Molecular surveillance system for global patterns of drug resistance in imported malaria. (Research).Analysis of imported malaria in travelers may represent a novel surveillance system for drug-resistant malaria. We analyzed consecutive falciparum malaria fal·cip·a·rum malaria n. Malaria caused by Plasmodium falciparum and characterized by severe malarial paroxysms that recur about every 48 hours and often by acute cerebral, renal, or gastrointestinal manifestations. isolates from Canadian travelers from 1994 to 2000, for polymorphisms in pfcrt, dhfr, and dhps linked to chloroquine chloroquine /chlo·ro·quine/ (klor´o-kwin) an antiamebic and anti-inflammatory used in the treatment of malaria, giardiasis, extraintestinal amebiasis, lupus erythematosus, and rheumatoid arthritis; used also as the hydrochloride and and pyrimethamine/sulfadoxine resistance. Forty percent of isolates possessed the K76 pfcrt allele allele (əlēl`): see genetics. allele Any one of two or more alternative forms of a gene that may occur alternatively at a given site on a chromosome. , suggesting that many imported falciparum infections are still responsive to chloroquine. Travelers who had recently taken chloroquine had a significantly increased risk of harboring isolates with pfcrt resistance alleles (odds ratio = 4.47; p=0.03). The presence of two or more mutations in dhfr or dhps was found in 64.8% (95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. [CI] 54.6 to 73.9) and in 30.4% (95% CI 21.7 to 40.3) of isolates, respectively, and increased significantly over the course of the study. These molecular markers Molecular marker is a term with a number of uses. It is any kind of molecule indicating the existence of a chemical or physical process. In particular, in the fields of geology and astrobiology, biomarkers (also known as biosignatures) are sometimes understood as molecules indicate that pyrimethamine/sulfadoxine resistance is increasing and is now too high to rely on this drug as a routine therapeutic agent to treat malaria in travelers. ********** Drug-resistant malaria is increasing, and novel strategies to monitor for resistance are needed. Over 50 million persons from the industrialized in·dus·tri·al·ize v. in·dus·tri·al·ized, in·dus·tri·al·iz·ing, in·dus·tri·al·iz·es v.tr. 1. To develop industry in (a country or society, for example). 2. world visit malaria-endemic countries annually, and record numbers of imported malaria cases are being reported in North America North America, third largest continent (1990 est. pop. 365,000,000), c.9,400,000 sq mi (24,346,000 sq km), the northern of the two continents of the Western Hemisphere. and Europe (1). The first well-documented cases of chloroquine-resistant and sulfadoxine-pyrimethamine (SP)--resistant Plasmodium falciparum Plasmodium fal·cip·a·rum n. A protozoan that causes falciparum malaria. malaria were identified in tourists visiting East Africa in the late 1970s and early 1980s, which suggests that travelers may represent an important sentinel population to monitor for drug-resistant malaria (2,3). Although assessing travelers for malaria treatment and prophylaxis prophylaxis (prō'fĭlăk`sĭs), measures designed to prevent the occurrence of disease or its dissemination. Some examples of prophylaxis are immunization against serious diseases such as smallpox or diphtheria; quarantine to confine failures may be an effective strategy for detecting emerging drug resistance, traditional methods of detecting resistance, including in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body. in vi·vo adj. Within a living organism. in vivo adv. treatment trials and in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment. in vi·tro adj. In an artificial environment outside a living organism. drug susceptibility testing susceptibility test Antimicrobial susceptibility test, see there , are time- and labor-intensive and are not well suited to large-scale surveillance of travelers (4). Molecular methods that detect genetic markers genetic marker n. A gene phenotypically associated with a particular, easily identified trait and used to identify an individual or cell carrying that gene. of drug resistance in parasites are potentially powerful tools to detect and track drug-resistant malaria. The molecular basis of resistance to antifolate drugs antifolate drug see folic acid antagonist. such as SP has been well characterized. High-level pyrimethamine pyrimethamine /pyr·i·meth·amine/ (pir?i-meth´ah-men) a folic acid antagonist, used in the treatment of malaria and of toxoplasmosis. py·ri·meth·a·mine n. resistance results from the accumulation of mutations in the dhfr gene dhfr gene see dhfrgene. , principally at codons 108, 59, and 51 (5,6). Similarly, point mutations point mutation n. A mutation that involves a single nucleotide and may consist of loss of a nucleotide, substitution of one nucleotide for another, or the insertion of an additional nucleotide. in dhps have been associated with decreased susceptibility to sulfadoxine in vitro (7). Chloroquine resistance has been linked to mutations in two genes, pfmdr1 and pfcrt, that encode (1) To assign a code to represent data, such