EHP Library Malaria Bulletin No. 32: March 1-15, 2002

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The malaria educational site from Royal Perth Hospital, is now available in French, English and Spanish. The English site can be accessed at:

The site contains sections on Diagnosis, Prophylaxis, Treatment and History as well as an innovative interactive “Test & Teach” self assessment module. It is an ideal site for Clinicians, Scientists, Healthcare Professionals and Students. The MK IV version of a trilingual (English/Spanish/French) CD-ROM (Proudly sponsored by Abbott Diagnostics) with the same content as the web site is now ready for distribution (FREE) to institutions without, or with only limited internet access. (The CD-ROM is now being used by medical/educational institutions in 126 countries).

Graham ICKE, A/Principal Scientist, Division of Laboratory Medicine  Royal Perth Hospital, Wellington St., Perth Western Australia 6000
E-Mail: [email protected]

Social Sciences and Malaria

West African Journal of Medicine. 20(2):152-7, 2001 Apr-Jun.

Knowledge and home management of malaria fever by mothers and care givers of under five children.

Fawole OI. Onadeko MO.

Department of Preventive and Social Medicine, College of Medicine, University College Hospital, Ibadan, Nigeria.

This study documents the knowledge and home management practices of 376 mothers and care givers of under five children on malaria fever. Results revealed that both the knowledge and case management practices were poor as only 179 (46.8%) knew how malaria was transmitted. Of those who knew malaria could be prevented, clearing of bushes and gutters was the commonly stated method (78 or 21.8%), followed by the use of traditional herbs. ‘Agbo’ by 75(20.9%) mothers. The elders and friends were stated to be the major source of knowledge about malaria by 141(37.5%) mothers.

Knowledge scores was significantly higher in older mothers, among the educated, and skilled mothers (P<0.05). As regards practices, self-medication with modern drugs was common, these drugs had been given in the home by 265(70.5%) mothers while “Agbo”, had been used by 95(25.5%) mothers before presenting at the clinic. Paracetamol was the modern drug often used (217 or 81.8%). Followed by chloroquine (57 or 21.5%). However, drug treatment practice were often incorrect. Chloroquine was prescribed correctly by 15(26.3%) mothers, while 109(50.2%) gave the correct dose of paracetamol. Only 16(4.3%) of the children received anti-malarial on the day the illness began. There is the need for education programmes on malaria for mothers, especially for young, illiterate and unskilled mothers, including the family elders. 

PUBMEDRev Saude Publica 2002 Feb;36(1):75-80

Intra-population plasticity of Anopheles darlingi’s (Diptera, Culicidae) biting activity patterns in the state of Amapa, Brazil.

Voorham J.

Instituto de Pesquisas Cientificas e Tecnologicas do Estado do Amapa (IEPA), Amapa, Brazil.

OBJECTIVE: To assess the variation in Anopheles darlingi’s biting activity compared to An. marajoara in the same locality and to biting activity data from other regions. METHODS: Using human bait, eight observations of the biting activity of An. darlingi and An. marajoara were carried out during 1999 and 2000 in the municipality of Sao Raimundo do Pirativa, state of Amapa, Brazil. Each observation consisted of three consecutive 13-hour collections, close to full moon. There were shifts of collectors in the observation points and nocturnal periods. RESULTS: An. darlingi revealed considerable plasticity of biting activity in contrast to An. marajoara, which showed well-defined crepuscular biting peaks. No significant correlation between density and biting activity was found, but a significant correlation existed between time and proportional crepuscular activity, indicating underlying ecological processes not yet understood. Two of the four available data sets having multiple observations at one locality showed considerable plasticity of this species’ biting patterns as well. CONCLUSION: Intra-population variation of biting activity can be as significant as inter-population variation. Some implications in malaria vector control and specific studies are also discussed.

Proc R Soc Lond B Biol Sci 2002 Feb 22;269(1489):431-6

A large gene family for putative variant antigens shared by human and rodent malaria parasites.

Janssen CS, Barrett MP, Turner CM, Phillips RS.

