Chapter 46 : Molecular Approaches for Diagnosis of Malaria and Characterization of Genetic Markers of Drug Resistance

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Molecular Approaches for Diagnosis of Malaria and Characterization of Genetic Markers of Drug Resistance, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816834/9781555814977_Chap46-1.gif /docserver/preview/fulltext/10.1128/9781555816834/9781555814977_Chap46-2.gif


The diagnosis of imported malaria is complicated by the lack of experience with traditional microscopic detection methods and expertise with clinical malaria among laboratory professionals and clinicians, respectively. The development of powerful molecular techniques has led to extensive genetic and proteomic characterization of the malaria parasite. This chapter reviews the application of these molecular approaches for the improvement of malaria diagnosis and detection of genetic markers of antimalarial resistance. Real-time PCR assays for malaria diagnosis offer advantages in several of these respects. SNP analysis by mass spectrometry has been applied to the characterization and surveillance of various pathogens, including malaria parasites. Molecular methods not only are useful for detecting known resistance markers in parasite isolates but also may identify novel resistance markers. Another approach is based on the observation that drug resistance loci often have little sequence variation in surrounding genomic regions; these regions may not have yet been diversified by genetic drift if the resistance locus was recently acquired, or they may be essential for the resistance phenotype. The power of molecular technologies has led to improvements in the accuracy and rapidity of malaria diagnostic tests and detection of antimalarial resistance markers. Importantly, high-quality artemisinin combination treatments (ACTs) must be made accessible and affordable in regions where malaria is endemic, which will reduce demand for ineffective antimalarials and counterfeit drugs and preserve ACT efficacy.

Citation: Erdman L, Hawkes M, Kain K. 2011. Molecular Approaches for Diagnosis of Malaria and Characterization of Genetic Markers of Drug Resistance, p 691-711. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch46

Key Concept Ranking

TaqMan Real-Time PCR Assay
Restriction Fragment Length Polymorphism
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Abdel-Muhsin, A. M.,, L. C. Ranford-Cartwright,, A. R. Medani,, S. Ahmed,, S. Suleiman,, B. Khan,, P. Hunt,, D. Walliker, and, H. A. Babiker. 2002. Detection of mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) gene by dot-blot hybridization. Am. J. Trop. Med. Hyg. 67:2427.
2. Adagu, I. S.,, and D. C. Warhurst. 1999. Allele-specific, nested, one tube PCR: application to Pfmdr1 polymorphisms in Plasmodium falciparum. Parasitology 119(Pt. 1):16.
3. Afonso, A.,, P. Hunt,, S. Cheesman,, A. C. Alves,, C. V. Cunha,, V. do Rosario, and, P. Cravo. 2006. Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic reticulum Ca2+ ATPase), tctp, mdr1, and cg10. Antimicrob. Agents Chemother. 50:480489.
4. Alifrangis, M.,, S. Enosse,, R. Pearce,, C. Drakeley,, C. Roper,, I. F. Khalil,, W. M. Nkya,, A. M. Ronn,, T. G. Theander, and, I. C. Bygbjerg. 2005. A simple, high-throughput method to detect Plasmodium falciparum single nucleotide polymorphisms in the dihydrofolate reductase, dihydropteroate synthase, and P. falciparum chloroquine resistance transporter genes using polymerase chain reaction- and enzyme-linked immunosorbent assay-based technology. Am. J. Trop. Med. Hyg. 72:155162.
5. Alker, A. P.,, V. Mwapasa, and, S. R. Meshnick. 2004. Rapid real-time PCR genotyping of mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum. Antimicrob. Agents Chemother. 48:29242929.
6. Alker, A. P.,, P. Lim,, R. Sem,, N. K. Shah,, P. Yi,, D. M. Bouth,, R. Tsuyuoka,, J. D. Maguire,, T. Fandeur,, F. Ariey,, C. Wongsrichanalai, and, S. R. Meshnick. 2007. Pfmdr1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border. Am. J. Trop. Med. Hyg. 76:641647.
7. Aubouy, A.,, J. Mayombo,, A. Keundjian,, M. Bakary,, J. Le Bras, and, P. Deloron. 2004. Short report: lack of prediction of amodiaquine efficacy in treating Plasmodium falciparum malaria by in vitro tests. Am. J. Trop. Med. Hyg. 71:294296.
8. Baker, J.,, J. McCarthy,, M. Gatton,, D. E. Kyle,, V. Belizario,, J. Luchavez,, D. Bell, and, Q. Cheng. 2005. Genetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic tests. J. Infect. Dis. 192:870877.
9. Barnes, D. A.,, S. J. Foote,, D. Galatis,, D. J. Kemp, and, A. F. Cowman. 1992. Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum. EMBO J. 11:30673075.
10. Basco, L. K.,, and P. Ringwald. 1998. Molecular epidemiology of malaria in Yaounde, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr 1) gene of Plasmodium falciparum. Am. J. Trop. Med. Hyg. 59:577581.
11. Basco, L. K.,, R. Tahar,, A. Keundjian, and, P. Ringwald. 2000. Sequence variations in the genes encoding dihydropteroate synthase and dihydrofolate reductase and clinical response to sulfadoxine-pyrimethamine in patients with acute uncomplicated falciparum malaria. J. Infect. Dis. 182:624628.
12. Basco, L. K.,, M. Ndounga,, V. F. Ngane, and, G. Soula. 2002. Molecular epidemiology of malaria in Cameroon. XIV. Plasmodium falciparum chloroquine resistance transporter (PFCRT) gene sequences of isolates before and after chloroquine treatment. Am. J. Trop. Med. Hyg. 67:392395.
13. Basco, L. K.,, and P. Ringwald. 2002. Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives. Am. J. Trop. Med. Hyg. 66:667671.
14. Basco, L. K. 2003. Molecular epidemiology of malaria in Cameroon. XVI. Longitudinal surveillance of in vitro pyrimethamine resistance in Plasmodium falciparum. Am. J. Trop. Med. Hyg. 69:174178.
15. Bell, D.,, C. Wongsrichanalai, and, J. W. Barnwell. 2006. Ensuring quality and access for malaria diagnosis: how can it be achieved? Nat. Rev. Microbiol. 4:S7S20.
16. Berry, A.,, A. Vessiere,, R. Fabre,, F. Benoit-Vical,, B. Marchou,, P. Massip, and, J. F. Magnaval. 2004. Pfcrt K76T mutation and its associations in imported Plasmodium falciparum malaria cases. Infect. Genet. Evol. 4:361364.
17. Bialasiewicz, S.,, D. M. Whiley,, M. D. Nissen, and, T. P. Sloots. 2007. Impact of competitive inhibition and sequence variation upon the sensitivity of malaria PCR. J. Clin. Microbiol. 45:16211623.
18. Calderaro, A.,, G. Piccolo,, C. Zuelli,, L. Galati,, L. Ricci,, F. Perandin,, M. L. Dell’Anna,, M. C. Arcangeletti,, M. C. Medici,, N. Manca,, G. Dettori, and, C. Chezzi. 2004. Evaluation of a new plate hybridization assay for the laboratory diagnosis of imported malaria in Italy. New Microbiol. 27:163171.
19. Calderaro, A.,, G. Piccolo,, F. Perandin,, C. Gorrini,, S. Peruzzi,, C. Zuelli,, L. Ricci,, N. Manca,, G. Dettori,, C. Chezzi, and, G. Snounou. 2007. Genetic polymorphisms influence Plasmodium ovale PCR detection accuracy. J. Clin. Microbiol. 45:16241627.
20. Carnevale, E. P.,, D. Kouri,, J. T. DaRe,, D. T. McNamara,, I. Mueller, and, P. A. Zimmerman. 2007. A multiplex ligase detection reaction-fluorescent microsphere assay for simultaneous detection of single nucleotide polymorphisms associated with Plasmodium falciparum drug resistance. J. Clin. Microbiol. 45:752761.
