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Biomedical subjects

O K Doumbo

Publications and source records attributed to O K Doumbo.

18 recordsLinked to original sources
PubMed2005

Spleen enlargement and genetic diversity of Plasmodium falciparum infection in two ethnic groups with different malaria susceptibility in Mali, West Africa.

The high resistance to malaria in the nomadic Fulani population needs further understanding. The ability to cope with multiclonal Plasmodium falciparum infections was assessed in a cross-sectional survey in the Fulani and the Dogon, their sympatric ethnic group in Mali. The Fulani had lower parasite prevalence and densities and more prominent spleen enlargement. Spleen rates in children aged 2-9 years were 75% in the Fulani and 44% in the Dogon (P<0.001). There was no difference in number of P. falciparum genotypes, defined by merozoite surface protein 2 polymorphism, with mean values of 2.25 and 2.11 (P=0.503) in the Dogon and Fulani, respectively. Spleen rate increased with parasite prevalence, density and number of co-infecting clones in asymptomatic Dogon. Moreover, splenomegaly was increased in individuals with clinical malaria in the Dogon, odds ratio 3.67 (95% CI 1.65-8.15, P=0.003), but not found in the Fulani, 1.36 (95% CI 0.53-3.48, P=0.633). The more susceptible Dogon population thus appear to respond with pronounced spleen enlargement to asymptomatic multiclonal infections and acute disease whereas the Fulani have generally enlarged spleens already functional for protection. The results emphasize the importance of spleen function in protective immunity to the polymorphic malaria parasite.

Adolescent↗
PubMed2005

Distinct interethnic differences in immunoglobulin G class/subclass and immunoglobulin M antibody responses to malaria antigens but not in immunoglobulin G responses to nonmalarial antigens in sympatric tribes living in West Africa.

The well-established relative resistance to malaria observed in the Fulani as compared with other sympatric tribes in West Africa has been attributed to their higher levels of serum immunoglobulin (Ig) G antibodies to malarial antigens. In this study, we confirm and extend the previous findings by analyses of the levels of IgM, IgG and IgG subclasses of anti-malarial antibodies in asymptomatic individuals of different sympatric tribes in Burkina Faso (Fulani/Mossi) and Mali (Fulani/Dogon). The Fulani showed significantly higher median concentrations of anti-malarial IgG and IgM antibodies than the sympatric tribes at both locations. Although the overall subclass pattern of antibodies did not differ between the tribes, with IgG1 and IgG3 as dominant, the Fulani showed consistently significantly higher levels of these subclasses as compared with those of the non-Fulani individuals. No significant differences were seen in the levels of total IgG between the tribes, but the Fulani showed significantly higher levels of total IgM than their neighbours in both countries. While the antibody levels to some nonmalarial antigens showed the same pattern of differences seen for antibody levels to malaria antigens, no significant such differences were seen with antibodies to other nonmalarial antigens. In conclusion, our results show that the Fulani in two different countries show higher levels of anti-malarial antibodies than sympatric tribes, and this appears not to be a reflection of a general hyper-reactivity in the Fulani.

Adolescent↗
PubMed2004

Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci.

