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J Le Bras

Publications and source records attributed to J Le Bras.

At least 19 recordsLinked to original sources
PubMed2006

Report of a case of congenital malaria Plasmodium malariae in France.

Congenital malaria (CM) has been considered to be rare, even in malaria-endemic areas but the disease can result in significant neonatal morbidity. Because of its rarity, the disease may go undiagnosed for a prolonged period in a seriously ill infant. We report the first case of Plasmodium malariae CM from a HIV mother. HIV could have facilitated the transfer of erythrocytic persistent P. malariae through the placenta to the fetus.

Adult↗
PubMed2006

[Antimalarial drug resistance].

Drug resistant malaria is mostly due to Plasmodium falciparum, the highly prevalent species in tropical Africa, Amazon, and Southeast Asia. P. falciparum is responsible for severe involvement of fever or anemia causing more than a million deaths per year. Rationale for treatment is becoming weak as multiple drug resistance against well-tolerated drugs develops. P. falciparum drug resistant malaria originates from chromosomal mutations. Analyses using molecular, genetic and biochemical approaches showed that: 1) impaired uptake of chloroquine by the parasite vacuole is a common characteristic of resistant strains, this phenotype correlates with pfmdr1 and pfcrt gene mutations; 2) one S108N to four (N51I, C59R, I164L) point mutations of dihydrofolate reductase, the enzyme target of antifolinics (pyrimethamine and proguanil), give moderate to high level of resistance to these drugs; 3) resistance to sulfonamides and sulfones involves mutations of dihydropteroate synthase (A437G, K540E), their enzyme target, impairing their capacity to potentiate antifolinic drugs; 4) resistance to atovaquone plus proguanil involves one single mutation on atovaquone target, cytochrome b (Y268S, C or N); 5) resistance to mefloquine is thought to be linked to the over expression of pfmdr1, a pump expelling toxic waste from eukaryotic cells. P. falciparum resistance levels may differ according to places and time, depending on malaria transmission and drug pressure. Coupling in vivo to in vitro tests, and using molecular tests is essential for the surveillance of replacement drugs. Low cost biochemical tools are urgently needed for a prospective monitoring of resistance.

Animals↗
PubMed2003

Molecular survey of Plasmodium falciparum resistance in south-eastern Iran.

In south-eastern Iran, the sulfadoxine-pyrimethamine (SP) combination has been used to treat malaria caused by chloroquine-resistant Plasmodium falciparum. To explore the molecular basis of antimalarial resistance in this region, the dhfr, dhps and pfcrt genes of 50 clinical isolates of P. falciparum, collected from cases of uncomplicated malaria in 2000-2001, were checked for the point mutations that appear associated with SP or chloroquine (CQ) resistance. The results of the study, which was based on a PCR followed by DNA sequencing, indicated that all 50 isolates presented the DHFR S108N mutation associated with pyrimethamine resistance. Seven isolates (14%) had a triple DHFR mutation (S108N, N51I, C59R) and 32 (64%) had a double mutation in this domain. Thirty-nine isolates (78%) had the wild-type DHFR 51 codon but only 15 (30%) had the wild-type DHFR 59 codon. Eleven isolates (22%) only had the DHFR S108N mutation. All isolates had the wild-type DHPS 436 and 540 codons and all but two of the isolates had the wild-type DHPS 437 codon. All isolates but one had the PFCRT K76T mutation associated with CQ treatment failure. The results of this preliminary investigation indicate that SP may remain the treatment of choice for cases of uncomplicated malaria in south-eastern Iran.

Adolescent↗
PubMed2003

[Imported malaria in 2000 in 2 northern Paris hospitals].

The number of travellers in malaria striken areas increases each year (2). The risk of infection is high in Sub-Saharan Africa, but appropriate chemoprophylaxis can reduce the morbidity and mortality rate of malaria. Half of the samples of malaria cases received by the National reference centre of malaria chemosensibility (CNRCP) for chemosensibility analysis came from two hospitals in the north of Paris: Bichat Claude Bernard in Paris and Delafontaine in Saint-Denis. In 2000, quite all the malaria cases (n = 387) observed at the Bichat and Delafontaine Hospitals came from Africa (99%). Plasmodium falciparum remains the most represented (87.6%) species, with an average parasitic density of 0.3%. Patients with P falciparum came for medical advice on the tenth day after return (median, extremes 0-174 days). More than half of the patients (58%) did not take any medication for chemoprophylaxis and even if they took some, it was irregular or inappropriate. The most used drug chemoprophylaxis is the association of chloroquine and proguanil or Savarine. In 15% of the cases, the travellers took chloroquine as a prophylaxis and 4% other medicine not recommended by the French authorities. An average of 43.7% of these travellers took inappropriate chemoprophylaxis. In total, 27 chemoprophylaxis failures are reported. Some patients (22%) have already taken self treatment which was readjusted during admission at hospital. The first treatment of malaria in 2000 was monotherapy with quinine (P. falciparum) and chloroquine (P. ovale, malariae, vivax). The treatment associations in case of suspicious resistance were quinine + doxycycline and atovaquone + proguanil. Treatment failure was infrequent and resulted above all from a bad observance. More information should be given to travellers as well as doctors about recommendations and treatments.

