EHP LIBRARY MALARIA BULLETIN 42 – AUG 5-18, 2002

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ANNOUNCEMENTS

WEEKLY EPIDEMIOLOGICAL RECORD, NO. 32, 9 AUGUST 2002

Web-based tool for early warning of malaria epidemics in Africa

Monitoring current rainfall anomalies in zones at epidemic risk  Rainfall is one of the major factors influencing malaria transmission in semi-arid and desert-fringe areas of Africa  Epidemics may occur after excessive rains, usually with a lag time of several weeks during which mosquito vector  populations and malaria infections gradually increase. Epidemics following drought and poor food security can   be especially severe.

During a recent meeting of the Roll Back Malaria (RBM) Technical Support Network (TSN) on Prevention and Control of Epidemics, it was decided to develop a simple tool to monitor epidemic risk in these marginal transmission areas. The tool would be based on the difference between rainfall currently and the short-term expected average; results would be made available on the Web in a frequently updated map format. The purpose would be to provide timely alerts to control programmes and RBM partners working in areas of increased epidemic risk.

Following discussion with members of the RBM-TSN these maps are now available in experimental form through the Africa Data Dissemination Service web site supported by USAID FEWS-NET. They provide a simple indicator of changes in malaria risk in marginal transmission areas, based solely on rainfall, and differences above and below expected levels. The maps are updated every 10 days.

The maps use a mask to exclude areas where malaria is considered to be endemic (as opposed to epidemic) or absent. This mask is based purely on climatic constraints to malaria transmission, and does not yet account for areas
in the northern and southern margins of the continent where control has eliminated epidemic risk. The maps have been tested against laboratory-confirmed malaria incidence figures in districts in Botswana, where they showed a strong association. Their use and validation elsewhere is encouraged.

To access the maps, visit website http://edcsnw4.cr.usgs.gov/adds/  select  Data, select  ” Current Browse Graphics ” Under  ” Choose an image ”  select  ” RFE Anomaly  Malaria, ”  and then click on the View button. The maps can also be accessed through the Epidemics page of the Roll Back Malaria website at http://www.rbm.who.int

Additional information including seasonal climate forecasts and considered impacts to a number of sectors,  including health, may also be found at http://iri.columbia.edu/climate/cid/

SOCIAL SCIENCES AND MALARIA

Social Science & Medicine. 55(3):403-13, 2002 Aug.

Medical syncretism with reference to malaria in a Tanzanian community.

Muela SH. Ribera JM. Mushi AK. Tanner M. Swiss Tropical Institute, Department of Public Health and Epidemiology,

Basel. [email protected]

What happens when new health information is introduced into a community? We have explored this question in a semi-rural community of Southeastern Tanzania whose population has been in contact with biomedicine for many decades. With the example of malaria, we illustrate how biomedical knowledge transmitted in health messages coexists, interacts and merges with local pre-existing ideas and logics. The results are syncretic models, which may deviate considerably from what health promoters intended to transmit. Some of those may have implications for treatment of malaria, which may include delay in seeking treatment and non-compliance with therapy. Analysing this medical syncretism clearly demonstrates that even if comprehension of health messages is accurate, the way in which people interpret these messages may not be. Disentangling syncretic processes permits us to understand the dynamics of how information is processed by the recipients, and provides orientations for health promoters for adapting messages to the local context.

Ann Trop Med Parasitol  2002 Jun;96(4):405-16 

Unit costs for house spraying and bednet impregnation with residual insecticides in Colombia: a management tool for the control of vector-borne disease.

Kroeger A, Ayala C, Lara AM.

Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, U.K.

A study of unit costs and cost components of two malaria-control strategies (house spraying and bednet impregnation with residual insecticides) was undertaken in 11 malaria-endemic states (departamentos) of Colombia, using data provided by control staff on self-administered questionnaires. The accuracy of the data was verified by personal visits, telephone conversations and complementary information from 10 other states. Allthe financial-cost components of the malaria-control operations carried out in the previous 6 months and the results of the control operations themselves (including the numbers of houses sprayed and numbers of bednets impregnated/day) were recorded. The information was stratified according to whether the target communities were ‘near’ or ‘far

away’ from an operational base, the far-away communities being those that needed overnight stays by the control staff. The main variables analysed were unit costs/house treated, and annual cost/person protected. The results show that house spraying was generally more expensive for the health services than bednet impregnation. This is particularly the case in ‘nearby’ communities, where most of those at-risk live. In such communities, spraying one house was 7.2 times more expensive than impregnating one bednet. Even if only those sleeping under an impregnated net were assumed to be protected, the unit costs/person protected in a ‘nearby’ community were twice as high for house spraying than for bednet impregnation. In ‘nearby’ communities, where technicians could return to the operational base each evening, insecticides made up 80% of the total spraying costs and 42% of the costs of bednet impregnation. In ‘far-away’ communities, however, salaries and ‘per diems’ were the most important cost components, representing, respectively, 23% and 22% of the costs of spraying, and 34% plus 27% of the costs of impregnation. Insecticide wastage and non-use of discounts on insecticide prices (available through the national Ministry of Health) increased the overall costs considerably. The multiple uses of these cost calculations for district health managers are presented.

Trop Med Int Health 2002 Aug;7(8):657-77 

The economic payoffs of integrated malaria control in the Zambian copperbelt between 1930 and 1950.

Utzinger J, Tozan Y, Doumani F, Singer BH.

Office of Population Research, Princeton University, Princeton, NJ, USA, Woodrow Wilson School of Public and International Affairs, Princeton University, Princeton, NJ, USA, World Bank, Washington, DC, USA.

It has long been suggested that malaria is delaying the economic development of countries that are most severely affected by the disease. Several studies have documented the economic consequences of malaria at the household level, primarily in communities engaged in subsistence farming. A missing element is the appraisal of the economic impact of malaria on the industrial and service sectors that will probably become the backbone of many developing economies. We estimate the economic effects of integrated malaria control implemented during the colonial period and sustained for 20 years in four copper mining communities of the former Northern Rhodesia (now Zambia). Integrated malaria control was characterized by strong emphasis on environmental management, while part of the mining communities also benefited from rapid diagnosis and treatment and the use of bednets. The programmes were highly successful as an estimated 14 122 deaths, 517 284 malaria attacks and 942 347 work shift losses were averted. Overall, 127 226 disability adjusted life years (DALYs) were averted per 3-year incremental period. The cumulative costs of malaria control interventions were US$ 11 169 472 (in 1995 US$). Because the control programmes were so effective, the mining companies attracted a large reservoir of migrant labourers and sustained healthy work forces. The programmes averted an estimated US$ 796 622 in direct treatment costs and US$ 5 678 745 in indirect costs as a result of reduced work absenteeism. Within a few years of programme initiation, Northern Rhodesia became the leading copper producer in Africa, and mining generated the dominant share of national income. Copper production and revenues, which increased dramatically during malaria control interventions, amounted to the equivalent of US$ 7.1 billion (in 1995 US$). Integrated malaria control in copper mining communities was a sound investment. It had payoff for public and occupational health, generally, and without it copper extraction and social and economic development would have been impossible.

PUBMED

Proc Natl Acad Sci U S A  2002 Aug 12; [epub ahead of print] 

Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum-infected erythrocytes.

Udomsangpetch R, Pipitaporn B, Silamut K, Pinches R, Kyes S, Looareesuwan S, Newbold C, White NJ.

*Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Department of Pathology, Faculty of Science, Rangsit University, Bangkok 12000, Thailand; Faculty of Tropical Medicine, Mahidol

University, Bangkok 10400, Thailand; and Molecular Parasitology Group, Institute of Molecular Medicine, and paragraph sign Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.