The allelic and haplotypic diversity of the HLA-A, HLA-B, and HLA-C loci was investigated in 852 subjects from five sub-Saharan populations from Kenya (Nandi and Luo), Mali (Dogon), Uganda, and Zambia. Distributions of genotypes at all loci and in all populations fit Hardy-Weinberg equilibrium expectations. There was not a single allele predominant at any of the loci in these populations, with the exception of A*3002 [allele frequency (AF) = 0.233] in Zambians and Cw*1601 (AF = 0.283) in Malians. This distribution was consistent with balancing selection for all class I loci in all populations, which was evidenced by the homozygosity F statistic that was less than that expected under neutrality. Only in the A locus in Zambians and the C locus in Malians, the AF distribution was very close to neutrality expectations. There were six instances in which there were significant deviations of allele distributions from neutrality in the direction of balancing selection. All allelic lineages from each of the class I loci were found in all the African populations. Several alleles of these loci have intermediate frequencies (AF = 0.020-0.150) and seem to appear only in the African populations. Most of these alleles are widely distributed in the African continent and their origin may predate the separation of linguistic groups. In contrast to native American and other populations, the African populations do not seem to show extensive allelic diversification within lineages, with the exception of the groups of alleles A*02, A*30, B*57, and B*58. The alleles of human leukocyte antigen (HLA)-B are in strong linkage disequilibrium (LD) with alleles of the C locus, and the sets of B/C haplotypes are found in several populations. The associations between A alleles with C-blocks are weaker, and only a few A/B/C haplotypes (A*0201-B*4501-Cw*1601; A*2301-B*1503-Cw*0202; A*7401-B* 1503-Cw*0202; A*2902-B*4201-Cw*1701; A*3001-B*4201-Cw*1701; and A*3601-B*5301-Cw*0401) are found in multiple populations with intermediate frequencies [haplotype frequency (HF) = 0.010-0.100]. The strength of the LD associations between alleles of HLA-A and HLA-B loci and those of HLA-B and HLA-C loci was on average of the same or higher magnitude as those observed in other non-African populations for the same pairs of loci. Comparison of the genetic distances measured by the distribution of alleles at the HLA class I loci in the sub-Saharan populations included in this and other studies indicate that the Luo population from western Kenya has the closest distance with virtually all sub-Saharan population so far studied for HLA-A, a finding consistent with the putative origin of modern humans in East Africa. In all African populations, the genetic distances between each other are greater than those observed between European populations. The remarkable current allelic and haplotypic diversity in the HLA system as well as their variable distribution in different sub-Saharan populations is probably the result of evolutionary forces and environments that have acted on each individual population or in their ancestors. In this regard, the genetic diversity of the HLA system in African populations poses practical challenges for the design of T-cell vaccines and for the transplantation medical community to find HLA-matched unrelated donors for patients in need of an allogeneic transplant.

Africa South of the Sahara↗
PubMed2004

Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls.

Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, <5 g/dl), 18 cases combined cerebral malaria with severe anemia, and 92 cases with hyperparasitemia (asexual trophozoites, >500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = <0.001), IL-10 (1,099.3 versus 14.1; P = <0.001), tumor necrosis factor alpha (10.1 versus 7.7; P = <0.001), and IL-12(p70) (48.9 versus 31.3; P = 0.004) in serum were found in severe cases versus healthy controls. Significantly elevated levels of IL-6 (485.2 versus 141.0; P = <0.001) and IL-10 (1,099.3 versus 133.9; P = <0.001) were seen in severe malaria cases versus uncomplicated malaria controls. Cerebral malaria was associated with significantly elevated levels of IL-6 (754.5 versus 311.4; P = <0.001) and IL-10 (1,405.6 versus 868.6; P = 0.006) compared to severe malaria cases without cerebral manifestations. Conversely, lower levels of IL-6 (199.2 versus 487.6; P = 0.03) and IL-10 (391.1 versus 1,160.9; P = 0.002) were noted in children with severe anemia compared to severe malaria cases with hemoglobin at >5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.

Adolescent↗
PubMed2002

Erythrocyte CR1 expression level does not correlate with a HindIII restriction fragment length polymorphism in Africans; implications for studies on malaria susceptibility.

Complement receptor 1 (CR1) expression level on erythrocytes is genetically determined, and in Caucasian populations is linked to high (H) and low (L) expression alleles identified by a HindIII restriction fragment length polymorphism (RFLP). Erythrocyte CR1 may be an important factor in determining malaria susceptibility, as low expression of CR1 reduces the rosetting of uninfected erythrocytes with Plasmodium falciparum-infected cells, a process that contributes to malaria pathogenesis. Prior to studying CR1 expression and malaria susceptibility, we have investigated whether the quantity of erythrocyte CR1 correlates with the H and L alleles in an African population. Mean erythrocyte CR1 in 149 Malian adults was 415 molecules per cell, which is comparable to Caucasian populations; however, there was no relationship between erythrocyte CR1 level and genotype for the HindIII RFLP (mean CR1 per erythrocyte HH = 414, HL = 419 and LL = 403, P > 0.1, Student's t-test). The conclusions of a previous study of erythrocyte CR1 expression level and malaria susceptibility in West Africa that was based on HindIII RFLP genotyping may therefore need to be re-evaluated.