21. Chiodini, P. L.,, C. P. Conlon,, D. B. Hutchinson,, J. A. Farquhar,, A. P. Hall,, T. E. Peto,, H. Birley, and, D. A. Warrell. 1995. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J. Antimicrob. Chemother. 36:10731078.
22. Chiodini, P. L.,, K. Bowers,, P. Jorgensen,, J. W. Barnwell,, K. K. Grady,, J. Luchavez,, A. H. Moody,, A. Cenizal, and, D. Bell. 2007. The heat stability of Plasmodium lactate dehydrogenase-based and histidine-rich protein 2-based malaria rapid diagnostic tests. Trans. R. Soc. Trop. Med. Hyg. 101:331337.
23. Coleman, R. E.,, J. Sattabongkot,, S. Promstaporm,, N. Maneechai,, B. Tippayachai,, A. Kengluecha,, N. Rachapaew,, G. Zollner,, R. S. Miller,, J. A. Vaughan,, K. Thimasarn, and, B. Khuntirat. 2006. Comparison of PCR and microscopy for the detection of asymptomatic malaria in a Plasmodium falciparum/vivax endemic area in Thailand. Malar. J. 5:121.
24. Cortese, J. F.,, and C. V. Plowe. 1998. Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutations expressed in yeast. Mol. Biochem. Parasitol. 94:205214.
25. Cowman, A. F.,, D. Galatis, and, J. K. Thompson. 1994. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc. Natl. Acad. Sci. USA 91:11431147.
26. Cowman, A. F. 2001. Functional analysis of drug resistance in Plasmodium falciparum in the post-genomic era. Int. J. Parasitol. 31:871878.
27. Crameri, A.,, J. Marfurt,, K. Mugittu,, N. Maire,, A. Regos,, J. Y. Coppee,, O. Sismeiro,, R. Burki,, E. Huber,, D. Laubscher,, O. Puijalon,, B. Genton,, I. Felger, and, H. P. Beck. 2007. Rapid microarray-based method for monitoring of all currently known single-nucleotide polymorphisms associated with parasite resistance to antimalaria drugs. J. Clin. Microbiol. 45:36853691.
28. Cruciani, M.,, S. Nardi,, M. Malena,, O. Bosco,, G. Serpelloni, and, C. Mengoli. 2004. Systematic review of the accuracy of the ParaSight-F test in the diagnosis of Plasmodium falciparum malaria. Med. Sci. Monit. 10:MT81MT88.
29. Decuypere, S.,, E. Elinck,, C. Van Overmeir,, A. O. Talisuna,, U. D’Alessandro, and, J. C. Dujardin. 2003. Pathogen genotyping in polyclonal infections: application of a fluorogenic polymerase-chain-reaction assay in malaria. J. Infect. Dis. 188:12451249.
30. de Langen, A. J.,, J. van Dillen,, P. de Witte,, S. Mucheto,, N. Nagelkerke, and, P. Kager. 2006. Automated detection of malaria pigment: feasibility for malaria diagnosing in an area with seasonal malaria in northern Namibia. Trop. Med. Int. Health 11:809816.
31. Demirev, P. A.,, A. B. Feldman,, D. Kongkasuriyachai,, P. Scholl,, D. Sullivan, Jr., and, N. Kumar. 2002. Detection of malaria parasites in blood by laser desorption mass spectrometry. Anal. Chem. 74:32623266.
32. de Monbrison, F.,, C. Angei,, A. Staal,, K. Kaiser, and, S. Picot. 2003. Simultaneous identification of the four human Plasmodium species and quantification of Plasmodium DNA load in human blood by real-time polymerase chain reaction. Trans. R. Soc. Trop. Med. Hyg. 97:387390.
33. Djimde, A.,, O. K. Doumbo,, J. F. Cortese,, K. Kayentao,, S. Doumbo,, Y. Diourte,, A. Dicko,, X. Z. Su,, T. Nomura,, D. A. Fidock,, T. E. Wellems,, C. V. Plowe, and, D. Coulibaly. 2001. A molecular marker for chloroquine-resistant falciparum malaria. N. Engl. J. Med. 344:257263.
34. Djimde, A.,, O. K. Doumbo,, R. W. Steketee, and, C. V. Plowe. 2001. Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria. Lancet 358:890891.
35. Djimde, A. A.,, A. Dolo,, A. Ouattara,, S. Diakite,, C. V. Plowe, and, O. K. Doumbo. 2004. Molecular diagnosis of resistance to antimalarial drugs during epidemics and in war zones. J. Infect. Dis. 190:853855.
36. Dromigny, J. A.,, R. Jambou,, C. S. Scott, and, J. D. Perrier-Gros-Claude. 2005. Performance evaluation of automated depolarization analysis for detecting clinically unsuspected malaria in endemic countries. Trans. R. Soc. Trop. Med. Hyg. 99:430439.
37. Duraisingh, M. T.,, J. Curtis, and, D. C. Warhurst. 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. Exp. Parasitol. 89:18.
38. Duraisingh, M. T.,, C. Roper,, D. Walliker, and, D. C. Warhurst. 2000. Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum. Mol. Microbiol. 36:955961.
39. Durand, R.,, J. Eslahpazire,, S. Jafari,, J. F. Delabre,, A. Marmorat-Khuong,, J. P. di Piazza, and, J. Le Bras. 2000. Use of molecular beacons to detect an antifolate resistance-associated mutation in Plasmodium falciparum. Antimicrob. Agents Chemother. 44:34613464.
40. Durand, R.,, V. Huart,, S. Jafari, and, J. Le Bras. 2002. Rapid detection of a molecular marker for chloroquine-resistant falciparum malaria. Antimicrob. Agents Chemother. 46:26842686.
41. East African Network for Monitoring Antimalarial Treatment. 2001. Monitoring antimalarial drug resistance within National Malaria Control Programmes: the EANMAT experience. Trop. Med. Int. Health 6:891898.
42. Eckstein-Ludwig, U.,, R. J. Webb,, I. D. Van Goethem,, J. M. East,, A. G. Lee,, M. Kimura,, P. M. O’Neill,, P. G. Bray,, S. A. Ward, and, S. Krishna. 2003. Artemisinins target the SERCA of Plasmodium falciparum. Nature 424:957961.
43. Fabre, R.,, A. Berry,, B. Morassin, and, J. F. Magnaval. 2004. Comparative assessment of conventional PCR with multiplex real-time PCR using SYBR Green I detection for the molecular diagnosis of imported malaria. Parasitology 128:1521.
44. Farcas, G. A.,, K. J. Zhong,, T. Mazzulli, and, K. C. Kain. 2004. Evaluation of the RealArt Malaria LC real-time PCR assay for malaria diagnosis. J. Clin. Microbiol. 42:636638.
45. Farcas, G. A.,, R. Soeller,, K. Zhong,, A. Zahirieh, and, K. C. Kain. 2006. Real-time polymerase chain reaction assay for the rapid detection and characterization of chloroquine-resistant Plasmodium falciparum malaria in returned travelers. Clin. Infect. Dis. 42:622627.
46. Farnert, A.,, J. Lindberg,, P. Gil,, G. Swedberg,, Y. Berqvist,, M. M. Thapar,, N. Lindegardh,, S. Berezcky, and, A. Bjorkman. 2003. Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports. BMJ 326:628629.
47. Ferrer-Rodriguez, I.,, J. Perez-Rosado,, G. W. Gervais,, W. Peters,, B. L. Robinson, and, A. E. Serrano. 2004. Plasmodium yoelii: identification and partial characterization of an MDR1 gene in an artemisinin-resistant line. J. Parasitol. 90:152160.
