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1 – The October 3, 2002 issue of Nature is a special issue on Plasmodium genomics.
Full-text articles from this issue are on the web site at: 

2 – The Mark V version of the trilingual (English/French/Spanish) Royal Perth Hospital Malaria Education CD-ROM is now ready for distribution to medical/educational institutions or centres FREE of charge, This CD-ROM should be particularly useful to those centres that do not have reliable internet access to our web site. The English  site can be accessed at:  The site contains sections on Diagnosis, Prophylaxis, Treatment and History as well as an innovative interactive “Test & Teach” self assessment module. It is an ideal site for Clinicians, Scientists, Healthcare Professionals and Students.

Graham ICKE, A/Principal Scientist, Division of Laboratory Medicine, Royal Perth Hospital Wellington St., Perth, Western Australia 6000.  Email: [email protected]
Malaria On-Line Project –



Trop Med Int Health 2002 Oct;7(10):813-22 

Prevention of malaria in Afghanistan through social marketing of insecticide-treated nets: evaluation of coverage and effectiveness by cross-sectional surveys and passive surveillance.

Rowland M, Webster J, Saleh P, Chandramohan D, Freeman T, Pearcy B, Durrani N, Rab A, Mohammed N.

HealthNet International, Peshawar, Pakistan. London School of Hygiene & Tropical Medicine, London, UK.

Malaria is often a major health problem in countries undergoing war or conflict owing to breakdown of health systems, displacement of vulnerable populations, and the increased risk of epidemics. After 23 years of conflict, malaria has become prevalent in many rural areas of Afghanistan. From 1993 to the present, a network of non-governmental organizations, co-ordinated by HealthNet International, has operated a programme of bednet sales and re-treatment in lowland areas. To examine whether a strategy based on insecticide-treated nets (ITN) is a viable public health solution to malaria, communities were given the opportunity to buy nets and then monitored to determine population coverage and disease control impact. This was carried out using two contrasting methods: cross-sectional surveys and passive surveillance from clinics using a case-control design. Nets were purchased by 59% of families. Cross sectional surveys demonstrated a 59% reduction in the risk of Plasmodium falciparum infection among ITN users compared with non-users (OR 0.41; 95% CI 0.25-0.66). The passive surveillance method showed a comparable reduction in the risk of symptomatic P. falciparum malaria among ITN users (OR 0.31; 95% CI 0.21-0.47). The cross-sectional method showed a 50% reduction in risk of P. vivax infection in ITN users compared with non-users (OR 0.50; 95% CI 0.17-1.49) but this effect was not statistically significant. The passive surveillance method showed a 25% reduction in the risk of symptomatic P. vivax malaria (OR 0.75; 95% CI 0.66-0.85). ITN appeared to be less effective against P. vivax because of relapsing infections; hence an effect took more than one season to become apparent. Passive surveillance was cheaper to perform and gave results consistent with cross-sectional surveys. Untreated nets provided some protection. Data on socioeconomic status, a potential confounding factor, was not collected. However, at the time of net sales, there was no difference in malaria prevalence between buyers and non-buyers. The abundance of Anopheles stephensi, the main vector, did not appear to be affected by ITN. ITN constitute one of the few feasible options for protection against malaria in chronic emergencies.

Trop Med Int Health 2002 Oct;7(10):846-50 

Too poor to pay: charging for insecticide-treated bednets in highland Kenya.

Guyatt HL, Ochola SA, Snow RW.

Wellcome Trust Research Laboratories/KEMRI, Nairobi, Kenya and Centre for Tropical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. Division of Malaria Control, Ministry of Health, Nairobi, Kenya.

WHO has proposed malaria control as a means to alleviate poverty. One of its targets includes a 30-fold increase in insecticide-treated nets (ITNs) in the next 5 years. How this service will be financed remains unclear. In July 2000, 390 homesteads in rural highland Kenya were interviewed on their willingness to pay for ITNs. The costs to a household of protecting themselves with ITNs were compared with current household expenditure. Homesteads expressed a willingness to pay for ITNs, but the amounts offered were not sufficient to cover the costs of providing this service without donor support to meet the difference. Furthermore, as most household expenditure was allocated to basic needs these interventions were ‘unaffordable’. The cost of protecting a household with ITNs would be equivalent to sending three children to primary school for a year. The aspiration by poor rural homesteads to protect themselves with ITNs is not compatible with their ability to pay. One option to have an immediate equitable impact on ITN coverage and break the cycle between malaria and poverty is to provide this service free of charge.


Parasite 2002 Sep;9(3):255-9 

Insecticide mixtures for mosquito net impregnation against malaria vectors.

Corbel V, Darriet F, Chandre F, Hougard JM.

IRD, 911, avenue Agropolis, BP 64501, 34394 Montpellier, France.

Insecticides belonging to the pyrethroid family are the only compounds currently available for the treatment of mosquito nets. Unfortunately, some malaria vector species have developed resistance to pyrethroids and the lack of alternative chemical categories is a great concern. One strategy for resistance management would be to treat mosquito nets with a mixture associating two insecticides having different modes of action. This study presents the results obtained with insecticide mixtures containing several proportions of bifenthrin (a pyrethroid insecticide) and carbosulfan (a carbamate insecticide). The mixtures were sprayed on mosquito net samples and their efficacy were tested against a susceptible strain of Anopheles gambiae, the major malaria vector in Africa. A significant synergism was observed with a mixture containing 25 mg/m2 of bifenthrin (half the recommended dosage for treated nets) and 6.25 mg/m2 of carbosulfan (about 2% of the recommended dosage). The observed mortality was significantly more than expected in the absence of any interaction (80% vs 41%) and the knock-down effect was maintained, providing an effective barrier against susceptible mosquitoes.

Parasite 2002 Sep;9(3):247-53 

Monitoring the drug-sensitivity of Plasmodium falciparum in coastal towns in  Madagascar by use of in vitro chemosensitivity and mutation detection tests.

Rason MA, Ariey F, Rafidimanantsoa L, Andrianantenaina BH, Sahondra Harisoa JL,

Randrianarivelojosia M.

Groupe de Recherche sur le Paludisme, Institut Pasteur de Madagascar, BP 1274, Antananarivo (101), Republique de Madagascar.

The dissemination of mutant and resistant strains of Plasmodium falciparum makes a considerable contribution to the spread of drug-resistant malaria. Populations around harbours and airports could be particularly exposed to Plasmodium isolates introduced with imported cases of malaria. The use of chloroquine as well as the use of and sulfadoxine/pyrimethamine is currently an effective method for treating uncomplicated cases of malaria in Madagascar. As part of a monitoring programme, in vitro methods were used to assess the sensitivity of P. falciparum isolates in two coastal towns in Madagascar: Mahajanga on the west coast and Toamasina on the east coast. All of the isolates from both sites were sensitive to amodiaquine, quinine, pyrimethamine and cycloguanil. All of the

isolates from Mahajanga were sensitive to chloroquine (n = 25; mean IC50 = 22.6 nM, 95% confidence interval: 16.8-28.7 nM), whereas three of the isolates from Toamasina were resistant to chloroquine (n = 18; mean IC50 = 66.3 nM; 95% confidence interval: 42.6-90 nM). The frequency of the Pfcrt Thr-76 and the dhfr Asn-108 mutations was estimated by PCR/RFLP. The 43 P. falciparum isolates examined, including the three in vitro chloroquine-resistant isolates from Toamasina were all wild-type (Lys-76). Phenotyping and genotyping studies suggested that the prevalence of chloroquine- and pyrimethamine-resistant isolates and of mutant strains of P. falciparum is very low. These results showed that in vitro test and genotyping of resistance markers approaches couldbe successfully used to monitor the emergence of drug-resistant malaria and totry to alleviate the lack of medical teams able to carry out in vivo test. The possible hazard/risk associated with imported cases of malaria is discussed.