Black or African American↗
PubMed2002

Expansion of the Knops blood group system and subdivision of Sl(a).

BACKGROUND: Complement receptor type 1 (CR1), which bears the Knops (Kn [KN]) blood group antigens, is involved in the rosetting of Plasmodium falciparum- infected RBCs with uninfected cells. As a first step in understanding this interaction, the molecular basis for the blood group antigens encoded by CR1 was investigated. STUDY DESIGN AND METHODS: An antibody from a white donor who exhibited an apparent anti-Sl(a) was used for population studies of several racial groups. The donor's genomic DNA was sequenced to identify the Sl(a) mutation and other mutations. RESULTS: The donor with anti-Sl(a) typed as Sl(a+) with some sera and had the CR1 genotype AA at bp 4828 (R1601). However, she was homozygous for a new mutation (GG) at bp 4855 changing amino acid 1610 from S1610 to T1610 (S1610T). This mutation occurred in heterozygous form in eight white and one Asian donor. The site is only nine amino acids from the previously described Sl(a) polymorphism and appears to produce a new conformational epitope. CONCLUSION: The antigen formerly known as Sl(a) can now be subdivided. A new terminology is proposed that recognizes both linear and conformational epitopes on the CR1 protein. At amino acid 1601, Sl 1 (Sl(a)) is represented by R, Sl 2 (Vil) is represented by glycine, and Sl 3 requires both R1601 and S1610. Sl 4 and Sl 5 are hypothetical epitopes represented by S1610 and T1610, respectively.

Amino Acid Sequence↗
PubMed2001

Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1.

Complement receptor 1 (CR1) has been implicated in rosetting of uninfected red blood cells to Plasmodium falciparum-infected cells, and rosette formation is associated with severe malaria. The Knops blood group (KN) is located on CR1 and some of these antigens, ie, McCoy (McC) and Swain-Langley (Sl(a)), show marked frequency differences between Caucasians and Africans. Thus, defining the molecular basis of these antigens may provide new insight into the mechanisms of P falciparum malaria. Monoclonal antibody epitope mapping and serologic inhibition studies using CR1 deletion constructs localized McC and Sl(a) to long homologous repeat D of CR1. Direct DNA sequencing of selected donors identified several single nucleotide polymorphisms in exon 29 coding for complement control protein modules 24 and 25. Two of these appeared to be blood group specific: McC associated with K1590E and Sl(a) with R1601G. These associations were confirmed by inhibition studies using allele-specific mutants. A sequence-specific oligonucleotide probe hybridization assay was developed to genotype several African populations and perform family inheritance studies. Concordance between the 1590 mutation and McC was 94%; that between Sl(a) and 1601 was 88%. All but 2 samples exhibiting discrepancies between the genotype and phenotype were found to be due to low red cell CR1 copy numbers, low or absent expression of some alleles, or heterozygosity combined with low normal levels of CR1. These data further explain the variability observed in previous serologic studies of CR1 and show that DNA and protein-based genetic studies will be needed to clarify the role of the KN antigens in malaria.

Animals↗
PubMed2001

A molecular marker for chloroquine-resistant falciparum malaria.

BACKGROUND: Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively. METHODS: To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine. RESULTS: The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P<0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1). CONCLUSIONS: This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria.

Adult↗
PubMed2000

Rapid selection of Plasmodium falciparum dihydrofolate reductase mutants by pyrimethamine prophylaxis.

