Maternal country of origin, breast milk characteristics and potential influences on immunity in offspring.

Breast milk contains pro- and anti-inflammatory cytokines and chemokines with potential to influence immunological maturation in the child. We have shown previously that country of birth is associated with the cytokine/chemokine profile of breast milk. In this study we have investigated how these differences in breast milk affect the cellular response of cord blood mononuclear cells (CBMCs) and intestinal epithelial cells (IECs, cell line HT-29) to microbial challenge. Ninety-five women were included: 30 from Mali in West Africa, 32 Swedish immigrants and 33 native Swedish women. CBMCs or IECs were stimulated in vitro with breast milk, alone or in combination with lipopolysaccharide (LPS) or peptidoglycan (PGN). Breast milk in general abrogated the LPS-induced down-regulation of surface CD14 and Toll-like receptor (TLR)-4 expression on CB monocytes, while inhibiting the PGN-induced TLR-2 up-regulation. However, breast milk from immigrant women together with LPS induced a lower CBMC release of interleukin (IL)-6 (P = 0·034) and CXCL-8/IL-8 (P = 0·037) compared with breast milk from Swedish women, while breast milk from Swedish women and Mali women tended to increase the response. The same pattern of CXCL-8/IL-8 release could be seen after stimulation of IECs (HT-29). The lower CBMC and IEC (HT-29) responses to microbial compounds by breast milk from immigrant women could be explained by the fact that breast milk from the immigrant group showed a divergent pro- and anti-inflammatory content for CXCL-8/IL-8, transforming growth factor-ß1 and soluble CD14, compared to the other two groups of women. This may have implications for maturation of their children's immune responses.

[Impact of migraine on life quality in school environment in Bamako, Mali]. / Migraine et qualite de vie en milieu scolaire dans le district de Bamako au Mali.

INTRODUCTION: Migraine is a disabiliting disease accounting for 3%. Its prevalence and impact on the schoolar population deserves to be known. METHODOLOGY: This is a five-month cross-sectional and descriptive study of students under 23 years of age at the high school in Bamako, Mali. The sampling was exhaustive and the population was stratified into school classes. Data related to the impact and disability of migraine were collected from a survey sheet integrating internationally validated items (GRIM, MIDAS, Headache Impact Test). RESULTS: The prevalence of migraine was 21.0%. The sex ratio was 0.58. The average age was 17 years. Headache was pulsatile in 88.3% of cases, exacerbated by physical activities in 5.4%, unilateral topography in 73.2% of students. Phonophobia, photophobia were the most described signs of accompaniment. The intensity of pain was between 9 -10 in 69.5%. School absenteeism was ranged from 1 to 14 days in 91.2% of cases. CONCLUSION: Migraine is a real public health concern in schools in Bamako because of its prevalence and its impact on academic performance.

INTRODUCTION: La migraine est responsable de 3% d'invalidité. Sa prévalence et son impact dans la population scolaire mérite d'être connus. MÉTHODOLOGIE: Il s'agit d'une étude transversale et descriptive sur cinq mois, auprès des élèves de moins de 23 ans d'un lycée du district de Bamako au Mali. L'échantillonnage était exhaustif et la population a été stratifiée en classe scolaire. Les données en rapport avec le retentissement et le handicap de la migraine ont été recueillies à partir d'une fiche d'enquête intégrant les items validés à l'échelle internationale (GRIM, MIDAS, Headache Impact- Test). RÉSULTATS: La prévalence de la migraine était de 21,0%.Le sex-ratio était de 0,58. L'âge moyen était de 17ans. La douleur était pulsatile dans 88,3% des cas, exacerbée par les activités physiques dans 5,4%, de topographie unilatérale chez 73,2% des élèves. La phonophobie, la photophobie étaient les signes d'accompagnement les plus décrits. L'intensité de la douleur était entre 9 -10 chez 69,5%. Dans 91,2 des cas on notait un absentéisme scolaire allant de 1 à 14 jours. CONCLUSION: La migraine constitue un véritable problème de santé publique en milieu scolaire à Bamako par sa prévalence et son impact sur le rendement scolaire.

[Dynamics of Egg Excretion of Schistosoma haematobium in a Longitudinal Cohort Under Treatment with Praziquantel over a Five-Year Period in Kalifabougou, Mali]. / Dynamique de l'excrétion ovulaire de Schistosoma haematobium dans une cohorte de Kalifabougou (Mali) sous traitement par le praziquantel (PZQ) durant cinq ans.

