EHP Library Malaria Bulletin No. 23:  October 5-18,  2001

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Social Sciences and Malaria

The Evidence Base for Interventions to Reduce Malaria Mortality in Low and Middle Income Countries. S. Meek, J. Hill, J. Webster, 2001.

The Evidence Base for Interventions to Reduce Under Five Mortality in Low and Middle Income Countries. H. Gelband, S. Stansfield, 2001.

Bull World Health Organ 2001;79(9):869-74

Global public goods and health: taking the agenda forward.

Kaul I, Faust M.

Office of Development Studies (ODS), United Nations Development Programme (UNDP), 336 East 45th St, 4th Floor, New York, USA. 
Email: [email protected]
We examined recent special health initiatives to control HIV/AIDS, malaria, and tuberculosis, and make four policy recommendations for improving the sustainability of such initiatives. First, international cooperation on health should be seen as an issue of global public goods that concerns both poor and rich countries. Second, national health and other sector budgets should be tapped to ensure that global health concerns are fully and reliably funded; industrialized countries should lead the way. Third, a global research council should be established to foster more efficient health-related knowledge management. Fourth, managers for specific disease issues should be appointed, to facilitate policy partnerships. Policy changes in these areas have already begun and can provide a basis for further reform.


Med Trop (Mars) 2001;61(1):91-8An evidence-based vector control strategy for military deployments: the British Army experience.

Croft AM, Baker D, von Bertele MJ.

Surgeon General’s Department, Ministry of Defence, Whitehall, London SW1A 2HB, UK. 
Email: [email protected] We describe the British Army’s current strategy for controlling arthropod vectors of disease during overseas deployments. Military commanders and medical officers have different, but complementary responsibilities in achieving vector control. In this paper we define a hierarchy of evidence-based vector control guidelines. Field guidelines must be based on the best available research evidence, preferably that derived from pragmatic randomised controlled trials (RCTs), and from systematic reviews of trials. Assessing the effectiveness of different vector control measures involves a trade-off between the relative benefits and harm of different technology options. There is compelling scientific evidence that bed nets and screens treated with a pyrethroid insecticide are highly effective in protecting against nocturnally active, anthropophilic arthropods (including ectoparasites), and will reduce the incidence of malaria, leishmaniasis, lymphatic filariasis and Chagas’ disease. Etofenprox and deltamethrin are the safest pyrethroids, and permethrin the least safe. Vector control strategies of probable effectiveness are the use of insecticide-treated clothing, the wearing of protective clothing, and the correct use of DEET-based topical insect repellents. Aerosol insecticides are of debatable effectiveness. Other effective vector control measures, of limited usefulness during deployments, include electric fans, mosquito coils/vaporising mats, and smoke. “Biological” vector control measures, and insect buzzers/electrocuters are ineffective. Practical insect avoidance measures, based on an understanding of vector biology, complete the military vector-control arsenal. We conclude that practical insect avoidance measures, combined with pyrethroid-treated nets and clothing, and DEET-based topical repellents, can achieve almost 100% protection against biting arthropods.

Med Trop (Mars) 2001;61(1):67-76Malaria prevention and control in the United States military.

Robert LL.

Uniformed Service, University of Health Sciences, Department of Preventive Medicine and Biometrics, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. [email protected]

Malaria continues to be a serious threat to deployed military forces in many areas of the World. United States experiences during, and lessons learned from, World War II, Viet Nam, and Somalia have significantly changed the way that military planners, medical and preventive medicine personnel are facing the malaria challenge. Currently, the US military has a powerful arsenal of educational courses and materials, personal protective measures, and malaria surveillance and control techniques in place to fight malaria. These new tools will hopefully reduce malaria morbidity and mortality during military deployments in the future.

Bull Entomol Res 2001 Oct;91(5):389-411Descriptions of the Anopheles (Cellia) farauti complex of sibling species (Diptera: Culicidae) in Australia.

Schmidt ER, Foley DH, Hartel GF, Williams GM, Bryan JH.

Tropical Health Program, ACITHN,.

Descriptions of the three sibling species of the Anopheles farauti complex in Australia, A. farauti Laveran (formerly A. farauti No. 1), A. hinesorum Schmidt sp.n. (formerly A. farauti No. 2) and A. torresiensis Schmidt sp.n. (formerly A. farauti No. 3) are provided. These species form a part of the punctulatus group, which contains the major malaria vectors in the southwest Pacific. Morphological markers are described for adult females, fourth instar larvae and pupae which identify most specimens, and are presented in keys.

Biochem J 2001 Oct 15;359(Pt 2):295-304Identification of a novel class of insect glutathione S-transferases involved in resistance to DDT in the malaria vector Anopheles gambiae.

Ranson H, Rossiter L, Ortelli F, Jensen B, Wang X, Roth CW, Collins FH, Hemingway J.

School of Biosciences, Main College, Cardiff University, PO Box 915, Cardiff CF10 3TL, Wales, U.K. and Department of Biological Sciences, University of Notre Dame, PO Box 369, Notre Dame, IN 46556, U.S.A.