as a parts code. Contrast with decode. (2) To convert from one format or signal to another. See codec and D/A converter. (3) The term is sometimes erroneously used for "encrypt. the digestive vacuole transmembrane proteins A transmembrane protein is a protein that spans the entire biological membrane. Transmembrane proteins aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents. Pgh1 and PfCRT, respectively (8-13). Transfection trans·fec·tion n. Infection of a bacterium or cell with DNA or RNA isolated from a bacteriophage or from an animal or a plant virus, resulting in replication of the complete virus. studies with pfmdr1 suggest that mutations in Pgh1 may modulate To insert a data signal into a carrier wave or direct current. See modulation. the chloroquine resistance phenotype phenotype (fē`nətīp'): see genetics. phenotype All the observable characteristics of an organism, such as shape, size, colour, and behaviour, that result from the interaction of its genotype (total genetic makeup) with in vitro; however, in vivo studies have shown an inconsistent association between mutations in Pgh1 and chloroquine resistance (9-12). More recently, a series of point mutations inpfcrt have been associated with chloroquine resistance (13). One mutation at position 76 (K76T) was present in all in vitro resistant parasites and has been proposed as a molecular marker for surveillance of chloroquine-resistant falciparum malaria, particularly in nonimmune populations such as travelers (10,13). The objectives of this study were to establish a molecular surveillance system for imported malaria, to determine and track the prevalence of putative molecular markers of drag resistance, and to examine risk factors for infection with isolates bearing resistance markers. Materials and Methods From January 1, 1994, to June 30, 2000, patients seen at the Toronto General Hospital The Toronto General Hospital (TGH), part of the University Health Network, is a major teaching hospital in downtown Toronto, Canada. It is located in the Discovery District, directly north of the Hospital for Sick Children, across Gerrard Street West, and east of Princess or the Hospital for Sick Children in Toronto, Canada, with microscopically confirmed falciparum malaria were enrolled. Patient interviews were conducted or medical charts were reviewed for potential risk factors for infection and drug resistance by using a standardized data extraction Data extraction is the act or process of retrieving (binary) data out of (usually unstructured or badly structured) data sources for further data processing or data storage (data migration). form. This study was approved by the Institutional Review Boards of the Toronto General Hospital and the Hospital for Sick Children. Falciparum isolates were characterized by polymerase chain reaction-restriction fragment length polymorphism polymorphism, of minerals, property of crystallizing in two or more distinct forms. Calcium carbonate is dimorphous (two forms), crystallizing as calcite or aragonite. Titanium dioxide is trimorphous; its three forms are brookite, anatase (or octahedrite), and rutile. analysis and sequencing for allelic al·lele n. One member of a pair or series of genes that occupy a specific position on a specific chromosome. [German Allel, short for Allelomorph, allelomorph, from English variants of pfcrt and pfmdr1, dhfr, and dhps as described (5-17). Proportions were compared by using the chi-square test chi-square test: see statistics. or Fisher exact test, as appropriate. The chi-square test for trend was used as required for variables that involved ordered categories. For the purpose of this analysis, we considered mixed isolates (e.g., isolates containing parasites with mutant and wild-type alleles) to be mutant ones and compared them against those possessing only wild-type alleles. Results During the study period, 105 consecutive cases of imported falciparum malaria were recorded (69 males, 36 females; age range 1-70 years [mean 30.5]). The geographic regions in which these persons acquired their infections are shown in Table 1. The prevalence of mutations in chloroquine-resistance markers (pfmdr1 and pfcrt) was significantly higher in isolates acquired in East Africa compared with West Africa West Africa A region of western Africa between the Sahara Desert and the Gulf of Guinea. It was largely controlled by colonial powers until the 20th century. West African adj. & n. (Table 1). Patients who acquired malaria infection in East Africa had a 4.5-fold higher risk of being infected by an isolate possessing the K76T mutation in pfcrt (odds ratio [OR] 4.53 [95% confidence interval (CI) 1.26 to 16.02]; p=0.03) than those visiting West Africa. The N86Y mutation in pfmdr1 was also found more often in isolates acquired in East Africa than in those acquired in West Africa (OR 3.56 [95% CI 1.16 to 10.80]; p=0.03). A linear trend for increasing prevalence of N86Y mutant isolates was evident during the study period (OR per year=1.21; p=0.07) (Table 2). We also examined the association between past chloroquine exposure and the prevalence of chloroquine-resistance markers. Nineteen (18.1%) patients