A prospective study was conducted to measure the selective effect of pyrimethamine prophylaxis on point mutations in Plasmodium falciparum dihydrofolate reductase (DHFR). A total of 109 Malian children were given pyrimethamine weekly for 5 weeks. P. falciparum infections were analyzed by polymerase chain reaction for DHFR mutations, which were dramatically more frequent among prophylaxis-breakthrough infections than at baseline: the prevalence of Asn-108 rose from 13% to 100%, Ile-51 from 4% to 50%, and Arg-59 from 11% to 90%. Eight persistent infections lacking detectable DHFR mutations at baseline developed multiple mutations within 1 week of the patients' starting pyrimethamine prophylaxis. Microsatellite analysis found no evidence of clonal identity among baseline and breakthrough infections. Analysis of these data demonstrates that under prophylaxis conditions, pyrimethamine is strongly selective for DHFR mutations, which arise extremely rapidly under drug pressure, even when undetectable in the initial infection. These findings have implications for prophylaxis regimens with other antifolate drugs.

Animals↗
PubMed1999

Pyrimethamine-sulfadoxine efficacy and selection for mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase in Mali.

To assess pyrimethamine-sulfadoxine (PS) efficacy in Mali, and the role of mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in in vivo PS resistance, 190 patients with uncomplicated P. falciparum malaria were treated with PS and monitored for 56 days. Mutation-specific polymerase chain reactions and digestion with restriction endonucleases were used to detect DHFR and DHPS mutations on filter paper blood samples from pretreatment and post-treatment infections. Only one case each of RI and RII level resistance and no cases of RIII resistance or therapeutic failure were observed. Post-PS treatment infections had significantly higher rates of DHFR mutations at codons 108 and 59. No significant selection for DHPS mutations was seen. Pyrimethamine-sulfadoxine is highly efficacious in Mali, and while the low level of resistance precludes assessing the utility of molecular assays for in vivo PS resistance, rapid selection of DHFR mutations supports their role in PS failure.

Animals↗
PubMed1998

P. falciparum dihydrofolate reductase and dihydropteroate synthase mutations: epidemiology and role in clinical resistance to antifolates.

Plasmodium falciparum resistance to the antifolates has arisen rapidly in Asia and South America, and threatens the usefulness of these drugs in Africa. In vitro resistance to the antifolates is determined by mutations in parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). The role of DHFR and DHPS mutations in therapeutic failure of antifolate antimalarials is less clear. This review summarizes molecular epidemiological surveys, studies of in vivo selection of mutant alleles by drug treatment, and prospective studies of the ability of mutation-specific assays to predict clinical outcomes, and discusses the potential use of these assays for surveillance of resistance.

Journal Article↗
PubMed1998

Doctoral training of African scientists.

There are two principal rationales for doctoral training of African scientists in health: 1) these scientists are essential for the nations of sub-Saharan Africa to define and implement their own health priorities, and 2) the research they perform is essential for development. However, this training is difficult because of its expense (> $20,000 per year), because many developed country mentors are unaware of the realities of research in sub-Saharan Africa, and because major differences in salary provide a financial disincentive to return. We describe a training strategy that reduces attrition because it is linked to the investigators' responsibilities before and after training, and to home country priorities. This strategy requires a close relationship between the developing country (on-site) and developed country (off-site) mentors, with joint participation in the selection and funding process, followed by course work and short-term, independent projects off-site that lead to a thesis project in the developing country, and subsequently to a defined professional position in the developing country after completion of the doctoral degree. For this strategy to succeed, the developed country mentor must have both field experience and investigative expertise; the developing country mentor must have an understanding of modern biology, as well as clinical and epidemiologic experience. In addition, we would like to emphasize that the long-term retention of these talented, highly-trained individuals requires a similar long-term commitment by their developed country mentors, well beyond the short term of most research funding.

Africa South of the Sahara↗
PubMed1997

Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance.

