EHP Library Malaria Bulletin 54

Feb 24 – Mar 9, 2003

Announcements

ICDDRB’s Dr. Yukiko Wagatsuma may convene a special session on malaria research in Asia for the Dec. 7-9, 2003 Asian Conference on Diarrheal Diseases and Nutrition. She is seeking malaria researchers from India, Nepal, Burma, and Thailand to present papers. Contact her directly at: [email protected]

Social Sciences and Malaria Control

Asia Pac J Public Health 2001;13(2):100-8 

Differing health and health-seeking behaviour: ethnic minorities of the Chittagong Hill Tracts, Bangladesh.

Ahmed SM.

Research and Evaluation Division, BRAC Centre, Dhaka, Bangladesh. Email: [email protected]

This study investigates the health and health-seeking behaviour of the indigenous population of Chittagong Hill Tracts, Bangladesh by surveying 2,550 randomly selected households from five major ethnic groups residing in the region. A structured questionnaire was used for collecting data. Morbidity prevalence (23%) and child malnutrition (19%) was highest among Bangalis.  Fever (40%), diarrhoeal diseases (37%) and malaria (16%) were the three most common illnesses reported among the study population. Around fifteen percent of the Bangalis sought care from the paraprofessionals while ‘unqualified’ allopaths were consulted more frequently by the Tripuras, Chakmas and the Marmas (60-70%). Qualified allopaths were mostly consulted by the Bangalis (26%). Sex, types of illness, ethnicity, household head’s education and household’s landholding were significant predictors of seeking treatment, and allopathic treatment in particular. The findings on the differential health and health-seeking behaviour among ethnic groups should help in the designing of any future health interventions in the area.

Health Policy & Planning. 17(4):402-11, 2002 Dec.

Willingness to pay for treated mosquito nets in Surat, India: the design and descriptive analysis of a household survey.

Bhatia MR. Fox-Rushby JA.

Department of Social Policy, London School of Economics and Political Science, London, UK. Email: [email protected]

For willingness to pay (WTP) studies to have an appropriate impact on policy making, it is essential that the design and analysis are undertaken carefully. This paper aims to describe and justify the design of the survey tool used to assess hypothetical WTP for treated mosquito nets (TMN) in rural Surat, India and report its findings. Results from qualitative work were used as an input for developing the WTP questionnaire. A total of 1200 households belonging to 80 villages in rural Surat were selected for the study. A bidding format was used to elicit WTP values, using three different starting bids. The scenario was constructed in a way to reduce the possibility of respondents acting strategically. The response rate was 100%. About 79% of the respondents were willing to buy TMNs and the mean WTP was Rs57. Descriptive results of economic and other taste and preference variables are also presented, which include preventive measures used by households and treatment seeking behaviour for malaria. It is observed that WTP as well as demographic variables and prevention methods differ significantly across arms of the trial. This paper suggests that policy-makers could use the evidence following further analysis, along with information on costs of implementation, to ascertain the levels of subsidy that may be needed at different levels of coverage.

PubMed

Brain Inj 2003 Mar;17(3):217-24 

Speech and language sequelae of severe malaria in Kenyan children.

Carter JA, Murira GM, Ross AJ, Mung’ala-Odera V, Newton CR.

The Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute, PO Box 230, Kilifi, Kenya.

Primary objective: To conduct a preliminary investigation into the occurrence of speech and language impairments following severe malaria in Kenyan children.
Research design: Cohort study comparing the prevalence of impairments in children exposed or unexposed to severe malaria. Methods and procedures: The study recruited 25 children who had previously been admitted to hospital with severe falciparum malaria and 27 unexposed to the disease. Assessments of comprehension, syntax, lexical semantics, higher level language abilities, pragmatics and phonology were administered to each child at 8-9 years of age, at least 2 years after admission to hospital in children exposed to severe malaria.
Main outcomes and results: Exposed children were found to have lower scores on each assessment and significantly lower scores on four aspects of language ability: comprehension (p = 0.02); syntax (p = 0.02); content words (p = 0.02) and function words (p = 0.004) components of lexical semantics. 
Conclusions: These data suggest that speech and language deficits may be an important and under-recognized sequela of severe falciparum malaria.

Indian J Exp Biol 2002 May;40(5):609-13

Ovary specific immune response during Plasmodium yoelii yoelii infection in malaria vector Anopheles stephensi (Diptera:Insecta).

Gakhar SK, Shandilya H.

Department of Biosciences, Maharshi Dayanand University, Rohtak 124 001, India. Email: [email protected]

Innate immune related polypeptides expression during three gonotrophic cycles in the ovaries of major disease vector mosquito A. stephensi has been analyzed following infection by malaria parasite, P. yoelii yoelii. Seventeen polypeptides were induced in the ovaries of various stages due to parasitic infection. Most of proteins were induced systemically during early stages of infection suggesting the possibility of immune related signalling process. The reduction in the quantity of protein contents in infected mosquitoes has been ascribed to the repression of seven polypeptides and in turn correlated with the fecundity reduction. The mechanism of these responses and their significance for
malaria transmission and fecundity reduction are discussed.

Ned Tijdschr Geneeskd 2003 Feb 15;147(7):291-5 

Three new antimalarial drugs registered in the Netherlands

Kager PA.

Academisch Medisch Centrum, afd. Infectieziekten, Tropische Geneeskunde en Aids, Postbus 22.700, 1100 DE Amsterdam. Email: [email protected]

Three new antimalarial drugs have recently been registered in the Netherlands: atovaquone-proguanil, artemether-lumefantrine and artemotil. These drugs are effective against parasites with multiple resistance. Atovaquone-proguanil and artemether-lumefantrine seem in practice to be equivalent for the treatment of non-severe Plasmodium falciparum infections for respectively persons of more
than 11 kg and persons aged 12 years and older (35 kg). Artemotil (intramuscular injection) is registered for the treatment of severe malaria in children up to 17 years of age. Atovaquone-proguanil is also registered for prophylactic use in adults. The intravenous administration of quinine is preferable in the case of seriously ill patients. In patients with non-severe malaria for whom parenteral treatment is indicated, artemotil is a good alternative for quinine.

