistry, University of Washington, 98105, Seattle, WA, USA.

The recent availability of the Plasmodium falciparum genome sequence has opened up convenient, large-scale analysis of transcriptional products in malaria. Protocols for cDNA labelling, cDNA hybridisation, and fluorescent signal detection developed for other organisms can be applied directly to malaria. However, P. falciparum offers unique challenges in data analysis due to stochastic variability in expression of some gene products, such as variable erythrocyte surface proteins. Careful comparison of global transcriptional patterns in two well-studied clones of P. falciparum (Dd2 and HB3) indicates that reliable, stable transcriptional alterations in malaria can be readily distinguished from stochastic processes. To do this, we utilised a complex experimental design which involves a combination of self-hybridisations and cross-hybridisations between two independently grown parasite populations for each clone being examined (for short, we call this a ‘2×2 CombiScan’). While even a simple 2×2 CombiScan required 12 microarray hybridisations, the effort generated output that was highly interpretable. Reliable RNA transcriptional differences between Dd2 and HB3 could be readily visualised using public algorithms for data normalisation and clustering. J Parasitol 2002 Oct;88(5):1042-4

Radical curative efficacy of five-day regimen of primaquine for treatment of Plasmodium vivax malaria in India.

Yadav RS, Ghosh SK. Malaria Research Centre, Field Station, Rourkela, Orissa, India. Email: [email protected]

For over 4 decades the antimalarial program in India has been prescribing a 5-day primaquine regimen as an antirelapse therapy to treat Plasmodium vivax malaria. In view of conflicting reports on the effectiveness of this regimen in the Indian subcontinent, and the varying prevalence of P. vivax in various ecosystems in India, the antirelapse efficacy of this regimen was evaluated in Orissa, a malaria endemic state in eastern India where P. falciparum predominates. In 723 cases of P. vivax infection treated with chloroquine alone and followed up weekly for 1 yr, the prevalence of recurrence of parasitaemia with fever was 8.6%. Among another 759 P. vivax cases treated with chloroquine and a 5-day regimen of primaquine at 15 mg/day (adult dose), the recurrence of infection was 6.5%. The difference in recurrence was not significant (P = 0.53). It is important to note that in a great majority of cases of P. vivax in this area, infection did not recur even without treatment with primaquine. This finding, that the use of the 5-day primaquine regimen with chloroquine had no significant advantage over the use of chloroquine alone, undermines the rationale of using primaquine as an antirelapse drug in forested areas with a high prevalence of P. falciparum. Clin Chem Lab Med 2002 Sep;40(9):937-40

Immunoglobulin G and subclass responses to Plasmodium falciparum antigens: a study in highly exposed Cameroonians. Titanji VP, Tamu VD, Nkuo Akenji TK, Joutchop AS.

Faculty of Science, Department of Life Sciences, University of Buea, South West Province, Cameroon. Email: [email protected]