Parasite 2002 Sep;9(3):239-46 

Entomological studies carried out in five villages of Senegal

Diop A, Molez JF, Konate L, Fontenille D, Gaye O, Diouf M, Diagne M, Faye O.

Laboratoire de Paludologie, Institut de Recherche pour le Developpement, IRD, BP 1386, Dakar, Senegal. Email: [email protected]

From June 1995 to January 1998, entomological studies carried out in five villages located in the Delta’s Saloum have allowed to better understand the contribution of An. melas Theobald (1903) to malaria transmission in mangrove swamp. Among the five villages studied, three of them (Simal, Djilor and Marlothie) located along the Saloum river, are colonised by An. arabiensis; the two others (Djifere and Diakhanor) located between the sea and the river, are colonised by An. melas. During the rainy season and at the begining of the dry season, An. melas and An. arabiensis are sympatric. The ratio of An. melas/An. arabiensis increases when we go closer the coast where An. melas becomes quite exclusive. When An. melas is predominant, endophagy, endophily and anthropophily are very marked. The parturity rates are lower in An. melas than in An. arabiensis. In the predominance area of each species, transmission is on the same level. During the period of sympatry, An. arabiensis is responsible for the transmission and when it is absent, An. melas carries on. Transmission occurs from July to March with a maximum at the beginning of the dry season. In thevillages of the mangrove swamp, its prolongation until the middle of the dry season is due to An. melas.

Eur J Clin Microbiol Infect Dis 2002 Sep;21(9):679-81 

Prospective Assessment of a New Polymerase Chain Reaction Target  (STEVOR) for Imported Plasmodium falciparum Malaria.

Filisetti D, Bombard S, N’Guiri C, Dahan R, Molet B, Abou-Bacar A, Hansmann Y, Christmann D, Candolfi E.

Institut de Parasitologie et de Pathologie Tropicale, 3 rue Koeberle, 67000 Strasbourg, France, Email: [email protected]

The diagnostic value of a polymerase chain reaction (PCR)-based method for amplifying a new target of repeated genes (STEVOR) in Plasmodium falciparum was prospectively assessed on samples from 210 febrile patients returning from areas endemic for malaria. This method is capable of detecting 0.01 parasites in one microliter of blood. Plasmodium falciparum STEVOR PCR confirmed the results of the thin- and thick-film direct examination method but identified Plasmodium falciparum in four patients in whom direct examination was inconclusive at the species level. Moreover, PCR was positive in two patients with a negative direct examination. Thus, Plasmodium falciparum STEVOR PCR had 100% sensitivity and specificity and could be used in selected parasitology laboratories when expert advice is required.

Nature 2002 Oct 3;419(6906):537-42 

Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry.

Lasonder E, Ishihama Y, Andersen JS, Vermunt AM, Pain A, Sauerwein RW, Eling WM, Hall N, Waters AP, Stunnenberg HG, Mann M.

Center for Experimental BioInformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.

The annotated genomes of organisms define a ‘blueprint’ of their possible gene products. Post-genome analyses attempt to confirm and modify the annotation and impose a sense of the spatial, temporal and developmental usage of genetic information by the organism. Here we describe a large-scale, high-accuracy (average deviation less than 0.02 Da at 1,000 Da) mass spectrometric proteome analysis of selected stages of the human malaria parasite Plasmodium falciparum. The analysis revealed 1,289 proteins of which 714 proteins were identified in asexual blood stages, 931 in gametocytes and 645 in gametes. The last two groups provide insights into the biology of the sexual stages of the parasite, and include conserved, stage-specific, secreted and membrane-associated proteins. A subset of these proteins contain domains that indicate a role in cell-cell interactions, and therefore can be evaluated as potential components of a malaria vaccine formulation. We also report a set of peptides with significant matches in the parasite genome but not in the protein set predicted by computational methods.

Mini Rev Med Chem 2002 Dec;2(6):573-83 

Malaria: new chemotherapeutic peroxide drugs.

Borstnik K, Paik IH, Posner GH.

Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA. Email: [email protected]

Chemical insights into artemisinin’s biological mechanism of action have allowed rational design of some new trioxane and endoperoxide antimalarial drug candidates that are efficacious and safe. This review summarizes recent achievements in this area of peroxide drug development for malaria chemotherapy.

Nature 2002 Oct 3;419(6906):534-7 

Sequence of Plasmodium falciparum chromosome 12.

Hyman RW, Fung E, Conway A, Kurdi O, Mao J, Miranda M, Nakao B, Rowley D, Tamaki T,  Wang F, Davis RW.

Stanford Genome Technology Center, 855 California Avenue, Palo Alto, California 94304 USA, and Departments of Biochemistry and Genetics, Stanford University Medical College, Stanford University, Stanford, California 94305, USA.

The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people every year. To stimulate basic research on the disease, and to promote the development of effective drugs and vaccines against the parasite, the complete genome of P. falciparum clone 3D7 has been sequenced, using a chromosome-by-chromosome shotgun strategy. Here we report the nucleotide sequence of the third largest of the parasite’s 14 chromosomes, chromosome 12, which comprises about 10% of the 23 megabase genome. As the most (A + T)-rich (80.6%) genome sequenced to date, the P. falciparum genome presented severe problems during the assembly of primary sequence reads. We discuss the methodology that yielded a finished and fully contiguous sequence for chromosome 12. The biological implications of the sequence data are more thoroughly discussed in an accompanying Article (ref. 3).

Nature 2002 Oct 3;419(6906):531-4 

Sequence of Plasmodium falciparum chromosomes 2, 10, 11 and 14.

Gardner MJ, Shallom SJ, Carlton JM, Salzberg SL, Nene V, Shoaibi A, Ciecko A, Lynn J, Rizzo M, Weaver B, Jarrahi B, Brenner M, Parvizi B, Tallon L, Moazzez A, Granger D, Fujii C, Hansen C, Pederson J, Feldblyum T, Peterson J, Suh B, Angiuoli S, Pertea M, Allen J, Selengut J, White O, Cummings LM, Smith HO, Adams MD, Venter JC, Carucci DJ, Hoffman SL, Fraser CM.

The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 20850, USA.

The mosquito-borne malaria parasite Plasmodium falciparum kills an estimated 0.7-2.7 million people every year, primarily children in sub-Saharan Africa. Without effective interventions, a variety of factors-including the spread of parasites resistant to antimalarial drugs and the increasing insecticide resistance of mosquitoes-may cause the number of malaria cases to double over the next two decades. To stimulate basic research and facilitate the development of new drugs and vaccines, the genome of Plasmodium falciparum clone 3D7 has been sequenced using a chromosome-by-chromosome shotgun strategy. We report here the nucleotide sequences of chromosomes 10, 11 and 14, and a re-analysis of the chromosome 2 sequence. These chromosomes represent about 35% of the 23 megabase P. falciparum genome.

Nature 2002 Oct 3;419(6906):527-31 

Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13.