Rev Soc Bras Med Trop 2002 Sep-Oct;35(5):421-9 

Mercury exposure and malaria prevalence among gold miners in Para, Brazil.

Silbergeld EK, Nash D, Trevant C, Strickland GT, de Souza JM, da Silva RS.

Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA. Email: [email protected]

Economic development, including resource extraction, can cause toxic exposures that interact with endemic infectious diseases. Mercury is an immunotoxic metal used in the amalgamation of gold, resulting in both occupational exposures and environmental pollution. A cross-sectional medical survey was conducted in 1997 on 135 garimpeiros in Para, Brazil, because of their risks of both mercury exposure and malaria transmission. Mean levels of blood and urine mercury were well above non-exposed background levels. Twenty-six subjects had malaria parasitemia: Health symptoms consistent with mercury exposure were reported, but neither symptoms nor signs correlated with mercury levels in blood or urine. We did not find a dose response relationship between mercury exposure and likelihood of prevalent malaria infection, but there was a possible reduction in acquisition of immunity that may be associated with conditions in gold mining, including mercury exposure.

Proc Natl Acad Sci U S A 2003 Mar 5

Link between immune response and parasite synchronization in malaria.

Rouzine IM, McKenzie FE.

*Department of Microbiology and Molecular Biology, Tufts University, 136 Harrison Avenue, Boston, MA 02111; and Department of Organismic and Evolutionary Biology and Division of Engineering and Applied Sciences, Harvard University, 142 Maxwell-Dworkin Laboratory, 33 Oxford Street, Cambridge, MA 
02138.

Anti-malaria vaccines and drugs could be greatly improved if we knew which phases of Plasmodium falciparum development in red blood cells are major inducers and which are major targets of natural immune responses. This information should focus attention on relevant immunogens and prove useful in developing immune-based therapies. Here we explore the hypothesis that innate immune responses mediate synchronization between the replication cycles of parasites in different red blood cells which is reflected in periodic fevers. Based on a recently developed, rather general mathematical model, we find that periodicity is highly sensitive to the position of both the inducing phase interval and the target phase interval in the parasite replication cycle. In addition, the degree of variability in the length of the replication cycle also strongly affects periodicity. To produce synchronization, the inducing and the target phase intervals must be developmentally distant from each other. We developed a computer program which prompts for information based on measurements of the numbers of erythrocytes in two replication cycle intervals chosen by the researcher, tests our model, and predicts the two phase intervals most critical to the synchronizing immune response. The program can be obtained from the authors.

J Struct Biol 2003 Feb;141(2):115-21 

Analysis of a Plasmodium falciparum EBA-175 peptide with high binding capacity to erythrocytes and their analogues using 1H NMR.

Cifuentes G, Guzman F, Patricia Alba M, Mary Salazar L, Elkin Patarroyo M.

Fundacion Instituto de Inmunologi;a de Colombia (FIDIC), Universidad Nacional de Colombia, Carrera 50 No. 26-00, Santa fe de Bogota, Colombia

A 175-erythrocyte-binding protein (EBA-175) conserved high-activity binding peptide (HABP), called 1783 (nonimmunogenic, nonprotective against Plasmodium falciparum malaria), was analyzed for antigenic and protective activity in Aotus monkeys, together with several of its analogues. 1H NMR studies of peptides 17912, 14016, and 22814 allowed their structure to be related to their biological function. These peptides showed helical regions having differences in their position and length. Nonimmunogenic, nonprotective peptides 1783 and 17912 showed an extensive helical region, while the 22814 immunogenic protective peptide’s alpha-helix was found in the N-terminal region. This suggests that the more flexible C-terminal region will allow better interaction between these peptides and immune system molecules as well as relating these peptides’ three-dimensional structure to their immunogenicity and protective activity, thus leading to a more rational development of the new malaria multicomponent vaccine.

Vaccine 2003 Mar 28;21(13-14):1432-44 

Gene gun-based co-immunization of merozoite surface protein-1 cDNA with IL-12 expression plasmid confers protection against lethal Plasmodium yoelii in A/J mice.

Sakai T, Hisaeda H, Nakano Y, Zhang M, Takashima M, Ishii K, Maekawa Y, Matsumoto S, Nitta Y, Miyazaki J, Yamamoto S, Himeno K.

Department of Parasitology and Immunology, University of Tokushima School of Medicine, 770-8503, Tokushima, Japan

The carboxyl-terminal region of the merozoite surface protein-1 (MSP1) is a leading candidate for a vaccine against malaria in the erythrocytic stage. In this study, we investigated the utility of interleukin-12 (IL-12) cDNA as an adjuvant for malaria DNA vaccine in a mouse challenge model. We found that co-immunization of expression plasmids encoding a C-terminal 15-kDa fragment of MSP1 (MSP1-15) with the IL-12 gene using a gene gun significantly increased  the protective immunity against malaria as compared with MSP1-15 DNA immunization alone. Co-immunization of IL-12 DNA potentiated MSP1-15-
specific T helper (Th)1-type immune responses as evaluated by in vivo antibody (Ab) responses and in vitro cytokine profiles. After the Plasmodium yoelii challenge, mice immunized with MSP1-15 plus IL-12 DNA showed a higher level of interferon gamma (IFN-gamma) production than did other groups of mice. In vivo neutralization of IFN-gamma or depletion of CD4(+) T cells completely abolished this protective immunity. Macrophages, but not nitric oxide (NO), were found to play an important role in this effector mechanism. The sera from mice in which the infection had been cleared by the vaccination showed strong protection against P. yoelii infection. Thus, in addition to cellular immune responses, Abs against parasites induced in the course of infection are essential for protection against P. yoelii. The results indicate that combined vaccination with DNA encoding antigenic peptides plus IL-12 DNA provides a strategy for improving the prophylactic efficacy of a vaccine for malaria infection.