Africa↗
PubMed2002

Molecular characterisation of airport malaria: four cases in France during summer 1999.

Four airport malaria cases have been observed in the vicinity of the Roissy-Charles-de-Gaulle International Airport, Paris, France. These cases were geographically very close to each other and clustered in a short period of time during the summer of 1999. The phenotype and genotype of the Plasmodium falciparum isolates obtained from these patients were determined in order to know whether a single mosquito could have infected more than one subject. The genomic characterisation of isolates was performed using the polymorphic markers merozoite surface protein 1 (Msp 1) and merozoite surface protein 2 (Msp 2) genes, the kappa and omega repeats domains of cg2 and the dihydrofolate reductase (DHFR) genotypes. Results showed identical genotypes for isolates 1, 2 and 4 whereas the genotype of isolate 3 differed at one locus. The molecular analysis was consistent with the hypothesis that all patients could have been bitten by the same mosquito and that patient 3, may have received a different clone and an additional species. In vitro susceptibility data did not confirm or rule out this hypothesis because isolates had the same profile of susceptibility to the tested drugs.

Adult↗
PubMed2002

Iron chelators as antimalarial agents: in vitro activity of dicatecholate against Plasmodium falciparum.

The present study was undertaken to explore the antimalarial effect of a series of dicatecholate iron chelators. They may be made more or less lipophilic by increasing or reducing the length of the R substituent on the nitrogen. In vitro activity against the W2 and 3D7 clones of Plasmodium falciparum, toxicity on Vero cells and toxicity on uninfected erythrocytes by measure of the released haemoglobin were assessed for each compound. These findings were compared with the ability of iron(III), iron(II) and ferritin to reverse the inhibitory effect of catecholates. This study shows that increased lipid solubility of catecholate iron chelators does not lead to improved antimalarial activity. However, their activity is well correlated with their interaction with iron and with their toxicity against Vero cells. This study demonstrates a potent antimalarial effect of FR160 (R = C9H19) on five different strains of P. falciparum in vitro. FR160 inhibited parasite growth with an IC50 between 0.8 and 1.5 micro M. The effects of FR160 on mammalian cells were minimal compared with those obtained with malaria parasites. FR160 acted on parasites at considerably higher rates than desferrioxamine, and at all stages of parasite growth. The drug was more effective at the late trophozoite and young schizont stages, although FR160 affected rings and schizonts as well. Ascorbic acid, a free radical scavenger, reduced the activities of FR160 and artesunate. FR160 might induce formation of free radicals, which could explain why FR160 antagonized the effects of artesunate and dihydroartemisinin.

Animals↗
PubMed2002

Profile and evolution of the chemosusceptibility of falciparum malaria imported into France in 2000.

In 2000, the chemosusceptibility of imported malaria was stable in France. All countries of infection considered, the bi-resistance to chloroquine and cycloguanil has not changed from 1996 to 2000. The monotherapy using quinine or mefloquine remains the first-line treatment to falciparum malaria. Resistance to these two antimalarials is rare in Africa and has not evolved over the past 15 years.

Adolescent↗
PubMed2001

Analysis of pfcrt point mutations and chloroquine susceptibility in isolates of Plasmodium falciparum.