The sequence and cytological location of five Anopheles gambiae glutathione S-transferase (GST) genes are described. Three of these genes, aggst1-8, aggst1-9 and aggst1-10, belong to the insect class I family and are located on chromosome 2R, in close proximity to previously described members of this gene family. The remaining two genes, aggst3-1 and aggst3-2, have a low sequence similarity to either of the two previously recognized classes of insect GSTs and this prompted a re-evaluation of the classification of insect GST enzymes. We provide evidence for seven possible classes of insect protein with GST-like subunits. Four of these contain sequences with significant similarities to mammalian GSTs. The largest novel insect GST class, class III, contains functional GST enzymes including two of the A. gambiae GSTs described in this report and GSTs from Drosophila melanogaster, Musca domestica, Manduca sexta and Plutella xylostella. The genes encoding the class III GST of A. gambiae map to a region of the genome on chromosome 3R that contains a major DDT [1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane] resistance gene, suggesting that this gene family is involved in GST-based resistance in this important malaria vector. In further support of their role in resistance, we show that the mRNA levels of aggst3-2 are approx. 5-fold higher in a DDT resistant strain than in the susceptible strain and demonstrate that recombinant AgGST3-2 has very high DDT dehydrochlorinase activity.

Med Vet Entomol 2001 Sep;15(3):293-8Unexpected anthropophagic behaviour in Anopheles quadriannulatus.

Pates HV, Takken W, Curtis CF, Huisman PW, Akinpelu O, Gill GS.

Laboratory of Entomology, Wageningen Agricultural University, The Netherlands.

The strongly anthropophilic behaviour of Anopheles gambiae Giles sensu stricto (Diptera: Culicidae), the most important malaria vector in Africa, has been demonstrated by field and laboratory studies. Other members of the An. gambiae complex express varied degrees of anthropophily. Anopheles quadriannulatus (Theobald) species A and B are more zoophilic members of the complex and hence are considered to be of no medical importance. Olfactometer experiments with An. quadriannulatus species A have demonstrated attraction to both human and cow odour. To extend these olfactometer observations a choice experiment was conducted in an outdoor cage with a human and a calf as baits, using laboratory-reared mosquitoes. Anopheles gambiae s.s. (from Liberia) and two strains of An. quadriannulatus species A (SKUQUA from South Africa, SANGQUA from Zimbabwe), marked with different coloured fluorescent powders for identification purposes, were released simultaneously and given an equal opportunity to feed on either host. The experiment was repeated six times. Bloodmeals were identified using the precipitin technique. Anopheles gambiae s.s. showed highly anthropophagic behaviour, taking 88% of bloodmeals from the human host. In contrast, both strains of An. quadriannulatus fed with equal frequency on the human or the calf; the response to either host was not significantly different. These results confirm the olfactometer findings and demonstrate anthropophagic behaviour not previously recorded in this species. This finding has implications for prospective manipulation of host preference for genetic control purposes.

Med Vet Entomol 2001 Sep;15(3):287-92Repellent effects on Anopheles arabiensis biting humans in Kruger Park, South Africa.

Govere J, Braack LE, Durrheim DN, Hunt RH, Coetzee M.

Mpumalanga Department of Health, Nelspruit, South Africa. 
Email: [email protected]
Distribution of biting sites on the human body by the malaria vector Anopheles arabiensis Patton (Diptera: Culicidae) was investigated near a source of mosquitoes in the Kruger National Park, South Africa. Eight adult male volunteers (2 teams x 2 pairs of subjects) conducted human bait collections while seated on camp chairs in the open-air, wearing only short trousers (no shirt, socks or shoes). Mosquito collections during 18.30-22.30 hours on five consecutive nights in April 1998 yielded a total of 679 An. arabiensis females biting subjects with or without their ankles and feet treated with deet insect repellent (15% diethyl-3-methylbenzamide, Tabard lotion). On subjects whose feet and ankles were smeared with repellent, 160 An. arabiensis females were captured biting in 60 manhours: 88.1% on the legs, 1.4% on the arms and 1.2% on other parts of the body, but none on the repellent-treated feet or ankles. On subjects without repellent treatment, 519 An. arabiensis were caught biting in 60 man-hours: 81.1% on feet and ankles, 16.4% on legs, 1.4% on arms and 1.2% on the rest of the body. For individual subjects, the reduction of An. arabiensis bites ranged from 36.4 to 78.2% (mean protection 69.2%). Results of this study confirm previous findings that, in this part of South Africa – inhabited only by wildlife – when people sit outside during the evening An. arabiensis prefers to bite their lower limbs: 97.5% below the knees. Overall, the number of bites by the malaria vector An. arabiensis was reduced more than three-fold (from 26 to 8/person/evening), simply by treating ankles and feet with a consumer brand of deet repellent. Whether or not this provides a satisfactory degree of protection against malaria risk would depend on the malaria sporozoite rate in the malaria vector population.

Med Vet Entomol 2001 Sep;15(3):267-74Mapping distributions of chromosomal forms of Anopheles gambiae in West Africa using climate data.

Bayoh MN, Thomas CJ, Lindsay SW.

Department of Biological Sciences, University of Durham, UK.