Mol Biochem Parasitol 2003 Mar;127(1):47-57 

Characterisation of the rhoph2 gene of Plasmodium falciparum and Plasmodium yoelii.

Ling IT, Kaneko O, Narum DL, Tsuboi T, Howell S, Taylor HM, Scott-Finnigan TJ, Torii M, Holder AA.

Divisions of Parasitology and Protein Structure, National Institute for Medical Research, NW7 1AA, London, UK

The high molecular mass protein complex (RhopH) in the rhoptries of the malaria parasite consists of three distinct polypeptides with estimated sizes in Plasmodium falciparum of 155kDa (PfRhopH1), 140kDa (PfRhopH2) and 110kDa (PfRhopH3). Using a number of reagents, including a new mAb 4E10 that is specific for the PfRhopH complex, it was shown that the RhopH complex is synthesised during schizogony and transferred intact to the ring stage in newly invaded erythrocytes. The genes encoding RhopH1 and RhopH3 have already been identified and characterised in both P. falciparum and Plasmodium yoelii. In this report, we describe the identification of the gene for RhopH2 in both these parasite species. Peptide sequences were obtained from purified RhopH2 proteins and used to generate oligonucleotide primers and search malaria sequence databases. In a parallel approach, mAb 4E10 was used to identify a clone coding for RhopH2 from a P. falciparum cDNA library. The sequences of both P. falciparum and P. yoelii genes for RhopH2 were completed and compared. They both contain nine introns and there is a high degree of similarity between the deduced amino acid sequences of the two proteins. The P. falciparum gene is a single copy gene located on chromosome 9, and is transcribed in schizonts.

Exp Parasitol 2002 Sep;102(1):57-9 

Detergent-resistant erythrocyte membrane rafts are modified by a plasmodium falciparum infection.

Nagao E, Seydel KB, Dvorak JA.

Laboratory of Malaria and Vector Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Room 126, 4 Center Drive MSC 0425, 20892-0425, Bethesda, MD, USA 

Detergent resistant membranes (DRMs) have been implicated in numerous cellular processes including signal transduction, membrane trafficking, and molecular sorting. Flotillins-1 and -2 have recently been shown to be large components of erythrocyte DRMs. In this study, we show that a Plasmodium falciparum infection disrupts the association of flotillins with erythrocyte DRMs. 
Flotillins are probably released from erythrocyte DRMs through the reduction of cholesterol and sphingomyelin levels during the course of a P. falciparum-infection. Although it is well known that a P. falciparum infection can modify the host erythrocyte membrane, this is the first report that P. falciparum can alter the DRM components of erythrocyte membranes.INDEX DESCRIPTORS: Malaria, Plasmodium falciparum, Lipid rafts, Detergent resistant membranes (DRMs), Erythrocytes.

Bioorg Med Chem 2003 Mar;11(6):827-841 

Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II.

Dahlgren A, Kvarnstrom I, Vrang L, Hamelink E, Hallberg A, Rosenquist A, Samuelsson B.

Department of Chemistry, Linkoping University, S-581 83, Linkoping, Sweden

With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5&mgr;M (K(i) for Plm II=5.4&mgr;M).

Lancet Infect Dis 2003 Mar;3(3):162-7 

The development of Lapdap, an affordable new treatment for malaria.

Lang T, Greenwood B.

TL and BG are at the London School of Hygiene and Tropical Medicine, London, 
UK

There is much discussion on how new drugs can be developed for use in developing countries at a price that makes them accessible to those who need them most. The development of a new antimalarial, chlorproguanil/dapsone (Lapdap), provides an example of a way this can be achieved. The idea of combining chlorproguanil with dapsone came from studies done in east Africa in the 1980s. These studies showed, both in vivo and in vitro, that chlorproguanil/dapsone had advantages over sulphadoxine/pyrimethamine. A public-private partnership was established subsequently to manage a development programme of a fixed ratio tablet of this drug combination. The partnership comprised GlaxoSmithKline (formerly SmithKline Beecham), the World Health Organization (WHO), and the UK’s Department for International Development (DFID). All clinical, toxicological, and pharmaceutical chemistry studies are complete and the findings have been submitted for regulatory approval. The question now is how Lapdap might be used safely and appropriately if it receives regulatory approval. A public-health group has been formed by WHO (with funding from DFID and the Gates Foundation)
to research into this issue. The Lapdap development team completed its objective of submitting Lapdap for drug registration within a period of 5 years and at a low cost. Experience with the development of Lapdap may provide a model for the introduction of other new drugs developed primarily for use in developing countries.

J Mol Biol 2003 Mar 14;327(1):173-181 

Novel Uncomplexed and Complexed Structures of Plasmepsin II, an Aspartic Protease from Plasmodium falciparum.

Asojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM.

Structural Biochemistry Program, National Cancer Institute/SAIC, 21702, Frederick, MD, USA

Malaria remains a human disease of global significance and a major cause of high infant mortality in endemic nations. Parasites of the genus Plasmodium cause the disease by degrading human hemoglobin as a source of amino acids for their growth and maturation. Hemoglobin degradation is initiated by aspartic proteases, termed plasmepsins, with a cleavage at the alpha-chain between residues Phe33 and Leu34. Plasmepsin II is one of the four catalytically active plasmepsins that has been identified in the food vacuole of Plasmodium falciparum. Novel crystal structures of uncomplexed plasmepsin II as well as the complex with a potent inhibitor have been refined with data extending to resolution limits of 1.9A and 2.7A, and to R factors of 17% and 18%, respectively. The inhibitor, N-(3-{(2-benzo[1,3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-y l)-propionyl]-amino}-1-benzyl-2-(hydroxypropyl)-4-benzyloxy-3,5-dimethoxy-benzam ide, belongs to a family of potent non-peptidic inhibitors that have large P1′ groups. Such inhibitors could not be modeled into the binding cavity of the structure of plasmepsin II in complex with pepstatin A. Our structures reveal that the binding cavities of the new complex and uncomplexed plasmepsin II are considerably more open than 
that of the pepstatin A complex, allowing for larger heterocyclic groups in the P1′, P2′ and P2 positions. Both complexed and uncomplexed plasmepsin II crystallized in space group P2, with one monomer in the asymmetric unit. The structures show extensive interlocking of monomers around the crystallographic axis of symmetry, with areas in excess of 2300A(2) buried at the interface, and a loop of one monomer interacting with the binding cavity of the 2-fold related monomer. Electron density for this loop is only fully ordered in the complexed structure.