Division of Infection and Immunity, IBLS, University of Glasgow, Glasgow G12 8QQ, UK.

A major mechanism whereby malaria parasites evade the host immune response to give chronic infections in patients’ blood for months, or even years, is antigenic variation. In order to generate variant antigens, parasites require large multigene families. Although several gene families involved in these phenomena have been identified in the human malaria Plasmodium falciparum, to date no variant antigen gene families have been identified in malaria species that will infect widely used rodent laboratory hosts. Here we present, for the first time, to our knowledge, a large multigene family conserved in both rodent and human malarias, which is a strong candidate as a major variant antigen gene family. In each of four species of Plasmodium, three rodent malarias and the human pathogen P. vivax, homologues of the gene family were found to have a conserved three-exon structure. In the rodent malaria P. chabaudi, transcription of members of the gene family was developmentally regulated with maximum expression in late trophozoite stages, which is the developmental stage known to express variant antigen proteins.

Mol Ecol 2001 Nov;10(11):2577-91

Population genetic structure of the malaria mosquito Anopheles arabiensis across Nigeria suggests range expansion.

Onyabe D Y, Conn J E.

Department of Biology, The University of Vermont, Burlington 05405, USA.

Ten microsatellite loci, four located within and six outside chromosome inversions, were employed to study the genetic structure of Anopheles arabiensis across the ecological zones of Nigeria (arid savannah in the north gradually turns into humid forest in the south). Regardless of location within or outside inversions, genetic variability at all loci was characterized by a reduction in both the number of alleles per locus and heterozygosity from savannah to forest. Across all loci, all but one allele in the forest also occurred in the savannah, whereas at least 78 alleles in the savannah were missing in the forest. Genetic differentiation increased with geographical distance; consequently, genetic distances between zones exceeded those within zones. The largest genetic distances were between localities at the extremes of the transect (range F(ST) = 0.196-0.258 and R(ST) = 0.183-0.468) and were as large as those between A. arabiensis and Anopheles gambiae s.s. Gene flow across the country was very low, so that Nm between the extremes of the transect was < 1. These data suggest that A. arabiensis has extended its range from the savannah into the forest during which it experienced a reduction in effective population size due to sequential founder effects. Gene flow post range expansion appears too restricted by geographical distance to homogenize the gene pool of A. arabiensis across Nigeria.

Clin Exp Immunol 2002 Jan;127(1):158-64

High prevalence of co-factor independent anticardiolipin antibodies in malaria exposed individuals.

Consigny PH, Cauquelin B, Agnamey P, Comby E, Brasseur P, Ballet JJ, Roussilhon C.

Laboratoire de Parasitologie, UPRES-3234, Faculte de Medecine-Pharmacie, Rouen, France.

Anticardiolipin antibodies (aCL) were investigated in 137 individuals chronically exposed to malaria and living in Africa and Asia. They belonged to several groups according to parasite (Plasmodium falciparum or vivax) and clinical manifestations (i.e. asymptomatic parasite carriers, acute uncomplicated attack or severe malaria episodes). aCL were measured in an enzyme immunoassay (ELISA) performed in the presence of either goat serum (aCLs) or gelatin (aCLg). In a group of 53 patients with autoimmune manifestations (i.e. antiphospholipid syndrome and/or lupus), detection of IgG but not IgM aCL was markedly reduced in the presence of gelatin. In malaria donors, high prevalence of serum co-factor-independent IgG and IgM were detected, and the presence of goat serum in the assay consistently decreased their detection. aCLg levels were found to be related to the clinical/endemic status of donors. IgG aCLg were found to be higher in asymptomatic P. falciparum carriers than in patients with uncomplicated acute or cerebral malaria. IgM aCLg were higher in the cerebral malaria group than in groups with uncomplicated acute malaria patients or asymptomatic individuals. Data suggest that using a serum co-factor independent, sensitive ELISA, aCL are commonly detected during malarial infections and related to malarial infection status.