Hall N, Pain A, Berriman M, Churcher C, Harris B, Harris D, Mungall K, Bowman S, Atkin R, Baker S, Barron A, Brooks K, Buckee CO, Burrows C, Cherevach I, Chillingworth C, Chillingworth T, Christodoulou Z, Clark L, Clark R, Corton C, Cronin A, Davies R, Davis P, Dear P, Dearden F, Doggett J, Feltwell T, Goble A, Goodhead I, Gwilliam R, Hamlin N, Hance Z, Harper D, Hauser H, Hornsby T, Holroyd S, Horrocks P, Humphray S, Jagels K, James KD, Johnson D, Kerhornou A, Knights A, Konfortov B, Kyes S, Larke N, Lawson D, Lennard N, Line A, Maddison M, McLean J, Mooney P, Moule S, Murphy L, Oliver K, Ormond D, Price C, Quail MA, Rabbinowitsch E, Rajandream MA, Rutter S, Rutherford KM, Sanders M, Simmonds M,  Seeger K, Sharp S, Smith R, Squares R, Squares S, Stevens K, Taylor K, Tivey A, Unwin L, Whitehead S, Woodward J, Sulston JE, Craig A, Newbold C, Barrell BG.

The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Since the sequencing of the first two chromosomes of the malaria parasite, Plasmodium falciparum, there has been a concerted effort to sequence and assemble the entire genome of this organism. Here we report the sequence of chromosomes 1, 3-9 and 13 of P. falciparum clone 3D7-these chromosomes account for approximately 55% of the total genome. We describe the methods used to map, sequence and annotate these chromosomes. By comparing our assemblies with the optical map, we indicate the completeness of the resulting sequence. During annotation, we assign Gene Ontology terms to the predicted gene products, and observe clustering of some malaria-specific terms to specific chromosomes. We identify a highly conserved sequence element found in the intergenic region of internal var genes that is not associated with their telomeric counterparts.

Nature 2002 Oct 3;419(6906):512-9 

Genome sequence and comparative analysis of the model rodent malaria  parasite Plasmodium yoelii yoelii.

Carlton JM, Angiuoli SV, Suh BB, Kooij TW, Pertea M, Silva JC, Ermolaeva MD, Allen JE, Selengut JD, Koo HL, Peterson JD, Pop M, Kosack DS, Shumway MF, Bidwell SL, Shallom SJ, Van Aken SE, Riedmuller SB, Feldblyum TV, Cho JK, Quackenbush J, Sedegah M, Shoaibi A, Cummings LM, Florens L, Yates JR, Raine JD, Sinden RE, Harris MA, Cunningham DA, Preiser PR, Bergman LW, Vaidya AB, Van Lin LH, Janse CJ, Waters AP, Smith HO, White OR, Salzberg SL, Venter JC, Fraser CM, Hoffman SL, Gardner MJ, Carucci DJ.

The Institute for Genomic Research, 9712 Medical Center Drive,Rockville, Maryland 20850, USA.

Species of malaria parasite that infect rodents have long been used as models for malaria disease research. Here we report the whole-genome shotgun sequence of one species, Plasmodium yoelii yoelii, and comparative studies with the genome of the human malaria parasite Plasmodium falciparum clone 3D7. A synteny map of 2,212 P. y. yoelii contiguous DNA sequences (contigs) aligned to 14 P.

falciparum chromosomes reveals marked conservation of gene synteny within the body of each chromosome. Of about 5,300 P. falciparum genes, more than 3,300 P. y. yoelii orthologues of predominantly metabolic function were identified. Over 800 copies of a variant antigen gene located in subtelomeric regions were found. This is the first genome sequence of a model eukaryotic parasite, and it provides insight into the use of such systems in the modelling of Plasmodium biology and disease. 

Nature 2002 Oct 3;419(6906):498-511 

Genome sequence of the human malaria parasite Plasmodium falciparum.

Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM,  Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B.

The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 20850, USA.

The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in  antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria. Cases can be made with a RBC-deformability distribution (RBC-DD). Methods. This paper explores RBC-DDs of healthy individuals and of cells with anomalous mechanical properties (sickle cell disease, dialysis patients, elliptocytosis, and cultivated malaria tropica). The distributions were measured with an automated rheoscope, which uses advanced image analysis techniques to obtain the deformability index of a large number of individual cells subjected to simple shear flow. Results. The RBC-DD of healthy volunteers is close to a normal distribution. In the investigated patients, distributions were markedly different and yielded significant changes in the mean, in the standard deviation, or in both. The presence of hypodeformable and hyperdeformable celL  fractions can qualitatively and quantitatively be assessed from the deformability distribution (DD). In elliptocytosis, cells orient differently with respect to the streamlines, compared to normal cells. This causes the DD to be biased. Conclusions. The RBC-DD is a powerful representation to establish subpopulations with anomalous deformability. Fractions of hypodeformable and hyperdeformable cells and the standard deviation of the DD are new and excellent quantitative parameters to assess alterations in RBC deformability.

Science 2002 Oct 4;298(5591):213-6 

Genetic loci affecting resistance to human malaria parasites in a West African mosquito vector population.

Niare O, Markianos K, Volz J, Oduol F, Toure A, Bagayoko M, Sangare D, Traore SF, Wang R, Blass C, Dolo G, Bouare M, Kafatos FC, Kruglyak L, Toure YT, Vernick KD.

Department of Medical and Molecular Parasitology, New York University School of Medicine, 341 East 25th Street, New York, NY 10010, USA.

Successful propagation of the malaria parasite Plasmodium falciparum within a susceptible mosquito vector is a prerequisite for the transmission of malaria. A field-based genetic analysis of the major human malaria vector, Anopheles gambiae, has revealed natural factors that reduce the transmission of P. falciparum. Differences in P. falciparum oocyst numbers between mosquito isofemale families fed on the same infected blood indicated a large genetic component affecting resistance to the parasite, and genome-wide scanning in pedigrees of wild mosquitoes detected segregating resistance alleles. The apparently high natural frequency of resistance alleles suggests that malaria parasites (or a similar pathogen) exert a significant selective pressure on vector populations.

Science 2002 Oct 4;298(5591):210-3 

Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by  pfcrt mutations.

Sidhu AB, Verdier-Pinard D, Fidock DA.

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance. Here, we provide

conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria.

Science 2002 Oct 4;298(5591):182-5 

Inversions and gene order shuffling in Anopheles gambiae and A. funestus.

Sharakhov IV, Serazin AC, Grushko OG, Dana A, Lobo N, Hillenmeyer ME, Westerman R,  Romero-Severson J, Costantini C, Sagnon N, Collins FH, Besansky NJ.

Center for Tropical Disease Research and Training, University of Notre Dame, Notre Dame, IN 46556-0369, USA.

In tropical Africa, Anopheles funestus is one of the three most important malaria vectors. We physically mapped 157 A. funestus complementary DNAs (cDNAs) to  the polytene chromosomes of this species. Sequences of the cDNAs were mapped in silico to the A. gambiae genome as part of a comparative genomic study of synteny, gene  order, and sequence conservation between A. funestus and A. gambiae. These species are in the same subgenus and diverged about as recently as humans and  chimpanzees. Despite nearly perfect preservation of synteny, we found substantial shuffling of gene order along corresponding chromosome arms. Since the divergence of these species, at least 70 chromosomal inversions have been fixed, the highest  rate of rearrangement of any eukaryote studied to date. The high incidence of  paracentric inversions and limited colinearity suggests that locating genes in one anopheline species based on gene order in another may be limited to closely related taxa.

Science 2002 Oct 4;298(5591):179-81 

Evolution of supergene families associated with insecticide resistance.

Ranson H, Claudianos C, Ortelli F, Abgrall C, Hemingway J, Sharakhova MV, Unger MF, Collins FH, Feyereisen R.