Epidemiol Infect 2003 Feb;130(1):93-100 

Non-specific alert system for dengue epidemic outbreaks in areas of endemic malaria. A hospital-based evaluation in Cayenne (French Guiana).

Carme B, Sobesky M, Biard MH, Cotellon P, Aznar C, Fontanella JM.

Parasitologie, Mycologie, Equipe EA3593, Centre Hospitalier de Cayenne et UFR Medecine Antilles Guyane, F-97 306 Cayenne, Guyane Francaise.

The emergence of dengue haemorrhagic fever is a public health problem in Latin America and the Caribbean. This study, carried out in French Guiana where malaria is endemic, evaluated the value and the limitations of a non-specific alert system including all patients admitted to the emergency department of Cayenne Hospital, between 1 January 1996 and June 2001. Four indices were studied on a weekly basis: the emergency malaria negative index (EMN), the EMN thrombocytopenia index (EMNT), the dengue suspected index: EMNT/EMN ratio; and the number of hospitalized patients with dengue fever according to the Department of Medical Information. These indices were retrospectively 
compared with data from the Arbovirus Reference Centre at the Pasteur Institute in French Guiana. Using the non-specific indices, we were able to identify four clear epidemics, two of which were shown to be linked to dengue. Variations in the incidence of malaria had no marked effect on this alert system. We propose that this simple, cheap, sensitive and reactive alert system be used to improve the serological and virological monitoring of dengue and to facilitate adequate and timely vector control measures. It could be used in all regions at risk of dengue and malaria.

CNS Drugs 2003;17(3):153-65 

Cerebral malaria : optimising management.

Mturi N, Musumba C, Wamola B, Ogutu B, Newton C.

Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine Research, Kilifi, Kenya.

Cerebral malaria is one of the most common nontraumatic encephalopathies in the world. Children living in sub-Saharan Africa bear the brunt of the disease, but cerebral malaria is being seen increasingly in adults throughout the world, including outside malarious areas. There are differences in the clinical presentation and pathophysiology between African children and nonimmune adults from any region. Mortality is high (10-20%).Parenteral antimalarials are the only interventions that have been shown to affect outcome. The cinchona alkaloids (quinine and quinidine) are the mainstay of antimalarial treatment, but the artemisinin derivatives are increasingly being used. Aggressive treatment and prevention of convulsions may be important, particularly in children. Other ancillary treatments that can be used to augment standard antimalarial drugs, such as exchange blood transfusions, osmotic diuretics and pentoxifylline, may improve outcome but have not been subjected to rigorous clinical trials. There is little support for corticosteroids or deferoxamine (desferrioxamine) in cerebral malaria. Other adjuncts have not been adequately tested.Further research is required on drugs that interfere with the pathophysiological processes to prevent neurological complications and death.

J Environ Biol 2002 Jan;23(1):95-100 

Physico-chemical characteristics of breeding habitats of Anopheles dirus (diptera:culicidae) in Assam, India.

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

Regional Medical Research Centre, NE Region (ICMR), Post Box # 105, Dibrugarh-786 001, Assam, India. Email: [email protected]

Larval ecology of Anopheles dirus, the main vector of forest malaria in north-eastern region of India, was studied in relation to physico-chemical characteristics of its breeding habitats in a rain forest area of Assam, India. Shady stream side pools, positive for the breeding of An. dirus, had significantly higher amounts of total hardness (P < 0.024) in comparison to negative pools of similar type. When compared with An. dirus negative breeding habitats, in hot-wet as well as in cool-dry seasons, An. dirus positive shady ground pools showed higher mean values of total alkalinity, hardness and chloride content, whereas lower pH, dissolved oxygen along with higher total alkalinity and hardness were possessed by An. dirus positive stream side pools. Specificity of breeding habitats of An. dirus in relation to its ecology has been discussed.

Rev Soc Bras Med Trop 2002 Nov-Dec;35(6):665-8 

[Association between reported annual gold mining extraction and incidence of malaria in Mato Grosso-Brazil, 1985-1996]

Duarte EC, Fontes CJ.

Funda o Nacional de Sa de, Cuiab , MT.

A secondary data analysis was performed using an ecological design to study the association between malaria incidence rates, the reported annual production of gold mining extraction and monetary investments for the control of malaria from 1985 to 1996 in Mato Grosso, Brazil. A positive and statistically significant (p<0.001) association between the amount of gold extracted and MIR was obtained in multivariate regression analysis, even after allowing for financial investments in malaria control activities. This finding contributes to an understanding of the decrease observed in malaria incidence in Mato Grosso during the last decade, in view of the significant decrease in gold mining within the region during this period.

Eur J Clin Pharmacol 2003 Feb;58(10):649-52 

Intrarectal pharmacokinetics of two formulations of quinine in children with falciparum malaria.

Barennes H, Sterlingot H, Nagot N, Meda H, Kabore M, Sanou M, Nacro B, Bouree P, Pussard E.

Centre Muraz, Bobo Dioulasso, Burkina Faso.