Communicated by David Weatherall, University of Oxford, Oxford, United Kingdom, July 3, 2002 (received for review March 8, 2002) In falciparum malaria, the malaria parasite induces changes at the infected red blood cell surface that lead to adherence to vascular endothelium and other red blood cells. As a result, the more mature stages of Plasmodium falciparum are sequestered in the microvasculature and cause vital organ dysfunction, whereas the ring stages circulate in the blood stream. Malaria is characterized by fever. We have studied the effect of febrile temperatures on the cytoadherence in vitro of P. falciparum-infected erythrocytes. Freshly obtained ring-stage-infected red blood cells from 10 patients with acute falciparum malaria did not adhere to the principle vascular adherence receptors CD36 or intercellular adhesion molecule-1 (ICAM-1). However, after a brief period of heating to 40 degrees C, all ring-infected red blood cells adhered to CD36, and some isolates adhered to ICAM-1, whereas controls incubated at 37 degrees C did not. Heating to 40 degrees C accelerated cytoadherence and doubled the maximum cytoadherence observed (P < 0.01). Erythrocytes infected by ring-stages of the ICAM-1 binding clone A4var also did not cytoadhere at 37 degrees C, but after heating to febrile temperatures bound to both CD36 and ICAM-1. Adherence of red blood cells infected with trophozoites was also increased considerably by brief heating. The factor responsible for heat induced adherence was shown to be the parasite derived variant surface protein PfEMP-1. RNA analysis showed that levels of var mRNA did not differ between heated and unheated ring-stage parasites. Thus fever-induced adherence appeared to involve increased trafficking of PfEMP-1 to the erythrocyte membrane. Fever induced cytoadherence is likely to have important pathological consequences and may explain both clinical deterioration with fever in severe malaria and the effects of antipyretics on parasite clearance.

J Biol Chem 2002 Aug 12;  

Infectivity-associated changes in the transcriptional repertoire of the malaria parasite sporozoite stage.

Matuschewski K, Ross J, Brown SM, Kaiser K, Nussenzweig V, Kappe SH.

Department of Parasitology, Heidelberg University School of Medicine, Heidelberg 69120.

Injection of Plasmodium salivary gland sporozoites into the vertebrate host by Anopheles mosquitoes initiates malaria infection. Sporozoites develop within oocysts in the mosquito midgut, and then enter and mature in the salivary glands. Although morphologically similar, oocyst sporozoites and salivary gland sporozoites differ strikingly in their infectivity to the mammalian host, ability to elicit protective immune responses and cell motility. Here, we show that differential gene expression coincides with these dramatic phenotypic differences. Using suppression subtractive cDNA hybridization we identified highly upregulated mRNAs transcribed from 30 distinct genes in salivary gland sporozoites. Of those genes, 29 are not significantly expressed in the parasite’s blood stages. The most frequently recovered transcript encodes a protein kinase. Developmental upregulation of specific mRNAs in the infectious transmission stage of Plasmodium indicates that their translation products may have unique roles in hepatocyte infection and/or development of liver stages.

Trans R Soc Trop Med Hyg  2002 May-Jun;96(3):327-8 

Haptoglobin genotypes are not associated with resistance to severe malaria in The Gambia.

Aucan C, Walley AJ, Greenwood BM, Hill AV.

Wellcome Trust Centre For Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. [email protected]

The influence of haptoglobin polymorphisms on severe malaria occurrence was assessed in 1183 individuals from The Gambia. No significant association was found between severe malaria and either haptoglobin genotypes or phenotypes. The advantages of using a deoxyribonucleic acid-based haptoglobin typing method are discussed.

Trans R Soc Trop Med Hyg  2002 May-Jun;96(3):310-7 

Intensity of malaria transmission, antimalarial-drug use and resistance in Uganda: what is the relationship between these three factors?

Talisuna AO, Langi P, Bakyaita N, Egwang T, Mutabingwa TK, Watkins W, Van Marck E, D’Alessandro U.

Ministry of Health, P. O. Box 7272, Kampala, Uganda.  [email protected] 

We studied (in 1998 and 1999) some factors that may be linked to the spread of chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) resistance in 7 discrete communities in Uganda. Exposure to malaria infection was measured by parasitological surveys in children aged 1-9 years, drug use by community surveys and drug resistance by in-vivo tests on children aged 6-59 months with clinical malaria. CQ use was inversely related to parasite prevalence (r = -0.85, P = 0.01). CQ and SP treatment failure rates varied significantly according to parasite prevalence (P = 0.001 and 0.04 respectively). The highest CQ (42.4%, 43.8%) and SP (12.5%, 14.8%) treatment failure rates were observed in sites characterized by high parasite prevalence. Using areas with medium parasite prevalence as reference, the relative risk (RR) for CQ treatment failure was 3.2 (95% CI 1.6-6.4) in high parasite prevalence sites and 3.1 (95% CI 1.2-7.7) in low parasite prevalence sites. The RR for SP treatment failure was also higher in sites with high parasite prevalence but low in those with low parasite prevalence. According to our findings, drug resistance seems to spread faster in higher transmission areas, regardless of drug pressure. In low transmission areas, drug pressure seems to be the critical factor. A decrease in transmission coupled with rational use of drugs may delay the spread of resistance.

Trans R Soc Trop Med Hyg 2002 May-Jun;96(3):304-9 

Treatment of uncomplicated malaria in children in Guinea-Bissau with chloroquine, quinine, and sulfadoxine-pyrimethamine.

Kofoed PE, Co F, Johansson P, Dias F, Cabral C, Hedegaard K, Aaby P, Rombo L.

Department of Paediatrics, Kolding Hospital, Denmark.  [email protected]

With the increasing resistance to commonly used antimalarial drugs, different untested ‘local’ treatment regimens for malaria will arise. We compared commonly used treatment regimens for children in Guinea-Bissau. Symptomatic children with Plasmodium falciparum mono-infection were allocated at random to one of 4 treatments: 15 mg/kg quinine twice a day for 3 d (group 1); 10 mg/kg quinine twice a day for 3 d followed by a total dose of 25 mg chloroquine base given over 3 d (group 2); a total dose of 50 mg/kg chloroquine base given in 2 daily doses for 3 d (group 3), or sulfadoxine-pyrimethamine (group 4). On day 28 more children from group 1 (33%; relative risk [RR] = 2.9, 95% confidence interval [CI] 1.5-5.7) and group 2 (26%; RR = 2.1, CI 1.0-4.3) had had parasitaemia than in group 4 (12%), whereas no significant difference was found between group 3 (17%; RR = 1.3, CI 0.6-2.2) and group 4. No severe adverse reaction was observed in any of the groups. Chloroquine is still effective in Guinea-Bissau at an increased dose of 50 mg/kg, which appears safe when given orally in 2 daily doses for 3 d. Sulfadoxine-pyrimethamine could serve as an efficient, cheap and easy to administer second-line drug, leaving quinine to be used for third-line treatment. Quinine should not be used in short courses, nor does the combination of quinine and chloroquine have any advantage.

Trans R Soc Trop Med Hyg 2002 May-Jun;96(3):282-6 

The role of reduced red cell deformability in the pathogenesis of severe falciparum malaria and its restoration by blood transfusion.

Dondorp AM, Nyanoti M, Kager PA, Mithwani S, Vreeken J, Marsh K.

Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, The Netherlands.  [email protected]

As reduced red cell deformability (RCD) can contribute to derangement of the microcirculation, a central feature in the pathogenesis of severe malaria, RCD was measured with a laser diffraction technique in 232 consecutive patients with falciparum malaria on the Kenyan coast, of whom 99 had severe disease. RCD on admission (measured as elongation index [EI] at shear stress = 1.7 Pa) was reduced in proportion with severity of disease (fatal outcome: EI = 0.182 (SD = 0.048), survivors from severe disease: EI = 0.217 (SD = 0.043), uncomplicated malaria: EI = 0.249 (SD = 0.030), healthy controls: EI = 0.268 (SD = 0.022). All but 2 survivors with severe malaria and rigid erythrocytes received a blood transfusion restoring RCD. Reduced RCD may contribute to impaired

microcirculatory flow and a fatal outcome in falciparum malaria. RCD can be improved by blood transfusion. Since severely reduced RCD has a strong predictive value for mortality, blood transfusion possibly improves disease outcome not only through its beneficial effect on anaemia but also on RCD.

Trans R Soc Trop Med Hyg 2002 May-Jun;96(3):278-81 

Severe falciparum malaria in children: a comparative study of 1990 and  2000 WHO criteria for clinical presentation, prognosis and intensive care in Dakar, Senegal.