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

The emergence of insecticide resistance in the mosquito poses a serious threat to the efficacy of many malaria control programs. We have searched the Anopheles gambiae genome for members of the three major enzyme families- the carboxylesterases, glutathione transferases, and cytochrome P450s-that are primarily responsible for metabolic resistance to insecticides. A comparative genomic analysis with Drosophila melanogaster reveals that a considerable expansion of these supergene families has occurred in the mosquito. Low gene orthology and little chromosomal synteny paradoxically contrast the easily identified orthologous groups of genes presumably seeded by common ancestors. In A. gambiae, the independent expansion of paralogous genes is mainly a consequence of the formation of clusters among locally duplicated genes. These expansions may reflect the functional diversification of supergene families consistent with major differences in the life history and ecology of these organisms. These data provide a basis for identifying the resistance-associated enzymes within these families. This will enable the resistance status of mosquitoes, flies, and possibly other holometabolous insects to be monitored. The analyses also provide the means for identifying previously unknown molecules involved in fundamental biological processes such as development.

Science 2002 Oct 4;298(5591):172-5 

Neuropeptides and peptide hormones in Anopheles gambiae.

Riehle MA, Garczynski SF, Crim JW, Hill CA, Brown MR.

Department of Entomology, University of Georgia, Athens, GA 30602, USA.

The African malaria mosquito, Anopheles gambiae, is specialized for rapid completion of development and reproduction. A vertebrate blood meal is required for egg production, and multiple feedings subsequently allow transmission of malaria parasites, Plasmodium spp. Regulatory peptides from 35 genes annotated from the A. gambiae genome likely coordinate these and other physiological

processes. Plasmodium parasites may affect actions of newly identified insulin-like peptides, which coordinate growth and reproduction of its vector, A. gambiae, as in Drosophila melanogaster, Caenorhabditis elegans, and mammals. This genomic information provides a basis to expand understanding of hematophagy and pathogen transmission in this mosquito. 

Science 2002 Oct 4;298(5591):129-49 

The genome sequence of the malaria mosquito Anopheles gambiae.

Holt RA, Subramanian GM, Halpern A, Sutton GG, Charlab R, Nusskern DR, Wincker P, Clark AG, Ribeiro JM, Wides R, Salzberg SL, Loftus B, Yandell M, Majoros WH, Rusch DB, Lai Z, Kraft CL, Abril JF, Anthouard V, Arensburger P, Atkinson PW, Baden H, de Berardinis V, Baldwin D, Benes V, Biedler J, Blass C, Bolanos R, Boscus D, Barnstead M, Cai S, Center A, Chatuverdi K, Christophides GK, Chrystal MA, Clamp M, Cravchik A, Curwen V, Dana A, Delcher A, Dew I, Evans CA, Flanigan M, Grundschober-Freimoser A, Friedli L, Gu Z, Guan P, Guigo R, Hillenmeyer ME, Hladun SL, Hogan JR, Hong YS, Hoover J, Jaillon O, Ke Z, Kodira C, Kokoza E, Koutsos A, Letunic I, Levitsky A, Liang Y, Lin JJ, Lobo NF, Lopez JR, Malek JA, McIntosh TC, Meister S, Miller J, Mobarry C, Mongin E, Murphy SD, O’Brochta DA, Pfannkoch C, Qi R, Regier MA, Remington K, Shao H, Sharakhova MV, Sitter CD, Shetty J, Smith TJ, Strong R, Sun J, Thomasova D, Ton LQ, Topalis P, Tu Z, Unger MF, Walenz B, Wang A, Wang J, Wang M, Wang X, Woodford KJ, Wortman JR, Wu M, 

Yao A, Zdobnov EM, Zhang H, Zhao Q, Zhao S, Zhu SC, Zhimulev I, Coluzzi M, della Torre A, Roth CW, Louis C, Kalush F, Mural RJ, Myers EW, Adams MD, Smith HO, Broder S, Gardner MJ, Fraser CM, Birney E, Bork P, Brey PT, Venter JC, Weissenbach J, Kafatos FC, Collins FH, Hoffman SL.

Celera Genomics, 45 West Gude Drive, Rockville, MD 20850, USA. Email: [email protected]

Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91% of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency (“dual haplotypes”) in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that

showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.

Science 2002 Oct 4;298(5591):124-6 

Plasmodium chloroquine resistance and the search for a replacement antimalarial drug.

Wellems TE.

Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. Email: [email protected]

Genetic and biochemical research is providing new information on the mechanism of chloroquine resistance. Drug discovery initiatives are finding new leads that have favorable pharmaceutical properties and efficacy against chloroquine-resistant malaria. 

Science 2002 Oct 4;298(5591):122-4 

A new global effort to control malaria.

Sachs JD.

Earth Institute, Columbia University, New York, NY 10027, USA.

The time has come to resurrect a worldwide effort to control malaria, following decades of neglect during which the disease has resurged in many parts of sub-Saharan Africa and other endemic regions.

Science 2002 Oct 4;298(5591):121-2 

Malaria–a shadow over Africa.

Miller LH, Greenwood B.

Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

Reduction in severe disease and death from falciparum malaria in Africa requires new, more effective and inexpensive public health measures. The completed genomes of Plasmodium falciparum and its vector Anopheles gambiae represent a big step toward the discovery of these needed tools.

Science 2002 Oct 4;298(5591):119-21 

Malaria control with genetically manipulated insect vectors.

Alphey L, Beard CB, Billingsley P, Coetzee M, Crisanti A, Curtis C, Eggleston P, Godfray C, Hemingway J, Jacobs-Lorena M, James AA, Kafatos FC, Mukwaya LG, Paton M, Powell JR, Schneider W, Scott TW, Sina B, Sinden R, Sinkins S, Spielman A, Toure Y, Collins FH.

Oxford University, UK.

At a recent workshop, experts discussed the benefits, risks, and research priorities associated with using genetically manipulated insects in the control of vector-borne diseases.

Science 2002 Oct 4;298(5591):115-7 

Speciation within Anopheles gambiae–the glass is half full.

della Torre A, Costantini C, Besansky NJ, Caccone A, Petrarca V, Powell JR, Coluzzi M.

Parasitology Unit, Department of Public Health, University of Rome “La Sapienza,” P.le Aldo Moro 5, 00185 Rome, Italy. Email: [email protected]

Restrictions to gene flow among molecular forms of the mosquito Anopheles gambiae sensu stricto reveal an ongoing speciation process affecting the epidemiology of malaria in sub-Saharan Africa.

Science 2002 Oct 4;298(5591):96-7 

An overview of insecticide resistance.

Hemingway J, Field L, Vontas J.

Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.

Insecticide resistance poses a serious threat to current malaria control efforts. The Anopheles gambiae genome will enable identification of new resistance genes and will provide new molecular targets for the design of more effective insecticides.

Science  2002 Oct 4;298(5591):79 

The mosquito genome–a breakthrough for public health.

Morel CM, Toure YT, Dobrokhotov B, Oduola AM.

Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, 20 Avenue Appia, CH-1211 Geneva 27, Switzerland. Email: [email protected]

The Anopheles gambiae genome sequence will accelerate identification of new Insect vector target genes leading to improved strategies for malaria control. 

Science 2002 Oct 4;298(5591):33-4 

Malaria research. Parasite genome sequenced, scrutinized.

Pennisi E.

This week, an almost complete DNA sequence of Plasmodium falciparum–one of the parasites that causes malaria–appears in Nature, and on page 129 of this issue of Science, other researchers report the DNA sequence of Anopheles gambiae, one of the mosquitoes that transmits P. falciparum to humans. Together with the human genome sequence, researchers now have in hand the genetic blueprints for the parasite, its vector, and its victim.

Science 2002 Oct 3; [epub ahead of print] 

A Polytene Chromosome Analysis of the Anopheles gambiae Species Complex.

Coluzzi M, Sabatini A, Della Torre A, Di Deco MA, Petrarca V.