Clin Exp Immunol 2002 Jan;127(1):151-7

Cytokine production and apoptosis among T cells from patients under treatment for Plasmodium falciparum malaria.

Kemp K, Akanmori BD, Adabayeri V, Goka BQ, Kurtzhals JA, Behr C, Hviid L.

Centre for Medical Parasitology at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet) and Institute for Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark. 
Email: [email protected]

Available evidence suggests that Plasmodium falciparum malaria causes activation and reallocation of T cells, and that these in vivo primed cells re-emerge into the periphery following drug therapy. Here we have examined the cytokine production capacity and susceptibility to programmed cell death of peripheral T cells during and after the period of antimalarial treatment. A high proportion of peripheral CD3+ cells had an activated phenotype at and shortly after time of admission (day 0) and initiation of therapy. This activation peaked around day 2, and at this time-point peripheral T cells from the patients could be induced to produce cytokines at conditions of limited cytokine response in cells from healthy control donors. Activated CD8hi and TCR-gammadelta+ cells were the primary IFN-gamma producers, whereas CD4+ cells constituted an important source of TNF-alpha. The proportion of apoptotic T cells was elevated at admission and peaked 2 days later, while susceptibility to activation-induced cell death in vitro remained increased for at least 1 week after admission. Taken together, the data are consistent with the concept of malaria-induced reallocation of activated T cells to sites of inflammation, followed by their release back into the peripheral blood where they undergo apoptotic death to re-establish immunological homeostasis as inflammation subsides. However, the high proportion of pre-apoptotic cells from the time of admission suggests that apoptosis also contributes to the low frequency and number of T cells in the peripheral circulation during active disease.

Insect Mol Biol 2001 Oct;10(5):427-35

A multiplex PCR-based method derived from random amplified polymorphic DNA (RAPD) markers for the identification of species of the Anopheles minimus group in Southeast Asia.

Kengne P, Trung H D, Baimai V, Coosemans M, Manguin S.

IRD, Department of Societe & Sante, Montpellier, France.

Effective control of Anopheles minimus s.l., an important malaria vector in Southeast Asia, is based on the accurate identification of species within An. minimus complex, which cannot be distinguished using morphological characters. Derived from individual random amplified polymorphic DNA markers, sequence characterized amplified regions were analysed for the design of species-specific paired-primers. Combination of these primers resulted in the development of a simple, robust multiplex PCR able to identify both species An. minimus A and C belonging to the complex, hybrids AC, and three sympatric and closely related species, An. aconitus, An. pampanai and An. varuna. Hybrids AC do not possess alleles of both parents but exhibit novel adaptive potentials resulting from recombination among parental genes leading to hybrizyme.

Parasitol Int 2002 Mar;51(1):99-103

Stage specificity of Plasmodium falciparum telomerase and its inhibition by berberine.

Sriwilaijareon N, Petmitr S, Mutirangura A, Ponglikitmongkol M, Wilairat P.

Department of Biochemistry, Faculty of Science, Mahidol University, Rama 6 Road, 10400, Bangkok, Thailand

Telomerase activity in synchronized Plasmodium falciparum during its erythrocytic cycle was examined using the TRAP assay. Telomerase activity was detected at all stages of the parasite intraerythrocyte development, with higher activity in trophozoite and schizont stages compared with ring form. Berberine, extracted from Arcangelisia flava (L.) Merr., inhibited telomerase activity in a dose-dependent manner over a range of 30–300 &mgr;M, indicating that P. falciparum telomerase might be a potential target for future malaria chemotherapy.

Parasitol Int 2002 Mar;51(1):17-23

A rodent malaria, Plasmodium berghei, is experimentally transmitted to mice by merely probing of infective mosquito, Anopheles stephensi.

Matsuoka H, Yoshida S, Hirai M, Ishii A.