Recent transfection based studies demonstrated that cg2, a candidate gene for chloroquine resistance in Plasmodium falciparum, was not the resistance determinant. A further analysis of the initial 36 kb locus comprising the cg2 gene led to the discovery of another gene, pfcrt, which was absolutely associated with chloroquine resistance in forty parasite lines [Fidock DA, Nomura T, Talley AT, Su XZ, Cooper R, Dzekunov SM, Ferdig MT, Ursos LMB, Sidhu ABS, Naudé B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 2000;6:861-71]. The aim of this study was to evaluate, in 146 unselected clinical isolates obtained mostly from non-immune travellers returning from various endemic countries to France in years 1995-1999, the association between in vitro chloroquine resistance and the sequence of a part of the pfcrt gene. For comparison, the determination of the cg2 kappa and the pfmdr1 codon 86 genotypes were also performed on the same isolates. As determined by an isotopic semi-microtest, 70 isolates were susceptible to chloroquine (50% inhibitory concentration<80 nM) and 76 were resistant. The amplification of a portion of the pfcrt gene spanning codons 72-76, followed by sequencing showed three distinct genotypes: one type associated with susceptible isolates, one type associated mostly with resistant isolates and one type found in a resistant isolate originating from South America. Three different zones could be defined according to the status of codon 76. For 50% inhibitory concentration values< or =40 nM (n=47), all isolates but one had K76 (wild type). For 50% inhibitory concentration values located between 40 and 60 nM, isolates had either K76 (n=5) or K76T (mutant type) (n=6). For 50% inhibitory concentration values>60 nM (n=88), all isolates had K76T. A lack of a strong association between the pfmdr1 N86Y mutation and in vitro chloroquine resistance was observed. Cg2 genotypes were less strongly linked than pfcrt genotypes with in vitro chloroquine susceptibility in isolates located below 40 and above 60 nM. Further studies are needed to determine the reliability of the pfcrt gene as a genetic marker for chloroquine resistance.

Adolescent↗
PubMed2001

[Molecular aspects of chloroquine and antifols resistance in P. falciparum].

Drug resistant malaria is mostly due to Plasmodium falciparum, a species highly prevalent in tropical Africa, Amazon and Southeast Asia. P. falciparum is responsible for severe involvement of fever or anaemia prompting more than a million deaths per year. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality in some human populations from endemic regions. Rationale for chemoprophylaxis is becoming week as multiple drug resistance against well tolerated drugs develops. Plasmodium falciparum drug resistant malaria originate from chromosomal mutations. Analysis using molecular, genetic and biochemical approaches has shown that Epidemiological studies have established that the frequency of chloroquine resistant mutants varies among parasites isolates populations while resistance to antifolinics is highly prevalent in most malarial endemic countries. An established and strong drug pressure and a low antiparasitic immunity probably explains the multidrug-resistance encountered in forests of Southeast Asia and South America. In Africa, frequent genetic recombinations in Plasmodium originate from a high level of malaria transmission, and falciparum chloroquine-resistant prevalence seems to stabilise at an equal level as chloroquine-sensitive malaria. Nevertheless, resistance levels may differs according to places and time. In vivo and in vitro tests are insufficient to give an accurate map of resistance. Biochemical tools at a low cost are urgently needed for a prospective monitoring of resistance.

Animals↗
PubMed2001

[Plasmodium falciparum: point mutations of pcfrt and chloroquine susceptibility].

Recent transfection based studies demonstrated that cg2, a candidate gene for chloroquine resistance in Plasmodium faiciparum, was not the resistance determinant. A further analysis of the initial 36 kb locus comprising the cg2 gene led to the discovery of another gene, pfcrt, which was absolutely associated with chloroquine resistance in forty parasite lines. The aim of this study was to evaluate, in 146 unselected clinical isolates obtained mostly from non-immune travellers returning from various endemic countries to France in years 1995-1999, the association between in vitro chloroquine resistance and the sequence of a part of the pfcrt gene. For comparison, the determination of the cg2 kappa and the pfmdr1 codon 86 genotypes were also performed on the same isolates. As determined by an isotopic semi-microtest, 70 isolates were susceptible to chloroquine (50% inhibitory concentration < 80 nM) and 76 were resistant. The amplification of a portion of the pfcrt gene spanning codons 72 to 76, followed by sequencing showed three distinct genotypes: one type associated with susceptible isolates, one type associated mostly with resistant isolates and one type found in a resistant isolate originating from South America. Three different zones could be defined according to the status of codon 76. For 50% inhibitory concentration values < or = 40 nM (n = 47), all isolates but one had K76 (wild type). For 50% inhibitory concentration values located between 40 and 60 nM, isolates had either K76 (n = 5) or K76T (mutant type) (n = 6). For 50% inhibitory concentration values > 60 nM (n = 88), all isolates had K76T. A lack of a strong association between the pfmdr1 N86Y mutation and in vitro chloroquine resistance was observed. Cg2 genotypes were less strongly linked than pfcrt genotypes with in vitro chloroquine susceptibility in isolates located below 40 nM and above 60 nM. Further studies are needed to determine the reliability of the pfcrt gene as a genetic marker for chloroquine resistance.

Animals↗
PubMed2000

Use of molecular beacons to detect an antifolate resistance-associated mutation in Plasmodium falciparum.

A PCR-based technique using new fluorescent probes, called molecular beacons, was developed to detect the antifolate resistance-associated S108N point mutation in Plasmodium falciparum. One hundred African clinical isolates were tested by the new method in comparison with the PCR-restriction fragment length polymorphism method. This new molecular technique appears to be a promising tool for epidemiological studies.