Dipartimento di Scienze di Sanita Pubblica and Istituto Pasteur-Cenci Bolognetti, Universita “La Sapienza,” Rome, Italy., Dipartimento di Genetica e Biologia Molecolare, Universita “La Sapienza,” Rome, Italy.

Field collected specimens of all known taxa in the Anopheles gambiae complex were analyzed on the basis of chromosome inversions with reference to a standard polytene chromosome map. The phylogenetic relationship among the seven described species in the complex could be inferred from the distribution of fixed inversions. Nonrandom patterns of inversion distribution were observed and, particularly on chromosome arm 2R, provided evidence for genetically distinct populations in A. gambiae, A. arabiensis, and A. melas. In A. gambiae from Mali, stable genetic differentiation was observed even in populations living in the same region, suggesting a process of incipient speciation. The possible role of chromosome differentiation in speciation of the A. gambiae complex and in the emergence of distinct chromosomal forms within the nominal species is discussedin relation to human malaria.

Clin Microbiol Rev 2002 Oct;15(4):595-612 

History of human parasitology.

Cox FE.

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.

Humans are hosts to nearly 300 species of parasitic worms and over 70 species of protozoa, some derived from our primate ancestors and some acquired from the animals we have domesticated or come in contact with during our relatively short history on Earth. Our knowledge of parasitic infections extends into antiquity,and descriptions of parasites and parasitic infections are found in the earliest writings and have been confirmed by the finding of parasites in archaeological material. The systematic study of parasites began with the rejection of the theory of spontaneous generation and the promulgation of the germ theory. Thereafter, the history of human parasitology proceeded along two lines, the discovery of a parasite and its subsequent association with disease and the recognition of a disease and the subsequent discovery that it was caused by a parasite. This review is concerned with the major helminth and protozoan infections of humans: ascariasis, trichinosis, strongyloidiasis, dracunculiasis, lymphatic filariasis, loasis, onchocerciasis, schistosomiasis, cestodiasis, paragonimiasis, clonorchiasis, opisthorchiasis, amoebiasis, giardiasis, African trypanosomiasis, South American trypanosomiasis, leishmaniasis, malaria,toxoplasmosis, cryptosporidiosis, cyclosporiasis, and microsporidiosis.

Clin Microbiol Rev 2002 Oct;15(4):564-94 

Evolutionary and historical aspects of the burden of malaria.

Carter R, Mendis KN.

University of Edinburgh, Division of Biological Sciences, ICAPB, Ashworth Laboratories, Edinburgh EH9 3JT, United Kingdom. Roll Back Malaria Project, World Health Organization, Geneva 27, Switzerland.

Malaria is among the oldest of diseases. In one form or another, it has infected and affected our ancestors since long before the origin of the human line. During our recent evolution, its influence has probably been greater than that of any other infectious agent. Here we attempt to trace the forms and impacts of malaria from a distant past through historical times to the present. In the last sections, we review the current burdens of malaria across the world and discuss present-day approaches to its management. Only by following, or attempting to follow, malaria throughout its evolution and history can we understand its character and so be better prepared for our future management of this ancient ill.

Am J Trop Med Hyg 2002 Jul;67(1):8-16 

Alterations in Plasmodium falciparum genotypes during sequential infections suggest the presence of strain specific immunity.

Eisen DP, Saul A, Fryauff DJ, Reeder JC, Coppel RL.

Department of Microbiology, Monash University, Clayton, Victoria, Australia.

Many of the asexual stage Plasmodium falciparum proteins that are the targets of host protective responses are markedly polymorphic. The full repertoire of diversity is not defined for any antigen. Most studies have focused on the genes encoding merozoite surface proteins 1 and 2 (MSP1, MSP2). We explored the extent of diversity of some of the less studied merozoite surface antigens and analyzed the degree of complexity of malaria field isolates by deriving nucleotide sequences of several antigens. We have determined the genotype of apical membrane antigen 1 (AMA1) in a group of 30 field samples, collected over 29 months, from individuals living in an area of intense malaria transmission in Irian Jaya, identifying 14 different alleles. AMA1 genotyping was combined with previously determined MSP2 typing. AMA1 had the greatest power in distinguishing between isolates but methodological problems, especially when mixed infections are present, suggest it is not an ideal typing target. MSP1, MSP3, and glutamate-rich protein genotypes were also determined from a smaller group of samples, and all results were combined to derive an extended antigenic haplotype. Within this subset of 10 patients, nine different genotypes could be discerned; however, five patients were all infected with the same strain. This strain was present in individuals from two separate villages and was still present 12 months later. This strain was predominant at the first time point but had disappeared at the fourth time point. This significant change in malaria genotypes could be due to strain-specific immunity developing in this population.

Am J Trop Med Hyg 2002 Jul;67(1):64-6 

Short report: Molecular evaluation of the efficacy of chloroquine treatment of uncomplicated Plasmodium falciparum malaria in East Timor.

Chen N, Baker J, Ezard N, Burns M, Edstein MD, Cheng Q.

Australian Army Malaria Institute, Brisbane, Queensland, Australia.

The efficacy of chloroquine treatment of uncomplicated Plasmodium falciparum malaria in East Timor was investigated via molecular tools. Genotyping of the polymorphic markers msp1 and msp2 was performed to investigate the number and type of parasite alleles in pre- and posttreatment blood samples collected from 48 patients. Patients were infected with a minimum of 8 msp1 and 14 msp2 allelic types of parasite, and 43% of the patients had more than one allelic type before treatment. The genotyping also revealed that 66.7% of the patients were infected with at least one identical allelic type of parasite before and after treatment and therefore were likely to have experienced recrudescence. All parasites in pre- and posttreatment blood samples carried the K76T mutation in pfcrt,

regardless of the clinical response to chloroquine. The sequence polymorphism patterns in pfcrt in the majority of parasites examined were identical to those observed in Bougainville, Papua New Guinea.

Am J Trop Med Hyg 2002 Jul;67(1):61-3 

Ocular lesions associated with malaria in children in Mali.

Schemann JF, Doumbo O, Malvy D, Traore L, Kone A, Sidibe T, Keita M.

Institute of African Tropical Ophthalmology, Bamako, Mali. Email: [email protected]

This study sought to estimate the frequency of ocular complications in malaria and its prognostic value in Mali. A total of 140 children (aged 6 months to 9 years) with severe malaria (105 with cerebral malaria, 35 without neurological complications) were compared with 34 children with mild malaria and 82 children with nonmalarial fever. Ocular lesions were rare in the mild malaria group (5.8%). Retinal hemorrhages occurred in 11.8% of the children in the severe noncerebral malaria group. Cerebral malaria was associated with retinal hemorrhages (22.9%) and retinal edema (10.5%). No association was found between ocular signs such as retinal hemorrhages or retinal edema and mortality. Exudates, papilledema, and the presence of cottonwool spots were associated with an increased risk of death. Coma score and convulsions were significantly associated with death but not with ocular signs. The presence of retinal signs in a child in a malaria-endemic area may signal a case of severe malaria.

Am J Trop Med Hyg 2002 Jul;67(1):54-60 

The effects of antimalarial drugs on ventricular repolarization.

Touze JE, Heno P, Fourcade L, Deharo JC, Thomas G, Bohan S, Paule P, Riviere P, Kouassi E, Buguet A.

Service de Cardiologie, Hospital d’Instruction des Armees, Marseille, France.