We conducted a cross-sectional study in Bolifamba village in the South West Province of Cameroon to determine antibody responses to crude Plasmodium falciparum antigens. A total of 347 subjects were examined. Parasite counts were obtained on thick blood films stained with Field’s stain. Total immunoglobulin (Ig)G and IgG subclass levels were determined in serum samples from four groups comprising children 1 to 5 years old and adults > or = 18 years with or without falciparum malaria parasites, using enzyme-linked immunosorbent assay with crude blood-stage antigens of Plasmodium falciparum strain F32 as target. Depending on the age group, malaria prevalence varied between 10% and 65% with a mean of 30.8%. Prevalence rate and parasite density declined with increasing age. Total IgG and IgG1-3 levels were significantly higher in adults than in children (p < 0.05). Parasite-bearing individuals in both age groups had higher IgG titres than their non-infected counterparts, while subtype levels were not significantly different (p = 0.05). These findings indicate that Bolifamba village could be a convenient site to study further the protective immunity to malaria. J R Coll Physicians Edinb 2002;32(3):189-96 Plants against malaria. Part 1: Cinchona or the Peruvian bark. Lee MR. On of the most compelling sagas in the history of medicine and therapeutics is the emergence of the Peruvian bark (Cinchona) and also of the pharmacologically active substance derived from it, quinine. Its discovery involved exploration, exploitation and secrecy, and it came, in the nineteenth century, to reflect the struggles of the major European powers for domination, territory and profit. This short history shows how the use of Cinchona enabled the exploration of dangerous malarial areas and in this way facilitated imperial expansion by the Western powers. Blood 2002 Nov 14; [epub ahead of print] Heparan sulfate on endothelial cells mediates the binding of Plasmodium falciparum-infected erythrocytes via the DBL1{alpha} domain of PfEMP1. Vogt AM, Barragan A, Chen Q, Kironde F, Spillmann D, Wahlgren M. Plasmodium falciparum may cause severe forms of malaria when excessive sequestration of infected and uninfected erythrocytes occurs in vital organs. The capacity of wild isolates of P. falciparum-infected erythrocytes (pRBC) to bind glycosamoinoglycans (GAG) such as heparin has been identified as a marker for severe disease. Here we report that pRBC of the parasite FCR3S1.2 and wild clinical isolates from Uganda adhere to heparan sulfate (HS) on endothelial cells. Binding to human umbilical vein endothelial cells (HUVEC) and to human lung endothelial cells (HLEC) was found to be inhibited by HS/heparin or enzymes that remove HS from cell surfaces.(35)S-labeled HS extracted from HUVECs bound directly to the pRBCs membrane. Using recombinant proteins corresponding to the different domains of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) we identified Duffy-binding-like domain-1alpha (DBL1alpha) as the ligand for HS. DBL1alpha bound in a HS dependent way to endothelial cells and blocked the adherence of pRBC in a dose-dependent manner. (35)S-labeled HS bound to DBL1alpha-columns and eluted as a distinct peak at 0.4 mM NaCl. (35)S-labeled chondroitin sulfate (CS) of HUVECs did not bind to PfEMP1 or to the pRBCs membrane. Adhesion of pRBC of FCR3S1.2 to PECAM-1/CD31, mediated by the cystein-rich-interdomain region 1alpha (CIDR1alpha), was found to be co-operative with but independent of the binding to HS. HS and the previously identified HS-like GAG on uninfected erythrocytes may act as co-receptors in endothelial and erythrocyte binding of rosetting parasites causing excessive sequestration of both pRBC and RBC. Lancet 2002 Nov 9;360(9344):1468-75

A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children.

Hobbs MR, Udhayakumar V, Levesque MC, Booth J, Roberts JM, Tkachuk AN, Pole A, Coon H, Kariuki S, Nahlen BL, Mwaikambo ED, Lal AL, Granger DL, Anstey NM, Weinberg JB.

Department of Internal Medicine, University of Utah and VA Medical Centers, Salt Lake City, UT, USA.