Department of Medical Zoology, Jichi Medical School, Minami-kawachi, 329-0498, Tochigi, Japan

We found that infection of a rodent malaria, Plasmodium berghei, occurred when the sporozoites were injected into the skin, the muscle, the peritoneal cavity and the tail end. Mice, which were injected with sporozoites in the tail end and had the site cut 5 min later, did not develop malaria. We also found that mice developed malaria when malaria infective mosquitoes, Anopheles stephensi, were forced not to take blood but only to probe into the skin. Moreover, the mice probed by the infective mosquitoes were protected from malaria infection if the site was treated with Kyu (heat treatment) after the mosquitoes had probed. These findings indicate that malaria infection occurs not only by blood feeding of the infective mosquito but also by probing of the mosquito. Sporozoites injected into the skin remain at the injected site for at least 5 min, then migrate to the blood vessels and invade into the blood stream. At present, the mechanism is not clear, although we propose here the existence of the skin stage of malaria parasites before the liver stage and the blood stage.

Parasitol Int 2002 Mar;51(1):1-7

Recombinant Mycobacterium bovis BCG producing the circumsporozoite protein of Plasmodium falciparum FCC-1/HN strain induces strong immune responses in BALB/c mice.

Zheng C, Xie P, Chen Y.

Institute of Infectious and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, PR China

The current vaccine against tuberculosis, Mycobacterium bovis strain bacillue Calmette–Guerin (BCG), offers potential advantages as a live, innately immunogenic vaccine vehicle for expression and delivery of protective recombinant antigens. Malaria is one of the severest parasitic diseases in humans especially in the developing world. No efficacious vaccine is currently available. However, circumsporozoite protein (CSP) is a malaria vaccine candidate currently undergoing clinical trials. We analyzed the immune response to recombinant BCG (rBCG) vaccine expressing Plasmodium falciparum CSP (BCG-CSP) under the control of heat shock protein 70 promoter in BALB/c mice. The lymphocytes proliferative response to P. falciparum soluble antigen was significantly higher than those in the groups of BCG and normal saline, and the production of cytokines (IFN-gamma and IL-2) in response to malaria antigen was significantly higher in rBCG and BCG groups than control group of normal saline. A specific IgG antibody response against P. falciparum antigen of CSP was also characterized. The booster injection could enhance the production of cytokine, proliferation responses of spleen lymphocytes and the antibodies titer of BCG-CSP. The results in the study demonstrated that rBCG vaccine producing CSP is an appropriate vaccine for further evaluation in non-human primates.

Microbes Infect 2002 Feb;4(2):175-82

Basis for antifolate action and resistance in malaria.

Yuthavong Y.

National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Rama 6 Road, 10400, Bangkok, Thailand

Resistance to antifolates of the malaria parasite Plasmodium falciparum stems from stepwise mutations of the target enzyme dihydrofolate reductase (DHFR). New drugs can be developed against resistant parasites, which are assumed to have limited possibilities in mutations. Mechanisms of resistance other than reduced binding of inhibitors to mutant enzymes may be possible and need to be further explored. New synergistic combinations of drugs targeting DHFR and dihydropteroate synthase may be employed, with new provisions against development of resistance.

Microbes Infect 2002 Feb;4(2):165-74

Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs.

Hyde JE.

Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, M60 1QD, Manchester, UK

Chemotherapy and chemoprophylaxis are the principal means of combating malaria parasite infections in the human host. In the last 75 years, since the introduction of synthetic antimalarials, only a small number of compounds have been found suitable for clinical usage, and this limited armoury is now greatly compromised by the spread of drug-resistant parasite strains. Our current knowledge of the molecular mechanisms underlying resistance in the lethal species Plasmodium falciparum is reviewed here.

Int J Pharm 2002 Mar 20;235(1-2):229-236

Triclosan: release from transdermal adhesive formulations and in vitro permeation across human epidermal membranes.

Chedgzoy P, Winckle G, Heard CM.