Cardiotoxicity has become a major concern during treatment with antimalarial drugs. Lengthening of the QTc and severe cardiac arrhythmia have been observed, particularly after treatment with halofantrine for chloroquine-resistant Plasmodium falciparum malaria. The purpose of this prospective study was to evaluate whether antimalarial agents alter dispersion of the QTc and ventricular repolarization dynamicity. Sixty patients with uncomplicated falciparum malaria were randomly allocated in four groups of 15 patients and treated with quinine, mefloquine, artemether, or halofantrine at recommended doses. Patients in treatment groups were compared with a group including 15 healthy controls with no history of malaria and/or febrile illness within the last month. QTc dispersion was measured on surface electrocardiograms. Repolarization dynamicity was analyzed from Holter recordings, which allow automatic beat-to-beat measurement of QT and RR intervals. Plasma drug concentration was determined by reversed-phase high-performance liquid chromatography. No change in QTc dispersion was observed after treatment with quinine, mefloquine, or artemether. Treatment with halofantrine was followed by a significant increase in QTcdispersion at 9 hours (P < 0.0001) and 24 hours (P < 0.01). Assessment of QT heart rate variability by QT/RR nychtohemeral regression slope demonstrated no significant difference between the artemether (mean +/- SEM = 0.170 +/- 0.048), mefloquine (0.145 +/- 0.044), and the control groups (0.172 +/- 0.039). A significant decrease in the Q-eT/RR slope was observed in the quinine group compared with the control and artemether groups (0.135 +/- 0.057; P < 0.04). With halofantrine, a significant increase in the QT/RR regression slope (0.289 +/- 0.118) was observed (P < 0.0002). QTc interval, QT dispersion, and QT regression slope were significantly correlated with halofantrine and quinine plasma concentration. Mefloquine and artemether did not alter ventricular repolarization. Quinine induced a significant decrease in QT/RR slope of the same order of magnitude as those previously observed with quinidine. Both QTc dispersion and QT/RR slope were significantly modified by halofantrine. These repolarization changes were related to a class-III antiarrhythmic drug effect and may explain the occurrence of ventricular arrhythmia and/or sudden deaths reported after halofantrine intake.

Am J Trop Med Hyg 2002 Jul;67(1):44-53 

Malaria and human immunodeficiency virus infection as risk factors for anemia in infants in Kisumu, western Kenya.

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

Kenya Medical Research Institute, Center for Vector Biology and Control Research, Kisumu. Emasil: [email protected]

The role of maternal and pediatric infection with human immunodeficiency virus type 1 (HIV-1) and malaria as risk factors for anemia was determined in a birth cohort of infants born to mothers participating in a study of the interaction between placental malaria and HIV infection, in Kisumu, Kenya. Between June 1996 and April 2000, 661 infants born to 467 HIV-seropositive and 194 HIV-seronegative mothers were monitored monthly from birth. At each visit a questionnaire was completed and a blood sample was collected for the determination of hemoglobin levels and detection of malaria and HIV. Anemia was common and increased from 13.6% at one month to 75% at six months and remained high throughout the second half of infancy. Placental malaria, infant malaria, and HIV infection of the infant were all associated with infant anemia in a multivariate model,  adjusting for other co-variates found to be associated with infant anemia. The  HIV-infected infants with malaria parasitemia had lower mean hemoglobin levels  compared with HIV-uninfected infants, or HIV-infected infants without malaria, suggesting that HIV-infected infants are particularly vulnerable to the adverse consequences of malaria at this age. Early detection and prompt treatment of infant malaria and treatment of anemia as part of the study protocol failed to prevent most of the infants from becoming anemic. Although not proven effective in this study, micronutrient supplementation should be prospectively assessed in HIV-infected infants as a means of preventing anemia.

Am J Trop Med Hyg 2002 Jul;67(1):39-43 

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

Ramharter M, Noedl H, Thimasarn K, Wiedermann G, Wernsdorfer G, Wernsdorfer WH.

Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, University of Vienna, Austria.

Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area wit multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC50, and 1,414 nmol/L for the EC90. Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC50, but not at the EC90. The EC50, and EC90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for

treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.

Am J Trop Med Hyg 2002 Jul;67(1):32-8 

Influence of host and larval habitat distribution on the abundance of African malaria vectors in western Kenya.

Minakawa N, Seda P, Yan G.

Department of Biological Sciences, State University of New York, Buffalo 14260, USA.

The abundance of anopheline mosquitoes varies substantially among houses within

the same villages. Anopheles gambiae sensu stricto is highly anthropophilic, and

Anopheles arabiensis is zoophilic; thus, it is often hypothesized that the

abundance of An. gambiae and An. arabiensis in a house is associated with the

distribution of livestock and humans. In this paper we examined the influence of

livestock and human host availability on the distribution and abundance of

malaria vectors in the basin region of Lake Victoria in western Kenya. Larvae

and adults of An. gambiae, An. arabiensis and Anopheles funestus were collected

in the beginning and the end of the rainy season in 1999. Anopheles gambiae was

the predominant species in both larval and adult samples. Multiple regression

analyses found that the ratio of distance between houses and larval habitats to

distance between cowsheds and larval habitats had a significant and negative

association with the relative abundance of An. gambiae larvae for both sampling

periods. The ratio of human density to cow density was positively correlated

with the relative abundance of An. gambiae larvae in the late rainy period. For

the adult samples, distance from a house to its nearest larval habitats was the

only variable that showed a significant correlation with the An. gambiae density

in houses in both sample periods. More than 90% of anopheline adults were found

in the houses within 300 meters from the nearest larval habitats. Anopheline

mosquito density was not correlated to the density of cows or humans, or the

distance to cowsheds from houses. These results suggest that livestock and human

host availability affect the relative abundance of An. gambiae larvae in aquatic

habitats, but the distribution of anopheline adults in houses is determined by

the distance from houses to larval habitats.

Am J Trop Med Hyg 2002 Jul;67(1):28-31 

Treatment of children with Plasmodium falciparum malaria with chloroquine

in Guinea-Bissau.

Kofoed PE, Lopez F, Johansson P, Sandstrom A, Hedegaard K, Aaby P, Rombo L.

Projecto de Saude de Bandim, Bissau, Guinea-Bissau. Email: [email protected]

Children with symptomatic malaria in Bissau, Guinea-Bissau were randomly assigned to treatment with a 25 mg/kg total dose of chloroquine as recommended by the National Malaria Program or with a higher total dose of 50 mg/kg. Sixty-seven and 62 children, respectively, completed the treatment and were then followed once a week for five weeks. Treatment with a dose of 50 mg/kg was significantly more effective than treatment with 25 mg/kg in preventing recrudescence. The cumulative relative risk (95% confidence interval) of havingparasitemia in the low-dose group during follow-up was 0.20 (0.08-0.52) on day 21, 0.38 (0.17-0.86) on day 28, and 0.48 (0.23-0.98) on day 35. Few adverse events were reported, although more children complained of vomiting and diarrhea on day 2 in the high-dose group compared with those in the low-dose group. However, this difference was not statistically significant. We conclude that a dose of 50 mg/kg of chloroquine could be recommended for treatment of Plasmodium falciparum malaria in Bissau. To minimize the risk of side effects, this higher dose should be given divided into two daily doses over a three-day period.

Am J Trop Med Hyg 2002 Jul;67(1):17-23 

The safety and efficacy of sulfadoxine-pyrimethamine, amodiaquine, and their combination in the treatment of uncomplicated Plasmodium falciparum malaria.

Schellenberg D, Kahigwa E, Drakeley C, Malende A, Wigayi J, Msokame C, Aponte JJ, Tanner M, Mshinda H, Menendez C, Alonso PL.

Unidad de Epidemiologia, Hospital Clinic, Barcelona, Spain.