The mosquito Anopheles gambiae Giles sensu stricto (Diptera: Culicidae), the principal vector of malaria in West Africa, comprises several chromosomal forms (e.g. Bissau, Forest, Mopti, Savanna) associated with climatic zones. Here we show how climate data can be used to map the geographical distribution of these chromosomal forms. The climate at 144 sites surveyed for mosquitoes in West Africa between 1971 and 92 was determined using computerized climate surfaces. Forest and Bissau forms occurred at relatively wet sites: median annual precipitation 1325 mm and 1438 mm, respectively, interquartile ranges (IQR) 1144-1858 mm and 1052-1825 mm), whilst the Mopti form was found at dry sites (annual 938 mm, IQR 713-1047 mm) and the Savanna form at sites intermediate between the wet and dry forms (annual 1067 mm, IQR 916-1279). Logistic regression analyses of the climate variables were carried out on a stratified random sample of half the sites. The resulting models correctly classified over 80% of the sites for presence or absence of each chromosomal form. When these models were tested against excluded sites they were also correct at over 80% of sites. The combined data produced models that were correct at over 86% of sites. Mean annual precipitation, evapotranspiration, minimum temperature and maximum temperature were the most important climate variables correlated with the distribution of these forms of An. gambiae. We used the logistic models to map the distribution of each chromosomal form within the reported range for An. gambiae s.s. in West Africa employing a geographical information system. Our maps indicate that each chromosomal form favours particular climate envelopes in well-defined ecoclimatic zones, although these forms are sympatric at the edges of their ranges. This study demonstrates that climate can be used to map the distribution of chromosomal forms of insects across large areas.

Med Vet Entomol 2001 Sep;15(3):259-66Electroantennogram and behavioural responses of the malaria vector Anopheles gambiae to human-specific sweat components.

Costantini C, Birkett MA, Gibson G, Ziesmann J, Sagnon NF, Mohammed HA, Coluzzi M, Pickett JA.

Istituto di Parassitologia, University of Rome, La Sapienza, Rome, Italy.

Afrotropical malaria vectors of the Anopheles gambiae complex (Diptera: Culicidae), particularly An. gambiae sensu stricto, are attracted mainly to human hosts. A major source of human volatile emissions is sweat, from which key human-specific components are the carboxylic acids (E)- and (Z)-3-methyl-2-hexenoic acid and 7-octenoic acid. Electrophysiological studies on the antennae of An. gambiae s.s. showed selective sensitivity to these compounds, with a threshold at 10(-6) g comparable to that of known olfactory stimulants 1-octen-3-ol, p-cresol, isovaleric acid, and lower than threshold sensitivity to L-lactic acid and the synthetic mosquito repellent N,N-diethyltoluamide (DEET). A combination of the acids released at concentrations > 10(-5) g in wind tunnel bioassays significantly reduced the response to CO2, the major attractant released by human hosts, for strains of An. gambiae s.s. originating from East and West Africa. Field trials with odour-baited entry traps (OBETs) in Burkina Faso showed that 7-octenoic acid significantly increased (by 1.7-fold) the catch of females of An. gambiae sensu lato (comprising two sibling species: An. arabiensis Patton and An. gambiae s.s.) in OBETs baited with CO2, whereas combinations of the acids significantly reduced the catch in CO2-baited traps (by 2.1-fold) and in whole human odour-baited traps (by 1.5-fold). The pure (E) and (Z) geometric isomers of 3-methyl-2-hexenoic acid gave comparable results to the (EIZ) isomer mixture. These results provide the first experimental evidence that human-specific compounds affect the behaviour of highly anthropophilic An. gambiae s.l. mosquitoes. The compounds appear to inhibit the upwind flight’ response to known long-range attractants, and may serve either to mask’ the attractants present or, more probably, to ‘arrest’ upwind flight when mosquitoes arrive at a host under natural conditions. In the final approach to hosts, vectors are known to reduce their flight speed and increase their turning rate, to avoid overshooting the source. In our experimental apparatus, these changes in flight behaviour would reduce the number of mosquitoes entering the ports of the collection devices.

Med Vet Entomol 2001 Sep;15(3):236-48Breeding of Anopheles mosquitoes in irrigated areas of South Punjab, Pakistan.

Herrel N, Amerasinghe FP, Ensink J, Mukhtar M, van der Hoek W, Konradsen F.

International Water Management Institute, Lahore, Pakistan. 
Email: [email protected] As part of investigations on potential linkages between irrigation and malaria transmission, all surface water bodies in and around three villages along an irrigation distributary in South Punjab, Pakistan, were surveyed for anopheline mosquito larvae (Diptera: Culicidae) from April 1999 to March 2000. Samples were characterized according to exposure to sunlight, substratum, presence of vegetation, fauna, inorganic matter and physical water condition (clear/turbid/foul). Also water temperature, dissolved oxygen (DO), electroconductivity (EC) and pH of sites were recorded. A total of 37982 Anopheles larvae of six morphological types were collected from 2992 samples taken from irrigation/agricultural and village/domestic aquatic habitats. Anopheles subpictus Grassi sensu lato was by far the most abundant (74.3%), followed by An. culicifacies Giles s.l. (4.1%), An. stephensi Liston s.l. (2.6%), An. pulcherrimus Theobald (1.8%), An. peditaeniatus Leicester (0.3%) and An. nigerrimus Giles (0.1%). The four most abundant species were significantly associated with waterlogged fields and communal village drinking-water tanks. Habitat characteristics most correlated with occurrence of anophelines were the physical water condition and the absence/presence of fauna, particularly predators. Occurrence and abundance of Anopheles immatures were not significantly correlated with water temperature, DO, EC or pH. Malaria vectors of the Anopheles culicifacies complex occurred at relatively low densities, mainly in irrigated and waterlogged fields. In South Punjab, where rainfall is very low, it should be possible to reduce anopheline breeding through water management, as larvae develop mainly in water bodies that are directly or indirectly related to the extensive canal-irrigation system.