Welsh School of Pharmacy, Cardiff University, CF10 3XF, Cardiff, UK

Malarial resistance is an escalating global problem and consequently new and more efficacious treatments to combat malaria are urgently needed. The transdermal delivery of anti-malarials may provide an effective alternative or adjunct to conventional regimens. Triclosan is widely used as an anti-bacterial agent and it has recently been demonstrated that this compound has anti-malarial properties. Its high lipophilicity makes it a potential candidate for delivery across the skin and this paper examines in vitro the potential for the transdermal delivery of triclosan from ‘drug-in-glue’ formulations. Model patches were prepared using DuroTak(R) 2287, 2516 and 2051 acrylic polymer adhesives loaded with 0, 30 and 50 mg per 0.785 cm(minus sign2) triclosan and dissolution was measured over a 12-h period. There was no apparent difference between the adhesives at the 30 mg patch loading, but at 50 mg, the trend for increased release was 2051>2516>2287. No significant burst effect was apparent. Patches of 50 mg per 0.785 cm(2) were then used to determine the permeation of triclosan across heat-separated human epidermal membranes in Franz diffusion cells, over a period of 48 h. The above general trend was reflected in the steady state flux values obtained: 2051:16.91 &mgr;g cm(minus sign2) h(minus sign1) (S.E.M. 1.29), 2516:15.05 &mgr;g cm(minus sign2) h(minus sign1) (S.E.M. 1.00), 2287 12.83 &mgr;g cm(minus sign2) h(minus sign1) (S.E.M. 2.81). Although pharmacokinetic data are not currently available to permit calculation of an efficacious patch size, the transdermal delivery of triclosan is feasible.

Int J Pharm 2002 Mar 20;235(1-2):219-227

Binding of doxycycline to keratin, melanin and human epidermal tissue.

Banning TP, Heard CM.

Welsh School of Pharmacy, Cardiff University, CF10 3XF, Cardiff, UK

Doxycycline is licensed for the prophylaxis of malaria and recent research has indicated the feasibility of delivering this drug across the skin. The binding of doxycycline to keratin could influence skin permeation rates and it has been suggested that the interaction of anti-malarials with melanin may contribute to side effects, such as retinal damage. Doxycycline HCl was incubated with keratin (bovine horn), melanin (Sepia officinalis) and human epidermal samples (native and delipidised). Dose dependent binding of doxycycline to keratin and melanin was observed, and was of similar magnitude for each protein. However, the binding of doxycycline to melanin was lower by an order of magnitude relative to data previously reported for some other anti-malarials, and may indicate reduced side-effects. Doxycycline also demonstrated significantly greater affinity for native epidermal skin than for delipidised skin showing that doxycycline, a charged polar molecule, has affinity for the intercellular lipid matrix in addition to the proteinaceous domain. For native skin it was estimated that saturation would be reached at approximately 140 &mgr;g cm(minus sign2); for delipidised skin it was estimated to be 60 &mgr;g cm(minus sign2). Overall, the data suggested that the partition-diffusion steps that are involved in transcellular permeation are possible.

J Exp Med 2002 Mar 4;195(5):617-624

Natural Killer T Cell Ligand alpha-Galactosylceramide Enhances Protective Immunity Induced by Malaria Vaccines.

Gonzalez-Aseguinolaza G, Van Kaer L, Bergmann CC, Wilson JM, Schmieg J, Kronenberg M, Nakayama T, Taniguchi M, Koezuka Y, Tsuji M.

Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10010. Howard Hughes Medical Institute, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232. Department of Neurology, University of Southern California, Los Angeles, CA 90033. Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, PA 19104. Division of Developmental Immunology, La Jolla Institute of Allergy and Immunology, San Diego, CA 92121. Department of MolecularImmunology, Chiba University School of Medicine, Chiba 260, Japan. Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma 370, Japan.