had used chloroquine for prophylaxis (n=13) or treatment (n=6) while abroad. These persons had a significantly increased risk of being infected by an isolate harboring the K76T mutation when compared with other travelers (OR=4.47 [95% CI 1.13 to 25.45]; p=0.03). We grouped the parasite dhfr and dhps genotypes into four categories on the basis of the cumulative number of mutations that have been linked to escalating SP resistance (Table 1). More mutations in dhps were found in isolates from travelers returning from West Africa versus East Africa (p=0.001, Fisher exact test). We found that the proportion of isolates with at least two mutations increased during the study period in both dhfr (OR for a 1-unit increase in year = 1.28; p=0.02, chi-square test for trend) and dhps (OR=1.29; p=0.03) (Table 2). Discussion In this study, we demonstrate "proof-of-principle" that a molecular surveillance strategy based on imported malaria in travelers can be used to detect and track drug-resistant malaria. Monitoring travelers for imported drug-resistant malaria is a surveillance strategy that offers several potential advantages. Recommendations regarding treatment regimens and chemoprophylaxis chemoprophylaxis /che·mo·pro·phy·lax·is/ (-pro?fi-lak´sis) prevention of disease by means of a chemotherapeutic agent. che·mo·pro·phy·lax·is n. Disease prevention by use of chemicals or drugs. for travelers should ideally be made on the basis of the efficacy of these drugs in nonimmune travelers rather than on partially immune persons residing in malaria-endemic areas. However, to date there has been little information on the rates of drug resistance in cases of imported malaria. Using travelers as a sentinel system provides a mechanism to study large numbers of persons returning from diverse malaria-endemic areas. In contrast, traditional studies have often been based on relatively small numbers of persons residing in geographically restricted areas. Travelers are generally nonimmune, facilitating the interpretation of treatment and prophylaxis studies since outcome measures are not confounded by reinfections and by the varying degrees of immunity present in residents of malaria-endemic areas. Similarly, correlating the molecular mechanisms of drug resistance to treatment outcome in travelers may be more straightforward since these confounding variables A confounding variable (also confounding factor, lurking variable, a confound, or confounder) is an extraneous variable in a statistical or research model that should have been experimentally controlled, but was not. can largely be excluded. Knowledge of the resistance genotypes of malaria parasites obtained from returning travelers can provide credible and complementary data for evidence-based recommendations for both chemoprophylaxis and therapy of malaria in travelers. The high correlation between mutations in DHFR and DHPS and in vitro resistance to pyrimethamine and sulfadoxine, further supported by site-directed mutagenesis Site-directed mutagenesis is a molecular biology technique in which a mutation is created at a defined site in a DNA molecule, usually a circular molecule known as a plasmid. In general, site-directed mutagenesis requires that the wild-type gene sequence be known. and transfection experiments, suggests that the epidemiology of antifolate resistance in P falciparum can be monitored by molecular techniques (5-7, 14-17). Furthermore, evidence exists for an association between a stepwise stepwise incremental; additional information is added at each step. stepwise multiple regression used when a large number of possible explanatory variables are available and there is difficulty interpreting the partial regression increase in the number of mutations in DHFR and DHPS and a corresponding increase in the level of clinical resistance to SP. In recent in vivo studies in partially immune persons in Cameroon and Kenya, multiple mutations in DHFR (e.g., triple mutation at codons 108, 59, and 51) were associated with early treatment failure, suggesting that these could be useful markers for predicting the in vivo efficacy of SP (18-20). Using molecular markers of antifolate resistance, our study provides important data on the appropriateness of drugs such as SP that are currently recommended in North America and Europe for treatment or self-treatment of malaria in travelers. We observed that 75%, 66%, and 28% of consecutive imported isolates had at least one, two, and three mutations in DHFR, respectively. In DHPS, corresponding figures were 80%, 30%, and 5%. Furthermore, we found a linear trend for increasing prevalence mutations in dhfr and dhps during this study. These results suggest that antifolate resistance in imported falciparum malaria is now common and escalating over time, These observations question the rationale of continued recommendation of SP as either standby therapy or combination therapy with quinine quinine (kwī`nīn', kwĭnēn`), white crystalline alkaloid with a bitter taste. Before the development of more effective synthetic drugs such as quinacrine, chloroquine, and primaquine, quinine was the specific agent in the treatment of for the treatment