Med Trop (Mars) 2001;61(2):153-7OptiMal test should be used with great caution

[Article in French]

Hernandez E, De Pina JJ, Fabre R, Garrabe E, Raphenon G, Cavallo JD.

Laboratoire de microbiologie, Hopital d’Instruction des Armees Begin, Saint-Mande, France. 
Email: [email protected]
The OptiMal test is an immuno-chromatographic dipstick test that permits indiscriminate detection of Plasmodium falciparum and other species of human malaria. The purpose of this study was to evaluate the efficacy of the test for diagnosis of imported malaria. A total of 244 patients with a presumptive diagnosis of imported malaria in France were included during the study period. The reference test, i.e., combined thick and thin blood films, demonstrated infection by Plasmodium falciparum in 58 cases, Plasmodium vivax in 12, P. ovale in 8 and Plasmodium malariae in 2. The OptiMal test detected only 46 of the 55 Plasmodium falciparum cases. The sensitivity of the test for diagnosis of that species was 80%, its specificity was 98%, and its positive and negative predictive values were 95 and 93% respectively. Parsitemia studies showed poor test reliability for densities lower than 150/ul. Detection of other species was accurate in 21 out of 22. The results of this study demonstrate that the current version of the OptiMal test should be used with great caution for the diagnosis of malarial infection in hospital practice.

Chin Med J (Engl) 1999 Aug;112(8):686-90Effects of the configuration of a multi-epitope chimeric malaria DNA vaccine on its antigenicity to mice.

Jiang Y, Lin C, Yin B, He X, Mao Y, Dong M, Xu P, Zhang L, Liu B, Wang H.

Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, Peking Union Medical College, School of Basic Medicine, Beijing 100005, China.

OBJECTIVE: Four B and Th cell epitopes were selected from conservative domain of Plasmodium falciparum antigens to construct two groups of chimeric malaria DNA vaccines with different configurations and their antigenicities were studied. METHODS: The partially synthesized oligonucleotide was annealed, PCR amplified and cloned into a mammalian cell expression vector. By using a pair of isocaudamers on the vector, different single copies of B epitopes were multiplied and were tenderly stringed into two groups of chimeric DNA vaccine with different configurations. BALB/c mice were immunized with these DNA plasmids by either intramuscular or intradermal injections. RESULTS: The antisera from the immunized mice tested by ELISA showed that only the configuration which had a single copy of universal T helper cell epitope, CS. T3, located at the C terminal of the multi-copy B cell epitopes induced a high antibody response. The T helper cell epitope at any other position of the peptide, or the double T helper cell epitopes configured with the B cell epitopes did not enhance antibody response, and some configurations even decreased the humoral response to a B cell epitope. CONCLUSION: This study demonstrated that both combination and configuration of the epitope may affect the antigenicity of a chimeric multiple antigen.

Antimicrob Agents Chemother 2001 Nov;45(11):3171-4Reversal of Chloroquine Resistance in Plasmodium falciparum Using Combinations of Chemosensitizers.

van Schalkwyk DA, Walden JC, Smith PJ.

Department of Pharmacology, University of Cape Town, Observatory 7925, South Africa.

Research into chloroquine resistance reversal in Plasmodium falciparum has revealed a widespread range of functionally and structurally diverse chemosensitizers. However, nearly all of these chemosensitizers reverse resistance optimally only at concentrations that are toxic to humans. Verapamil, desipramine, and trifluoperazine were shown to potentiate chloroquine accumulation in a chloroquine-resistant (CQ(r)) strain of P. falciparum, while progesterone, ivermectin, and cyclosporin A were not shown to potentiate chloroquine accumulation. The simultaneous use of two or even three of these chemosensitizers at concentrations within their therapeutic ranges in humans displayed an additive effect in potentiating chloroquine accumulation in the CQ(r) strain. The levels of resistance reversal achieved with these multiple combinations were comparable to those achieved with high concentrations of the single agents used to enhance the activity of chloroquine. No chemosensitizer, whether used singly or in combination, potentiated any change in chloroquine accumulation or a shift in the 50% inhibitory concentration for the chloroquine-sensitive strain. The use of combinations of chemosensitizers at concentrations not toxic to humans could effectively reverse chloroquine resistance without the marked toxicity from the use of a single agent at high concentrations. This cocktail of chemosensitizers may serve as a viable treatment to restore the efficacy of chloroquine in patients with malaria.

Antimicrob Agents Chemother 2001 Nov;45(11):3122-7Association of Genetic Mutations in Plasmodium vivax dhfr with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates.