BACKGROUND: Nitric oxide (NO) is a mediator of immunity to malaria, and genetic polymorphisms in the promoter of the inducible NO synthase gene (NOS2) could modulate production of NO. We postulated that NOS2 promoter polymorphisms would affect resistance to severe malaria. METHODS: We assessed genomic DNA from healthy children and from those diagnosed with malaria from Tanzania (n=47 and n=138, respectively) and Kenya (n=1106) for polymorphisms by single-stranded conformational polymorphism (SSCP) analysis and sequencing. We also measured in-vivo NO production in Tanzanian children. FINDINGS: We identified a novel single nucleotide polymorphism, -1173 C–>T, in the NOS2 promoter that was significantly associated with protection from symptomatic malaria (odds ratio 0.12, 95% CI 0.03-0.48, p=0.0006) in 179 Tanzanian children, and significantly associated with protection from severe malarial anaemia (adjusted relative risk 0.25, 95% CI 0.09-0.66, p=0.0005) in 1106 Kenyan children studied over 5 years. The risk of parasitaemia was not significantly different in wild-type or -1173 C–>T individuals. -1173 C–>T protection in Tanzanians was independent of the previously recognised NOS2-954 G–>C polymorphism. The (CCTTT)(n) NOS2 polymorphism (Tanzania and Kenya) was not associated with severe malaria outcomes. -1173 C–>T was associated with increased fasting urine and plasma NO metabolite concentrations in Tanzanian children, suggesting that the polymorphism was functional in vivo.Interpretation The NOS2 promoter -1173 C–>T single nucleotide polymorphism is associated with protection against cerebral malaria and severe malarial anaemia. Increased NO production in individuals with the -1173 C–>T polymorphism lends support to a protective role for NO against these syndromes. Targeted interventions to increase NO delivery or production could provide novel preventive and therapeutic strategies against these major causes of mortality in African children. J Health Popul Nutr 2002 Sep;20(3):205-14 Relationship between carotenoids and anaemia during acute uncomplicated Plasmodium falciparum malaria in children. Nussenblatt V, Mukasa G, Metzger A, Ndeezi G, Eisinger W, Semba RD. Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA. A clinic-based cohort study in Kampala, Uganda, was conducted to examine the relationship between severe malarial anaemia and plasma micronutrients. Plasma carotenoids, retinol, vitamin E, and four trace metal concentrations were measured at enrollment and seven days later in 273 children, aged 1-10 year(s), with acute, uncomplicated Plasmodium falciparum malaria. Concentrations of plasma provitamin A carotenoids (p < 0.0001), non-provitamin A carotenoids (p < 0.0001), retinol (p < 0.0001), all four trace elements (all p < 0.001), and vitamin E (p < 0.0001) rose significantly by day 7 among children without severe anaemia (haemoglobin 70 g/L). There was no change in provitamin A carotenoids (p = 0.24) among children with severe anaemia (haemoglobin <70 g/L), whereas non-provitaminAcarotenoids (p < 0.0001), retinol (p < 0.0001), and vitamin E (p = 0.011) increased. These observations also support the hypothesis that the use of provitamin A carotenoids increases during malaria infection. Acta Trop 2002 Nov;84(2):151-7 Use of the Plasmodium vivax merozoite surface protein 1 gene sequence analysis in the investigation of an introduced malaria case in Italy. Severini C, Menegon M, Gradoni L, Majori G. Laboratorio di Parassitologia, Istituto Superiore di Sanita, viale Regina Elena 299, 00161, Rome, Italy Malaria due to Plasmodium vivax is globally widespread and is associated with substantial morbidity. The parasite was previously prevalent in temperate areas from which it has been eradicated, however there is a risk of re-introduction because of increased international travel and migration. Following the occurrence of an autochthonous case of P. vivax malaria in Italy after decades of malaria eradication, we applied a molecular approach to compare parasites involved in the introduced case and to determine whether a highly polymorphic gene marker could be useful to tag a P. vivax isolate geographically. To this end, the sequence encompassing the