of P falciparum malaria in travelers. However, some caution is needed in extrapolating our data to predict the in vivo efficacy of SP. Additional prospective in vivo studies, especially in the nonimmune host, are required to definitively link antifolate molecular markers with in vivo resistance (18-20). We have also collected data on the occurrence of mutations associated with chloroquine resistance in consecutive imported falciparum isolates. The overall prevalence of the N86Y mutation in pfmdr1 and K76T mutation in pfcrt was 47.0% and 60.2%, respectively. Recent in vivo studies have assessed the association between pfcrt mutations and chloroquine response and determined that the K76 allele correctly predicted successful outcome (9-11). A rapid assay to detect pfcrt K76T in travelers' malaria may be useful, since the presence of the K76 allele would indicate the probable effectiveness of treatment with chloroquine alone. On the basis of these findings, we anticipate that at least 40% of our patients would have responded to chloroquine. However, in the absence of a rapid test, current recommendations from the World Health Organization and the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. must be applied, and P falciparum infections acquired in areas of known chloroquine resistance should not be treated with chloroquine. Chloroquine and SP resistance has been selected by drug pressure (5,6,10,21). In Mall, the K76T mutation in pfcrt was observed in persons with persistent or recurrent infection after chloroquine therapy, indicating selection for this mutation. Our study extends these observations to travelers; those who had taken chloroquine for prophylaxis or treatment had a 4.5-fold higher risk of being infected with an isolate carrying the K76T mutation. Although the number of isolates studied was relatively small, our results also indicate that the prevalence of genotypes associated with chloroquine resistance was significantly higher in isolates acquired in East Africa than in those acquired in West Africa. This observation is consistent with currently reported epidemiologic patterns (22). The distribution of chloroquine- and SP-resistant parasites and their degree of resistance are far from uniform, and regular assessment of the therapeutic efficacy of chloroquine and SP, such as obtained with World Health Organization in vivo studies, is required. Studies such as ours, using travelers as sentinels, can contribute in a novel and complementary way to the continuous monitoring and tracking of geographic drug-resistance patterns. A network of digitally linked sites in the developed world that are performing these analyses in cases of imported malaria could provide global and timely monitoring. In summary, our study demonstrates that a molecular surveillance strategy based on imported malaria in travelers can be used to detect and track patterns of drug-resistant malaria. Given the high prevalence of observed mutations in dhfr and dhps, our data provide evidence that raises questions about the rationale of continued use of SP to treat falciparum malaria in returned travelers. Our data also indicate that a considerable proportion of imported falciparum infections are still responsive to chloroquine.
Table 1. Prevalence of molecular markers of drug resistance by region
of malaria acquisition
Area of endemicity n (%)
Genotypes West Africa (a) East Africa (b)
pfmdr1
N86 (wild) 40 (59.7) 5 (29.4)
86Y (mutant) 27 (40.3) 12 (70.6)
pfcrt
K76 (wild) 32 (49.2) 3 (17.6)
76T (mutant) 33 (50.8) 14 (82.4)
dhfr (g)
Wild-type 17 (25.0) 3 (17.6)
Single mutants 6 (8.8) 0
Double mutants 25 (36.8) 8 (47.1)
Triple mutants 20 (29.4) 6 (35.3)
dhps (h)
Wild-type 3 (4.4) 7 (41.2)
Single mutants 40 (58.8) 5 (29.4)
Double mutants 21 (30.9) 5 (29.4)
Triple mutants 4 (5.9) 0
No. of infected patients 71 (67.6) 17 (16.2)
Area of endemicity n (%)
Genotypes Central Africa (c) Southern Africa (d)
pfmdr1
N86 (wild) 1 (20.0) 1 (33.3)
86Y (mutant) 4 (80.0) 2 (66.7)
pfcrt
K76 (wild) 3 (60.0) 0
76T (mutant) 2 (40.0) 2 (100)
dhfr (g)
Wild-type 3 (60.0) 1 (33.3)
Single mutants 0 0
Double mutants 1 (20.0) 2 (66.7)
Triple mutants 1 (20.0) 0
dhps (h)
Wild-type 0 2 (66.7)
Single mutants 5 (100) 1 (33.3)
Double mutants 0 0
Triple mutants 0 0
No. of infected patients 5 (4.8) 3 (2.9)
Area of
endemicity n (%) Total
Genotypes Other (e) n (%; 95%CI) (f)
pfmdr1
N86 (wild) 6 (75.0) 53 (53.0; 42.8 to 63.1)
86Y (mutant) 2 (25.0) 47 (47.0; 36.9 to 57.2)
pfcrt
K76 (wild) 1 (11.1) 39 (39.8; 30.0 to 50.2)
76T (mutant) 8 (88.9) 59 (60.2; 49.8 to 70.0)
dhfr (g)
Wild-type 2 (22.2) 26 (25.5; 17.4 to 35.1)
Single mutants 3 (33.3) 9 (8.8; 4.1 to 16.1)
Double mutants 3 (33.3) 39 (38.2; 28.8 to 48.4)
Triple mutants 1 (11.1) 28 (27.5; 19.1 to 37.2)
dhps (h)
Wild-type 8 (88.9) 20 (19.6; 12.4 to 28.6)
Single mutants 0 51 (50.0; 40.0 to 60.1)
Double mutants 0 26 (25.5; 17.4 to 35.l)
Triple mutants 1 (11.1) 5 (4.9; 1.6 to 11.1)
No. of infected patients 9 (8.6) 105
(a) Two patients had visited more than one country: Ghana
(45 patients), Nigeria (21), The Gambia (2 patients), Sierra Leone
(3 patients), Burkina Faso (1 patient), Mali (1 patient), and
Guinea (1 patient).