48. Fidock, D. A.,, T. Nomura,, A. K. Talley,, R. A. Cooper,, S. M. Dzekunov,, M. T. Ferdig,, L. M. Ursos,, A. B. Sidhu,, B. Naude,, K. W. Deitsch,, X. Z. Su,, J. C. Wootton,, P. D. Roepe, and, T. E. Wellems. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6:861871.
49. Fivelman, Q. L.,, G. A. Butcher,, I. S. Adagu,, D. C. Warhurst, and, G. Pasvol. 2002. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malar. J. 1:1.
50. Fivelman, Q. L.,, I. S. Adagu, and, D. C. Warhurst. 2004. Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum. Antimicrob. Agents Chemother. 48:40974102.
51. Flüeck, T. P.,, T. Jelinek,, A. H. Kilian,, I. S. Adagu,, G. Kabagambe,, F. Sonnenburg, and, D. C. Warhurst. 2000. Correlation of in vivo-resistance to chloroquine and allelic polymorphisms in Plasmodium falciparum isolates from Uganda. Trop. Med. Int. Health 5:174178.
52. Foote, S. J.,, D. Galatis, and, A. F. Cowman. 1990. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc. Natl. Acad. Sci. USA 87:30143017.
53. Fortina, P.,, S. Surrey, and, L. J. Kricka. 2002. Molecular diagnostics: hurdles for clinical implementation. Trends Mol. Med. 8:264266.
54. Francis, D.,, S. L. Nsobya,, A. Talisuna,, A. Yeka,, M. R. Kamya,, R. Machekano,, C. Dokomajilar,, P. J. Rosenthal, and, G. Dorsey. 2006. Geographic differences in antimalarial drug efficacy in Uganda are explained by differences in endemicity and not by known molecular markers of drug resistance. J. Infect. Dis. 193:978986.
55. Fry, M.,, and M. Pudney. 1992. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem. Pharmacol. 43:15451553.
56. Funk, M.,, P. Schlagenhauf,, A. Tschopp, and, R. Steffen. 1999. MalaQuick versus ParaSight F as a diagnostic aid in travellers’ malaria. Trans. R. Soc. Trop. Med. Hyg. 93:268272.
57. Gilbert, G. L. 2002. Molecular diagnostics in infectious diseases and public health microbiology: cottage industry to postgenomics. Trends. Mol. Med. 8:280287.
58. Grobusch, M. P.,, T. Hanscheid,, K. Gobels,, H. Slevogt,, T. Zoller,, G. Rogler, and, D. Teichmann. 2003. Comparison of three antigen detection tests for diagnosis and follow-up of falciparum malaria in travellers returning to Berlin, Germany. Parasitol. Res. 89:354357.
59. Grobusch, M. P.,, T. Hanscheid,, B. Kramer,, J. Neukammer,, J. May,, J. Seybold,, J. F. Kun, and, N. Suttorp. 2003. Sensitivity of hemozoin detection by automated flow cytometry in non- and semi-immune malaria patients. Cytometry B 55:4651.
60. Hamel, M. J.,, A. Poe,, P. Bloland,, A. McCollum,, Z. Zhou,, Y. P. Shi,, P. Ouma,, K. Otieno,, J. Vulule,, A. Escalante,, V. Udhayakumar, and, L. Slutsker. 2008. Dihydrofolate reductase I164L mutations in Plasmodium falciparum isolates: clinical outcome of 14 Kenyan adults infected with parasites harbouring the I164L mutation. Trans. R. Soc. Trop. Med. Hyg. 102:338345.
61. Han, E. T.,, R. Watanabe,, J. Sattabongkot,, B. Khuntirat,, J. Sirichaisinthop,, H. Iriko,, L. Jin,, S. Takeo, and, T. Tsuboi. 2007. Detection of four Plasmodium species by genus- and species-specific loop-mediated isothermal amplification for clinical diagnosis. J. Clin. Microbiol. 45:25212528.
62. Hanscheid, T.,, B. G. Pinto,, I. Pereira,, J. M. Cristino, and, E. Valadas. 1999. Avoiding misdiagnosis of malaria: a novel automated method allows specific diagnosis, even in the absence of clinical suspicion. Emerg. Infect. Dis. 5:836838.
63. Hanscheid, T.,, E. Valadas, and, M. P. Grobusch. 2000. Automated malaria diagnosis using pigment detection. Parasitol. Today 16:549551.
64. Hastings, I. M. 2007. Molecular markers as indicators of antimalarial drug failure rates. Trop. Med. Int. Health 12:12981301.
65. Hastings, I. M.,, E. L. Korenromp, and, P. B. Bloland. 2007. The anatomy of a malaria disaster: drug policy choice and mortality in African children. Lancet Infect. Dis. 7:739748.
66. Hastings, M. D.,, S. J. Bates,, E. A. Blackstone,, S. M. Monks,, T. K. Mutabingwa, and, C. H. Sibley. 2002. Highly pyrimethamine-resistant alleles of dihydrofolate reductase in isolates of Plasmodium falciparum from Tanzania. Trans. R. Soc. Trop. Med. Hyg. 96:674676.
67. Hoffmann, J. J.,, and J. M. Pennings. 1999. Pseudoreticulocytosis as a result of malaria parasites. Clin. Lab. Haematol. 21:257260.
68. Holland, C. A.,, and F. L. Kiechle. 2005. Point-of-care molecular diagnostic systems—past, present and future. Curr. Opin. Microbiol. 8:504509.
69. Humar, A.,, M. A. Harrington, and, K. C. Kain. 1997. Evaluation of a non-isotopic polymerase chain reaction-based assay to detect and predict treatment failure of Plasmodium vivax malaria in travellers. Trans. R. Soc. Trop. Med. Hyg. 91:406409.
70. Hunt, P.,, A. Afonso,, A. Creasey,, R. Culleton,, A. B. Sidhu,, J. Logan,, S. G. Valderramos,, I. McNae,, S. Cheesman,, V. do Rosario,, R. Carter,, D. A. Fidock, and, P. Cravo. 2007. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Mol. Microbiol. 65:2740.
71. Hyde, J. E. 2008. Antifolate resistance in Africa and the 164-dollar question. Trans. R. Soc. Trop. Med. Hyg. 102:301303.
72. Ittarat, W.,, A. L. Pickard,, P. Rattanasinganchan,, P. Wilairatana,, S. Looareesuwan,, K. Emery,, J. Low,, R. Udomsangpetch, and, S. R. Meshnick. 2003. Recrudescence in artesunate-treated patients with falciparum malaria is dependent on parasite burden not on parasite factors. Am. J. Trop. Med. Hyg. 68:147152.
73. Jambou, R.,, E. Legrand,, M. Niang,, N. Khim,, P. Lim,, B. Volney,, M. T. Ekala,, C. Bouchier,, P. Esterre,, T. Fandeur, and, O. Mercereau-Puijalon. 2005. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 366:19601963.
74. Jamjoom, G. A. 1983. Dark-field microscopy for detection of malaria in unstained blood films. J. Clin. Microbiol. 17:717721.
75. Jamjoom, G. A. 1991. Improvement in dark-field microscopy for the rapid detection of malaria parasites and its adaptation to field conditions. Trans. R. Soc. Trop. Med. Hyg. 85:3839.
76. Jarra, W.,, and G. Snounou. 1998. Only viable parasites are detected by PCR following clearance of rodent malarial infections by drug treatment or immune responses. Infect. Immun. 66:37833787.
77. Jeffares, D. C.,, A. Pain,, A. Berry,, A. V. Cox,, J. Stalker,, C. E. Ingle,, A. Thomas,, M. A. Quail,, K. Siebenthall,, A. C. Uhlemann,, S. Kyes,, S. Krishna,, C. Newbold,, E. T. Dermitzakis, and, M. Berriman. 2007. Genome variation and evolution of the malaria parasite Plasmodium falciparum. Nat. Genet. 39:120125.