interspecies conserved blocks 5 and 6 of the gene encoding for merozoite surface protein 1 (msp-1) was determined in 16 P. vivax isolates from different regions, and analysed along with 24 pvmsp-1 sequences downloaded from published data. Results have shown that: (i) parasites from the introduced case and the putative source of infection identified following epidemiological investigation, although very similar, differed in three nucleotide substitutions, of which one non synonymous; ii) some geographical isolates looked tightly clustered (e.g. Korean and Punjab isolates), but others were less so. Acta Trop 2002 Nov;84(2):83-92 Diversity of Plasmodium falciparum clones infecting children living in a holoendemic area in north-eastern Tanzania. Magesa SM, Mdira KY, Babiker HA, Alifrangis M, Farnert A, Simonsen PE, Bygbjerg IC, Walliker D, Jakobsen PH. National Institute for Medical Research, Ubwari Field Station, P.O. Box 81, Muheza, Tanzania The diversity of Plasmodium falciparum clones and their role in progression from asymptomatic to symptomatic condition in children have been investigated. Attempts to identify whether particular parasite genotypes were associated with the development of clinical symptoms have been made. A cohort of 34 initially asymptomatic parasitaemic children aged 1-5 years were followed daily for 31 days. Clinical examinations were made each day for signs and symptoms of clinical malaria, followed by parasitological investigation. Nineteen children developed symptoms suggestive of clinical malaria during this period. Daily blood parasite samples from 13 children who developed clinical malaria symptoms and 7 who remained asymptomatic were genotyped by PCR-amplification of the polymorphic regions of the merozoite surface proteins 1 and 2 (MSP1 and MSP2) and the glutamate rich protein (GLURP) genes. Infections were found to be highly complex in both groups of children. Every isolate examined from both groups had a mixture of parasite clones. Daily changes were observed in both parasite density and genotypic pattern. The mean number of genotypes per individual was estimated at 4.9 and 2.7 for asymptomatic and symptomatic groups of children, respectively. Analysis of allele frequency distributions showed that these differed significantly for the MSP1 locus only. Methods Find Exp Clin Pharmacol 2002 Sep;24(7):397-401 Studies on the antiplasmodial properties of some South African medicinal plants used as antimalarial remedies in Zulu folk medicine. Nundkumar N, Ojewole JA. Department of Biochemistry, Faculty of Science, University of Durban-Westville, Durban, South Africa. The parasite lactate dehydrogenase (pLDH) assay method, a recently developed in vitro enzymatic method for evaluating antimalarial compounds, was used to examine the antiplasmodial activities of the aqueous leaf, stem-bark and fruit extracts of some plants used for the treatment and/or prophylaxis of malaria in KwaZulu-Natal province of South Africa. The in vitro antiplasmodial assay was carried out using a chloroquine-sensitive strain of malarial parasite, Plasmodium falciparum D10. A preliminary phytochemical analysis of the plant extracts was carried out using UV spectral analysis and thin-layer chromatography (TLC) to separate the chemical constituents of the extracts. Their chemical components were subsequently identified by treating the TLC plates with various spray reagents. Of the 14 plant extracts investigated, only 10 were found to have IC50 values of 10-50 micrograms/ml. The two most active extracts were Psidium guajava stem-bark extract and Vangueria infausta leaf extract, both of which showed IC50 values of 10-20 micrograms/ml. Phytochemical analysis of these two active plant extracts revealed the presence of anthraquinones, flavonoids, seccoirridoids and terpenoids. J Biol Chem 2002 Nov 8; [epub ahead of print] Acidification of the malaria parasite’s digestive vacuole by a H(+)-ATPase and a H(+)-pyrophosphatase. Saliba KJ, Allen RJ, Zissis S, Bray PG, Ward SA, Kirk K. School of Biochemistry and Molecular Biology, Australian National University, Canberra, A.C.T. 0200. As it grows within the human erythrocyte, the malaria parasite, Plasmodium falciparum, ingests