(b) Three patients had visited more than one country: Kenya
(9 patients), Uganda (6 patients), Tanzania (3 patients), Rwanda
(1 patient), and Burundi (1 patient).
(c) Central African Republic (2 patients), Congo (2 patients), and
Cameroon (1 patient)
(d) Angola (2 patients) and Madagascar (1 patient).
(e) India (5 patients), Malaysia (1 patient), Bali/New Guinea
(1 patient), Brazil (1 patient), and Haiti (1 patient).
(f) CI, confidence interval.
(g) dhfr: Wild-type: parasites with A16 / C50 / N51 / C59 / S108 /
I164 (n = 26). Single mutants: isolates with the S108N alone (n=9).
Double mutants: parasites with mutations at codons N511 and S108N
(n=11), C59R and S 108N (n=27), or A 16V and S 108T (n=1). Triple
mutants: parasites with the genotypes of N511 / C59R / S108N (n=27)
or C50R / N51I / S108N (n=1). Of note, the falciparum isolate with
the A16V/S 108T mutations was acquired in 1996 by a 12-year-old in
Ghana. Those mutations in dhfr were not accompanied by the mutant
codon I164L, previously associated with pyrimethamine and cycloguanil
resistance (17).
(h) dhps: Wild-type parasites: parasites with S436 / A437 / K540 /
A581 / A613 (n=20). Single mutants: isolates with the S436A (n=19) or
A437G (n=32) mutation alone. Double mutants: parasites with mutations
at codons S436A and A437G (n=18), A437G and K540E (n=6), or S436F
and A613S (n=2). Triple mutants: parasites with S436A / A437G / A613S
(n=3), S436A / A437G / A581G (n=1), or A437G / K540E / A581G (n=1).
Note: Some isolates could not be amplified at all loci and account
for occasional missing values.
Table 2. Proportions of falciparum isolates with chloroquine- or
sulfadoxine-pyrimethamine-associated resistance markers by year of
acquisition
Proportions of mutant isolates
Year pfmdr1 (N86Y) (b) pfcrt (K76T)
1994 42.9% 9/21 71.4% 15/21
1995 25.0% 2/8 55.6% 5/9
1996 31.6% 6/19 50.0% 9/18
1997 52.9% 9/17 66.7% 10/15
1998 64.3% 9/14 50.0% 7/14
1999 50.0% 7/14 64.3% 9/14
2000 (e) 71.4% 5/7 57.1% 4/7
Total 47.0% 47/100 60.2% 59/98
(95% CI) (36.9 to 57.2) (49.8 to 70.0)
Proportions of isolates with at least 2 mutant codons
Year dhfr (c) dhps (d)
1994 45.5% 10/22 14.3% 3/21
1995 62.5% 5/8 33.3% 3/9
1996 52.4% 11/21 25.0% 5/20
1997 88.2% 15/17 35.3% 6/17
1998 85.7% 12/14 21.4% 3/14
1999 78.6% 11/14 57.1% 8/14
2000 (e) 50.0% 3/6 42.9% 3/7
Total 65.7% 67/102 30.4% 31/102
(95% CI) (54.6 to 73.9) (21.7 to 40.3)
(a) OR, odds ratio; CI, confidence interval.