OBJECTIVE. To compare the intrarectal bioavailabilities of two parenteral formulations of quinine most available in French- (Cinchona alkaloid mixture) and English (hydrochloride salt) -speaking areas of Africa. METHODS. The pharmacokinetics of quinine was investigated in four groups of 12 children with
acute Plasmodium falciparum malaria receiving 8 mg/kg quinine base every 8 h either as hydrochloride salt or Cinchona alkaloid mixture by a slow 4-h intravenous infusion or intrarectal administration. Body temperature and parasitaemia were monitored, and blood quinine concentrations were measured 
by means of high-performance liquid chromatography. RESULTS. At 72 h, all the children were aparasitaemic and apyretic. Quinine C(max) values were higher after intravenous infusion of the hydrochloride salt and Cinchona alkaloid mixture (6.9+/-1.9 micro g/ml and 5.2+/-1.3 micro g/ml) than after intrarectal administration (3.5+/-1.4 micro g/ml and 3.1+/-1.6 micro g/ml), but t(max)
values were similar (3.6+/-1.5, 4.2+/-1.0, 4.0+/-1.9, and 4.7+/-2.0 h, respectively). Intrarectal relative bioavailabilities of h ydrochloride salt solution (57%) and Cinchona alkaloid mixture (62%) were similar. 
CONCLUSION. Whatever the parenteral formulation of quinine, the blood concentration-time profiles of quinine were similar after intrarectal administration. Intrarectal administration of hydrochloride salt solution is a possible mode of quinine delivery in remote rural areas of Africa.

Lancet 2003 Feb 22;361(9358):676-8 

Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production.

Lopansri BK, Anstey NM, Weinberg JB, Stoddard GJ, Hobbs MR, Levesque MC, Mwaikambo ED, Granger DL.

Division of Infectious Diseases, VA and University of Utah Medical Centers, Salt Lake City, UT, USA.

Nitric oxide (NO) production and mononuclear cell NO synthase 2 (NOS2) expression are high in healthy Tanzanian children but low in those with cerebral malaria. Factors that downregulate NOS2 also diminish factors involved in cellular uptake and biosynthesis of L-arginine, the substrate for NO synthesis. We therefore postulated that L-arginine concentrations would be low in individuals with cerebral malaria. We measured concentrations of L-arginine in cryopreserved plasma samples from Tanzanian children with and without malaria. L-arginine concentrations were low in individuals with cerebral malaria (mean 46 micromol/L, SD 14), intermediate in those with uncomplicated malaria (70 micromol/L, 20), and within the normal range in healthy controls (122 micromol/L, 22; p<0.0001). Analysis by logistic regression showed that hypoargininaemia was significantly associated with cerebral malaria
case-fatality. Hypoargininaemia may contribute to limited NO production in children with cerebral malaria and to severe disease.

Malar J 2003 Feb 11;2(1):1 

Sex-specific and blood meal-induced proteins of Anopheles gambiae midguts: analysis by two-dimensional gel electrophoresis.

Prevot G, Laurent-Winter C, Rodhain F, Bourgouin C.

Ecologie des Systemes Vectoriels, Institut Pasteur, 25 Rue du Dr Roux, 75724 Paris Cedex15, France. 
Email: [email protected]

BACKGROUND: Anopheles gambiae is the main vector of Plasmodium falciparum in Africa. The mosquito midgut constitutes a barrier that the parasite must cross if it is to develop and be transmitted. Despite the central role of the mosquito midgut in the host/parasite interaction, little is known about its protein composition. Characterisation of An. gambiae midgut proteins may identify the proteins that render An. gambiae receptive to the malaria parasite. METHODS:We carried out two-dimensional gel electrophoresis of An. gambiae midgut proteins and compared protein profiles for midguts from males, sugar-fed females and females fed on human blood. RESULTS: Very few differences were 
detected between male and female mosquitoes for the approximately 375 silver-stained proteins. Male midguts contained ten proteins not detected in sugar-fed or blood-fed females, which are therefore probably involved in male-specific functions; conversely, female midguts contained twenty-three proteins absent from male midguts. Eight of these proteins were specific to sugar-fed females, and another ten, to blood-fed females. CONCLUSION: Mass spectrometry analysis of the proteins found only in blood-fed female midguts, together with data from the recent sequencing of the An. gambiae genome, should make it possible to determine the role of these proteins in blood digestion or parasite receptivity.

Public Health Rep 2003 Jan-Feb;118(1):65-71 

Climatic variables and transmission of malaria: a 12-year data analysis in Shuchen County, China.

Bi P, Tong S, Donald K, Parton KA, Ni J.

Centre for Healthcare Related Infection Surveillance and Prevention, Princess Alexandra Hospital, Brisbane, QLD, Australia. Email: [email protected]

OBJECTIVE: The objective of this study was to explore the impact of climate variability on the transmission of malaria, a vector-borne disease, in a county of China and provide suggestions to similar regions for disease prevention. METHODS: A time-series analysis was conducted using data on monthly climatic variables and monthly incidence of malaria in Shuchen County, China, for the period 1980-1991. RESULTS: Spearman’s correlation analysis showed that monthly mean maximum and minimum temperatures, two measures of monthly mean relative humidity, and monthly amount of precipitation were positively correlated with the monthly incidence of malaria in the county. Regression analysis suggested that monthly mean minimum temperature and total monthly rainfall, with a one-month lagged effect, were significant climatic variables in the transmission of malaria in Shuchen County. Seasonality was also significant in the regression model and there was a declining secular trend in the incidence of malaria. 
CONCLUSION: The results indicate that climatic variables should be considered as possible predictors for regions with similar geographic, climatic, and socioeconomic conditions to those of Shuchen County.

Antimicrob Agents Chemother 2003 Mar;47(3):901-4 

Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon.

Borrmann S, Adegnika AA, Missinou MA, Binder RK, Issifou S, Schindler A, Matsiegui PB, Kun JF, Krishna S, Lell B, Kremsner PG.