78. Jelinek, T.,, L. Amsler,, M. P. Grobusch, and, H. D. Nothdurft. 1999. Self-use of rapid tests for malaria diagnosis by tourists. Lancet 354:1609.
79. Jelinek, T.,, M. P. Grobusch, and, H. D. Nothdurft. 2000. Use of dipstick tests for the rapid diagnosis of malaria in nonimmune travelers. J. Travel Med. 7:175179.
80. Jelinek, T.,, G. Peyerl-Hoffmann,, N. Muhlberger,, O. Wichmann,, M. Wilhelm,, N. Schmider,, M. P. Grobusch,, F. von Sonnenburg,, J. Gascon,, H. Laferl,, C. Hatz,, M. Alifrangis,, G. Burchard,, P. McWhinney,, M. Schulze,, H. Kollaritsch,, S. da Cunha,, J. Beran,, P. Kern,, I. Gjorup, and, J. Cuadros. 2002. Molecular surveillance of drug resistance through imported isolates of Plasmodium falciparum in Europe. Malar. J. 1:11.
81. Jelinek, T. 2004. Malaria self-testing by travellers: opportunities and limitations. Travel Med. Infect. Dis. 2:143148.
82. John, C. C.,, M. M. McHugh,, A. M. Moormann,, P. O. Sumba, and, A. V. Ofulla. 2005. Low prevalence of Plasmodium falciparum infection among asymptomatic individuals in a highland area of Kenya. Trans. R. Soc. Trop. Med. Hyg. 99:780786.
83. Johnson, D. J.,, D. A. Fidock,, M. Mungthin,, V. Laksh-manan,, A. B. Sidhu,, P. G. Bray, and, S. A. Ward. 2004. Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol. Cell 15:867877.
84. Jorgensen, P.,, L. Chanthap,, A. Rebueno,, R. Tsuyuoka, and, D. Bell. 2006. Malaria rapid diagnostic tests in tropical climates: the need for a cool chain. Am. J. Trop. Med. Hyg. 74:750754.
85. Kain, K. C.,, D. E. Kyle,, C. Wongsrichanalai,, A. E. Brown,, H. K. Webster,, S. Vanijanonta, and, S. Looareesuwan. 1994. Qualitative and semiquantitative polymerase chain reaction to predict Plasmodium falciparum treatment failure. J. Infect. Dis. 170:16261630.
86. Kain, K. C.,, M. A. Harrington,, S. Tennyson, and, J. S. Keystone. 1998. Imported malaria: prospective analysis of problems in diagnosis and management. Clin. Infect. Dis. 27:142149.
87. Kain, K. C.,, D. W. MacPherson,, T. Kelton,, J. S. Keystone,, J. Mendelson, and, J. D. MacLean. 2001. Malaria deaths in visitors to Canada and in Canadian travellers: a case series. Can. Med. Assoc. J. 164:654659.
88. Karl, S.,, M. David,, L. Moore,, B. T. Grimberg,, P. Michon,, I. Mueller,, M. Zborowski, and, P. A. Zimmerman. 2008. Enhanced detection of gametocytes by magnetic deposition microscopy predicts higher potential for Plasmodium falciparum transmission. Malar. J. 7:66.
89. Kean, B. H. 1979. Chloroquine-resistant falciparum malaria from Africa. JAMA 241:395.
90. Korenromp, E. L.,, B. G. Williams,, E. Gouws,, C. Dye, and, R. W. Snow. 2003. Measurement of trends in childhood malaria mortality in Africa: an assessment of progress toward targets based on verbal autopsy. Lancet Infect. Dis. 3:349358.
91. Korsinczky, M.,, N. Chen,, B. Kotecka,, A. Saul,, K. Rieckmann, and, Q. Cheng. 2000. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drugbinding site. Antimicrob. Agents Chemother. 44:21002108.
92. Krudsood, S.,, M. Imwong,, P. Wilairatana,, S. Pukrittayakamee,, A. Nonprasert,, G. Snounou,, N. J. White, and, S. Looareesuwan. 2005. Artesunate-dapsone-proguanil treatment of falciparum malaria: genotypic determinants of therapeutic response. Trans. R. Soc. Trop. Med. Hyg. 99:142149.
93. Kublin, J. G.,, F. K. Dzinjalamala,, D. D. Kamwendo,, E. M. Malkin,, J. F. Cortese,, L. M. Martino,, R. A. Mukadam,, S. J. Rogerson,, A. G. Lescano,, M. E. Molyneux,, P. A. Winstanley,, P. Chimpeni,, T. E. Taylor, and, C. V. Plowe. 2002. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J. Infect. Dis. 185:380388.
94. Kublin, J. G.,, J. F. Cortese,, E. M. Njunju,, R. A. Mukadam,, J. J. Wirima,, P. N. Kazembe,, A. A. Djimde,, B. Kouriba,, T. E. Taylor, and, C. V. Plowe. 2003. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J. Infect. Dis. 187:18701875.
95. Kuhn, S.,, M. J. Gill, and, K. C. Kain. 2005. Emergence of atovaquone-proguanil resistance during treatment of Plasmodium falciparum malaria acquired by a non-immune North American traveller to west Africa. Am. J. Trop. Med. Hyg. 72:407409.
96. Labbe, A. C.,, S. Patel,, I. Crandall, and, K. C. Kain. 2003. A molecular surveillance system for global patterns of drug resistance in imported malaria. Emerg. Infect. Dis. 9:3336.
97. Laufer, M. K.,, P. C. Thesing,, N. D. Eddington,, R. Masonga,, F. K. Dzinjalamala,, S. L. Takala,, T. E. Taylor, and, C. V. Plowe. 2006. Return of chloroquine antimalarial efficacy in Malawi. N. Engl. J. Med. 355:19591966.
98. Laufer, M. K.,, A. A. Djimde, and, C. V. Plowe. 2007. Monitoring and deterring drug-resistant malaria in the era of combination therapy. Am. J. Trop. Med. Hyg. 77:160169.
99. Lee, N.,, J. Baker,, K. T. Andrews,, M. L. Gatton,, D. Bell,, Q. Cheng, and, J. McCarthy. 2006. Effect of sequence variation in Plasmodium falciparum histidine-rich protein 2 on binding of specific monoclonal antibodies: implications for rapid diagnostic tests for malaria. J. Clin. Microbiol. 44:27732778.
100. Legrand, E.,, M. Demar,, B. Volney,, M. T. Ekala,, M. Quinternet,, C. Bouchier,, T. Fandeur,, C. Rogier,, B. Carme,, O. M. Puijalon, and, P. Esterre. 2007. First case of emergence of atovaquone resistance in Plasmodium falciparum during second-line atovaquone-proguanil treatment in South America. Antimicrob. Agents Chemother. 51:22802281.
101. Looareesuwan, S.,, C. Viravan,, H. K. Webster,, D. E. Kyle,, D. B. Hutchinson, and, C. J. Canfield. 1996. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am. J. Trop. Med. Hyg. 54:6266.
102. Lynch, C.,, R. Pearce,, H. Pota,, J. Cox,, T. A. Abeku,, J. Rwakimari,, I. Naidoo,, J. Tibenderana, and, C. Roper. 2008. Emergence of a dhfr mutation conferring high-level drug resistance in Plasmodium falciparum populations from southwest Uganda. J. Infect. Dis. 197:15981604.
103. Mangold, K. A.,, R. U. Manson,, E. S. Koay,, L. Stephens,, M. Regner,, R. B. Thomson, Jr.,, L. R. Peterson, and, K. L. Kaul. 2005. Real-time PCR for detection and identification of Plasmodium spp. J. Clin. Microbiol. 43:24352440.