Imbert P, Gerardin P, Rogier C, Ka AS, Jouvencel P, Brousse V, Guyon P.

Service des Maladies Infectieuses et Tropicales, Hopital d’Instruction des Armees Begin, 69 Avenue de Paris, 94163 Saint-Mande, France. [email protected]

The relevance of WHO criteria for severe and complicated malaria has been debated for a while, especially as regards children. Recent data led WHO experts to modify the definition of severe malaria. The objective of this study was to evaluate retrospectively the significance of the new definition on severity, lethality and intensive care distribution in children admitted with falciparum malaria (in 1997-99) to Hopital Principal de Dakar, Senegal. We used the paediatric risk of mortality score (PRISM) to compare the 2 definitions, WHO 2000 and WHO 1990. Finally, we evaluated the impact of the new definition in terms of major therapeutic interventions (MTIs): mechanical ventilation, haemodynamic support, transfusion, haemodialysis, and the use of sedatives. Among 311 patients, the frequencies of severe malaria cases and case-fatality rates thereof were 52% (n = 161) and 17% (n = 28) respectively using the 1990 WHO criteria, and 75% (n = 233) and 12% (n = 28) using the 2000 WHO criteria. Mean PRISM score among severe cases decreased with the new definition (6.5 versus 8.6). Both definitions predicted neurological sequelae and deaths with 100% sensitivity. One or more MTIs were required in severe malaria cases in 86% (n = 139) under the 1990 criteria and 73% (n = 170) under the 2000 criteria. In this area of low and seasonal transmission, the 2000 WHO definition of severe malaria proved broader and less specific, but was easier to apply and retained the high sensitivity of the earlier definition in identifying life-threatening infections.

Trans R Soc Trop Med Hyg 2002 May-Jun;96(3):258-65 

Field and laboratory comparative evaluation of ten rapid malaria diagnostic tests.

Craig MH, Bredenkamp BL, Williams CH, Rossouw EJ, Kelly VJ, Kleinschmidt I, Martineau A, Henry GF.

Malaria Research Programme, Medical Research Council, 491 Ridge Road, P.O. Box 70380, Overport 4067, Durban, South Africa.  [email protected]

The paper reports on a comparative evaluation of 10 rapid malaria tests available in South Africa in 1998: AccuCheck (AC, developmental), Cape Biotech (CB), ICT Malaria Pf (ICT1) and Pf/Pv (ICT2), Kat Medical (KAT), MakroMal (MM), OptiMAL (OP), ParaSight-F (PS), Quorum (Q), Determine-Malaria (DM). In a laboratory study, designed to test absolute detection limits, Plasmodium

falciparum-infected blood was diluted with uninfected blood to known parasite concentrations ranging from 500 to 0.1 parasites per microlitre (P/microL). The 50% detection limits were: ICT1, 3.28; ICT2, 4.86; KAT, 6.36; MM, 9.37; CB, 11.42; DM, 12.40; Q, 16.98; PS, 20; AC, 31.15 and OP, 91.16 P/microL. A field study was carried out to test post-treatment specificity. Blood samples from

malaria patients were tested with all products (except AC and DM) on the day of treatment and 3 and 7 days thereafter, against a gold standard of microscopy and polymerase chain reaction (PCR). OP and PS produced fewer false-positive results on day 7 (18 and 19%, respectively) than the other rapid tests (38-56%). However, microscopy, PCR, OP and PS disagreed largely as to which individuals remained positive. The tests were further compared with regard to general specificity, particularly cross-reactivity with rheumatoid factor, speed, simplicity, their ability to detect other species, storage requirements and general presentation.

Trans R Soc Trop Med Hyg 2002 May-Jun;96(3):254-7 

Validity, reliability and ease of use in the field of five rapid tests for the diagnosis of Plasmodium falciparum malaria in Uganda.

Guthmann JP, Ruiz A, Priotto G, Kiguli J, Bonte L, Legros D.

Epicentre, 4 rue Saint Sabin, 75011 Paris, France.  [email protected]

A study was conducted to measure the overall performance of several rapid diagnostic tests for Plasmodium falciparum infection, in order to select the most appropriate test to be used in the field. A total of 742 patients attending the out-patient department of Mbarara Hospital with a clinical suspicion of malaria were included in the study. For each patient, a thick/thin film and 5 rapid tests based on the detection of histidine-rich protein II (HRP-II) (Paracheck Pf dipstick and device, ParaHIT f, Malaria Rapid and BIO P.F.) were performed. Outcomes were validity, inter-reader reliability and ‘ease of use in the field’, measured by both the general characteristics of the test and by the opinion of the readers. About half (57%) of the patients were positive for P. falciparum. The Paracheck Pf (dipstick and device) was considered as the most appropriate for the use in the field, being sensitive (97%), moderately specific (88%), reliable (kappa coefficient = 0.97), easy to use and cheap (about US$ 0.5/test). The ParaHIT f represented a good alternative.

Trans R Soc Trop Med Hyg 2002 May-Jun;96(3):225-31 

Traditional use of mosquito-repellent plants in western Kenya and their evaluation in semi-field experimental huts against Anopheles gambiae: ethnobotanical studies and application by thermal expulsion and direct burning.

Seyoum A, Palsson K, Kung’a S, Kabiru EW, Lwande W, Killeen GF, Hassanali A, Knols BG.

International Centre of Insect Physiology and Ecology, P.O. Box 30772, Nairobi, [email protected]

Ethnobotanical survey in 2 communities in western Kenya revealed that the most commonly known repellent plants were Ocimum americanum L. (64.1%), Lantana camara L. (17.9%), Tagetes minuta L. (11.3%) and Azadirachta indica A. Juss (8.7%) on Rusinga Island, and Hyptis suaveolens Poit. (49.2%), L. camara (30.9%) and O. basilicum L. (30.4%) in Rambira. Direct burning of plants is the most common method of application for O. americanum (68.8%), L. camara (100%) and O.  basilicum (58.8%). Placing branches or whole plants inside houses is most common for H. suaveolens (33.3 and 57.8% for the respective locations), A. indica (66.7 and 100%),  and T. minuta (54.8 and 56.0%). The repellency of plants suggested by the ethnobotanical survey and other empirical information was evaluated against the malaria vector Anopheles gambiae s.s. Giles in experimental huts within a screenwalled greenhouse. Thermal expulsion and direct burning were tested as alternative application methods for the selected plants O. americanum, O. kilimandscharicum Guerke, O. suave Willd., L. camara,  A. indica, H. suaveolens, Lippia uckambensis Spreng and Corymbia citriodora Hook.  When thermally expelled, only H. suaveolens failed to repel mosquitoes, whereas the leaves of C. citriodora (74.5%, P < 0.0001), leaves and seeds of O. suave (53.1%, P < 0.0001) and O. kilimandscharicum (52.0%, P < 0.0001) were the most effective. Leaves of C. citriodora also exhibited the highest repellency (51.3%, P < 0.0001) by direct burning, followed by leaves of L. uckambensis (33.4%, P = 0.0004) and leaves and seeds of O. suave (28.0%, P = 0.0255). The combination of O. kilimandscharicum with L. uckambensis repelled 54.8% of mosquitoes (P < 0.0001) by thermal expulsion. No combination of plants increased repellency by either method. The semi-field system described appears a promising alternative to full-field trials for screening large numbers of candidate repellents without risk of malaria exposure.

Parasitol Res 2002 Sep;88(9):855-60 

A direct sandwich ELISA to detect antibodies against the C-terminal region  of merozoite surface protein 1 could be a useful diagnostic method to identify Plasmodium vivax exposed persons.

Lim J, Park W, Sohn J, Lee S, Oh H, Kim C, Bahk Y, Kim S.

Department of Biochemistry, College of Science, Protein Network Research Center, Yonsei University, Seoul, 120-749, Republic of Korea. 