(b) OR for a 1-unit increase in year = 1.21 (95% CI 0.99 to 1.49);
p=0.07, chi-square test for trend.
(c) OR for a 1-unit increase in year = 1.28 (95% CI 1.0 to 1.59);
p=0.02, chi-square test for trend.
(d) OR for a 1-unit increase in year = 1.29 (95% CI 1.03 to 1.61);
p=0.03, chi-square test for trend.
(e) Data for year 2000 are from January 1 to June 30.
This work was supported in part by the Physician Services Incorporated Foundation of Ontario and the Canadian Institutes of Health Research Canadian Institutes of Health Research (CIHR) is the major federal agency responsible for funding health research in Canada. It is the successor to the Medical Research Council of Canada. (MT-13721 to KCK KCK Kansas City, Kansas KCK Kohl's Cares for Kids KCK Kilkenny College, Kilkenny (Ireland) KCK Key Certification Key KCK Key Component Enciphering KCK Key Confirmation Key ). A.-C. Labbe is recipient of the Bayer Healthcare/University of Toronto fellowship in Medical Microbiology Medical microbiology is a branch of microbiology which deals with the study of microorganisms including bacteria, viruses, fungi and parasites which are of medical importance and are capable of causing diseases in human beings. . K.C. Kain is supported by a Canada Research Chair Canada Research Chairs (CRCs) are Canadian university research professorships created through the Canada Research Chairs Program. Program goals The program, established in 2000, is an integral part of a Government of Canada plan to drive Canadian research and development and a Career Scientist Award from the Ontario Ministry of Health. References (1.) Ryan ET, Kain KC. Health advice and immunizations for travelers. N Engl J Med 2000;342:1716-25. (2.) Kean B. Chloroquine-resistant falciparum from Africa. JAMA JAMA abbr. Journal of the American Medical Association 1979;241:395. (3.) Onori E. The problem of Plasmodium falciparum drug resistance in Africa south of the Sahara. Bull World Health Organ 1984;62:55-62. (4.) Lobel HO, Varma JK, Miani M, Green M, Todd GD, Grady K, et al. Monitoring for mefloquine-resistant Plasmodium falciparum in Africa: implications for travelers' health. Am J Trop Med Hyg 1998;59:129-32. (5.) 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Sequence variations in the genes encoding See encode. dihydropteroate synthase and dihydrofolate reductase and clinical response to sulfadoxine-pyrimethamine in patients with acute uncomplicated falciparum malaria. J Infect Dis 2000;182:624-8. (19.) Nzila AM, Mberu EK, Sulo J, Dayo H, Winstanley PA, Sibley CH, et al. Towards an understanding of the mechanism of pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: genotyping Genotyping refers to the process of determining the genotype of an individual with a biological assay. Current methods of doing this include PCR, DNA sequencing, and hybridization to DNA microarrays or beads. of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites. Antimicrob Agents Chemother 2000;44:991-6. (20.) Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, et al. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 2002;185:380-8. (21.) Curtis J, Duraisingh MT, Warhurst DC. In vivo selection for a specific genotype genotype (jēn`ətīp'): see genetics. genotype Genetic makeup of an organism. The genotype determines the hereditary potentials and limitations of an individual. of dihydropteroate synthetase of Plasmodium falciparum by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment. J Infect Dis 1998;177:1429-33. (22.) World Health Organization. The world health report 1999: making a difference. Geneva Geneva, canton and city, Switzerland Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. : The Organization; 1999. Address for correspondence: Kevin C. Kain, Toronto General Hospital, EN G224, 200 Elizabeth St., EN G-224, Toronto, ON, Canada, M5G 2C4; fax: 416595-5826; e-mail: kevin.kain@uhn.on.ca Annie-Claude Labbe, * Samir Patel Samir Patel (born January 14, 1994) is an academic competitor, from Colleyville, Texas, who won the North South Foundation National Spelling Bee, and has placed 2nd, 3rd, 14th, 27th, and 34th in the Scripps National Spelling Bee. , * Ian Crandall, * and Kevin C. Kain * * Toronto General Hospital, University of Toronto Research at the University of Toronto has been responsible for the world's first electronic heart pacemaker, artificial larynx, single-lung transplant, nerve transplant, artificial pancreas, chemical laser, G-suit, the first practical electron microscope, the first cloning of T-cells, , Canada Dr. Labbe is microbiologist and infectious diseases infectious diseases: see communicable diseases. consultant in the Department of Microbiology, Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada. |
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