104. Mann, M. 2002. Mass tool for diagnosis. Nature 418:731732.
105. Marks, F.,, C. G. Meyer,, J. Sievertsen,, C. Timmann,, J. Evans,, R. D. Horstmann, and, J. May. 2004. Genotyping of Plasmodium falciparum pyrimethamine resistance by matrix-assisted laser desorption ionization–time-of-flight mass spectrometry. Antimicrob. Agents Chemother. 48:466472.
106. Martens, P.,, and L. Hall. 2000. Malaria on the move: human population movement and malaria transmission. Emerg. Infect. Dis. 6:103109.
107. Marx, A.,, D. Pewsner,, M. Egger,, R. Nuesch,, H. C. Bucher,, B. Genton,, C. Hatz, and, P. Juni. 2005. Meta-analysis: accuracy of rapid tests for malaria in travelers returning from endemic areas. Ann. Intern. Med. 142:836846.
108. McCollum, A. M.,, A. C. Poe,, M. Hamel,, C. Huber,, Z. Zhou,, Y. P. Shi,, P. Ouma,, J. Vulule,, P. Bloland,, L. Slutsker,, J. W. Barnwell,, V. Udhayakumar, and, A. A. Escalante. 2006. Antifolate resistance in Plasmodium falciparum: multiple origins and identification of novel dhfr alleles. J. Infect. Dis. 194:189197.
109. McCutcheon, K. R.,, J. A. Freese,, J. A. Frean,, B. L. Sharp, and, M. B. Markus. 1999. Two mutations in the multidrug-resistance gene homologue of Plasmodium falciparum, pfmdr1, are not useful predictors of in-vivo or in-vitro chloroquine resistance in southern Africa. Trans. R. Soc. Trop. Med. Hyg. 93:300302.
110. Mens, P. F.,, G. J. Schoone,, P. A. Kager, and, H. D. Schallig. 2006. Detection and identification of human Plasmodium species with real-time quantitative nucleic acid sequence-based amplification. Malar. J. 5:80.
111. Mens, P. F.,, A. van Amerongen,, P. Sawa,, P. A. Kager, and, H. D. Schallig. 2008. Molecular diagnosis of malaria in the field: development of a novel 1-step nucleic acid lateral flow immunoassay for the detection of all 4 human Plasmodium spp. and its evaluation in Mbita, Kenya. Diagn. Microbiol. Infect. Dis. 61:421427.
112. Meshnick, S. R.,, T. E. Taylor, and, S. Kamchonwong-paisan. 1996. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol. Rev. 60:301315.
113. Miller, R. S.,, P. McDaniel, and, C. Wongsrichanalai. 2001. Following the course of malaria treatment by detecting parasite lactate dehydrogenase enzyme. Br. J. Haematol. 113:558559.
114. Moody, A. 2002. Rapid diagnostic tests for malaria parasites. Clin. Microbiol. Rev. 15:6678.
115. Moody, A. H.,, and P. L. Chiodini. 2002. Nonmicroscopic method for malaria diagnosis using OptiMAL IT, a second-generation dipstick for malaria pLDH antigen detection. Br. J. Biomed. Sci. 59:228231.
116. Morassin, B.,, R. Fabre,, A. Berry, and, J. F. Magnaval. 2002. One year’s experience with the polymerase chain reaction as a routine method for the diagnosis of imported malaria. Am. J. Trop. Med. Hyg. 66:503508.
117. Mu, J.,, P. Awadalla,, J. Duan,, K. M. McGee,, D. A. Joy,, G. A. McVean, and, X. Z. Su. 2005. Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol. 3:e335.
118. Mu, J.,, P. Awadalla,, J. Duan,, K. M. McGee,, J. Keebler,, K. Seydel,, G. A. McVean, and, X. Z. Su. 2007. Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome. Nat. Genet. 39:126130.
119. Mueller, I.,, I. Betuela,, M. Ginny,, J. C. Reeder, and, B. Genton. 2007. The sensitivity of the OptiMAL rapid diagnostic test to the presence of Plasmodium falciparum gametocytes compromises its ability to monitor treatment outcomes in an area of Papua New Guinea in which malaria is endemic. J. Clin. Microbiol. 45:627630.
120. Mugittu, K.,, M. Ndejembi,, A. Malisa,, M. Lemnge,, Z. Premji,, A. Mwita,, W. Nkya,, J. Kataraihya,, S. Abdulla,, H. P. Beck, and, H. Mshinda. 2004. Therapeutic efficacy of sulfadoxine-pyrimethamine and prevalence of resistance markers in Tanzania prior to revision of malaria treatment policy: Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase mutations in monitoring in vivo resistance. Am. J. Trop. Med. Hyg. 71:696702.
121. Musset, L.,, O. Bouchaud,, S. Matheron,, L. Massias, and, J. Le Bras. 2006. Clinical atovaquone-proguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations. Microbes Infect. 8:25992604.
122. Nair, S.,, A. Brockman,, L. Paiphun,, F. Nosten, and, T. J. Anderson. 2002. Rapid genotyping of loci involved in antifolate drug resistance in Plasmodium falciparum by primer extension. Int. J. Parasitol. 32:852858.
123. Nair, S.,, J. T. Williams,, A. Brockman,, L. Paiphun,, M. Mayxay,, P. N. Newton,, J. P. Guthmann,, F. M. Smithuis,, T. T. Hien,, N. J. White,, F. Nosten, and, T. J. Anderson. 2003. A selective sweep driven by pyrimethamine treatment in Southeast Asian malaria parasites. Mol. Biol. Evol. 20:15261536.
124. Nelson, A. L.,, A. Purfield,, P. McDaniel,, N. Uthaimongkol,, N. Buathong,, S. Sriwichai,, R. S. Miller,, C. Wongsrichanalai, and, S. R. Meshnick. 2005. pfmdr1 genotyping and in vivo mefloquine resistance on the Thai-Myanmar border. Am. J. Trop. Med. Hyg. 72:586592.
125. Newton, P. N.,, R. McGready,, F. Fernandez,, M. D. Green,, M. Sunjio,, C. Bruneton,, S. Phanouvong,, P. Millet,, C. J. Whitty,, A. O. Talisuna,, S. Proux,, E. M. Christophel,, G. Malenga,, P. Singhasivanon,, K. Bojang,, H. Kaur,, K. Palmer,, N. P. Day,, B. M. Greenwood,, F. Nosten, and, N. J. White. 2006. Manslaughter by fake artesunate in Asia—will Africa be next? PLoS Med 3:e197.
126. Nyunt, M.,, J. Pisciotta,, A. B. Feldman,, P. Thuma,, P. F. Scholl,, P. A. Demirev,, J. S. Lin,, L. Shi,, N. Kumar, and, D. J. Sullivan, Jr. 2005. Detection of Plasmodium falciparum in pregnancy by laser desorption mass spectrometry. Am. J. Trop. Med. Hyg. 73:485490.
127. Nzila, A. M.,, E. K. Mberu,, J. Sulo,, H. Dayo,, P. A. Winstanley,, C. H. Sibley, and, W. M. Watkins. 2000. Towards an understanding of the mechanism of pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: genotyping of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites. Antimicrob. Agents Chemother. 44:991996.
128. Ochola, L. B.,, P. Vounatsou,, T. Smith,, M. L. Mabaso, and, C. R. Newton. 2006. The reliability of diagnostic techniques in the diagnosis and management of malaria in the absence of a gold standard. Lancet Infect. Dis. 6:582588.
129. Oliveira, D. A.,, Y. P. Shi,, A. J. Oloo,, D. A. Boriga,, B. L. Nahlen,, W. A. Hawley,, B. P. Holloway, and, A. A. Lal. 1996. Field evaluation of a polymerase chain reaction-based nonisotopic liquid hybridization assay for malaria diagnosis. J. Infect. Dis. 173:12841287.