We expressed a C-terminal 108-aa region of the Plasmodium vivax merozoite surface protein 1 (PvMSP1c) excluding the C-end transmembrane region in Escherichia coli in order to evaluate the antibody level to MSP in Korean malaria patients. We optimized a direct sandwich enzyme-linked immunosorbent assay (ELISA) method to simultaneously determine the total antibody levels, including IgG and IgM, to PvMSP1c. If the cut-off for seropositivity was determined as the mean+3SD of the antibody levels of the negative control group, the antibody levels were positive in 99.5% of the patient group (sensitivity 199/200). The antibody levels were negative in 99.4% of the negative control group (specificity 504/507). The positive reactions in the negative control group came from non-specific reactions, as confirmed by a competition assay. This direct sandwich ELISA for PvMSP1c antibody could prove to be a useful tool for the diagnosis of malaria patients and for blood screening in blood banks.

Ann Trop Med Parasitol 2002 Jun;96(4):349-59 

Patterns of rainfall and malaria in Madhya Pradesh, central India.

Singh N, Sharma VP.

Malaria Research Centre, Field Station, I.C.M.R., Medical College Building, Jabalpur-482003, Madhya Pradesh, India.

Some recent outbreaks of Plasmodium falciparum malaria have been attributed, at least in part, to increases in the intensity and duration of rainfall caused by the El Nino southern oscillation (ENSO), a periodic climatic phenomenon. Since it takes time for unusually heavy rainfall to translate into unusually high densities of the vector mosquitoes, it has been suggested that data on recent rainfall might be used to predict climate-related epidemics of malaria. This possibility was explored by comparing the patterns in the incidence of malaria in (1) Dungaria, a highly malarious village in the central-Indian district of Mandla, and (2) Mandla district as a whole, for the periods 1986-2000 and 1967-2000, respectively, with data on rainfall for the same areas and periods. Unfortunately, no clear relationship was observed between rainfall and malaria incidence, although a major development project to improve water resources in the study area (which resulted in local villages being partially or completely submerged in water) may have masked any significant association. A useful method for predicting which years are going to be high- or low-risk years for malaria epidemics, in the present and other epidemiological settings, remains a futuregoal.

Ann Trop Med Parasitol 2002 Jun;96(4):339-48 

Chloroquine for the treatment of uncomplicated malaria in Guyana.

Baird JK, Tiwari T, Martin GJ, Tamminga CL, Prout TM, Tjaden J, Bravet PP, Rawlins S, Ferrel M, Carucci D, Hoffman SL.

U.S. Naval Medical Research Unit #2, American Embassy Jakarta, Fleet Post Office-Asia/Pacific 96520-8132, U.S.A.

At a public hospital in Georgetown, Guyana, 44 patients seeking treatment for symptomatic, slide-confirmed malaria were given standard chloroquine (CQ) therapy and followed for 28 days. The patients apparently had pure infections with Plasmodium falciparum (14), P. vivax (13) or P. malariae (one), or mixed infections either of P. falciparum and P. vivax (17) or of P. falciparum, P. malariae and P. vivax (two). Each received supervised treatment with 10 mg CQ base/kg on each of days 0 and 1, and 5 mg/kg on day 2. On the day of enrollment (day 0), the patients complained of fever (100%), headache (100%), malaise (94%), myalgia (79%), nausea (67%), vertigo (49%) and vomiting (33%). Many (39%) were ill enough to confine themselves to bed. On day 4, fewer of the subjects complained of fever (15%), headache (15%), malaise (6%), myalgia (21%), nausea (6%), vertigo (24%) or vomiting (0%) despite the relatively high (>48%) risk of therapeutic failure. The cumulative incidence of parasitological failure against P. falciparum was 15% at day 4, 33% at day 7 and 48% at day 14. All of the P. vivax and P. malariae infections cleared before day 4 and none recurred by day 7. Two infections with P. vivax recurred later (on day 14 or 28) but in the presence of less than adequate, whole-blood concentrations of CQ plus desethyl-chloroquine (i.e. <100 ng/ml). Taken together, the results indicate a high risk of therapeutic failure of CQ against P. falciparum but also indicate that resistance to CQ in P. vivax occurs infrequently in Guyana.

J Commun Dis 2001 Jun;33(2):88-95 

Malaria outbreak in the Indira Gandhi Nahar Pariyojna command area in Jaisalmer district, Thar Desert, India.

Tyagi BK, Yadav SP, Sachdev R, Dam PK.

Desert Medicine Research Centre (ICMR), New Pali Road, Jodhpur 342005.

A focal outbreak of malaria occurred in the villages situated close to the main Indira Gandhi canal near Ramgarh in Jaisalmer district, western Rajasthan. Stagnation of water over a month’s period in the main canal as well as long standing rain water in the form of expansive lakes near these villages formed vast breeding grounds for the vectors like Anopheles culicifacies, along with A. stephensi already breeding in the ‘tanka’ and ‘beri’ in the epidemichit villages. Rapid mass blood surveys along with other entomological and parasitological investigations were conducted in four of the ten affected villages, viz., Seuva, Raghwa, Raimala and Sadhna. A total of 992 specimens belonging to four vector species were sampled, namely, A. stephensi (47.4%), A. culicifacies (41.0%), A. subpictus (11.2%) and A. annularis (0.4%). Epidemiologically, about one-fourth of the examined persons were positive (SPR 25.5%), although Plasmodium falciparum dominated the parasitaemia (49.5%). Available data are indicative of changed malariological scenario in the Indira Gandhi Nahar Pariyojna command area, where epidemics are regular features every year.

J Commun Dis 2001 Jun;33(2):83-7 

Artemether vs quinine therapy in Plasmodium falciparum malaria in  Manipur—a preliminary report.

Singh NB, Bhagyabati Devi S, Singh TB, Singh MA, Singh NB.

Regional Institute of Medical Sciences, Imphal, Manipur.

Qinghaosu and its derivatives are rapidly effective antimalarial drugs derived from a Chinese plant (sweet worm wood). Preliminary studies suggest that these drugs may be more effective than quinine in the treatment of Plasmodium falciparum malaria. A randomised double blind trial was conducted in 52 cases of Plasmodium falciparum malaria cases. In all 26 cases were given artemether and another 26 were given quinine. There were 2 (7.5%) deaths in artemether group and 4 (15%) deaths in quinine group. The parasites were cleared more quickly from the blood in artemether group when compared to quinine group (mean-72 hrs vs 96 hrs). Resolution of fever was comparable in both artemether and quinine group (mean-84 hrs vs 78 hrs) and also the average time of recovery from coma was more earlier in artemether group (mean-60 hrs vs 72 hrs). The only side effect noticed with artemether therapy was gastrointestinal (GI) intolerance while quinine therapy was associated with myocarditis, hypotension, hypoglycemia and GI intolerance.

J Commun Dis 2001 Jun;33(2):116-20 

Comparative toxicity of selected larvicidal formulations against Anopheles

stephensi Liston and Aedes aegypti Linn.

Mittal PK, Adak T, Batra CP.

Malaria Research Centre, 2, Nanak Enclave, Delhi-110 009.

Toxicity of selected larvicidal formulations of Bacillus sphaericus, Bacillus thuringiensis H-14 israelensis (Bti) and insect growth regulators was determined against Anopheles stephensi and Aedes aegypti, the two major urban mosquito vectors of malaria and dengue fever in India respectively. The study revealed that the formulations of Bacillus thuringiensis H-14 and IGR compounds were highly toxic against both the mosquito species but Bacillus sphaericus formulation was less toxic against Aedes aegypti and has a limited potential for use against Aedes aegypti. Of the two Bti formulations, ‘Vectobac’ formulation was more toxic against both the species than ‘BMP-1442X’ formulation. Bti formulations were more toxic against Aedes aegypti (LC50 = 0.06 and 0.14 mg/Litre) than against An. stephensi (LC50 = 0.14 and 0.81 mg/Litre), while B. sphaericus formulation was more toxic against An. stephensi LC50 = 0.031 mg/Litre than Aedes aegypti LC50 = 0.294 mg/Litre. Among different larvicidal formulations tested in this study, IGR compounds were found to be toxic against both the mosquito species at very low concentrations (EC50 values ranging between 0.0001 and 0.0004 ppm).

Biochem J 2002 Aug 8;Pt [epub ahead of print] 

Critical role of amino acid 23 in mediating activity and specificity of vinckepain-2, a papain-family cysteine protease of rodent malaria parasites.