Imwong M, Pukrittakayamee S, Looareesuwan S, Pasvol G, Poirreiz J, White NJ, Snounou G.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Mutations in the Plasmodium falciparum gene (dhfr) encoding dihydrofolate reductase are associated with resistance to antifols. Plasmodium vivax, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the dhfr gene of P. vivax (pvdhfr) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (n = 100), India (n = 16), and Madagascar and the Comoros Islands (n = 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of P. vivax dhfr (pvdhfr), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (P < 0.0001). The dhfr PCR products of P. vivax from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (P = 0.01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax. These mutations presumably arose from selection pressure.

EMBO J 2001 Oct 15;20(20):5636-5649Trafficking and assembly of the cytoadherence complex in Plasmodium falciparum-infected human erythrocytes.

Wickham ME, Rug M, Ralph SA, Klonis N, McFadden GI, Tilley L, Cowman AF.

The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Melbourne 3050, Department of Biochemistry, La Trobe University, Melbourne and Plant Cell Biology Research Centre, School of Botany, University of Melbourne, Melbourne, Australia Corresponding author e-mail: 
Email: [email protected]
After invading human erythrocytes, the malarial parasite Plasmodium falciparum, initiates a remarkable process of secreting proteins into the surrounding erythrocyte cytoplasm and plasma membrane. One of these exported proteins, the knob-associated histidine-rich protein (KAHRP), is essential for microvascular sequestration, a strategy whereby infected red cells adhere via knob structures to capillary walls and thus avoid being eliminated by the spleen. This cytoadherence is an important factor in many of the deaths caused by malaria. Green fluorescent protein fusions and fluorescence recovery after photobleaching were used to follow the pathway of KAHRP deployment from the parasite endomembrane system into an intermediate depot between parasite and host, then onwards to the erythrocyte cytoplasm and eventually into knobs. Sequence elements essential to individual steps in the pathway are defined and we show that parasite-derived structures, known as Maurer’s clefts, are an elaboration of the canonical secretory pathway that is transposed outside the parasite into the host cell, the first example of its kind in eukaryotic biology.

J Eukaryot Microbiol 2001 Sep-Oct;48(5):556-64Differential antibody recognition of four allelic variants of the merozoite surface protein-2 (MSP-2) of Plasmodium falciparum.

Tonhosolo R, Wunderlich G, Ferreira MU.

Department of Parasitology, Institute for Biomedical Sciences, University of Sao Paulo, SP, Brazil.

The merozoite surface protein-2 (MSP-2) is a major vaccine candidate for the asexual blood stage of Plasmodium falciparum. MSP-2 is essentially dimorphic, and allelic families are named after the representative isolates FC27 and IC1. The polymorphic central region contains immunodominant repeats, which vary in number, length, and sequence within and between allelic families. We have examined the antibody recognition of repeat regions from both MSP-2 allelic families expressed as recombinant fusion peptides. The results are summarized as follows. (1) Immunization of mice with the fusion peptides elicited IgG antibodies that cross-reacted with the native MSP-2 molecule in an allelic family-specific manner. (2) These mouse antibodies recognized the recombinant proteins in both a variant-specific and a family-specific manner, as shown in inhibition immunoassays. Antibodies raised against the peptide FC27 seemed to be essentially variant-specific, since the soluble form of the S20 antigen (a member of FC27 family) had relatively little inhibitory effect on them. (3) The overall pattern of human IgG antibody responses to MSP-2 in Karitiana Indians, a population continuously exposed to hypoendemic malaria in the Brazilian Amazon Region, differs from that described in hyperendemic areas in Africa and Papua New Guinea in two important features: there was no clear age-dependent increase in the prevalence and mean concentration of specific IgG antibodies, and there was no skewing towards the IgG3 subclass in antibody responses. (4) The relatively poor correlation between concentrations of IgG antibodies that are specific for members of the same allelic family suggests that recognition of MSP-2 peptides by naturally acquired antibodies was largely variant-specific in this population. The potential role of naturally acquired variant-specific antibodies in immune evasion, by selecting mutant parasites carrying insertions or deletions of repeat sequences, is briefly discussed.

Int J Parasitol 2001 Nov;31(13):1499-502Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR.

Bruna-Romero O, Hafalla JC, Gonzalez-Aseguinolaza G, Sano G, Tsuji M, Zavala F.

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

We describe a highly sensitive real-time PCR to detect and measure the development of the liver-stages of malaria parasites in mice infected with sporozoites ranging in number from 25 to more than 164,000, using the same reaction conditions. Furthermore, this assay detects and measures parasite loads in the livers of mice exposed to the bite of a single malaria-infected Anopheles mosquito. This unique method should greatly facilitate studies aimed at evaluating very precisely the efficacy of anti-malarial experimental drug treatments and vaccination regimens in conditions of infection resembling those found in the field.

Chin Med J (Engl) 1999 Apr;112(4):349-51A diagnostic kit to screen individuals with glucose-6-phosphate dehydrogenase defect and its application on anti-malaria spot in the countryside.

Nie C, Zhao S.

Department of Parasitology, Medical College of Jinan University, Guangzhou 510632, China.