130. Omar, S. A.,, P. F. Mens,, G. J. Schoone,, A. Yusuf,, J. Mwangi,, S. Kaniaru,, G. A. Omer, and, H. D. Schallig. 2005. Plasmodium falciparum: evaluation of a quantitative nucleic acid sequence-based amplification assay to predict the outcome of sulfadoxine-pyrimethamine treatment of uncomplicated malaria. Exp. Parasitol. 110:7379.
131. Onori, E. 1984. The problem of Plasmodium falciparum drug resistance in Africa south of the Sahara. Bull. W. H. O. 62(Suppl.):5562.
132. Padial, M. M.,, M. Subirats,, S. Puente,, M. Lago,, S. Crespo,, G. Palacios, and, M. Baquero. 2005. Sensitivity of laser light depolarization analysis for detection of malaria in blood samples. J. Med. Microbiol. 54:449452.
133. Palacios, G.,, P. L. Quan,, O. J. Jabado,, S. Conlan,, D. L. Hirschberg,, Y. Liu,, J. Zhai,, N. Renwick,, J. Hui,, H. Hegyi,, A. Grolla,, J. E. Strong,, J. S. Towner,, T. W. Geisbert,, P. B. Jahrling,, C. Buchen-Osmond,, H. Ellerbrok,, M. P. Sanchez-Seco,, Y. Lussier,, P. Formenty,, M. S. Nichol,, H. Feldmann,, T. Briese, and, W. I. Lipkin. 2007. Panmicrobial oligonucleotide array for diagnosis of infectious diseases. Emerg. Infect. Dis. 13:7381.
134. Pearce, R. J.,, C. Drakeley,, D. Chandramohan,, F. Mosha, and, C. Roper. 2003. Molecular determination of point mutation haplotypes in the dihydrofolate reductase and dihydropteroate synthase of Plasmodium falciparum in three districts of northern Tanzania. Antimicrob. Agents Chemother. 47:13471354.
135. Peel, S. A.,, P. Bright,, B. Yount,, J. Handy, and, R. S. Baric. 1994. A strong association between mefloquine and halofantrine resistance and amplification, overexpression, and mutation in the P-glycoprotein gene homolog (pfmdr) of Plasmodium falciparum in vitro. Am. J. Trop. Med. Hyg. 51:648658.
136. Perandin, F.,, N. Manca,, A. Calderaro,, G. Piccolo,, L. Galati,, L. Ricci,, M. C. Medici,, M. C. Arcangeletti,, G. Snounou,, G. Dettori, and, C. Chezzi. 2004. Development of a real-time PCR assay for detection of Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale for routine clinical diagnosis. J. Clin. Microbiol. 42:12141219.
137. Perkins, B. A.,, J. R. Zucker,, J. Otieno,, H. S. Jafari,, L. Paxton,, S. C. Redd,, B. L. Nahlen,, B. Schwartz,, A. J. Oloo,, C. Olango,, S. Gove, and, C. C. Campbell. 1997. Evaluation of an algorithm for integrated management of childhood illness in an area of Kenya with high malaria transmission. Bull. W. H. O. 75(Suppl. 1):3342.
138. Pickard, A. L.,, C. Wongsrichanalai,, A. Purfield,, D. Kamwendo,, K. Emery,, C. Zalewski,, F. Kawamoto,, R. S. Miller, and, S. R. Meshnick. 2003. Resistance to antimalarials in Southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob. Agents Chemother. 47:24182423.
139. Pillai, D. R.,, G. Hijar,, Y. Montoya,, W. Marouino,, T. K. Ruebush II,, C. Wongsrichanalai, and, K. C. Kain. 2003. Lack of prediction of mefloquine and mefloquineartesunate treatment outcome by mutations in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene for P. falciparum malaria in Peru. Am. J. Trop. Med. Hyg. 68:107110.
140. Plowe, C. V.,, J. F. Cortese,, A. Djimde,, O. C. Nwanyanwu,, W. M. Watkins,, P. A. Winstanley,, J. G. Estrada-Franco,, R. E. Mollinedo,, J. C. Avila,, J. L. Cespedes,, D. Carter, and, O. K. Doumbo. 1997. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J. Infect. Dis. 176:15901596.
141. Plowe, C. V.,, C. Roper,, J. W. Barnwell,, C. T. Happi,, H. H. Joshi,, W. Mbacham,, S. R. Meshnick,, K. Mugittu,, I. Naidoo,, R. N. Price,, R. W. Shafer,, C. H. Sibley,, C. J. Sutherland,, P. A. Zimmerman, and, P. J. Rosenthal. 2007. World Antimalarial Resistance Network (WARN) III: molecular markers for drug resistant malaria. Malar. J. 6:121.
142. Poon, L. L.,, B. W. Wong,, E. H. Ma,, K. H. Chan,, L. M. Chow,, W. Abeyewickreme,, N. Tangpukdee,, K. Y. Yuen,, Y. Guan,, S. Looareesuwan, and, J. S. Peiris. 2006. Sensitive and inexpensive molecular test for falciparum malaria: detecting Plasmodium falciparum DNA directly from heat-treated blood by loop-mediated isothermal amplification. Clin. Chem. 52:303306.
143. Price, R. N.,, C. Cassar,, A. Brockman,, M. Duraisingh,, M. van Vugt,, N. J. White,, F. Nosten, and, S. Krishna. 1999. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob. Agents Chemother. 43:29432949.
144. Price, R. N.,, A. C. Uhlemann,, A. Brockman,, R. McGready,, E. Ashley,, L. Phaipun,, R. Patel,, K. Laing,, S. Looareesuwan,, N. J. White,, F. Nosten, and, S. Krishna. 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364:438447.
145. Purfield, A.,, A. Nelson,, A. Laoboonchai,, K. Congpuong,, P. McDaniel,, R. S. Miller,, K. Welch,, C. Wongsrichanalai, and, S. R. Meshnick. 2004. A new method for detection of pfmdr1 mutations in Plasmodium falciparum DNA using real-time PCR. Malar. J. 3:9.
146. Rafael, M. E.,, T. Taylor,, A. Magill,, Y. W. Lim,, F. Girosi, and, R. Allan. 2006. Reducing the burden of childhood malaria in Africa: the role of improved. Nature 444(Suppl. 1):3948.
147. Reed, M. B.,, K. J. Saliba,, S. R. Caruana,, K. Kirk, and, A. F. Cowman. 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403:906909.
148. Rennie, W.,, R. Phetsouvanh,, S. Lupisan,, V. Vanisaveth,, B. Hongvanthong,, S. Phompida,, P. Alday,, M. Fulache,, R. Lumagui,, P. Jorgensen,, D. Bell, and, S. Harvey. 2007. Minimising human error in malaria rapid diagnosis: clarity of written instructions and health worker performance. Trans. R. Soc. Trop. Med. Hyg. 101:918.
149. Reyburn, H.,, R. Mbatia,, C. Drakeley,, I. Carneiro,, E. Mwakasungula,, O. Mwerinde,, K. Saganda,, J. Shao,, A. Kitua,, R. Olomi,, B. M. Greenwood, and, C. J. Whitty. 2004. Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study. BMJ 329:1212.
150. Reyburn, H.,, H. Mbakilwa,, R. Mwangi,, O. Mwerinde,, R. Olomi,, C. Drakeley, and, C. J. Whitty. 2007. Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial. BMJ 334:403.
151. Rohrbach, P.,, C. P. Sanchez,, K. Hayton,, O. Friedrich,, J. Patel,, A. B. Sidhu,, M. T. Ferdig,, D. A. Fidock, and, M. Lanzer. 2006. Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. EMBO J. 25:30003011.
152. Rolland, E.,, F. Checchi,, L. Pinoges,, S. Balkan,, J. P. Guthmann, and, P. J. Guerin. 2006. Operational response to malaria epidemics: are rapid diagnostic tests cost-effective? Trop. Med. Int. Health 11:398408.