The important role played by CD8(+) T lymphocytes in the control of parasitic and viral infections, as well as tumor development, has raised the need for the development of adjuvants capable of enhancing cell-mediated immunity. It is well established that protective immunity against liver stages of malaria parasites is primarily mediated by CD8(+) T cells in mice. Activation of natural killer T (NKT) cells by the glycolipid ligand, alpha-galactosylceramide (alpha-GalCer), causes bystander activation of NK, B, CD4(+), and CD8(+) T cells. Our study shows that coadministration of alpha-GalCer with suboptimal doses of irradiated sporozoites or recombinant viruses expressing a malaria antigen greatly enhances the level of protective anti-malaria immunity in mice. We also show that coadministration of alpha-GalCer with various different immunogens strongly enhances antigen-specific CD8(+) T cell responses, and to a lesser degree, Th1-type responses. The adjuvant effects of alpha-GalCer require CD1d molecules, Valpha14 NKT cells, and interferon gamma. As alpha-GalCer stimulates both human and murine NKT cells, these findings should contribute to the design of more effective vaccines against malaria and other intracellular pathogens, as well as tumors.

J Biol Chem 2002 Mar 4

Thioredoxin-2 but not thioredoxin-1 is a substrate of thioredoxin peroxidase-1 from Drosophila melanogaster – Isolation and characterization of a second thioredoxin in D. melanogaster and evidence for distinct biological functions of Trx-1 and Trx-2.

Bauer H, Kanzok SM, Schirmer RH.

Biochemiezentrum Heidelberg, Heidelberg University, Heidelberg, Baden-Wrttemberg 69120.

As Drosophila melanogaster does not contain glutathione reductase the thioredoxin system has a key function for glutathione disulfide reduction in insects (Kanzok S. M., Fechner A., Bauer H. et al. Science 291, 643-647). In view of these unique conditions, the protein systems participating in peroxide metabolism and in redox signaling are of special interest. The genes for a second thioredoxin (DmTrx-2) and a thioredoxin peroxidase (DmTPx-1) were cloned and expressed, and the proteins were characterized. In its disulfide form, the 13 kDa protein thioredoxin-2 is a substrate of thioredoxin reductase-1 (K(m) = 5.2 &mgr;M, k(cat) = 14.5 s(-1)) and in its dithiol form an electron donor of TPx-1 (K(m) = 9 &mgr;M, k(cat) = 5.4 s(-1) ). DmTrx-2 is capable to reduce glutathione disulfide with a second order rate constant of 0.01 &mgr;M(-1) min(-1) at pH 7.4 and 25 C. Western blot analysis indicated that this thioredoxin represents up to 1% of the extractable protein of D. melanogaster Schneider cells or whole fruit flies. Recombinant thioredoxin peroxidase-1 (subunit M(r) = 23 kDa) was found to be a decameric protein that can efficiently use Trx-2 but not Trx-1 as a reducing substrate. The new electron pathway found in D. melanogaster is also representative for insects that serve as vectors of disease. As a first step we have cloned and functionally expressed the gene that is the orthologue of DmTrx-2 in the malaria mosquito Anopheles gambiae.

Ultrasound Obstet Gynecol 2002 Feb;19(2):165-170

Impaired uteroplacental blood flow in pregnancies complicated by falciparum malaria.

Dorman EK, Shulman CE, Kingdom J, Bulmer JN, Mwendwa J, Peshu N, Marsh K.

Kenya Medical Research Institute (KEMRI), Centre for Geographical Medicine Research, Coast, Kilifi, Kenya, London School of Hygiene and Tropical Medicine, London, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, Department of Pathology, University of Newcastle, Royal Victoria Infirmary, Newcastle upon Tyne, UK, Department of Maternal-Fetal Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada and Department of Obstetrics and Gynaecology, Homerton Hospital, London, UK.