This study aim was to evaluate the dynamics of Schistosoma haematobium eggs excretion after the scaling up of "Mass Drug Administration" (MDA) with praziquantel (PZQ) from 2011 to 2016 in a cohort of volunteers living in the village of Kalifabougou, Mali. We conducted a cross-sectional study on 676 volunteers in May 2011 niched in cohort study from 696 volunteers aged three months to 25 years. The eggs of Schistosoma haematobium (Sh) were tested by urine filtration technique, Soil-transmitted helminth and Schistosoma mansoni by the Kato-Katz technique. Maximal MDA/ PZQ population coverage was 83% in 2015 and no MDA/PZQ n 2014. A total of 676 volunteers was included in this prospective cohort. The prevalence rate of Sh showed a significate decreasing from 2011, 2013 to 2014 with respectively 10.2% [95% CI=10.04-10,18], 5.32% [95% CI=5.30-5.33], and 5.25% [95% CI=524.-5.31], followed by an increase to 10.6% [95% CI = 10.47-10.63] in 2015 and a significative decrease in 2016 to 5.4% [95% CI=3.5-7,3]. Children aged from six to 10 years and mostly boys were more infected with Sh, then could serve of parasite reservoir. MDA with PZQ remains an effective strategy for schistosomiasis control against Sh in Kalifabougou. Additional studies on MDA/PZQ average treatment covering human-water contact behaviors and population migration are necessary to understand the persistence of the 5% annual prevalence rate of egg shedding in the cohort of volunteers periodically treated with PQZ. Testing eggs shed viability will be also an added value.

L'objectif de cette étude était d'évaluer la dynamique de l'excrétion ovulaire de Schistosoma haematobium (Sh) après la mise à échelle du « traitement de masse ¼ (TDM) avec le praziquantel (PZQ) de 2011 à 2016 dans une cohorte de volontaires vivant dans le village de Kalifabougou au Mali. Nous avons conduit une étude transversale sur 676 volontaires au mois de mai 2011 nichée dans une étude de cohorte de 695 volontaires, âgés de 3 mois à 25 ans et suivis de 2011 à 2016. Les œufs de Sh ont été recherchés par la technique de filtration d'urines et ceux des géo helminthes et de Schistosoma mansoni avec le Kato-Katz. Le taux de couverture maximum de la population cible de Kalifabougou en TDM/PZQ était de 83 % en 2015 et il n'a pas eu de TDM/PZQ en 2014. Le taux de prévalence de Sh montrait une réduction significative entre 2011, 2013 et 2014 avec respectivement 10,20 % [95 % CI = 10,04-10,18]- 5,32 % [95 % CI = 5,30- 5,33], et 5,25 % [95 % CI = 5,24-5,31], suivi d'une augmentation à 10,60 % [95 % CI = 10,47-10,63] en 2015 et d'une baisse significative en 2016 à 5,40 % [95 % CI = 3,5-7,3]. Les enfants âgés de six à dix ans, et majoritairement les garçons, seraient plus infectés par Sh, et pourraient servir de réservoir de parasites. Le TDM avec le PZQ reste une stratégie efficace pour le contrôle de la schistosomose à Sh à Kalifabougou. Des études complémentaires sur la couverture moyenne en TDM-PZQ, les comportements de contact homme-eau et les mouvements de population sont nécessaires pour comprendre la persistance du taux de prévalence annuel de 5 % de l'excrétion ovulaire dans la cohorte de volontaires traités périodiquement par le PQZ. Un test de viabilité des œufs excrétés serait aussi une valeur ajoutée.

[Randomized clinical trial of two malaria prophylaxis regimens for pregnant women in Faladie, Mali]. / Essai clinique randomisé de deux schémas de prévention contre le paludisme au cours de la grossesse à Faladiè (Mali).