153. Romagosa, C.,, C. Menendez,, M. R. Ismail,, L. Quinto,, B. Ferrer,, P. L. Alonso, and, J. Ordi. 2004. Polarisation microscopy increases the sensitivity of hemozoin and Plasmodium detection in the histological assessment of placental malaria. Acta Trop. 90:277284.
154. Roper, C.,, R. Pearce,, B. Bredenkamp,, J. Gumede,, C. Drakeley,, F. Mosha,, D. Chandramohan, and, B. Sharp. 2003. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 361:11741181.
155. Roper, C.,, R. Pearce,, S. Nair,, B. Sharp,, F. Nosten, and, T. Anderson. 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305:1124.
156. Rose, G. W.,, K. N. Suh,, K. C. Kain,, N. Le Saux, and, A. E. McCarthy. 2008. Atovaquone-proguanil resistance in imported falciparum malaria in a young child. Pediatr. Infect. Dis. J. 27:567569.
157. Rougemont, M.,, M. Van Saanen,, R. Sahli,, H. P. Hinrikson,, J. Bille, and, K. Jaton. 2004. Detection of four Plasmodium species in blood from humans by 18S rRNA gene subunit-based and species-specific real-time PCR assays. J. Clin. Microbiol. 42:56365643.
158. Rubio, J. M.,, A. Benito,, J. Roche,, P. J. Berzosa,, M. L. Garcia,, M. Mico,, M. Edu, and, J. Alvar. 1999. Seminested, multiplex polymerase chain reaction for detection of human malaria parasites and evidence of Plasmodium vivax infection in Equatorial Guinea. Am. J. Trop. Med. Hyg. 60:183187.
159. Ryan, E. T.,, and K. C. Kain. 2000. Health advice and immunizations for travelers. N. Engl. J. Med. 342:17161725.
160. Sampath, R.,, K. L. Russell,, C. Massire,, M. W. Eshoo,, V. Harpin,, L. B. Blyn,, R. Melton,, C. Ivy,, T. Pennella,, F. Li,, H. Levene,, T. A. Hall,, B. Libby,, N. Fan,, D. J. Walcott,, R. Ranken,, M. Pear,, A. Schink,, J. Gutierrez,, J. Drader,, D. Moore,, D. Metzgar,, L. Addington,, R. Rothman,, C. A. Gaydos,, S. Yang,, K. St. George,, M. E. Fuschino,, A. B. Dean,, D. E. Stallknecht,, G. Goekjian,, S. Yingst,, M. Monteville,, M. D. Saad,, C. A. Whitehouse,, C. Baldwin,, K. H. Rudnick,, S. A. Hofstadler,, S. M. Lemon, and, D. J. Ecker. 2007. Global surveillance of emerging Influenza virus genotypes by mass spectrometry. PLoS ONE 2:e489.
161. Scholl, P. F.,, D. Kongkasuriyachai,, P. A. Demirev,, A. B. Feldman,, J. S. Lin,, D. J. Sullivan, Jr., and, N. Kumar. 2004. Rapid detection of malaria infection in vivo by laser desorption mass spectrometry. Am. J. Trop. Med. Hyg. 71:546551.
162. Schoone, G. J.,, L. Oskam,, N. C. Kroon,, H. D. Schallig, and, S. A. Omar. 2000. Detection and quantification of Plasmodium falciparum in blood samples using quantitative nucleic acid sequence-based amplification. J. Clin. Microbiol. 38:40724075.
163. Schwartz, E.,, S. Bujanover, and, K. C. Kain. 2003. Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin. Infect. Dis. 37:450451.
164. Scott, C. S.,, D. Van Zyl,, E. Ho,, L. Ruivo,, D. Kunz, and, T. L. Coetzer. 2002. Patterns of pseudoreticulocytosis in malaria: fluorescent analysis with the Cell-Dyn CD4000. Clin. Lab. Haematol. 24:1520.
165. Senescau, A.,, A. Berry,, F. Benoit-Vical,, O. Landt,, R. Fabre,, J. Lelievre,, S. Cassaing, and, J. F. Magnaval. 2005. Use of a locked-nucleic-acid oligomer in the clamped-probe assay for detection of a minority Pfcrt K76T mutant population of Plasmodium falciparum. J. Clin. Microbiol. 43:33043308.
166. Shekalaghe, S. A.,, J. T. Bousema,, K. K. Kunei,, P. Lushino,, A. Masokoto,, L. R. Wolters,, S. Mwakalinga,, F. W. Mosha,, R. W. Sauerwein, and, C. J. Drakeley. 2007. Submicroscopic Plasmodium falciparum gametocyte carriage is common in an area of low and seasonal transmission in Tanzania. Trop. Med. Int. Health 12:547553.
167. Sibley, C. H.,, and P. Ringwald. 2006. A database of antimalarial drug resistance. Malar. J. 5:48.
168. Sidhu, A. B.,, A. C. Uhlemann,, S. G. Valderramos,, J. C. Valderramos,, S. Krishna, and, D. A. Fidock. 2006. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J. Infect. Dis. 194:528535.
169. Sirawaraporn, W.,, T. Sathitkul,, R. Sirawaraporn,, Y. Yuthavong, and, D. V. Santi. 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. USA 94:11241129.
170. Snounou, G.,, S. Viriyakosol,, W. Jarra,, S. Thaithong, and, K. N. Brown. 1993. Identification of the four human malaria parasite species in field samples by the polymerase chain reaction and detection of a high prevalence of mixed infections. Mol. Biochem. Parasitol. 58:283292.
171. Snow, R. W.,, J. F. Trape, and, K. Marsh. 2001. The past, present and future of childhood malaria mortality in Africa. Trends Parasitol. 17:593597.
172. Srinivasan, S.,, A. H. Moody, and, P. L. Chiodini. 2000. Comparison of blood-film microscopy, the OptiMAL dipstick, Rhodamine-123 fluorescence staining and PCR, for monitoring antimalarial treatment. Ann. Trop. Med. Parasitol. 94:227232.
173. Srivastava, I. K.,, and A. B. Vaidya. 1999. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob. Agents Chemother. 43:13341339.
174. Suh, I. B.,, H. J. Kim,, J. Y. Kim,, S. W. Lee,, S. S. An,, W. J. Kim, and, C. S. Lim. 2003. Evaluation of the Abbott Cell-Dyn 4000 hematology analyzer for detection and therapeutic monitoring of Plasmodium vivax in the Republic of Korea. Trop. Med. Int. Health 8:10741081.
175. Sutherland, C. J.,, T. Haustein,, N. Gadalla,, M. Armstrong,, J. F. Doherty, and, P. L. Chiodini. 2007. Chloroquine-resistant Plasmodium falciparum infections among UK travellers returning with malaria after chloroquine prophylaxis. J. Antimicrob. Chemother. 59:11971199.
176. Swan, H.,, L. Sloan,, A. Muyombwe,, P. Chavalitshewinkoon-Petmitr,, S. Krudsood,, W. Leowattana,, P. Wilairatana,, S. Looareesuwan, and, J. Rosenblatt. 2005. Evaluation of a real-time polymerase chain reaction assay for the diagnosis of malaria in patients from Thailand. Am. J. Trop. Med. Hyg. 73:850854.
177. Tjitra, E.,, and N. M. Anstey. 2001. Will the high rates of post-treatment sexual stage parasitaemia seen in malaria-endemic areas make the OptiMAL antigen test unreliable in predicting malaria treatment outcome? Br. J. Haematol. 113:255257.
178. Tost, J.,, and I. G. Gut. 2005. Genotyping single nucleotide polymorphisms by MALDI mass spectrometry in clinical applications. Clin. Biochem. 38:335350.