Singh A, Shenai BR, Choe Y, Gut J, Sijwali PS, Craik CS, Rosenthal PJ.

Cysteine proteases of Plasmodium falciparum, known as falcipains, have been identified as hemoglobinases and potential drug targets. As antimalarial drug discovery requires analysis of non-primate malarias, genes encoding related cysteine proteases of the rodent malaria parasites Plasmodium vinckei (vinckepain-2) and Plasmodium berghei (berghepain-2) were characterized. These

genes encoded fairly typical papain-family proteases, but they contained an unusual substitution of Gly23 with Ala (papain numbering). Vinckepain-2 was expressed in Escherichia coli, solubilized, refolded, and auto-processed to an active enzyme. The protease shared important features with the falcipains, including an acid pH optimum, preference for reducing conditions, optimal

cleavage of peptide substrates with P2 Leu, and ready hydrolysis of hemoglobin. However, key differences between the plasmodial proteases were identified. In particular, vinckepain-2 showed very different kinetics against many substrates and an unusual preference for peptide substrates with P1 Gly. Replacement of Ala23 with Gly remarkably altered vinckepain-2, including loss of the P1 Gly substrate preference, markedly increased catalytic activity (kcat/Km increased about 100-fold), and more rapid autohydrolysis. Our studies identify key animal model parasite targets, indicate that drug discovery studies must take into account important differences between plasmodial proteases, and shed light on the critical role of amino acid 23 in catalysis by papain-family proteases.

J Biol Chem 2002 Aug 7; [epub ahead of print] 

Bee venom phospholipase inhibits malaria parasite development in transgenic mosquitoes.

Moreira LA, Ito J, Ghosh A, Devenport M, Zieler H, Abraham EG, Crisanti A, Nolan T, Catteruccia F, Jacobs-Lorena M.

Department of Genetics, Case Western Reserve University, Cleveland, OH 44106-4955.

Malaria kills millions of people every year and new control measures are urgently needed. The recent demonstration that (effector) genes can be introduced into the mosquito germ line to diminish their ability to transmit the malaria parasite offers new hope toward the fight of the disease (Ito et al., Nature, 417, 452-455, 2002). Because of the high selection pressure that an effector gene imposes on the parasite population, development of resistant strains is likely to occur. In search of additional anti-parasitic effector genes we have generated transgenic Anopheles stephensi mosquitoes that express

the bee venom phospholipase A2 (PLA2) gene from the gut-specific and blood-inducible An. gambiae carboxypeptidase (AgCP) promoter. Northern blot analysis indicated that the PLA2 mRNA is specifically expressed in the guts of transgenic mosquitoes, with peak expression at ~4 h after blood ingestion. Western blot and immunofluorescence analyses detected PLA2 protein in the midgut epithelia of transgenic mosquitoes from 8 to 24 h after a blood meal. Importantly, transgene expression reduced Plasmodium berghei oocyst formation by 87% on average, and greatly impaired transmission of the parasite to nave mice. The results indicate that PLA2 may be used as an additional effector gene to block the development of the malaria parasite in mosquitoes.

Trop Med Int Health 2002 Aug;7(8):652-6 

Plasmodium falciparum: use of a NANP19 antibody-test for the detection of infection in non-immune travellers.

Knappik M, Peyerl-Hoffmann G, Jelinek T.

Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany.

Circumsporozoite (CS) antibodies are a reliable serological marker for the infection of Plasmodium falciparum. The purpose of this investigation was to construct and evaluate an enzyme-linked immunosorbent assay test for the detection of CS antibodies. While the sensitivity of the newly developed test reached 78%, the specificity was 99%. In addition, the optimized kit was used to test for infection with P. falciparum in 1903 travellers that were recruited from a prospective study for malaria chemoprophylaxis. Sixty-six of the 1903 patients (3.5%) showed elevated CS antigen antibody titres. However, seroconversion could only be demonstrated in 18 (0.95%) patients. Among those seroconverting, there was a significantly higher percentage of male travellers (1.28%) than female travellers (0.56%). Positive reactions were more frequent among returnees from West and East Africa (1.49 and 1.14%, respectively) than among those from other endemic areas, e.g. South America (n=0). Despite its limited sensitivity, this newly developed kit for CS antibody testing may be a valuable tool for the estimation of the risk for travellers in malarious regions

to acquire an infection with P. falciparum. It may also be useful for the determination of the efficacy of malaria chemoprophylaxis for inhibiting outbreak of disease.

Mol Biochem Parasitol 2002 Aug;123(1):35 

Identification, expression, and functional characterization of MAEBL, a sporozoite and asexual blood stage chimeric erythrocyte-binding protein of Plasmodium falciparum.

Ghai M, Dutta S, Hall T, Freilich D, Ockenhouse C.

Department of Immunology, Walter Reed Army Institute of Research, 20910, Silver Spring, MD, USA

MAEBL is a chimeric erythrocyte binding protein reported in rodent malaria parasites Plasmodium yoelii and Plasmodium berghei, that has the gene structure similar to erythrocyte binding proteins, but N-terminal homology to subdomains I and II of Apical membrane antigen-1. We report here the sequence analysis and gene structure of the Plasmodium falciparum maebl gene. We have cloned and expressed a putative red cell binding domain, M2, of this gene in Escherichia coli, purified the recombinant protein (r-PfM2) and studied its in vitro binding specificity to human red cells. Binding of r-PfM2 protein to red cells was abolished by pretreatment with papain, while increased binding was observed to neuraminidase-treated red cells. Polyclonal antibodies to r-PfM2 recognized native MAEBL protein in blood stage schizont extracts of the parasite on Western blots and within the apical complex of free merozoites, by indirect immunofluorescent assay (IFA). MAEBL expression in P. falciparum sporozoites was also detected by reverse transcriptase polymerase chain reaction (RT-PCR) and IFA. High titer antibodies to r-PfM2 were observed in human sera obtained from a malaria endemic region some of which inhibited r-PfM2 binding to red cells. Individuals immunized with irradiated sporozoites tested positive for anti-MAEBL antibodies by ELISA. The dual stage expression of MAEBL makes it an excellent pre-erythrocytic and erythrocytic stage vaccine target antigen.

Mol Biochem Parasitol  2002 Aug;123(1):23 

Bacterially expressed and refolded receptor binding domain of Plasmodium falciparum EBA-175 elicits invasion inhibitory antibodies.

Pandey K, Singh S, Pattnaik P, Pillai C, Pillai U, Lynn A, Jain S, Chitnis C.

Malaria Research Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), P. O. Box 10504, Aruna Asaf Ali Marg, 110067, New Delhi, India

Malaria parasites make specific receptor-ligand interactions to invade erythrocytes. A 175 kDa Plasmodium falciparum erythrocyte binding antigen (EBA-175) binds sialic acid residues on glycophorin A during invasion of human erythrocytes. The receptor-binding domain of EBA-175 lies in a conserved, amino-terminal, cysteine-rich region, region F2 of EBA-175 (PfF2), that is homologous to the binding domains of other erythrocyte binding proteins such as Plasmodium vivax Duffy binding protein. We have developed methods to produce recombinant PfF2 in its functional form. Recombinant PfF2 was expressed in Escherichia coli, purified from inclusion bodies, renatured by oxidative refolding and purified to homogeneity by ion-exchange and gel filtration chromatography. Refolded PfF2 has been characterized using biochemical and biophysical methods and shown to be pure, homogenous and functional in that it binds human erythrocytes with specificity. Immunization with refolded PfF2 yields high titre antibodies that efficiently inhibit P. falciparum invasion of erythrocytes in vitro. Importantly, antibodies raised against PfF2 block invasion by a P. falciparum field isolate that invades erythrocytes using multiple pathways. These observations support the development of recombinant PfF2 as a vaccine candidate for P. falciparum malaria.

Mol Biochem Parasitol  2002 Aug;123(1):11 

Characterisation of a delta-COP homologue in the malaria parasite,  Plasmodium falciparum.

Adisa A, Rug M, Foley M, Tilley L.