the erythrocyte cytosol, depositing it via an endocytotic feeding mechanism in the digestive vacuole, a specialised acidic organelle. The digestive vacuole is the site of hemoglobin degradation, the storage site for hemozoin (an inert biocrystal of toxic heme), the site of action of many antimalarial drugs and the site of proteins known to be involved in antimalarial drug resistance. The acidic pH of this organelle is thought to play a critical role in its various functions; however the mechanisms by which the pH within the vacuole is maintained are not well understood. In this study we have used a combination of techniques to demonstrate the presence on the P. falciparum digestive vacuole membrane of two discrete H(+) pumping mechanisms, both capable of acidifying the vacuole interior. One is a V-type H(+)-ATPase, sensitive to concanamycin A and bafilomycin A(1). The other is a H(+)-pyrophosphatase which was inhibited by NaF and showed a partial dependence on K(+). The operation of the H+-pyrophosphatase was dependent on the presence of a Mg(2+)/pyrophosphate complex and kinetic experiments gave results consistent with free pyrophosphate acting as an inhibitor of the protein. The presence of the combination of a H(+)-ATPase and a H(+)-pyrophosphatase on the P. falciparum digestive vacuole is similar to the situation in the acidic tonoplasts (vacuoles) of plant cells. Exp Parasitol 2002 Jun;101(2-3):121-8 Plasmodium chabaudi: rosetting in a rodent malaria model. Mackinnon MJ, Walker PR, Rowe JA. Institute of Cell, Animal and Population Biology, University of Edinburgh, West Mains Rd., Edinburgh, EH9 3JT, East Lothian, UK Rosetting is a property of many malaria parasite species that has been linked to virulence in the major species infecting humans, Plasmodium falciparum. Here, the basic properties of rosettes in the rodent malaria laboratory model, P. chabaudi, were studied with a view to future studies on the role of rosetting in malaria parasite virulence and transmission. Rosetting occurred in 14 out of the 15 P. chabaudi clones studied, varied consistently between clones, and ranged between 9 and 37% at full parasite maturity. Rosetting frequency markedly declined after the mouse reached peak parasitemia, possibly due to host immunity. Consistent with P. falciparum and P. vivax, rosettes in P. chabaudi were disrupted by treatment with trypsin and EDTA. However, P. chabaudi rosettes were insensitive to sulfated glycoconjugates (heparin, heparan sulfate and fucoidan). The molecular basis of rosetting in P. chabaudi is unknown at present, but the results suggest that the molecules involved may differ from those in human-infecting species.Index Descriptors and Abbreviations: Plasmodium chabaudi chabaudi, P. c. adami; rodent malaria; rosette; CI, confidence interval; EDTA, ethylene-diamine-tetraacetic acid; SEM, standard error of mean; BSA, bovine serum albumin. Exp Parasitol 2002 Jun;101(2-3):111-20 Plasmodium falciparum: analysis of transcribed var gene sequences in natural isolates from the Brazilian Amazon region. Afonso Nogueira P, Wunderlich G, Shugiro Tada M, d’Arc Neves Costa J, Jose Menezes M, Scherf A, Pereira-da-Silva LH. Centro de Pesquisa em Medicina Tropical, CP 87, Correio Central, 78.910-210 Porto Velho, Rondonia, Brazil Parasite isolates from Brazilian Western Amazonian patients suffering from uncomplicated falciparum malaria were matured in vitro and their var gene transcripts were analysed by RT-PCR and sequencing. Additionally, the cytoadherence patterns of these isolates were determined by panning techniques using transfected CHO cell lines expressing different surface receptors. All of the isolates tested showed between 4 and 13 different var gene transcripts per isolate. Several of these transcripts were present in more than one isolate and three sequences appeared to be preferentially expressed in natural infections. In most of the isolates, cytoadherence occurred to the receptors ICAM-1 and CD36. Several isolates showed a multiadherent profile. Analysis of MSP1 and MSP2 allelic polymorphism indicated polyclonal infections, that could be responsible for the multiadherent phenotype. Cell Microbiol 2002 Nov;4(11):713-24