OBJECTIVE: To prepare a kit for screening individuals with glucose-6-phosphate dehydrogenase (G6PD) defect. The kit is easy to use and to get the fast as well as reliable results. Especially it is suitable for the anti-malaria spots usually located in the remote countryside where no electricity is available. METHODS: The double filter paper method and other 2 techniques, the quantitative method and the single filter paper method, were used to determine G6PD activity in 70 samples of human erythrocytes. It was found that the results of the double filter paper method and those of the single filter paper method in the first 8 hours after the drying of the blood-soaked filter paper were consistent with those of the quantitative method. When a piece of blood-soaked paper is left under room temperature more than 24 hours, G6PD in the erythrocytes deteriorated spontaneously and consequently the number of positive cases increased along with the elapse of time. RESULTS: Satisfactory results were achieved when the kit was used to screen cases of G6PD defect from 151 farmers who were receiving anti-mararia therapy. The kit was made according to a technique named “double filter paper” method. CONCLUSIONS: These findings suggest that the double filter paper method can reveal the level of G6PD activity and the results are rapidly obtained when the method is used on the anti-malaria spot.

Eur J Immunol 2001 Oct;31(10):2970-8Direct activation of dendritic cells by the malaria parasite, Plasmodium chabaudi chabaudi.

Seixas E, Cross C, Quin S, Langhorne J.

Division of Parasitology, National Institute for Medical Research, Mill Hill, London, GB.

A primary infection of mice with Plasmodium chabaudi chabaudi (AS) is characterized by a rapid and marked inflammatory response. Typically, IL-12, TNF-alpha and IFN-gamma are produced in the spleen, and are transiently present in plasma. The cells involved in this early response are unknown. Here we show that dendritic cells derived from GM-CSF-stimulated mouse bone marrow cultures produce TNF-alpha within 30 min of exposure to P.c.chabaudi schizonts. IL-6, IL-12p40 and p70 follow this. The production of these cytokines was not dependent on the presence of T cells or NK cells and did not require CD40. Incubation of dendritic cells with P.c.chabaudi schizonts also resulted in up-regulation of MHC class II, CD40 and CD86 but not CD80. In contrast to some strains of the human parasite, P. falciparum, P.c. chabaudi (AS) did not inhibit the up-regulation of MHC class II, CD86 or CD40 induced by LPS. Therefore, the erythrocytic stages of P.c.chabaudi are able to activate dendritic cells directly. The consequences of such an interaction could be rapid activation of TH1 cells and induction of immunity, and in the event of a large response also induction of TNF-alpha associated pathology.

J Cell Sci 2001 Sep;114(Pt 18):3377-86Evidence for a role for a Plasmodium falciparum homologue of Sec31p in the export of proteins to the surface of malaria parasite-infected erythrocytes.

Adisa A, Albano FR, Reeder J, Foley M, Tilley L.

Department of Biochemistry, La Trobe University, Melbourne, Victoria, Australia. Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.

The malaria parasite, Plasmodium falciparum, spends part of its life cycle inside the enucleated erythrocytes of its human host. The parasite modifies the cytoplasm and plasma membrane of its host cell by exporting proteins beyond the confines of its own plasma membrane. We have previously provided evidence that a plasmodial homologue of the COPII protein, Sar1p, is involved in the trafficking of proteins across the erythrocyte cytoplasm. We have now characterised an additional plasmodial COPII protein homologue, namely Sec31p. Recombinant proteins corresponding to the WD-40 and the intervening domains of the PfSec31p sequence were used to raise antibodies. The affinity-purified antisera recognised a protein with an apparent relative molecular mass of 1.6×10(5) on western blots of malaria parasite-infected erythrocytes but not on blots of uninfected erythrocytes. PfSec31p was shown to be largely insoluble in nonionic detergent, suggesting cytoskeletal attachment. Confocal immunofluorescence microscopy of malaria parasite-infected erythrocytes was used to show that PfSec31p is partly located within the parasite and partly exported to structures outside the parasite in the erythrocyte cytoplasm. We have also shown that PfSec31p and PfSar1p occupy overlapping locations. Furthermore, the location of PfSec31p overlaps that of the cytoadherence-mediating protein PfEMP1. These data support the suggestion that the malaria parasite establishes a vesicle-mediated trafficking pathway outside the boundaries of its own plasma membrane – a novel paradigm in eukaryotic biology.

J Immunol 2001 Oct 15;167(8):4729-37Unique T cell effector functions elicited by Plasmodium falciparum epitopes in malaria-exposed Africans tested by three T cell assays.

Flanagan KL, Lee EA, Gravenor MB, Reece WH, Urban BC, Doherty T, Bojang KA, Pinder M, Hill AV, Plebanski M.

Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom. 
Email: [email protected]
Natural immunity to malaria is characterized by low level CD4 T cell reactivity detected by either lymphoproliferation or IFN-gamma secretion. Here we show a doubling in the detection rate of responders to the carboxyl terminus of circumsporozoite protein (CS) of Plasmodium falciparum by employing three T cell assays simultaneously: rapid IFN-gamma secretion (ex vivo ELISPOT), IFN-gamma secretion after reactivation of memory T cells and expansion in vitro (cultured ELISPOT), and lymphoproliferation. Remarkably, for no individual peptide did a positive response for one T cell effector function correlate with any other. Thus these CS epitopes elicited unique T cell response patterns in malaria-exposed donors. Novel or important epitope responses may therefore be missed if only one T cell assay is employed. A borderline correlation was found between anti-CS Ab levels and proliferative responses, but no correlation was found with ex vivo or cultured IFN-gamma responses. This suggested that the proliferating population, but not the IFN-gamma-secreting cells, contained cells that provide help for Ab production. The data suggest that natural immunity to malaria is a complex function of T cell subgroups with different effector functions and has important implications for future studies of natural T cell immunity.

J Postgrad Med 2001 Jan-Mar;47(1):24-6Severe acute renal failure in malaria.

Mehta KS, Makwana PD, Torane PP, Satija PS, Shah VB.

Departments of Nephrology and Pathology, B.Y.L. Nair Hospital and T.N. Medical College, Mumbai, India. 
Email: [email protected]
BACKGROUND: We have noticed a recent rise in the incidence and severity of acute renal failure (ARF) in malaria. AIM: To study the incidence, severity and outcome of ARF in malaria. SETTING and DESIGN: It is a retrospective analysis of data of one year from a tertiary medical centre in a metropolitan city. MATERIALS AND METHODS: Patients with ARF and smear positive malaria were evaluated. STATISTICAL ANALYSIS: Results were expressed as mean, range and standard deviation. RESULTS: Out of 402 detected smear positive malaria, 24 had ARF. Eighteen were of the age group 21-40 years. Plasmodium falciparum (PF) was detected in 16, Plasmodium vivax in three, and mixed infection in five. Non-oliguric ARF was seen in 14. Eighteen showed severe ARF (Serum creatinine >5 mg%). Twenty-two patients needed dialysis. Prolonged ARF lasting for 2-6 weeks was seen in eight. Seventeen patients recovered completely, while seven showed fatal combination of disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), severe ARF and PF malaria. No response was seen to chloroquine and artesunate given alone and twenty patients required quinine. CONCLUSION: ARF necessitating dialysis was seen in 92% of patients with ARF in malaria. PF infection, severe ARF, DIC and ARDS were poor prognostic factors. Resistance was noted to both chloroquine and artesunate.

Parasite Immunol 2001 Sep;23(9):491-501Nitric oxide and reactive nitrogen intermediates during lethal and nonlethal strains of murine malaria.

Nahrevanian H, Dascombe MJ.

School of Biological Sciences, The University of Manchester, Manchester, UK.

The virulence of Plasmodia depends partly on the strain of parasite and partly on the host. In this study, Plasmodium berghei N/13/1A/4/203 caused the death of mice, whereas Plasmodium chabaudi chabaudi AS was not lethal. Current opinion is that nitric oxide (NO) and other reactive nitrogen intermediates (RNI) are produced in several host organs during malaria to resist infection or produce tissue damage. NO and RNI production in blood or plasma, brain, liver and spleen in MF1 mice was investigated during P. berghei and P. c. chabaudi infection, in order to help determine whether changes in NO production are beneficial or detrimental to the host in vivo. NO production was measured both directly and indirectly as nitrites and nitrates, to represent RNI. No changes in blood NO were detected in P. berghei infected mice, but increases were observed in brain, liver and spleen. In P. c. chabaudi infected mice, rises in NO concentration were observed in blood and spleen, whereas a decline in liver NO was seen, but there were no changes in brain. Liver contained the highest concentration of RNI, but increasing concentrations were seen in both plasma and spleen in both P. berghei and P. c. chabaudi infected mice. These results show that NO and RNI production alters during murine malaria. The changes depend upon the tissue, the day of infection, the degree of parasitaemia, the strain of Plasmodia and the method of measuring NO biosynthesis. Lethal P. berghei induced NO production in the mid and late stages of infection in mice when parasitaemia was high, whereas in nonlethal P. c. chabaudi infection, NO production was increased in the early and late stages when parasitaemia was low. These data are consistent with a role for NO in the protection of the MF1 mouse against Plasmodia. Failure to clear the parasite is associated with evidence of increased NO production in brain and liver, which may contribute to the pathology of malaria, but this hypothesis requires confirmation from other experimental approaches.

Bull Entomol Res 2001 Aug;91(4):265-73Bioassay and biochemical analyses of insecticide resistance in southern African Anopheles funestus (Diptera: Culicidae).

Brooke BD, Kloke G, Hunt RH, Koekemoer LL, Temu EA, Taylor ME, Small G, Hemingway J, Coetzee M.

Medical Entomology, Department of Clinical Microbiology and Infectious Diseases, School of Pathology of the South African Institute for Medical Research and the University of the Witwatersrand, PO Box 1038, Johannesburg, 2000, South Africa.

ANOPHELES FUNESTUS: Giles has been implicated as a major malaria vector in sub-Saharan Africa where pyrethroid insecticides are widely used in agriculture and public health. Samples of this species from northern Kwazulu/Natal in South Africa and the Beluluane region of southern Mozambique showed evidence of resistance to pyrethroid insecticides. Insecticide exposure, synergist and biochemical assays conducted on A. funestus suggested that elevated levels of mixed function oxidases were responsible for the detoxification of pyrethroids in resistant mosquitoes in these areas. The data suggested that this mechanism was also conferring cross-resistance to the carbamate insecticide propoxur.