179. Trachsler, M.,, P. Schlagenhauf, and, R. Steffen. 1999. Feasibility of a rapid dipstick antigen-capture assay for self-testing of travellers’ malaria. Trop. Med. Int. Health 4:442447.
180. Trape, J. F. 2001. The public health impact of chloroquine resistance in Africa. Am. J. Trop. Med. Hyg. 64:1217.
181. Triglia, T.,, J. G. Menting,, C. Wilson, and, A. F. Cowman. 1997. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 94:1394413949.
182. Uhlemann, A. C.,, A. Cameron,, U. Eckstein-Ludwig,, J. Fischbarg,, P. Iserovich,, F. A. Zuniga,, M. East,, A. Lee,, L. Brady,, R. K. Haynes, and, S. Krishna. 2005. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat. Struct. Mol. Biol. 12:628629.
183. Uhlemann, A. C.,, R. McGready,, E. A. Ashley,, A. Brockman,, P. Singhasivanon,, S. Krishna,, N. J. White,, F. Nosten, and, R. N. Price. 2007. Intrahost selection of Plasmodium falciparum pfmdr1 alleles after antimalarial treatment on the northwestern border of Thailand. J. Infect. Dis. 195:134141.
184. Veiga, M. I.,, P. E. Ferreira,, A. Bjorkman, and, J. P. Gil. 2006. Multiplex PCR-RFLP methods for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum. Mol. Cell. Probes 20:100104.
185. Vessiere, A.,, A. Berry,, R. Fabre,, F. Benoit-Vical, and, J. F. Magnaval. 2004. Detection by real-time PCR of the Pfcrt T76 mutation, a molecular marker of chloroquine-resistant Plasmodium falciparum strains. Parasitol. Res. 93:57.
186. Vestergaard, L. S.,, and P. Ringwald. 2007. Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies. Am. J. Trop. Med. Hyg. 77:153159.
187. Vo, T. K.,, P. Bigot,, P. Gazin,, V. Sinou,, J. J. De Pina,, D. C. Huynh,, F. Fumoux, and, D. Parzy. 2007. Evaluation of a real-time PCR assay for malaria diagnosis in patients from Vietnam and in returned travellers. Trans. R. Soc. Trop. Med. Hyg. 101:422428.
188. Volkman, S. K.,, P. C. Sabeti,, D. DeCaprio,, D. E. Neafsey,, S. F. Schaffner,, D. A. Milner, Jr.,, J. P. Daily,, O. Sarr,, D. Ndiaye,, O. Ndir,, S. Mboup,, M. T. Duraisingh,, A. Lukens,, A. Derr,, N. Stange-Thomann,, S. Waggoner,, R. Onofrio,, L. Ziaugra,, E. Mauceli,, S. Gnerre,, D. B. Jaffe,, J. Zainoun,, R. C. Wiegand,, B. W. Birren,, D. L. Hartl,, J. E. Galagan,, E. S. Lander, and, D. F. Wirth. 2007. A genome-wide map of diversity in Plasmodium falciparum. Nat. Genet. 39:113119.
189. von Seidlein, L.,, M. T. Duraisingh,, C. J. Drakeley,, R. Bailey,, B. M. Greenwood, and, M. Pinder. 1997. Polymorphism of the Pfmdr1 gene and chloroquine resistance in Plasmodium falciparum in The Gambia. Trans. R. Soc. Trop. Med. Hyg. 91:450453.
190. Walker, D. J.,, J. L. Pitsch,, M. M. Peng,, B. L. Robinson,, W. Peters,, J. Bhisutthibhan, and, S. R. Meshnick. 2000. Mechanisms of artemisinin resistance in the rodent malaria pathogen Plasmodium yoelii. Antimicrob. Agents Chemother. 44:344347.
191. Wang, P.,, D. R. Brooks,, P. F. Sims, and, J. E. Hyde. 1995. A mutation-specific PCR system to detect sequence variation in the dihydropteroate synthetase gene of Plasmodium falciparum. Mol. Biochem. Parasitol. 71:115125.
192. Wang, P.,, M. Read,, P. F. Sims, and, J. E. Hyde. 1997. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Mol. Microbiol. 23:979986.
193. Weber, M. W.,, E. K. Mulholland,, S. Jaffar,, H. Troedsson,, S. Gove, and, B. M. Greenwood. 1997. Evaluation of an algorithm for the integrated management of childhood illness in an area with seasonal malaria in the Gambia. Bull. W. H. O. 75(Suppl. 1):2532.
194. Wever, P. C.,, Y. M. Henskens,, P. A. Kager,, J. Dankert, and, T. van Gool. 2002. Detection of imported malaria with the Cell-Dyn 4000 hematology analyzer. J. Clin. Microbiol. 40:47294731.
195. Whitty, C. J. M.,, M. Armstrong, and, R. H. Behrens. 2000. Self-testing for falciparum malaria with antigen-capture cards by travelers with symptoms of malaria. Am. J. Trop. Med. Hyg. 63:295297.
196. Wichmann, O.,, T. Jelinek,, G. Peyerl-Hoffmann,, N. Muhlberger,, M. P. Grobusch,, J. Gascon,, A. Matteelli,, C. Hatz,, H. Laferl,, M. Schulze,, G. Burchard,, S. da Cunha,, J. Beran,, P. McWhinney,, H. Kollaritsch,, P. Kern,, J. Cuadros,, M. Alifrangis, and, I. Gjorup. 2003. Molecular surveillance of the antifolate-resistant mutation I164L in imported African isolates of Plasmodium falciparum in Europe: sentinel data from TropNetEurop. Malar. J. 2:17.
197. Wichmann, O.,, N. Muehlberger,, T. Jelinek,, M. Alifrangis,, G. Peyerl-Hoffmann,, M. Muhlen,, M. P. Grobusch,, J. Gascon,, A. Matteelli,, H. Laferl,, Z. Bisoffi,, S. Ehrhardt,, J. Cuadros,, C. Hatz,, I. Gjorup,, P. McWhinney,, J. Beran,, S. da Cunha,, M. Schulze,, H. Kollaritsch,, P. Kern,, G. Fry, and, J. Richter. 2004. Screening for mutations related to atovaquone/proguanil resistance in treatment failures and other imported isolates of Plasmodium falciparum in Europe. J. Infect. Dis. 190:15411546.
198. Wichmann, O.,, M. Muehlen,, H. Gruss,, F. P. Mockenhaupt,, N. Suttorp, and, T. Jelinek. 2004. Malarone treatment failure not associated with previously described mutations in the cytochrome b gene. Malar. J. 3:14.
199. Wilson, P. E.,, W. Kazadi,, D. D. Kamwendo,, V. Mwapasa,, A. Purfield, and, S. R. Meshnick. 2005. Prevalence of pfcrt mutations in Congolese and Malawian Plasmodium falciparum isolates as determined by a new Taqman assay. Acta Trop. 93:97106.
200. Wootton, J. C.,, X. Feng,, M. T. Ferdig,, R. A. Cooper,, J. Mu,, D. I. Baruch,, A. J. Magill, and, X. Z. Su. 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418:320323.
201. World Bank. 2007. RBM Board endorses proposal to make malaria medicines cheaper and available to all. World Bank press release. http://web.worldbank.org/WBSITE/EXTERNAL/NEWS/0,,contentMDK:21568855~menuPK:51062077~pagePK:34370~piPK:34424~theSitePK:4607,00.html. Accessed 7 June 2010.
202. World Health Organization. 2000. New Perspectives: Malaria Diagnosis. Report of a Joint WHO /USAID Informal Consultation. World Health Organization, Geneva, Switzerland. http://www.who.int/tdrold/publications/publications/pdf/malaria_diagnosis.pdf. Accessed 7 June 2010.
203. World Health Organization. 2005. World Malaria Report 2005. World Health Organization, Geneva, Switzerland.