Medical Research Unit, Albert Schweitzer Hospital, Lambarene, Gabon. Email: [email protected]

Artesunate is one of the most important antimalarial agents available, since it is effective against parasites that have developed resistance to conventional antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have been proposed. However, the efficacy of a 3-day course of artesunate 
alone has never been evaluated in individuals in Africa (which has 90% of the worldwide malaria burden) living in regions of hyperendemicity, where a considerable degree of immunity might substantially enhance the efficacy of short courses of artesunate compared to those in regions where the levels of endemicity are low. This lack of information does not permit a systematic
assessment of the value of artesunate-based combination chemotherapies in Africa. Therefore, we studied the efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight, orally, once daily) for the treatment of uncomplicated Plasmodium falciparum malaria in Gabonese patients aged 4 to 15 years (n = 50). Artesunate was well tolerated, and no severe adverse event 
was reported. Parasite elimination was rapid and was achieved in all patients within < or =72 h (geometric mean time to elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50 patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that a 3-day course of artesunate fails to achieve sufficiently high cure rates for uncomplicated falciparum malaria in Gabonese children.

Ann Epidemiol 2003 Mar;13(3):158-162 

Preterm Birth in Relation to Maternal Organochlorine Serum Levels.

Torres-Arreola L, Berkowitz G, Torres-Sanchez L, Lopez-Cervantes M, Cebrian ME, Uribe M, Lopez-Carrillo L.

Epidemiology and Health Services Research Unit, CMN Century XXI, Institute of Social Security, Mexico City, Mexico

PURPOSE: To evaluate the associations of serum levels of p,pacute;-DDE and two other persistent organochlorine pesticides, beta-HCH and HCB, in relation to preterm birth.METHODS: During 1995 we performed a case-cohort study and 233 mothers were recruited at three large maternity hospitals in Mexico City. Serum levels were obtained shortly after delivery.RESULTS: A non-significant increased risk of preterm birth in relation to serum p,p’-DDE levels was observed. There was also a suggestion of an increased risk of preterm birth among women in the highest tertile of beta-HCH (adjusted odds ratio 1.85, 95% CI = 0.94-3.66, p value for test of trend p = 0.08) compared with the lowest tertile. No association was found between HCB serum levels and preterm births. CONCLUSIONS: These findings suggest that p,pacute;-DDE and other organochlorine pesticides may pose a risk to preterm birth in countries that continue to use such insecticides for malaria control.

J Infect Dis 2003 Feb 15;187(4):667-74 

Kinetics of Antibody Responses to Plasmodium falciparum-Infected Erythrocyte Variant Surface Antigens.

Kinyanjui SM, Bull P, Newbold CI, Marsh K.

Kenya Medical Research Institute Centre for Geographic Medicine Research Coast, Kilifi, Kenya. Email: [email protected]

The kinetics of antibody responses to the Plasmodium falciparum malaria parasite-induced erythrocyte surface antigens (PIESAs) in 26 Kenyan children were examined by use of flow cytometry and agglutination assays. Although 19 of the 26 children mounted a primary antibody response to PIESAs within 2 weeks of experiencing an acute episode and maintained high antibody levels for at least 12 weeks, the remaining 7 children had responses that were weak and brief. Resistance to reparasitization was decreased in the children with short-lived responses. Isotype profiles of responses in 11 of the children studied suggest that they may have failed to switch to IgG after the initial IgM response. These data suggest that children vary widely in their ability to respond to PIESAs and that, in some individuals or with certain PIESA variants, short-lived antibody responses are induced that may be associated with poor antibody class switching.

J Infect Dis 2003 Feb 15;187(4):658-66 

Randomized, controlled trial of daily iron supplementation and intermittent sulfadoxine-pyrimethamine for the treatment of mild childhood anemia in western Kenya.

Desai MR, Mei JV, Kariuki SK, Wannemuehler KA, Phillips-Howard PA, Nahlen BL, Kager PA, Vulule JM, ter Kuile FO.

Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA. Email: [email protected]

A randomized, placebo-controlled treatment trial was conducted among 546 anemic (hemoglobin concentration, 7-11 g/dL) children aged 2-36 months in an area with intense malaria transmission in western Kenya. All children used bednets and received a single dose of sulfadoxine-pyrimethamine (SP) on enrollment, followed by either intermittent preventive treatment (IPT) with SP at 4 and 8 weeks and daily iron for 12 weeks, daily iron and IPT wi th SP placebo, IPT and daily iron placebo, or daily iron placebo and IPT with SP placebo (double placebo). The mean hemoglobin concentration at 12 weeks, compared with that for the double-placebo group, was 1.14 g/dL (95% confidence interval [CI], 
0.82-1.47 g/dL) greater for the IPT+iron group, 0.79 g/dL (95% CI, 0.46-1.10 g/dL) greater for the iron group, and 0.17 g/dL (95% CI, -0.15-0.49 g/dL) greater for the IPT group. IPT reduced the incidence of malaria parasitemia and clinic visits, but iron did not. The combination of IPT and iron supplementation was most effective in the treatment of mild anemia. Although IPT prevented 
malaria, the hematological benefit it added to that of a single dose of SP and bednet use was modest.

AIDS 2003 Mar 7;17(4):595-603 

HIV increases the risk of malaria in women of all gravidities in Kisumu, Kenya.

Van Eijk AM, Ayisi JG, Ter Kuile FO, Misore AO, Otieno JA, Rosen DH, Kager PA, Steketee RW, Nahlen BL.

Kenya Medical Research Institute, Center for Vector Biology and Control Research, Kisumu, Kenya; Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Kenya Ministry of Health, Kisumu, Kenya; and Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Co Control and Prevention, Atlanta, Georgia, USA.

OBJECTIVE To study the importance of HIV infection for malaria in pregnancy in Kisumu, Kenya.SUBJECTS AND METHODS Healthy women with an uncomplicated pregnancy of 32 weeks or more attending the prenatal clinic in the Provincial Hospital between June 1996 and March 1999 were tested for HIV and malaria after consent had been obtained. For participating women who delivered in the same hospital, a blood smear of the mother and the placenta were obtained.