J Chromatogr B Biomed Sci Appl 2001 Sep 25;761(2):255-9High-performance liquid chromatographic determination of diazepam in plasma of children with severe malaria.

Muchoh SN, Ogutu BR, Newton CR, Kokwar GO.

Kenya Medical Research Institute/Wellcome Trust Collaborative Research Programme, Nairobi. 
Email: [email protected]
A sensitive, selective and reproducible reversed-phase HPLC method with ultraviolet detection was developed for the quantification of diazepam in small plasma samples from children with severe malaria. The method involves plasma deproteinization with acetonitrile, followed by liquid-liquid extraction with ethyl acetate-n-hexane. Diazepam was eluted at ambient temperatures from a reversed-phase C18 column with an acidic (pH 3.5) aqueous mobile phase (10 mM KH2PO4-acetonitrile, 69:31, v/v). Calibration curves in spiked plasma were linear from 10 to 200 ng (r2 > or = 0.99). The limit of detection was 5.0 ng/ml, and relative recoveries at 25 and 180 ng were >87%. Intra- and inter-assay relative standard deviations were <15%. There was no interference from drugs commonly administered to children with severe malaria (phenobarbitone, phenytoin, chloroquine, quinine, sulfadoxine, pyrimethamine, halofantrine, cycloguanil, chlorcycloguanil, acetaminophen and salicylate). This method has been used for monitoring plasma diazepam concentrations in children with seizures associated with severe malaria.

Clin Microbiol Rev 2001 Oct;14(4):810-20Pathogenesis of cerebral malaria: recent experimental data and possible applications for humans.

Lou J, Lucas R, Grau GE.

Department of Surgery, CH-1211 Geneva 14, Switzerland, and INSERM EMI 0019, UFR Pharmacie, Universite de la Mediterranee, F-13385 Marseilles, France.

Malaria still is a major public health problem, partly because the pathogenesis of its major complication, cerebral malaria, remains incompletely understood. Experimental models represent useful tools to better understand the mechanisms of this syndrome. Here, data generated by several models are reviewed both in vivo and in vitro; we propose that some pathogenic mechanisms, drawn from data obtained from experiments in a mouse model, may be instrumental in humans. In particular, tumor necrosis factor (TNF) receptor 2 is involved in this syndrome, implying that the transmembrane form of TNF may be more important than the soluble form of the cytokine. It has also been shown that in addition to differences in immune responsiveness between genetically resistant and susceptible mice, there are marked differences at the level of the target cell of the lesion, namely, the brain endothelial cell. In murine cerebral malaria, a paradoxical role of platelets has been proposed. Indeed, platelets appear to be pathogenic rather than protective in inflammatory conditions because they can potentiate the deleterious effects of TNF. More recently, it has been shown that interactions among platelets, leukocytes, and endothelial cells have phenotypic and functional consequences for the endothelial cells. A better understanding of these complex interactions leading to vascular injury will help improve the outcome of cerebral malaria.

Parasite 2001 Sep;8(3):243-50Gametocytaemia in Senegalese children with uncomplicated falciparum malaria treated with chloroquine, amodiaquine or sulfadoxine + pyrimethamine.

Sokhna CS, Trape JF, Robert V.

Laboratoire de Paludologie, UR Paludologie Afrotropicale, Institut de Recherche pour le Developpement, B.P. 1386 Dakar, Senegal.

Plasmodium falciparum gametocytaemia was studied in 266 Senegalese children (median 4 years, range 0.5-16) with uncomplicated malaria treated with chloroquine (CQ), amodiaquine (AQ) or sulfadoxine + pyrimethamine (SP). The proportion of resistant infections in vivo to these drugs was 44%, 16% and 7%, respectively. Gametocytes were counted by microscopy in thick smears on days 0, 4, 7 and 14 after treatment. There was a peak of gametocytaemia one week after treatment; on days 0, 7 and 14 the gametocyte prevalences were 35%, 73% and 63%, and the geometric means of gametocyte densities were 1.3, 12.5 and 5.6/microliter of blood. Three factors were found to influence gametocytaemia: treatment, efficacy of treatment, and duration of symptoms before treatment. Gametocyte prevalence and density significantly appeared higher in children treated with SP than with CQ, and higher with CQ than with AQ. Gametocyte prevalence and density were higher in resistant than in sensitive infections. The period between the appearance of the first clinical symptoms and treatment was positively and significantly linked to gametocyte prevalence and density on days 0 and 4. Early treatment with AQ, against sensitive infection, was followed by the lowest gametocytaemia. By contrast, treatment with SP against resistant infection was followed by the highest gametocytaemia. No clear relationship was observed between the density of asexual stages on day 0 and the gametocytaemia at any day between days 0 and 14. The epidemiological significance of post-therapeutic gametocytaemia and its possible role in the spread of resistant parasites are underlined. Solutions are proposed in order to avoid or reduce this gametocytaemia.

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