To assess the relationship between mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) and clinical pyrimethamine-sulfadoxine resistance, polymerase chain reaction surveys and analyses for new mutations were conducted in four countries with increasing levels of pyrimethamine-sulfadoxine resistance: Mali, Kenya, Malawi, and Bolivia. Prevalence of mutations at DHFR codon 108 and a new mutation at DHPS 540 correlated with increased pyrimethamine-sulfadoxine resistance (P < .05). Mutations at DHFR 51, DHFR 59, and DHPS 437 correlated with resistance without achieving statistical significance. Mutations at DHFR 164 and DHPS 581 were common in Bolivia, where pyrimethamine-sulfadoxine resistance is widespread, but absent in African sites. Two new DHFR mutations, a point mutation at codon 50 and an insert at codon 30, were found only in Bolivia. DHFR and DHPS mutations occur in a progressive, stepwise fashion. Identification of specific sets of mutations causing in vivo drug failure may lead to the development of molecular surveillance methods for pyrimethamine-sulfadoxine resistance.

Africa↗
PubMed1996

Community pyrimethamine-sulfadoxine use and prevalence of resistant Plasmodium falciparum genotypes in Mali: a model for deterring resistance.

Pyrimethamine-sulfadoxine (PS, Fansidar; Hoffman-LaRoche, Basel, Switzerland) is now the first-line antimalarial therapy in parts of Africa with high rates of chloroquine-resistant Plasmodium falciparum. With PS resistance increasing and no suitably inexpensive and effective third antimalarial drug available, strategies for delaying the spread of PS resistance in Africa are needed. Community PS usage was measured in two Malian villages, one rural and one periurban, and prevalence of pyrimethamine-resistant P. falciparum genotypes was determined at these sites and two urban sites. The prevalence of resistant genotypes was 22.6% (n = 84) in the periurban village where PS was available from multiple sources and large stocks of PS were observed, and 13.5% (n = 89) and 23.4% (n = 77) in a large town and a city, respectively, where PS is widely available. No pyrimethamine-resistant genotypes (n = 58) were detected in Kolle, a rural village with a community-supported dispensary and clinic where PS is used sparingly and no PS was available in pharmacies or markets. The high rates of pyrimethamine resistant genotypes concurrent with higher PS usage argue for a policy of judicious PS use in Mali and in similar settings. A possible model for slowing the spread of drug-resistant malaria is illustrated by the example of the Kolle clinic.

Adolescent↗
PubMedDate not supplied

Case report: life-threatening hypoglycaemia associated with sulfadoxine-pyrimethamine, a commonly used antimalarial drug.

Due to chloroquine resistance, several African countries have changed their first-line malaria treatment to sulfadoxine-pyrimethamine (SP). In this report, we present a case of hypoglycaemic coma associated with SP, an adverse reaction that is likely to be underreported and expected to occur with greater frequency as the use of SP increases.

Antimalarials↗
PubMedDate not supplied

Chloroquine treatment of uncomplicated Plasmodium falciparum malaria in Mali: parasitologic resistance versus therapeutic efficacy.

Whether and when to replace chloroquine with other antimalarial drugs is an urgent public health question in much of Africa, where Plasmodium falciparum, which is increasingly resistant to chloroquine, continues to kill millions each year. Antimalarial drug efficacy has traditionally been measured as parasitologic resistance, but recent guidelines use both clinical and parasitologic criteria to monitor therapeutic efficacy. To assess the new efficacy protocol, we measured parasitologic and therapeutic outcomes in 514 patients treated with chloroquine for uncomplicated P. falciparum malaria in Mali. There was a general agreement between parasitologic and therapeutic outcomes at two sites, with 13-17% parasitologic resistance rates and 10-15% treatment failure rates. However, the new protocol overestimated early treatment failure rates (21-71% of cases classified as early treatment failure had sensitive or RI parasitologic responses), particularly where resistance was rare, and missed low-level parasitologic resistance. Modifications of the protocol for monitoring antimalarial therapeutic efficacy are recommended.

Adolescent↗