RESULTS In the third trimester, 5093 women consented to testing: the prevalence of malaria and HIV was 20.1 and 24.9%, respectively. Among the 2502 screened women who delivered in the hospital, the prevalence of HIV, peripheral parasitaemia and placental malaria was 24.5, 15.2, and 19.0%, respectively. Compared with HIV-seronegative women, HIV-seropositive women were more likely to be parasitaemic, to have higher parasite densities, and to be febrile when parasitaemic. Placental infections in HIV-seropositive women were more likely to be chronic, as indicated by the presence of moderate to heavy pigment depositions. When adjusted by age, the typical gravidity-specific pattern of malaria in pregnancy disappeared in HIV-seropositive women; HIV-seropositive primigravidae had a similar risk of malaria as HIV-seropositive multigravidae. The excess malaria attributable to HIV in the third trimester increased from 34.6% among HIV-seropositive primigravidae, to 41.5% among HIV-seropositive secundigravidae, and 50.7% among HIV-seropositive gravidae with three or more pregnancies.CONCLUSION HIV infection alters patterns of 
malaria in pregnant women; in areas with both infections, all pregnant women should use malaria prevention.

AIDS 2003 Mar 7;17(4):585-594 

The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya.

Ayisi JG, Van Eijk AM, Ter Kuile FO, Kolczak MS, Otieno JA, Misore AO, Kager PA, Steketee RW, Nahlen BL.

Centre for Vector Biology and Control Research, Kenya Medical Research Institute, Kisumu, Kenya; Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Division of Parasitic Diseases, NCID, Centers for Disease Control and Prevention, Atlanta, GA, USA; Ministry of Health, Kisumu, Kenya; and Roll Back Malaria, World Health Organization, Geneva, Switzerland.

OBJECTIVE To determine the effect of dual infection with HIV and malaria on birth outcomes and maternal anaemia among women delivering at a large public hospital in Kisumu, western Kenya.

SUBJECTS AND METHODS Data on obstetric and neonatal characteristics, maternal and placental parasitaemia, and postpartum haemoglobin levels were collected from women enrolled in a cohort study of the interaction between malaria and HIV during pregnancy.RESULTS  Between 1996 and 1999, data were available from 2466 singleton deliveries. The maternal HIV seroprevalence was 24.3%, and at delivery 22.0% of the women had evidence of malaria. Low birthweight, preterm delivery (PTD), intrauterine growth retardation (IUGR) and maternal anaemia (haemoglobin < 8 g/dl) occurred in 4.6, 6.7, 9.8 and 13.8% of deliveries, respectively. Maternal HIV, in the absence of malaria, was associated with a 99 g (95% CI 52-145) reduction in mean birthweight among all gravidae. Malaria was associated with both IUGR and PTD, resulting in a reduction in mean birthweight of 145 g (95% CI 82-209) among HIV-seronegative and 206 g (95% CI 115-298) among HIV-seropositive primigravidae, but not among multigravidae. Both HIV and malaria were significant risk factors for postpartum maternal anaemia, and HIV-seropositive women with malaria were twice as likely to have anaemia than HIV-seronegative
women with or without malaria.

CONCLUSION Women with dual infection are at particular risk of adverse birth outcomes. In areas with a moderate or high prevalence of HIV and malaria, all pregnant women should be the focus of malaria and anaemia control efforts to improve birth outcomes. 

Lancet 2003 Feb 15;361(9357):577-8 

The effect of providing fansidar (sulfadoxine-pyrimethamine) in schools on mortality in school-age children in Malawi.

Pasha O, Del Rosso J, Mukaka M, Marsh D.

Office of Health, International Programs, Save the Children Federation, Westport, CT 06881, USA.

Malaria is a major cause of death in school-age (5-18 years) children in Malawi. Save the Children Federation helped schools in Mangochi District, Malawi, to obtain pupil-treatment kits, which enabled teachers to dispense sulfadoxine-pyrimethamine tablets according to national guidelines. The overall and malaria-specific mortality rates were calculated for the 3 years before and 2 years after the intervention was introduced; rates dropped from 2.2 to 1.44 deaths/1000 student-years and from 1.28 to 0.44 deaths/1000 student-years, respectively. School-based interventions could play a part in mitigating malaria.

J Med Entomol 2003 Jan;40(1):58-63 

House-scale evaluation of bifenthrin indoor residual spraying for malaria vector control in India.

Yadav RS, Srivastava HC, Adak T, Nanda N, Thapar BR, Pant CS, Zaim M, Subbarao SK.

Malaria Research Center, Civil Hospital, Field Station, Nadiad 387001, Gujarat, India. Email: [email protected]

In an area of India where the main rural malaria vector, Anopheles culicifacies Giles, has developed triple resistance to DDT, HCH, and malathion sprayed indoors in antimalaria program, bifenthrin (10% wettable powder) was evaluated in a randomized house-scale trial between July 1999 and March 2000 Entomological impact of four serial doses of bifenthrin (25, 50, 100, and 200 mg/m2) sprayed in rooms in five villages was compared with malathion (2 g/m2) and unsprayed control. An. culicifacies was 100% susceptible to bifenthrin (0.1%), but only 57% to malathion (5%) test papers. Contact bioassays were carried out on sprayed surfaces for 24 wk, and 24 h mortality in An.culicifacies was recorded. Bifenthrin 100- and 200-mg doses caused > or = 80% mortality until 24 wk. The 50-mg dose caused > or = 80% mortality on tin, wood, and mud surfaces for 24 wk, and on brick walls for 16 wk. Bifenthrin 25-mg dose produced > or = 80% mortality for 24 wk on tin, 20 wk on mud walls, 16 wk on brick walls, and 8 wk on wood surfaces. Persistence of > or = 80% mortality did not differ for 25- and 50-mg doses on any surface except on wood (P < 0.05). Malathion sprayed in three rounds of 6 wk apart caused > or = 80% mortality for 16 wk on the brick and mud walls, and for 20 wk on the tin and wood surfaces. Bifenthrin 25- and 50-mg doses produced a similar impact on the densities of An. culicifacies and other mosquitoes but a superior one to malathion or control. Bifenthrin 25-mg dose caused least excitorepellency. Overall, efficacy of bifenthrin was superior to malathion. Considering the duration of the persistence of significant insecticidal action of bifenthrin on the most common surfaces (mud and brick walls), least excito-repellency and a relative impact on the mosquito densities, the 25-mg dose was the most superior among all the four doses evaluated.