The safety and efficacy of amodiaquine (AQ), sulfadoxine-pyrimethamine (SP), and coadministered AQ+SP was assessed in 351 Tanzanian children (age range, 6-59 months) with uncomplicated Plasmodium falciparum malaria. This open, randomized

study followed the 28-day World Health Organization (WHO) protocol and evaluated safety using clinical and laboratory parameters. Children receiving SP were more likely to vomit during follow-up (32% vs. 17%: P = 0.03), and SP alone resulted in prolonged fever clearance times. Although Day 7 and Day 14 clinical andparasitological cure rates were similar, by Day 28 45% of children treated with AQ demonstrated R1 resistance and 27.5% were clinical failures compared with 25% and 6.3%, respectively, for SP alone. Coadministered AQ+SP was safe, combined the greater clinical (96.2%) and parasitological (64.2%) efficacy of SP with the

more rapid symptom resolution of AQ, and reduced the incidence of gametocytemia during follow-up (AQ+SP 12.6% vs. SP 29.9%; P = 0.001). The level of R1 resistance to SP may herald a rapid decline in its efficacy as SP drug pressure increases. Coadministration of AQ+SP may delay this.

Indian J Med Res 2002 May;115:194-200 

Ruby-eye, a new autosomal mutant in the malaria mosquito, Anopheles stephensi Liston.

Madhyastha AD, Shetty NJ.

Centre for Applied Genetics, Bangalore University, Bangalore, India.

BACKGROUND & OBJECTIVES: Anopheles stephensi, an important vector of malaria continues to be distributed widely in the Indian subcontinent. This vector species has developed resistance for various insecticides. Therefore, it is desirable to develop alternate strategy, which does not involve resistance. In order to develop such strategy, it is mandatory that genetic studies of concerned vector species should be established. This paper describes the isolation and genetic studies of an eye colour mutant, ruby-eye (ru), and linkage studies involving another autosomal recessive mutant greyish brown larva (grb ru) in A. stephensi. METHODS: The stocks of mutants ruby-eye (ru), greyish brown (grb ru) and wild type mosquitoes were maintained in the laboratory. Crosses were made between the wild type and mutant to determine the mode of inheritance of ruby-eye. For linkage studies crosses were made between the

mutant ruby-eye and another autosomal recessive mutant greyish brown larva. The percentage cross over was calculated for the genes linkage relationship for ru and grb ru. RESULTS: Results of crosses between mutant and wild type show that the inheritance of ruby-eye in A. stephensi is monofactorial in nature. The ru allele is recessive to wild type and is autosomal. The linkage studies showed no linkage between grb and ru. INTERPRETATION & CONCLUSION: The mutant rustages with complete penetrance and high viability. This mutant can be used extensively to conduct basic and applied research.

Pediatrics 2002 Oct;110(4):e48 

Stunting may determine the severity of malaria-associated anemia in African children.

Verhoef H, West CE, Veenemans J, Beguin Y, Kok FJ.

Division of Human Nutrition and Epidemiology, Wageningen University, The Netherlands. .

OBJECTIVE: Evidence from previous studies that malnourished children are protected against malaria is controversial. In individuals repeatedly exposed to malaria, immunity may develop first against severe disease, then against pyrogens, and last, against parasites. If this is true, this would suggest that reduced immune function that may exist in stunted children exacerbates the severity of malarial signs and symptoms, rather than the occurrence of parasitemia. On the other hand, several studies have suggested that malnourished children are protected to some degree against malaria. Our aim was to evaluate whether observational data support the hypothesis that nutritional inadequacies that cause stunting modify the associations between malaria and hematologic indicators such as hemoglobin concentration and serum concentrations of C-reactive protein and soluble transferrin receptor (sTfR). We showed earlier

that increased serum concentrations of these receptors in asymptomatic malaria may be explained, at least in part, by increased erythropoiesis to compensate for malaria-induced hemolysis. 

METHODOLOGY: Community-based cluster survey  among Kenyan children aged 2 to 36 months asymptomatic for malaria or anemia  (n = 318). RESULTS: When adjusted for age and wasting, the malaria-associated  decrease in mean hemoglobin concentration was 8.5 g/L and 15.8 g/L in nonstunted and stunted children, respectively. The malaria-associated increase in geometric mean serum concentrations of sTfR was 1.1-fold and 1.8-fold in nonstunted and stunted children, respectively. The malaria-associated increase in geometric mean serum concentrations of C-reactive protein was 1.4-fold and 2.3-fold in nonstunted and stunted children, respectively. Thus, children with malaria and those who were stunted suffered from more severe anemia and had higher serum concentrations of C-reactive protein and sTfR than would be expected from the combined effect of the 2 working independently. 

CONCLUSIONS: Our results are consistent with the notion that the nutritional inadequacies causing stunting also impair host immunity, thus increasing the degree to which malaria is associated with decreased concentrations of hemoglobin, with increased inflammation, and with increased iron demand in developing erythroblasts. Increased intake of micronutrients may not only reduce stunting and nutritional anemia, but also reduce malaria-associated anemia.

Trop Med Int Health 2002 Oct;7(10):858-864 

Artemisinin or chloroquine for blood stage Plasmodium vivax malaria in Vietnam.

Phan GT, De Vries PJ, Tran BQ, Le HQ, Nguyen NV, Nguyen TV, Heisterkamp SH,

Kager PA.

Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, the Netherlands. Tropical Diseases Clinical Research Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam. Binh Thuan Provincial Malaria

Station, Phan Thiet, Vietnam. Mepu Health Post, Duc Linh District, Vietnam. Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, the Netherlands.

Chloroquine-resistant Plasmodium vivax has not yet occurred in Vietnam. The efficacy of artemisinin for P. vivax was not established. We conducted a double-blind randomized study involving 240 inpatients with P. vivax malaria who received artemisinin (40 mg/kg over 3 days) plus placebo chloroquine (Art) or chloroquine (25 mg/kg over 3 days) plus placebo artemisinin (Chl). Patients were followed up with weekly blood smears for 28 days. In each group 113 cases were analysed. All patients recovered rapidly. The median (range) parasite clearance time of regimen Art was 24 h (8-72) and of Chl 24 h (8-64; P = 0.3). Parasites reappeared in two cases in each group on day 14, in eight cases in each group (7%) on day 16 and in 25 (23%) and 18 (16%) cases, respectively, at the end of 4-week follow-up (P = 0.3). The population parasite clearance curve followed a mono-exponential decline. The parasite reduction ratio per 48 h reproduction cycle was 2.3 x 104 for both regimens. We conclude that artemisinin and chloroquine are equally effective in the treatment of P. vivax infections in Vietnam. Reappearance of parasites before day 16 (7%) suggests the emergence of chloroquine resistance. Three days of artemisinin monotherapy does not prevent recrudescence.

Trop Med Int Health 2002 Oct;7(10):851-857 

Forecasting malaria incidence from historical morbidity patterns in epidemic-prone areas of Ethiopia: a simple seasonal adjustment method performs best.

Abeku TA, De Vlas SJ, Borsboom G, Teklehaimanot A, Kebede A, Olana D, Van Oortmarssen GJ, Habbema JD. 

Department of Public Health, Erasmus MC, University Medical Center Rotterdam, The Netherlands. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK. Disease Prevention and Control Department, Ministry of Health, Addis Ababa, Ethiopia. Center for International Development, Harvard University, Cambridge, USA. Amhara Regional State Health Bureau, Bahir Dar, Ethiopia. Oromiya Regional State Health Bureau, Addis Ababa, Ethiopia.