Department of Biochemistry, La Trobe University, 3086, Vic., Melbourne, Australia

The mature human erythrocyte is a simple haemoglobin-containing cell with no internal organelles and no protein synthesis machinery. The malaria parasite invades this cell and develops inside a parasitophorous vacuole (PV). The parasite exports proteins into the erythrocyte to bring about extensive remodelling of its adopted cellular home. Plasmodial homologues of two COPII proteins, PfSar1p and PfSec31p, are exported to the erythrocyte cytosol where they appear to play a role in the trafficking of proteins across the erythrocyte cytoplasm [Eur. J. Cell Biol. 78 (1999) 453; J. Cell Sci. 114 (2001) 3377]. We have now characterised a homologue of the COPI protein, delta-COP. A recombinant protein corresponding to 90% of the Pfdelta-COP sequence was used to raise antibodies. The affinity-purified antiserum recognised a protein with an apparent M(r) of 58×10(3) on Western blots of malaria parasite-infected erythrocytes but not on blots of uninfected erythrocytes. Pfdelta-COP was shown to be largely insoluble in non-ionic detergent, possibly suggesting cytoskeletal attachment. Confocal immunofluorescence microscopy of parasitised erythrocytes was used to show that, in contrast to the COPII proteins, Pfdelta-COP is located entirely within the parasite. The location of Pfdelta-COP partly overlaps that of the endoplasmic reticulum (ER)-located protein, PfERC, and partly that of the trans-Golgi-associated protein, PfRab6. Treatment of ring-stage plasmodium-infected erythrocytes with brefeldin A (BFA) inhibited development of the ER structure within the parasite cytosol and prevented the trafficking of the P. falciparum erythrocyte membrane protein-1, PfEMP1, to the erythrocyte

cytosol. The Pfdelta-COP and PfSec31p populations each appear to be associated with the restricted ER structure in brefeldin-treated rings. When more mature stage parasites were treated with BFA, erythrocyte cytosol-located populations of parasite proteins were not reorganised, however, the overlap between Pfdelta-COP and PfERC in parasite cytosol was more complete suggesting a possible redistribution of the Golgi compartment into the ER. These data support the suggestion that both COPI and COPII proteins are involved in the trafficking of proteins within the parasite cytoplasm. However, only COPII proteins are exported to the erythrocyte cytosol to establish a vesicle-mediated protein trafficking pathway to the erythrocyte membrane.

Mol Biochem Parasitol 2002 Aug;123(1):1 

Rapid positive selection of stable integrants following transfection of Plasmodium falciparum.

Wang P, Wang Q, Sims P, Hyde J.

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

With the near-completion of the genome sequence of Plasmodium falciparum, further understanding of this major human pathogen urgently requires more effective genetic tools. These must include faster and more reliable gene replacement or gene knockout techniques, essential for the analysis of gene function. We describe a serial system which uses the blasticidin S deaminase (bsd) gene of Aspergillus and the neomycin phosphotransferase II (neo) gene from transposon Tn5 as selectable markers for, respectively, transient transfection of malaria parasites and the selection of stable integrants. Challenge with blasticidin S (BS) enriches the parasite population transiently expressing the bsd gene, laying the foundation for the subsequent, much less frequent, integration event. Positive selection for this rare event is enormously facilitated by fusing the neo gene in frame to the replacement or knockout  targeting gene. The sequence employed for the targeting (the polymorphic pppk-dhps gene of P. falciparum, as a model system) is truncated at the 5′ end with no promoter located upstream, therefore neo cannot be expressed without specifically integrating within the genomic copy of the target gene. After BS selection, the culture is immediately exposed to geneticin (G418), leading to an apparently homogenous population of mutant parasites. As well as excluding spurious integrants at non-targeted sequences, this system greatly reduces the lengthy selection period for obtaining the desired mutants by eliminating the drug-on and drug-off cycles for the production of stable integrants, which are normally required by the single marker systems currently in use for transfection of malaria parasites.

Clin Exp Immunol 2002 Aug;129(2):326-31 

Allelic family-specific humoral responses to merozoite surface protein 2 (MSP2) in

Gabonese residents with Plasmodium falciparum infections.

Ekala MT, Jouin H, Lekoulou F, Mercereau-Puijalon O, Ntoumi F.

Unite de Parasitologie, Centre International de Recherches Medicales,  Franceville (CIRMF) Gabon, Hopital Albert Schweitzer, Unite de Recherches, Gabon, and Unite Immunologie Moleculaire Des Parasites, Institut Pasteur de Paris, Paris, France.

Merozoite surface protein 2 (MSP2) expressed by Plasmodium falciparum asexual blood stages has been identified as a promising vaccine candidate. In order to explore allelic family-specific humoral responses which may be responsible for parasite neutralization during natural infections, isolates from individuals with either asymptomatic infections or uncomplicated malaria and residing in a Central African area where Plasmodium transmission is high and perennial, were analysed using MSP2 as polymorphic marker. The family-specific antibody responses were assessed by ELISA using MSP2 synthetic peptides. We observed an age-dependence of P. falciparum infection complexity. The decrease of infection complexity around 15 years of age was observed simultaneously with an increase in the mean number of MSP2 variants recognized. No significant difference in the P. falciparum genetic diversity and infection complexity was found in isolates from asymptomatic subjects and patients with uncomplicated malaria. The longitudinal follow-up showed a rapid development of immune responses to various regions of MSP2 variants within one week. Comparing humoral responses obtained with the other major antigen on the merozoite surface, MSP1, our findings suggest that different pathways of responsiveness are involved in antibody production to merozoite surface antigens.

Clin Exp Immunol 2002 Aug;129(2):318-325 

Antibody responses to the repetitive Plasmodium falciparum antigen Pf332 in humans naturally primed to the parasite.

Ahlborg N, Haddad D, Siddique AB, Roussilhon C, Rogier C, Trape JF, Troye-Blomberg M, Berzins K.

Department of Immunology, Stockholm University,Stockholm, Sweden; Immunology Unit, Pasteur Institut de Dakar, Senegal and Unite de Parasitologie Biomedicale, Institut Pasteur, Paris, France, Institut de Medecine Tropicale de Sante des Armees, Marseille, France, and Institut de Recherches pour le Developpement, Montpellier, France.

Antibodies to the degenerate repeats of EB200, a part of the Plasmodium falciparum antigen Pf332, are protective in monkeys. To analyse the prevalence, magnitude and specificity of antibodies to EB200 in malaria-exposed humans, the IgG antibody reactivity with recombinant EB200 protein as well as with crude malaria antigen was determined in Senegalese donors (n = 100; 4-87 years). Antibody reactivity with EB200 was low or absent in children below 15 years but was prevalent and significantly higher in older donors. In comparison, all individuals displayed reactivity with a crude malaria antigen preparation, which also increased with age. The reactivity with the crude malaria antigen was correlated to the reactivity with EB200, suggesting that the low levels of IgG to EB200 found in some adult donors reflected a limited degree of recent exposure to parasites rather than a selective non-responsiveness to Pf332. Comparison of serological and clinical data showed that high levels of antibodies to crude malaria antigen and to EB200 were predictive of fewer future clinical attacks of malaria. A reactivity pattern very similar to that found in Senegalese donors was observed in Liberian adults where 80% of the sera showed reactivity with EB200 and all peptides were recognized by between 60 and 100% of the donors. This strong reactivity with EB200-derived overlapping peptides suggests that the epitopes in EB200, to a large extent, are linear. In the light of previous data on the parasite neutralizing capacity of antibodies to Pf332, the present results emphasize the potential interest of Pf332-derived sequences for inclusion in a subunit vaccine against P. falciparum malaria.

Parasite Immunol 2002 Jul;24(7):387-389 

Increased levels of interleukin-12 in Plasmodium falciparum malaria: correlation  with the severity of disease.

Malaguarnera L, Imbesi RM, Pignatelli S, Simpore J, Malaguarnera M, Musumeci S.

Department of Biomedical Sciences, University of Catania, Italy, Centre Medical Saint Camille, Ouagadougou, Burkina Faso, Department of Internal Medicine, University of Catania, Italy, Department of Pediatrics, University of Sassari and Institute of Population Genetics, National Research Council (CNR), Alghero, Italy.