Asia Pac J Public Health 2001;13(2):85-90 

Variation in malaria endemicity in relation to microenvironmental conditions in the Admiralty Islands, Papua New Guinea.

Ataka Y, Ohtsuka R, Inaoka T, Kawabata M, Ohashi J, Matsushita M, Tokunaga K, Kano S, Suzuki M.

Department of Human Ecology, University of Tokyo, Japan.

For 197 adults and adolescents in four villages of three small islands in the Admiralty Islands, Papua New Guinea, antimalarial antibody titers were examined using the indirect fluorescent antibody test (IFAT) and malaria parasites were detected by the microtiter plate hybridisation (MPH) method using polymerase chain reaction (PCR) technique. The parasite rate (either Plasmodium falciparum or P. vivax, or both) averaged 39.2%, varying from 31.1% to 44.8% among the four villages due to natural and artificial microenvironmental conditions related to breeding sites of mosquitoes (Anopheles farauti). The lack of flat zones owing to geomorphological formation contributed to the lowest parasite rate in the extremely small island. However, human-modified environments such as a wet-land (naturally formed but artificially reformed) and an open well played significant roles in other inter-
village differences. The present findings imply significant roles of microenvironment in diversified malaria prevalence and suggest some ways of mitigation of malarial hazards.

Biomedica (Bogota) 2002 Dec;22(4):455-61 

Should the use of DDT be revived for malaria vector control?

Curtis CF.

London School of Hygiene and Tropical Medicine, London, United Kingdon.

Indoor residual spraying with DDT was the principle method by which malaria transmission was eradicated or greatly reduced in many countries between the late 1940s and 1970s. Since then, decreasing use of DDT has been associated with a resurgence of malaria in India, Sri Lanka, former Soviet Central Asia, Zanzibar, Venezuela and several other Latin American countries. In India and
Zanzibar, DDT resistance in vectors, as well as a decline in spray coverage, are probable causes of reduced effectiveness of DDT in recent decades. In southern Europe, eradication of malaria transmission was achieved by DDT spraying in the 1940s and 50s and eradication has been sustained by adequate treatment of imported human malaria cases. In the highlands of Madagascar and South Africa, recent reversion to DDT spraying has been successful in stemming resurgences of malaria. Continued use of DDT for vector control, but not for agriculture, is approved by the Stockholm Convention on Persistent Organic Pollutants. DDE residues in breast milk have been associated with DDT anti-malaria spraying in South Africa, but it is not known whether this is harmful. A claimed association of DDE residues with breast cancer have not been substantiated. There is a recent report of association of DDE residues with probability of premature birth; the possible relevance of this to anti-malarial use of DDT should be investigated. In Colombia, testing of the DDT stockpile for suspensibility, DDT resistance in Anopheles darlingi and investigation of the present affordability of widespread spraying with DDT, compared with alternative chemicals, arerecommended.

Bull Soc Pathol Exot 2002 Nov;95(4):262-4 

A study in vivo of Plasmodium falciparum sensitivity to chloroquine was carried out from April 1997 to February 2000 at Yamoussoukro, Kossou and Bouake in the central region of Cote d’Ivoire.

Adou-Bryn KD, Krelo K, Akoussi CF, Boni NM, Yapo GC, Penali LK, Ouhon J, Assoumou A, Ehouman A.

Laboratoire de parasitologie-mycologie, UFR des sciences medicales, B.P.V 166 Abidjan, Cote d’Ivoire.

A study in vivo of Plasmodium falciparum sensitivity to chloroquine was carried out from April 1997 to February 2000 at Yamoussoukro, Kossou and Bouake in the central region of Cote d’Ivoire. This study was included in the national Plasmodium falciparum-sensitivity program. One hundred and sixteen subjects consulting for suspected malaria were included according to the WHO’s standard of 14 days. Chloroquine was administered on a dosage of 25 mg/kg, spread over three days. Among 108 subjects who finished the treatment, 26.9% (29/108) had therapeutic failure to chloroquine (23 precocious therapeutic failure and 6 late therapeutic failure). Chloroquine was more efficacious in Yamoussoukro  (87.5% of clinical appropriate response) and Bouake (82.5%) than in Kossou  (61.7%). Parasitic reduction on subjects with therapeutic failure was higher than 85%. The risk of therapeutic failure is not linked to age of patient. Before a revaluation of this situation, chloroquine should always be recommended as a first-line treatment for uncomplicated malaria for the local populations.

Bull Soc Pathol Exot 2002 Nov;95(4):238-40

The biological diagnosis of malaria 

Yavo W, Ackra KN, Menan EI, Barro-Kiki PC, Kassi RR, Adjetey TA, Bamba A, Kone M.

Laboratoire de parasitologie-mycologie de l’Institut Pasteur de Cote d’Ivoire, UFR des sciences pharmaceutiques et biologiques d’Abidjan, Abidjan, Republique de Cote d’Ivoire.

The biological diagnosis of malaria plays an important part in the patients’ treatment for malaria. Thus, many techniques have been developed to reach this purpose. We have compared four of them concerning 196 patients from October, 1996 to January, 1997 in Abidjan. Thick blood film has been chosen as the technique for reference. It has come out that the plasmodic index was 18.3%. The Plasmodium falciparum has been the only encountered species. The different sensitivities of the QBC test and of the Parasight F test reached 100% against 83.3% in the case of the thin blood film. The QBC test and the thin blood film had each a specificity of 100% against 88.1% for the Parasight F test. Unlike
the QBC test, the thick blood film and the thin blood film have remained the most difficult to be realised. Therefore, the analysis of parameters of credibility (sensitivity, specificity), predictable values and the time involved will allow in a given situation to use the appropriate biological diagnosis technique.