Objective: In endemic areas, maternal malaria infection is usually asymptomatic. However, it is known that infected maternal erythrocytes sequester in the intervillous space of the placenta. There is a strong association between placental malaria infection and both low birth weight (LBW) and severe maternal anemia. We aimed to determine whether impaired uteroplacental blood flow might account for the low infant birth weight associated with maternal falciparum malaria infection. METHODS: This observational study was carried out during a large double-blind, randomized, controlled trial of an antimalarial drug intervention for primigravidae. Nine hundred and ninety-five women were recruited from the antenatal clinic at a district hospital on the Kenya coast and had at least one Doppler ultrasound scan. Uterine artery resistance index and the presence or absence of a diastolic notch were recorded. In the third trimester, blood was taken for hemoglobin and malaria film. RESULTS: Malaria infection at 32–35 weeks of gestation was associated with abnormal uterine artery flow velocity waveforms on the day of blood testing (relative risk (RR) 2.11, 95% confidence interval (CI) 1.24–3.59, P = 0.006). This association persisted after controlling for pre-eclampsia. Impaired uteroplacental blood flow in the women studied was also predictive of poor perinatal outcome, including low birth weight, preterm delivery and perinatal death. The risk of preterm delivery in women with histological evidence of past placental malaria infection was more than twice that of women without infection (RR 2.33, 95% CI 1.31–4.13, P = 0.004). CONCLUSIONS: Uteroplacental hemodynamics are altered in the presence of maternal falciparum malaria infection. This may account for some of the excess of LBW babies observed in malaria endemic areas. Strategies that prevent or clear placental malaria may confer perinatal benefit through preservation of placental function.

Clin Diagn Lab Immunol 2002 Mar;9(2):348-51

Role of Th1 and Th2 Cytokines in Immune Response to Uncomplicated Plasmodium falciparum Malaria.

Torre D, Speranza F, Giola M, Matteelli A, Tambini R, Biondi G.

Department of Infectious Diseases, Regional Hospital and Macchi Foundation. Institute of Infectious Diseases, University of Brescia Brescia, Italy.

The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-gamma), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-gamma, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 plus minus 2.8 pg/ml; controls, 3.2 plus minus 0.7 pg/ml) and IFN-gamma (39.2 plus minus 67.6 pg/ml; controls, 8.4 plus minus 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 plus minus 2.6 pg/ml), whereas IFN-gamma levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 plus minus 200.4 pg/ml and 56.6 plus minus 38.4 pg/ml, respectively; controls, 17.4 plus minus 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 plus minus 1.2 pg/ml; controls, 2.4 plus minus 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 plus minus 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-gamma levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-gamma may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.

Parasite Immunol 2002 Feb;24(2):77-82

Naturally acquired immunoglobulin (Ig)G subclass antibodies to crude asexual Plasmodium falciparum lysates: evidence for association with protection for IgG1 and disease for IgG2.

Ndungu FM, Bull PC, Ross A, Lowe BS, Kabiru E, Marsh K.

Kenya Medical Research Institute Centre for Geographical Medicine Research-Coast, Kilifi, Kenya, Zoology Department, Kenyatta University, Nairobi and Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.

There is longstanding evidence for a role of immunoglobulin (Ig)G in protection against malarial disease and infection. IgG1 and IgG3 have been shown to be particularly efficient at associating with monocytes in potentially protective mechanisms (i.e. antibody-dependent cellular inhibition, opsonization and phagocytosis). Conversely, there is some evidence that IgG2 (and possibly IgG4) antibodies may be antagonistic to this protection. The protective effect of IgG subclass antibody activity present before the beginning of a malaria transmission season (preseason antibody levels) against severe malaria has not been tested in longitudinal studies. We measured IgG class and subclass antibody levels specific to crude Plasmodium falciparum lysates by enzyme linked immunosorbent assay in a case–control study of 76 children on the coast of Kenya. The mean optical density values for both IgG class and subclass antibodies were not significantly different between the children who developed severe malaria and those who remained healthy during an observation period of two malaria transmission seasons. However, elevated levels of IgG1 in relation to levels of IgG2 and IgG4 antibodies were associated with protection from severe malaria (P = 0center dot02). Conversely, elevated levels of IgG2 in relation to IgG1 and IgG3 antibodies were associated with a higher risk of developing severe malaria (P = 0center dot006).

Trends Parasitol 2001 Nov;17(11):538-45

Decoding the language of var genes and Plasmodium falciparum sequestration.

Smith JD, Gamain B, Baruch DI, Kyes S.

