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The purpose of this review was to provide up-to-date information on the resistance of Plasmodium falciparum to the main antimalarials used in Madagascar and to assist implementation of the malaria control and elimination program. In 2006, the failure rate for chloroquine treatment was 44% (n = 300) and was comparable to the rate observed in continental Africa. Most treatment failures occurred after the first week of follow-up. P. falciparum resistance to chloroquine appeared to be special in Madagascar with only 3.2% of isolates showing in vitro resistance (n = 372, 7 sentinel sites) and less than 1% harbouring mutant parasites within the Pfcrt gene. Conversely, the Pfmdr1 N86Y point mutation was found in 64.3% (n = 174) of isolates in 2006 and in 51.7% (n = 343) in 2007. Failure of combined sulfadoxine-pyrimethamine therapy, i.e., the recommended intermittent preventive treatment for malaria during pregnancy, and in vitro resistance to pyrimethamine were rare. However, the Pfdhfr 51I/59R/108N allele showed consistently high prevalence levels reaching 33.3% in 2008. Moreover, the single Pfdhfr 164L mutant allele, a haplotype unique to Madagascar, was discovered in 2006 and showed prevalence rates up to 30% in some locations (southeast) in 2008. Up to now, the quadruple mutant allele Pfdhfr 51I/59R/108N/164L has not been observed. Susceptibility to the other antimalarials tested appeared excellent but the number of isolates showing in vitro susceptibility to artemisinin derivatives has been fallen in recent years and this decline may herald a decrease in the efficacy of these drugs.

Plasmodium falciparum resistance to chloroquine first arose in Africa 25 years ago. Nowadays most of African malaria control programmes have switched their first-line treatment of uncomplicated malaria cases towards artemisinin derivatives combination. After WHO guidelines, a survey network for malaria treatment resistance has been set up in the Niger valley around Niamey since December 2004. The association of the Niger national malaria control programme with the CERMES research center allowed collecting of samples from both health centers and hospitals of this region. Blood finger-pricks on filter papers were tested for detection of plasmodial antigen in health center without biological diagnosis capacity. Specimens found positive either in hospital laboratory or by using antigen method were tested by PCR/RFLP to detect K76T mutations on the pfcrt gene and S108N mutation on the pfdhfr gene. This simple procedure allows the screening of a large number of specimens. Moreover, a spatial distribution of mutations and evidence of resistance clusters were searched integrating the data in a geographic information system. The 76T mutation of pfcrt and 108N of pfdhfr were respectively found in 50.8% and 57% of the specimens tested. No statistically significant difference was found according to the level of sanitary formations or the age of the patients. No resistance cluster was identified and the prevalence of mutation seems homogeneous in the zone. By completing the clinical efficacy studies we think that our simple method for collecting and testing blood samples associated with clinical efficacy studies may be useful for building a network of malaria drug resistance in Africa.

Introduction: Homocysteine lies at an important metabolic branch point; it may be either converted to cystathionine through the transsulfuration pathway, or methylated to form methionine. Hyperhomocysteinemia may result from hereditary defects affecting one of these reactions., State of Art: Cystathionine beta synthase or 5,10-methylenetetrahydrofolate deficiency can both result in homocystinuria. Current knowledge about biochemical mechanisms leading to hyperhomocysteinemia, clinical and radiological features, pathogenesis and treatment are reviewed, focusing on late onset forms of these diseases which can be diagnosed in adulthood. CBS deficiency is characterized by lens dislocation, skeletal abnormalities, neurologic disturbances and thromboembolism. MTHFR deficiency leads to various neurological symptoms, ranging from developmental delay to encephalopathy, including motor and gait abnormalities, seizures, psychiatric manifestations and rarely strokes. The treatment of CBS deficiency depends on vitamin B6, whereas MTHFR deficiency can be efficiently treated by vitamin B12, folic acid, and betaine., Perspectives: Homocysteinemia should be measured in patients with unexplained neurological manifestations or thromboembolism.

A major endemic in Côte d'Ivoire, malaria is the first cause of hospital admissions and mortality in tropical Africa. The decrease of morbidity and mortality depends on early diagnosis and relevant treatment. This situation is hampered by an emerging resistance of P. falciparum to usual drugs such as chloroquine and sulfadoxine-pyrimethamine. In recognition of this problem, we established a monitoring system in the north of Abidjan (Yopougon) in order to better analyse P. falciparum resistance. The molecular basis of P. falciparum resistance to pyrimethamine is associated with point mutations in the dihydrofolate reductase (dhfr) gene. The presence of a wild-type codon 108-ser is defined by the presence of an Alu1 restriction site. A single base change resulting in the change of amino acid from 108-Ser to 108-Asn or 108-Thr results in the appearance of a Bsr1 or a Scrf1 restriction site respectively. In response to these needs, 42 children aged 6 to 59 months were enrolled in the study by using tests of therapeutic efficacy of chloroquine (14-day in vivo test of WHO). Before treatment, infected blood samples were stored at 20 C until P. falciparum DNA extraction. The results of the in vivo sensitivity of chloroquine showed 84.3% of plasmodic rate, 97.7 % of P. falciparum against 2.3% of P. malariae. However, 78.6% of adequate clinical response (ACR) was obtained and 21.4% of early therapeutic failure (ETF). At the end of the study, clearance of parasitemia and fever was obtained but the gametocytic rate was 4.8%. More, RFLP studies of amplified DNA fragment revealed that P. falciparum from 12 children (44.5%) had point mutation in the codon 108 of the dhfr gene. The mutation of these isolates was based on the change of amino-acid from 108-Ser to 108-Asn. Moreover, 51.8% of isolates were of the wild type. In conclusion, our results showed that chloroquine resistance is a reality in Abidjan just like anywhere else in West Africa. However, the number of isolates which had point mutation in the dhfr gene suggested that the future approach must be the study of possible correlation between the in vivo sulfadoxine-pyrimethamine test and point mutations in the dihydrofolate reductase and in the dihydropteroate synthase gene of P. falciparum from Côte d'Ivoire.

The in vitro susceptibility of chloroquine and the genomic profile of dihydrofolate reductase (DHFR) codon 108 was determined against african isolates of P. falciparum (Pf) from imported malaria cases without previous drug intake by an isotopic microtest or PCR + RFLP. Pf resistance to chloroquine or to the DHFR inhibitor was present in 49% and 46% of isolates, respectively. Pf drug resistance was more frequent in permanent than in seasonal malarial transmission areas and chloroquine plus DHFR resistance reached 28% in years 1995-97. Updating the guidelines for the prevention of malaria in travellers to Africa is necessary.

The trimethoprim-resistant dihydrofolate reductase specified in E. coli by plasmid R 67, when compared, with other enzymes catalyzing the same reaction, to have a dissimilar primary, secondary, tertiary and quaternary structure. In regard to the tertiary structure, we show here that the pteridine binding site, in the plasmid-encoded enzyme, has a geometrical similarity with that of other chromosomal specified reductases.