Animals↗
PubMed1999

Analysis of kappa and omega repeats of the cg2 gene and chloroquine susceptibility in isolates of Plasmodium falciparum from sub-Saharan Africa.

The correlation between the structure of two short sequences from the Plasmodium falciparum cg2 gene and parasite chloroquine susceptibility was evaluated in unselected clinical isolates obtained from travellers returning mainly from Africa to France in 1995 and 1996. As determined by an isotopic semi-microtest, 74 isolates were susceptible to chloroquine (50% inhibitory concentration < 80 nM), 13 were intermediate (80 nM < 50% inhibitory concentration < 110 nM) and 53 were resistant (50% inhibitory concentration > 110 nM). Two polymerase chain reaction assays were developed, one for the kappa and one for the omega repeat domains of cg2 gene. The kappa and the omega repeat domains of 99 isolates were sequenced. A variation in the unit number of kappa and omega repeats was observed. Variations in repetitive sequences, which were not previously described, were found: three for the kappa repeat region: kappa9; kappa10 and kappa11 and three for the omega repeat region: omega8; omega9 and omega22. A polymorphism was observed inside the repeat units of kappa and omega regions. There were six possible kappa repeat units and seven possible omega repeat units. The presence of a particular pattern, containing kappa14 and omega16 repeat units, was associated with a lack of chloroquine susceptibility in 44 out of 46 cases. However, not all resistant isolates had this 'resistant' genotype. Among 43 resistant isolates, 36 (84%) had the kappa14 repeats sequence and 36 had the omega16 repeats sequence. These results lend further support to linkage between cg2 polymorphisms and chloroquine resistance without excluding the existence of other resistance component(s).

Adolescent↗
PubMed1999

In vitro activities of benflumetol against 158 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs.

The 50% inhibitory concentration (IC50s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) for 158 Senegalese isolates were evaluated. Ten isolates (6%) showed decreased susceptibility to benflumetol. Benflumetol was slightly more potent against chloroquine-resistant isolates (P < 0.025). No correlation or weak correlations in the responses to benflumetol and pyrimethamine, chloroquine, amodiaquine, artemether, quinine, and pyronaridine were observed, and these correlations are insufficient to suggest cross-resistance. Benflumetol may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Animals↗
PubMed1999

[Diagnostic test to identify human Plasmodium species by the quantitative buffy coat test].

The quantitative buffy coat system (QBC Test) was designed for rapid diagnosis of malaria by identifying the presence of hemoparasites. The main drawback of the technique is failure to identify the Plasmodium species. The purpose of this study was to attempt to remedy this problem by studying the distribution of the parasites at the bottom of the test tube. Indeed since the QBC Test is based on gradient centrifugation of blood components, the distribution of the parasites in the test tube depends on density. Blind QBC Tests were performed on specimens obtained from two different batches, i.e., one from France and the other from Burkina Faso. Distribution curves were obtained by counting the number of parasites in all microscopic fields in the five-millimeter test tube. Our findings showed differences in distribution curve depending on species. For Plasmodium falciparum, the number of parasites was nearly the same in all fields suggesting that the arrangement of the parasites in the QBC Test tube was linear. For Plasmodium vivax and Plasmodium ovale, the number of parasites was markedly lower near the cap of the tube suggesting that a non-linear arrangement with a decreasing number of parasites toward the top of the tube. In 97 p. 100 of cases, we were able to propose a differential diagnosis of Plasmodium falciparum versus Plasmodium vivax or Plasmodium ovale. However it was not possible to distinguish between Plasmodium vivax and Plasmodium ovale. In case of mixed infection it would be difficult to distinguish Plasmodium falciparum from the other species. The ability to identify Plasmodium species would add to the advantages of the rapid and sensitive QBC Test.

Animals↗
PubMed1998

[Considering disparities in resistance of Plasmodium falciparum in Africa in chemoprevention decisions].

OBJECTIVES: Assess the efficacy of preventive and curative treatments of imported malaria. METHODS: The in vitro drug susceptibility of mefloquine, chloroquine and cycloguanil was determined against African isolates of Plasmodium falciparum from imported malaria cases by an isotopic in vitro test or a genomic approach. RESULTS: Plasmodium falciparum resistance to mefloquine, chloroquine or to the dihydrofolate reductase inhibitor was present in 5.2%, 46% and 42% of isolates respectively. Plasmodium falciparum drug resistance to chloroquine or antifolinics was more frequent in permanent than in seasonal malarial transmission areas. Simultaneous resistance to chloroquine and antifolinics was observed in 17% of isolates between 1991 and 1994 and in 28% between 1995 and 1997.

Africa↗