Interleukin (IL)-12, produced by mononuclear phagocytes, activates the T-helper 1 (Th1) cells and helps, as a mediator, the innate immune response to intracellular microbes. In Plasmodium falciparum infection, this proinflammatory cytokine has immunoregulatory functions with effects on the immune response to the blood stage of disease, but also induces protection and reduces malarial anaemia. In this study, the levels of IL-12 were determined in 73 African children, aged 2-144 months (median 19.5 months), who had severe or mild P. falciparum malaria. IL-12 was determined using the enzyme-linked immunosorbent assay. The levels of IL-12 were found to be significantly elevated (21.6 +/- 18.3 pg/ml) in patients who suffered less severely from the disease. In contrast, the levels of IL-12 were found to be lower (13.1 +/- 7.11 pg/ml) in patients who suffered more severely from the disease.

Arch Histol Cytol 2002 Jun;65(2):127-32 

Extrathymic T cells in malaria protection, including evidence for the onset of erythropoiesis in the liver during infection.

Abo T, Sekikawa H.

Department of Immunology and Medical Zoology, Niigata University Graduate School of Medical and Dental Sciences, Japan. [email protected]

This review proposes the possibility that malarial protection might not bemachieved through the process of acquired immunity in which the constituents are conventional T and B (B-2) cells. On the other hand, malarial protection might be achieved by the process of innate immunity in which the constituents are extrathymic T cells and autoantibody-producing B-1 cells. Accordingly, mice infected with malaria exhibited severe thymic atrophy, and the expansion of IL-2Rbeta+ CD3int cells and its subset of NK1.1-CD3int cells were simultaneously induced. In parallel with the expansion of extrathymic T cells in the liver, extramedullary erythropoiesis was found to begin in the liver of these mice. Interestingly, malarial protozoa were primarily seen in only these nucleated erythrocytes in the liver at the early stage of infection. These results suggest that malaria immunology falls into a new field of immunology, namely, innate

immunity. The similarity of the immune states among malaria, aging, and autoimmune diseases also suggest that the immunosuppression of a conventional, acquired immune system is more likely the common mechanism underlying these diseases or physiological responses.

Am J Trop Med Hyg 2002 Apr;66(4):379-83 

Field evaluation of the ICT Malaria Pf/Pv immunochromatographic test for the  detection of asymptomatic malaria in a Plasmodium falciparum/vivax endemic area in Thailand.

Coleman RE, Maneechai N, Rachapaew N, Kumpitak C, Soyseng V, Miller RS, Thimasarn K, Sattabongkot J.

Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Rapid antigen assays provide an effective tool for the detection of malaria in symptomatic patients. However, the efficacy of these devices for detecting asymptomatic malaria, where parasite levels are normally significantly lower than in symptomatic patients, is less well established. We evaluated the efficacy of a new combined Plasmodium falciparum-Plasmodim vivax immunochromatographic test (ICT Malaria Pf/Pv) in a cross-sectional malaria survey of the village of Ban Kong Mong Tha, Kanchanaburi Provice, Thailand, from August to December 2000. A total of 1,976 bleeds were made from 559 individuals over the course of the study. Blinded microscopy of thick and thin blood films was used as the gold standard; all discordant and 10% of concordant results wer cross-checked. Of 1,976 ICT Malaria Pf/Pv dipsticks tested, 98.3% (n = 1,943) performed as expected, as evidenced by the appearance of the control line. The ICT Malaria Pf/Pv test was both sensitive (100.0%) and specific (99.7 %) for the diagnosis of falciparum malaria with parasitemias of > or = 500 trophozoites/microL; however, only 15.9% (13/82) of infected individuals had parasitemia rates this high. When P. falciparum parasitemia rates were < 500/microL, the sensitivity of the diagnosis was only 23.3%, with a positive predictive value (PPV) and a negative predictive value (NPV) of 76.2 and 97.2%, respectively. The ICT Malaria Pf/Pv test was specific, but not sensitive, for the diagnosis of vivax malaria with parasite rates of > or = 500 trophozoites/microl, with sensitivity, specificity, PPV, and NPV of 66.7%, 99.9%, 66.7%, and 99.9%, respectively. At parasite rates of < 500/microL, corresponding values were 0.0%, 99.9%, 0%, and 95.1%. Because of the relatively high cost of these assays, low parasite rates found in the majority of asymptomatic individuals, and low sensitivity of this assay with rates of <500/microl, use of this assay as a tool for active case detection is of limited value in western Thailand.

Am J Trop Med Hyg 2002 Apr;66(4):372-8 

Lymphocyte proliferation and antibody responses to Plasmodium falciparum liver-stage antigen-1 in a highland area of Kenya with seasonal variation in malaria transmission.

John CC, Ouma JH, Sumba PO, Hollingdale MR, Kazura JW, King CL.

Division of Geographic Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Ohio 44106-4983, USA. [email protected]

Lymphocyte proliferation and antibody responses to five peptides corresponding to the N- and C-terminal non-repeat and central repeat regions of Plasmodium falciparum liver-stage antigen-1 (LSA-1) were examined in residents of a highland area of Kenya where malaria transmission is episodic and varies with rainfall. The frequency of lymphocyte proliferation responses (stimulation index > 2) by children (persons > or = 6 years old) and adults (persons > or = 18 years old) was similar and did not differ significantly across seasons. In contrast, the proportion of individuals with IgG antibodies to LSA-1 peptides was higher in the rainy than dry season, and the frequency of these responses was greater for adults than children (39.4% versus 18.7% during the period of high transmission; P = 0.009). Antibodies to LSA-1 were primarily of the IgG1 and IgG3 subclasses, and these also varied with season (30.1% and 32.5% of

individuals had IgG1 and IgG3 in the rainy season versus none and 10.9% in the dry season). There was no significant difference in the time to re-infection between groups of persons with or without IgG antibody or lymphocyte proliferation responses to LSA-1 peptides. These data indicate that age and transmission intensity independently affect IgG antibody responses to LSA-1 but do not influence lymphocyte proliferation in this highland area where malaria transmission is highly variable.

Bull World Health Organ  2002;80(7):538-45 

Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated  Plasmodium falciparum malaria in young children in Cameroon.

Basco LK, Same-Ekobo A, Ngane VF, Ndounga M, Metoh T, Ringwald P, Soula G.

Unite de Recherche Paludologie Afro-tropicale, Institut de Recherche pour le Developpement, Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la Lutte contre les Endemies en Afrique Centrale, Yaounde, Cameroon.

OBJECTIVE: To evaluate the therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine, and the sulfadoxine-pyrimethamine-amodiaquine combination for the treatment of uncomplicated Plasmodium falciparum malaria in young children in Cameroon. 

METHODS: In a randomized study we evaluated the effectiveness and tolerance of (i) sulfadoxine-pyrimethamine (SP) (25 mg/kg body weight of sulfadoxine and 1.25 mg/kg of pyrimethamine in a single oral dose), (ii) amodiaquine (AQ) (30 mg/kg body weight in three divided daily doses), and (iii) the sulfadoxine-pyrimethamine-amodiaquine combination (SP+AQ) (same doses as in the other two treatment groups, given simultaneously on day 0) in young children in southern Cameroon. The parasitological and clinical responses were studied until day 28 in accordance with the modified 1996 WHO protocol for the evaluation of the therapeutic efficacy of antimalarial drugs. FINDINGS: Of 191 enrolled patients, 6 and 8 were excluded or lost to follow-up before day 14 and between day 14 and day 28, respectively. For the AQ-treated patients, parasitological and clinical evaluation on day 14 showed late treatment failure in 2 of 61 (3.3%) and adequate clinical response with parasitological failure in one (1.6%). There was an adequate clinical response in all patients treated with SP or SP+AQ. Therapeutic failure rates on day 28 were 13.6%, 10.2% and 0% in the SP, AQ, and SP+AQ groups, respectively. Anaemia improved in all three regimens. AQ produced faster fever clearance but was associated with more transient minor side-effects than SP. SP+AQ reduced the risk of recrudescence between day 14 and day 28 but increased the incidence of minor side-effects. 