Dept of Pathology, Colorado State University, 80523, Fort Collins, CO, USA

Sequestration and rosetting are key determinants of Plasmodium falciparum pathogenesis. They are mediated by a large family of variant proteins called P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 proteins are multispecific binding receptors that are transported to parasite-induced, ‘knob-like’ binding structures at the erythrocyte surface. To evade immunity and extend infections, parasites clonally vary their expressed PfEMP1. Thus, PfEMP1 are functionally selected for binding while immune selection acts to diversify the family. Here, we describe a new way to analyse PfEMP1 sequence that provides insight into domain function and protein architecture with potential implications for malaria disease.

Trends Parasitol 2001 Nov;17(11):525-31

Evolution of gametocyte sex ratios in malaria and related apicomplexan (protozoan) parasites.

West SA, Reece SE, Read AF.

Institute of Cell, Animal and Population Biology, University of Edinburgh, EH9 3JT, Edinburgh, UK

‘Survival of the fittest’ is usually interpreted to mean that natural selection favours genes that maximize their transmission to the next generation. Here, we discuss recent applications of this principle to the study of gametocyte sex ratios in malaria and other apicomplexan parasites. Sex ratios matter because they are an important determinant of fitness and transmission success — and hence of disease epidemiology and evolution. Moreover, inbreeding rates can be estimated from gametocyte sex ratios. The sex ratio is also an excellent model trait for testing the validity of important components of what is being marketed as ‘Darwinian medicine’.

J Biochem (Tokyo) 2002 Mar;131(3):437-44

Effect of antifungal azoles on the heme detoxification system of malarial parasite.

Huy NT, Kamei K, Kondo Y, Serada S, Kanaori K, Takano R, Tajima K, Hara S.

Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. 
Email: [email protected]

The antimalarial activities of some antifungal azole agents (ketoconazole, miconazole, and clotrimazole) have been known for several years, however, their antimalarial mechanism remains equivocal. Our recent study showed that clotrimazole has a relative high affinity for heme, inhibits reduced glutathione-dependent heme catabolism, and enhances heme-induced hemolysis. In the present study, we have found that clotrimazole can remove heme from histidine rich peptide-heme complex, which initiates heme-polymerization in malaria. In addition, we show that two other azoles (ketoconazole and miconazole) behave similarly to clotrimazole in binding to heme: they bind to heme with similar affinities, remove heme from the histidine rich peptide-heme complex and from the reduced glutathione-heme complex to form stable heme-azole complexes with two nitrogenous ligands derived from the imidazole moieties of two azole molecules. We have also revealed that clotrimazole and miconazole have stronger promoting activities for heme-induced hemolysis than ketoconazole, implying that the stronger antimalarial activities of clotrimazole and miconazole might arise from their stronger ability to promote heme-induced hemolysis of clotrimazole and clotrimazole than that of ketoconazole. These results also suggest that ketoconazole and miconazole, like clotrimazole, might possess an antimalarial mechanism relating to their inhibition of heme polymerization and the degradation of reduced glutathione-dependent heme.

Lancet Infect Dis 2001 Nov;1(4):242-50

Modern chemotherapeutic options for malaria.

Winstanley P.

Department of Pharmacology and Therapeutics, and Wellcome Trust Centre for Research in Clinical Tropical Medicine, University of Liverpool, UK. 
Email: [email protected]

Unlike HIV disease or tuberculosis, both of which are also major threats to public health throughout the tropics, uncomplicated malaria of whatever species can be cheaply and rapidly cured, usually in outpatients. However, in common with both HIV and tuberculosis, control of malaria is threatened by inadequate resources and by drug resistance. Africa carries the greatest burden of malaria mortality and morbidity; by no coincidence, Africa is also the most resource-limited. The drugs for severe disease (quinine and the artemisinins) are largely unaffected by resistance so far, but the “first-line” drugs, mainly used by outpatients (eg, chloroquine and sulfadoxine-pyrimethamine), are a major cause for concern. Although effective drugs are available they are mostly too expensive for routine use. This article reviews the main drugs for malaria and outlines the therapeutic use of these drugs for uncomplicated and severe disease. The article then examines the challenges faced in the processes of changing policy, and the implementation of that policy shift.

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