The aim of this study was to assess the accuracy of different methods of forecasting malaria incidence from historical morbidity patterns in areas with unstable transmission. We tested five methods using incidence data reported from health facilities in 20 areas in central and north-western Ethiopia. The accuracy of each method was determined by calculating errors resulting from the difference between observed incidence and corresponding forecasts obtained for prediction intervals of up to 12 months. Simple seasonal adjustment methods outperformed a statistically more advanced autoregressive integrated moving average method. In particular, a seasonal adjustment method that uses mean deviation of the last three observations from expected seasonal values  consistently produced the best forecasts. Using 3 years’ observation to generate forecasts with this method gave lower errors than shorter or longer periods. Incidence during the rainy months of June-August was the most predictable with this method. Forecasts for the normally dry months, particularly December-February, were less accurate. The study shows the limitations of

forecasting incidence from historical morbidity patterns alone, and indicates the need for improved epidemic early warning by incorporating external predictors such as meteorological factors.

Trop Med Int Health 2002 Oct;7(10):823-830 

Risk factors for presentation to hospital with severe anaemia in Tanzanian children: a case-control study.

Kahigwa E, Schellenberg D, Sanz S, Aponte JJ, Wigayi J, Mshinda H, Alonso P, Menendez C.

Ifakara Health Research and Development Centre, Ifakara, Tanzania. St Francis Designated District Hospital, Ifakara, Tanzania. Unidad de Epidemiologia y Bioestadistica, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain.

In malaria endemic areas anaemia is a usually silent condition that nevertheless places a considerable burden on health services. Cases of severe anaemia often require hospitalization and blood transfusions. The objective of this study was to assess risk factors for admission with anaemia to facilitate the design of anaemia control programmes. We conducted a prospective case-control study of children aged 2-59 months admitted to a district hospital in southern Tanzania. There were 216 cases of severe anaemia [packed cell volume (PCV) < 25%] and 234 age-matched controls (PCV >/= 25%). Most cases [55.6% (n = 120)] were < 1 year of age. Anaemia was significantly associated with the educational level of parents, type of accommodation, health-seeking behaviour, the child’s nutritional status and recent and current medical history. Of these, the single most important factor was Plasmodium falciparum parasitaemia [OR 4.3, 95% confidence interval (CI) 2.9-6.5, P < 0.001]. Multivariate analysis showed that increased recent health expenditure [OR 2.2 (95% CI 1.3-3.9), P = 0.005], malnutrition [OR 2.4 (95%CI 1.3-4.3), P < 0.001], living > 10 km from the hospital [OR 3.0 (95% CI 1.9-4.9), P < 0.001], a history of previous blood transfusion [OR 3.8 (95% CI 1.7-9.1), P < 0.001] and P. falciparum parasitaemia [OR 9.5 (95% CI 4.3-21.3), P < 0.001] were independently related to risk of being admitted with anaemia. These findings are considered in terms of the pathophysiological pathway leading to anaemia. The concentration of anaemia in infants and problems of access to health services and adequate case management underline the need for targeted preventive strategies for anaemia control.

J Infect Dis 2002 Oct 15;186(8):1194-7 

Dichotomous Effects of Plasmodium falciparum Antigens on Expression of Human Immunodeficiency Virus (HIV) Coreceptors and on Infectability of CD4 Cells by HIV.

Moriuchi M, Moriuchi H, Mon HM, Kanbara H.

Division of Medical Virology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan. Email: [email protected]

Many microbial coinfections accelerate the progression of human immunodeficiency virus (HIV) disease. Coinfections of Plasmodium falciparum malaria and HIV-1 are common; however, past studies of the effects of P. falciparum malaria on HIV-1 infection have shown little effect. The present study found that P. falciparum antigens (PF-Ags) variably regulate the expression of HIV-1 coreceptors and modulate the infectability of CD4 cells by HIV-1. Shortly after PF-Ag stimulation, CCR5 expression was down-regulated, but CXCR4 expression was modestly up-regulated. Subsequently, CCR5 expression on CD4 cells was induced. Infectability of PF-Ag-stimulated peripheral blood mononuclear cells (PBMC) by R5 HIV-1 was decreased, regardless of the duration of PF-Ag stimulation or CCR5

expression levels. In contrast, X4 HIV-1 replication was enhanced briefly in PBMC stimulated with PF-Ags but was inhibited with longer stimulation. Decreased HIV-1 infectability resulted, in part, from endogenous production of interferon-gamma. These results may explain why malaria previously did not appear to accelerate HIV-1 disease progression.

Lancet 2002 Sep 21;360(9337):908 

Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial.

Verhoef H, West C, Nzyuko S, de Vogel S, van der Valk R, Wanga M, Kuijsten A, Veenemans J, Kok F.

Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, Netherlands

Background Iron supplementation is recommended for children at high risk of anaemia, but its benefits may not outweigh the associated risk of malaria in areas of seasonal transmission. We investigated the effect on haemoglobinconcentrations of intermittent administration of iron supplements and sulfadoxine-pyrimethamine in symptom-free children under intense health

surveillance. Methods In a trial of two by two factorial design, 328 anaemic Kenyan children were randomly assigned either iron or placebo and sulfadoxine-pyrimethamine or placebo (82 to each group). Primary outcomes were haemological indicators of iron status and inflammation at the end of the follow-up, and occurrence of malaria attacks. Morbidity surveillance consisted of medical examinations every 4 weeks, continuous passive case detection, and visits twice a week to community health-workers. Analyses were by intention to treat. Findings After 12 weeks, the groups assigned iron plus sulfadoxine-pyrimethamine, iron alone, or sulfadoxine-pyrimethamine alone had higher haemoglobin concentrations than the group assigned placebo (treatment effect adjusted for prognostic factors at baseline: 11.1 g/L [95% CI 7.5 to 14.7]; 10.7 g/L [7.1 to 14.3]; and 3.1 g/L [-0.5 to 6.7]). Administration of iron plus sulfadoxine-pyrimethamine also lowered the proportion with anaemia from 100% at baseline to 36% at 12 weeks, and of iron deficiency from 66% at baseline to 8% at 12 weeks. Survival analysis showed no evidence of substantially increased risk of malaria after iron supplementation.Interpretation Iron supplementation gives substantial health benefits, which may outweigh possible inherent risks caused by malaria. A larger study than ours is needed to assess benefits and risks of intermittent administration of sulfadoxine-pyrimethamine in reducing the incidence of malaria attacks in areas of seasonal malaria transmission.

Mol Microbiol 2002 Sep;45(6):1473-84 

A malaria scavenger receptor-like protein essential for parasite development.

Claudianos C, Dessens JT, Trueman HE, Arai M, Mendoza J, Butcher GA, Crompton T, Sinden RE.

Malaria parasites suffer severe losses in the mosquito as they cross the midgut, haemolymph and salivary gland tissues, in part caused by immune responses of the insect. The parasite compensates for these losses by multiplying during the oocyst stage to form the infectious sporozoites. Upon human infection, malaria parasites are again attenuated by sustained immune attack. Here, we report a single copy gene that is highly conserved amongst Plasmodium species that encodes a secreted protein named PxSR. The predicted protein is composed of a unique combination of metazoan protein domains that have been previously associated with immune recognition/activation and lipid/protein adhesion interactions at the cell surface, namely: (i) scavenger receptor cysteine rich (SRCR); (ii) pentraxin (PTX); (iii) polycystine-1, lipoxygenase, alpha toxin (LH2/PLAT); (iv) Limulus clotting factor C, Coch-5b2 and Lgl1 (LCCL). In our assessment the PxSR molecule is completely novel in biology and is only found in Apicomplexa parasites. We show that PxSR is expressed in sporozoites of both human and rodent malaria species. Disruption of the PbSR gene in the rodent malaria parasite P. berghei results in parasites that form normal numbers of oocysts, but fail to produce any sporozoites. We suggest that, in addition to a role in sporogonic development, PxSR may have a multiplicity of functions.

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