The aim of this study was to provide the first comprehensive spatiotemporal picture of Plasmodium falciparum resistance in various geographic areas in Madagascar. Additional data about the antimalarial resistance in the neighboring islands of the Comoros archipelago were also collected. We assessed the prevalence of pfcrt, pfmdr-1, pfdhfr, and pfdhps mutations and the pfmdr-1 gene copy number in 1,596 P. falciparum isolates collected in 26 health centers ( In recent decades, the emergence and subsequent spread of Plasmodium falciparum chloroquine (CQ)-and sulfadoxinepyrimethamine (SP)-resistant parasites across areas where malaria is endemic have been a challenge to malaria control programs (41, 44). Substantial advances toward gaining an understanding of the genetic basis of antimalarial drug resistance have been made (14). Molecular evolutionary studies have concluded that the CQ-resistant P. falciparum chloroquine resistance transporter (pfcrt) and high-level pyrimethamine-resistant dihydrofolate (pfdhfr) alleles have emerged in a limited number of independent foci, from which they have rapidly spread in the local vicinity and have then invaded areas continent-wide and transferred between continents (1, 36). These lessons of the past have, first, stimulated changes in antimalarial treatment policies by introducing combinations of drugs that act on different targets and, second, resulted in the implementation of effective monitoring systems to detect as early as possible the emergence of resistant parasites on the basis of the assessment of the therapeutic efficacies of antimalarials (25, 46), determination of the decreased sensitivity of the parasites to drugs in vitro (4), and the detection of an increasing prevalence of molecular markers related to drug resistance (24).According to data published from 2002 to 2006, the epidemiological features of P. falciparum CQ and SP resistance differ considerably between Madagascar and the Comoros Islands, two countries located close to each other in the southwestern Indian Ocean (43). In vitro CQ resistance was moderate in Madagascar (29,33,45), although the level of therapeutic efficacy was declining. During that time, the rate of CQ resistance was high in the Comoros Islands (22,23,30). Likewise, pyrimethamine resistance was absent in Madagascar (28, 32) but was present at high levels in the Comoros Islands (23). The most recent in vivo data obtained on the basis of the WHO 28-day follow-up protocol, conducted in 2006 and 2007 at multiple sites, have confirmed that resistance to all antimalarials except CQ in Madagascar remains rare. Indeed, the prevalence of the clinical failure of treatment with amodiaquine, SP and the combination artesunate and amodiaquine was Ͻ5%, while the rate of failure of treatment with CQ was 44% (19). However, the recent demonstration of the introduction of multidrug-resistant P. falciparum parasites into Madagascar from the Comoros Islands (18) and the emergence of the uncommon dihydrofolate reductase I164L genotype in P. falciparum parasi...
The main purpose of this study was to assess the accuracy of various techniques available for diagnosis of malaria. Blood samples were collected from 313 patients with clinical suspicion of uncomplicated malaria in 2 primary health centers in Madagascar. The presence of Plasmodium parasites was assessed by conventional microscopy, 2 rapid diagnostic tests (one HRP2-based test, PALUTOP(+4), and one pLDH-based test, OptiMAL-IT), and real-time polymerase chain reaction (PCR), which is used as the "gold standard" method. The degree of agreement observed was very high for microscopy (0.99) and the HRP2-based test (0.93) and high for the pLDH-based test (0.82). Public-health implications are also discussed in this paper.
Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt) play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1) act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44%) appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites <5%) or Pfcrt mutant isolates (<1%), strongly contrasting with sub-Saharan African countries. Previous studies showed a high frequency of Pfmdr-1 mutant parasites (>60% of isolates), but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6). The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days) was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days). In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important, particularly regarding the evolution and spread of Pfmdr-1 alleles in P. falciparum populations under changing drug pressure which may have important consequences in terms of antimalarial use management.
Abstract. We sought to test the association of polymorphisms in Plasmodium falciparum nhe-1 ( Pfnhe-1 , gene PF13_0019) with in vitro susceptibility to quinine, which was previously reported in a limited number of reference strains or culture-adapted isolates. Determination of in vitro susceptibility to quinine, genotyping of Pfnhe-1 ms4760 microsatellite and polymorphism in codon 76 of Pfcrt were performed for 83 isolates obtained from symptomatic malaria-infected travelers returning from various African countries to France or from subjects living in Madagascar. Nineteen different ms4760 microsatellite profiles of Pfnhe-1 were found including 14 not previously described. Multivariate analysis showed no significant association between the in vitro susceptibility to quinine with particular ms4760 profiles. Contrary to previous reports, we only observed that the number of NHNDNHNNDDD repeats was positively associated with the increased IC50 of QN ( P = 0.01). We concluded that the studied polymorphisms in Pfnhe-1 did not appear as valid molecular markers of in vitro susceptibility to quinine in P. falciparum isolates from Africa. Because we did not include any isolate of Asian origin in our series, these results did not exclude the possibility of regional associations, for example in South-East Asia.
Treatment of head lice has relied mainly on the use of topical insecticides. Today, conventional topical pediculicides have suffered considerable loss of activity worldwide. There is increasing interest in the use of natural products such as essential oils for head louse control, and many of them are now incorporated into various over-the-counter products presented as pediculicides, often without proper evaluation. The aim of the present study was to assess the in vitro efficacy of five essential oils against adults of Pediculus humanus capitis using a contact filter paper toxicity bioassay. The chemical composition of the essential oils from wild bergamot, clove, lavender, tea tree, and Yunnan verbena was analyzed by gas chromatography-mass spectrometry. All treatments and controls were replicated three times on separate occasions over a period of 11 months. In all, 1239 living lice were collected from the scalp of 51 subjects, aged from 1 to 69 years. Clove oil, diluted either in coco oil or sunflower oil, demonstrated the best adulticidal activity, reaching > 90% mortality within 2 h in lice submitted to a 30-min contact. Yunnan verbena oil diluted in coco oil showed also a significant efficacy. Other essential oils showed a lower efficacy. The oil's major component(s) differed according to the tested oils and appeared chemically diverse. In the case of clove oil, the eugenol appeared as the main component. This study confirmed the potential interest of some of the essential oils tested, but not all, as products to include possibly in a pediculicidal formulation.
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