Molecular interactions between Plasmodium and its insect vectors.

Sinden RE.

Biological Sciences Department, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK.

Our understanding of the intricate interactions between the malarial parasite and the mosquito vector is complicated both by the number and diversity of parasite and vector species, and by the experimental inaccessibility of phenomena under investigation. Steady developments in techniques to study the parasite in the mosquito have recently been augmented by methods to culture in their entirety the sporogonic stages of some parasite species. These, together with the new saturation technologies, and genetic transformation of both parasite and vector will permit penetrating studies into an exciting and largely unknown area of parasite-host interactions, an understanding of which must result in the development of new intervention strategies. This microreview highlights key areas of current basic molecular interest, and identifies numerous lacunae in our knowledge that must be filled if we are to make rational decisions for future control strategies. It will conclude by trying to explain why in the opinion of this reviewer understanding malaria-mosquito interactions may be critical to our future attempts to limit a disease of growing global importance. J Ethnopharmacol 2002 Dec;83(3):219-228 Evaluation of selected Sudanese medicinal plants for their in vitro activity against hemoflagellates, selected bacteria, HIV-1-RT and tyrosine kinase inhibitory, and for cytotoxicity. Ali H, Konig GM, Khalid SA, Wright AD, Kaminsky R. Institut fur Pharmazeutische Biologie, University of Bonn, Nussallee 6, D-53115, Bonn, Germany Ethnobotanical investigations led to the selection of 19 plant species, used traditionally in Sudan against malaria and other similar tropical diseases, for further studies. Pamianthe peruviana (Amaryllidaceae) exhibited significant activity against a chloroquine-resistant Plasmodium falciparum strain (K1) and a chloroquine-sensitive strain (NF54) with IC(50) values of 0.6 and 1.1 &mgr;g/ml, respectively. Additionally, P. peruviana showed considerable activities against Trypanosoma brucei rhodesiense (IC(50) 1.5 &mgr;g/ml) and T. cruzi (IC(50) 11.8 &mgr;g/ml). The antiplasmodial activity of the different extracts of Salvadora persica (Salvadoraceae) against P. falciparum NF54 strain were found to be 0.6 &mgr;g/ml (stems) and 0.7 &mgr;g/ml (leaves). Extracts of different parts of Combretum hartmannianum (Combretaceae) possessed significant activity against the chloroquine-sensitive P. falciparum strain (NF54) with IC(50) values of 0.2 &mgr;g/ml (bark), 0.4 &mgr;g/ml (stem) and 4.3 &mgr;g/ml (leaves). Most interestingly, the extracts of the leaves of C. hartmannianum totally inhibited the enzyme HIV-1 reverse transcriptase (HIV-1 RT) at a concentration of 66 &mgr;g/ml. A comparably strong activity against p56(lck) tyrosine kinase was also seen for this extract. Indian J Med Res 2002 Jan;115:17-21 Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria. Mohanty D, Ghosh K, Pathare AV, Karnad D. Institute of Immunohaematology (ICMR), KEM Hospital, Mumbai, India.

BACKGROUND & OBJECTIVES: Mortality due to Plasmodium falciparum infection remains high in India, hence any modality of treatment which can improve the outcome of this disease is worth exploring. The present study was undertaken to see whether addition of an oral iron chelator, deferiprone (L1) to the conventional treatment regime for P. falciparum infection improves the clinical course and final outcome. METHODS: In this prospective, randomised double blind trial, 45 consecutive patients with P. falciparum infection were randomised into two groups. Patients in Group I (control group, 21 patients) received standard quinine and doxycycline therapy along with supportive therapy and placebo capsules for 10 days. Patients in Group II (24 patients) received the same treatment as Group I but in place of placebo capsule received deferiprone capsules 75 mg/kg/day in 12 hourly divided doses. The parameters evaluated included the time taken in resolution of parasitaemia, fever and coma, differences in final outcome i.e., death or other severe complications, and side effects and deferiprone tolerance. RESULTS: Four patients in Group I and two in Group II died (P > 0.05). The resolution of fever and coma was significantly faster in Group II (P < 0.05) and parasitaemia cleared 24 h earlier in this Group. The drug was well tolerated and had no side effects.

INTERPRETATION & CONCLUSION: Deferiprone (L1) seems to be a promising agent as an adjuvant in the treatment for severe P. falciparum malaria infection.

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