CONCLUSION: SP+AQ can be recommended as a temporary means of slowing the spread of multidrug resistance in Plasmodium falciparum in Africa while the introduction of other combinations, including artemisinin derivatives, is awaited.

J Antimicrob Chemother 2002 Aug;50(2):177-87 

Iron chelators as antimalarial agents: in vitro activity of dicatecholate against Plasmodium falciparum.

Pradines B, Rolain JM, Ramiandrasoa F, Fusai T, Mosnier J, Rogier C, Daries W, Baret E, Kunesch G, Le Bras J, Parzy D.

Unite de Parasitologie, Institut de Medecine Tropicale du Service de Sante des Armees, Le Pharo, 13007 Marseille.

The present study was undertaken to explore the antimalarial effect of a series of dicatecholate iron chelators. They may be made more or less lipophilic by increasing or reducing the length of the R substituent on the nitrogen. In vitro activity against the W2 and 3D7 clones of Plasmodium falciparum, toxicity on Vero cells and toxicity on uninfected erythrocytes by measure of the released haemoglobin were assessed for each compound. These findings were compared with the ability of iron(III), iron(II) and ferritin to reverse the inhibitory effect of catecholates. This study shows that increased lipid solubility of catecholate iron chelators does not lead to improved antimalarial activity. However, their activity is well correlated with their interaction with iron and with their toxicity against Vero cells. This study demonstrates a potent antimalarial effect of FR160 (R = C(9)H(19)) on five different strains of P. falciparum in

vitro. FR160 inhibited parasite growth with an IC(50) between 0.8 and 1.5 micro M. The effects of FR160 on mammalian cells were minimal compared with those obtained with malaria parasites. FR160 acted on parasites at considerably higher rates than desferrioxamine, and at all stages of parasite growth. The drug was more effective at the late trophozoite and young schizont stages, although FR160 affected rings and schizonts as well. Ascorbic acid, a free radical scavenger, reduced the activities of FR160 and artesunate. FR160 might induce formation of free radicals, which could explain why FR160 antagonized the effects of artesunate and dihydroartemisinin. 

Curr Opin Microbiol 2002 Aug;5(4):431 

Cross-species regulation of malaria parasitaemia in the human host.

Bruce M, Day K.

Institute of Biomedical and Life Sciences, Division of Infection and Immunity,  Joseph Black Building, University of Glasgow, G12 8QQ, Glasgow, UK

Longitudinal genetic analysis of the composition of malaria parasites infecting humans has demonstrated that individuals living in endemic areas are chronically infected with multiple genotypes and species of Plasmodium. The accumulation of infections is a consequence of superinfection from the bites of many infected anopheline mosquitoes. The clinical outcome of infection is determined by the host’s ability to regulate the density of malaria parasites in the blood. Interestingly, most infections do not cause symptoms of malarial disease after a degree of immunity is acquired. Here, we review data from the first genetic study of the longitudinal dynamics of multiple Plasmodium species and genotypes in humans. The data show that the total parasite density of Plasmodium species oscillates around a threshold and that peaks of infection with each species do not coincide. We propose that malaria parasitaemia is controlled in a density-dependent manner in these semi-immune children. This implies that a cross-species mechanism of parasite regulation exists. A model of how multiple immune responses could act in concert to explain these within host dynamics is discussed in relation to known regulatory mechanisms.

Afr J Health Sci 1995 May;2(2):312-315 

Malaria infection, morbidity and transmission in two ecological zones Southern Ghana.

Afari EA, Appawu M, Dunyo S, Baffoe-Wilmot A, Nkrumah FK.

Epidemiology Unit, Noguchi Memorial Institute for Medical Research, P. O. Box 25, Legon, Ghana.

A one year survey was conducted in 1992 to compare malaria infection, morbidity and transmission patterns between a coastal savannah community (Prampram) and a community (Dodowa) in the forest zone in southern Ghana. The study population of  6682 at Prampram and 6558 at Dodowa were followed up in their homes once every  two weeks and all episodes of clinical malaria recorded. Blood films for microscopy were prepared from 600 participants randomly selected in each community in April and in August representing dry and wet seasons respectively. Mosquitoes biting humans between 1800 hrs and 0600 hrs, as well as indoor and outdoor resting mosquitoes were collected weekly. All mosquitoes collected were classified into species and examined for sporozoites by dissection and ELISA. The incidence rate of clinical malaria was higher in Dodowa (106.6/1000 pop.) than in Prampram (68.5/1000 pop.) It was highest in < 10 year age groups in both communities. It was also higher in the wet season than in the dry season. The prevalence of patent parasitaemia at Prampram and Dodowa in April in the dry season. The prevalence of patent parasitaemia at Prampram and Dodowa in April 1992 was 19.8% (117/590) and 42.2% (253/599) respectively. The corresponding figures for August were 26.6%(160/602)at Prampram and 51.3% (309/602) at Dodowa. Plasmodium falciparum infection contributed 78-85% of the parasitaemia in April and 93-99% in August. The average man-biting rate for Anopheles gambiae s.l was higher at Prampram than at Dodowa (1.54 vs 0.79 bites/man/night) but the average sporozoite rate was higher at Dodowa than at Prampram (2% vs 0.7%). The peak of biting density at Prampram occurred in June whilst that of Dodowa occurred in November.

Afr J Health Sci 1995 May;2(2):309-311 

In vitro antimalarial activity of extracts of Albizia gummifera, Aspilia mossambicensis, Melia azedarach and Azadirachta indica against Plasmodium falciparum.

Ofulla AV, Chege GM, Rukunga GM, Kiarie FK, Githure JI, Kofi-Tsekpo MW.

Biomedical Sciences Research Centre, Kenya Medical Research Institute, P. O. Box 54840, Nairobi, Kenya.

Since chemotherapy is presently the primary strategy of malaria control in the world, and some malaria parasites are developing resistance to the commonly used antimalarial drugs, new antimalarial compounds are required. Therefore, it is important to test antimalarial activities of medicinal plant extracts which most herbalists claim to cure malaria. We evaluated the antimalarial activities of extracts of Albizia gummiffera, Aspilia mossambicensis, Melia azedar and Azadirahchta indica against laboratory adapted isolates of Plasmodium falciparum using an in vitro radioisotopic uptake technique. Chloroquine was used as a reference antimalarial drug. Al. gummifera had the highest antimalarial activity (mean fifty percent inhibitory concentration {IC(50)S} in ug/ml of test culture =3.5 +1.6SD, n=3) followed by As. mossambicensis (mean IC(50)=29.3+11.8SD, n=4) and Me. Azedarach (mean IC(50) =299.7+202.0SD, n=4). And lastly Az.  Indica (mean IC(50)=349.9+213.1 SD, n=4). The antimalarial activities of the reference drug, chloroquine, was far much higher (mean IC(50)=0.065+0.057SD, n=)4). These findings show that Al. gummifera and As. mossambicensis plant extracts have potentantimalarial compounds. Phytochemical analyses should be done on these two plants to isolate the compound(s) containing he active principles(s).

J Health Popul Nutr 2000 Sep;18(2):115-8 

Association of malarial parasitaemia with dehydrating diarrhoea in Nigerian children.

Ibadin OM, Airauhi L, Omoigberale AI, Abiodun PO.

Records of 402 children–216 (53.7%) males and 186 (46.3%) females–aged 1-36 months, admitted to the Diarrhea Treatment and Training Unit of the University of Benin Teaching Hospital, Benin city, Nigeria, during July 1993 to June 1996, were reviewed to document the relationship between dehydration and malaria parasitemia. There was significant association between severity of dehydration and malaria parasitemia (p  0.0001). Association of parasitemia (p  0.006) with dehydration (p  0.0001) was significantly more marked in patients with acute watery diarrhea than in those with persistent and bloody diarrhea. Parasitemia was demonstrated in 50.5% of those not initially suspected to have malaria.  Parasitemia was also significantly associated with fever (p  0.001) and fever co-existing with vomiting (p  0.01).  The prevalence of malaria-associated diarrhea was 61.7%. More infants (75.6%) than older children had diarrhea. It was concluded that the prevalence of malaria-associated diarrhea was high and that children with dehydration are more likely to manifest malaria parasitemia.

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