From June 2003 to May 2004 we carried out a comparative study of two malaria prophylaxis regimens for pregnant women. The purpose was to compare the efficacy of two regimens using chloroquine (CQ) or sulfadoxine-pyrimethamine (SP) during pregnancy and delivery in a village located in an endemic area of Mali. The study was carried out in Faladié (District of Kati) located 80 km from Bamako. Prophylaxis was administered during the second and third trimesters of pregnancy (except the 9th month for SP). A total of 301 pregnant women were enrolled including 150 in the CQ group and 151 in the SP group. At the onset of the study, the two groups were comparable with regard to socio-demographic and malaria factors. At the time of delivery, malaria infection was reduced by 43.3% in the CQ group (P < 10-6), and by 79.1% in the SP group (p < 10-6). The anemia rate was reduced by 57.5% in the CQ group (Ch2 of McNemar = 0.017), and by 74.8% in the SP group (Ch2 of McNeamar = 0.025). The incidence of placental infection was 20.6 % in the CQ group versus 8.3 % in the SP group (p = 4.10-3). Overall 16.7% of newborns presented low birth weight at delivery including 70.4% in the CQ group. The findings of this study suggest that intermittent presumptive treatment using SP is more effective than intermittent presumptive treatment using CQ in protecting both the mother and newborn against intra-uterine malaria transmission and its consequences.

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.

[Prevalence of Plasmodium falciparum, anemia and molecular markers of chloroquine and sulfadoxine-pyriméthamine resistance in delivered women in Fana, Mali]. / Prévalence de Plasmodium falciparum, de l'anémie et des marqueurs moléculaires de la résistance à la chloroquine et à la sulfadoxine-pyrim éthamine chez les femmes accouchées à Fana, Mali.

The aim of this study was to describe the malaria morbidity and the frequencies of molecular markers of resistance to chloroquine and sulfadoxine-pyrimethamine in pregnant women at delivery in Mali. Two hundred pregnant women have been included at the delivery clinic in Fana. The age group of 14-19 years was predominant. Fifty two per cent (52.3%: 104/200) were malaria slides positive in their peripheral blood and 15% (30/200) of the women carried parasite in their placenta. The prevalence rate of anemia was 44.5% (89/200). PCR technique was successfully performed on 16 paired samples. The frequency of the Pfcrt K76T mutants in Plasmodium falciparum infections in peripheral blood was 68.8% (11/16) and 100% (16/16) in the placenta (p = 0.004). The frequency in peripheral blood of the DHFR N51I mutation was 12.5% (2/16) and 18.8% (3/16) in the placenta (p=0.12). The frequencies of the DHPS A437G mutants were similar in both sites 25% (4/16). No DHPS K540E and DHFR 164L mutations were found in the Fana pregnancy women samples.

Pharmacokinetics of sulfadoxine and pyrimethamine in intermittent preventive treatment of malaria in pregnancy.

Malaria during pregnancy is associated with maternal and fetal morbidity and mortality. In order to minimize the burden, sulfadoxine-pyrimethamine (SP) is widely used in Africa as an intermittent preventive treatment of malaria in pregnancy (IPTp). However, only limited data are available on the pharmacokinetics of sulfadoxine and pyrimethamine during pregnancy. We conducted a prospective, self-matched, multicenter study of 98 pregnant women in four African countries in order to determine the effects of pregnancy on SP pharmacokinetics. After adjusting for the effects of potential confounders, blood concentrations (associated with therapeutic efficacy) of pyrimethamine were higher (geometric mean ratio (GMR) 1.33; 95% confidence interval (CI) 1.18-1.51; P < 0.001) and those of sulfadoxine were lower (GMR 0.91; 95% CI 0.84-0.98; P = 0.013) on day 7 after SP administration during pregnancy than after the postpartum period. SP pharmacokinetic parameters differed significantly among the study sites. Given the inconsistency of changes in pharmacokinetic parameters between sulfadoxine and pyrimethamine as well as among the study sites, it is not possible to recommend any dose adjustment to prolong the therapeutic life span of the fixed dose combination of SP for IPTp on the basis of our study findings.

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.

Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S.

The malaria hypothesis proposes a survival advantage for individuals with hemoglobin variants in areas of endemic Plasmodium falciparum malaria. Hemoglobin C (HbC) is a possible example in West Africa, where this hemoglobin has a centric distribution with high frequencies among certain populations including the Dogon ethnic group. To test whether HbC is associated with protection from malaria, we performed a case-control study in the Dogon of Bandiagara, Mali. HbC was present in 68 of 391 (17.4%) of uncomplicated malaria control cases, whereas it was detected in only 3 of 67 cases (4.5%) of severe malaria (odds ratio [OR], 0.22; P =. 01). Further, HbC was present in only 1 of 34 cases (2.9%) with cerebral manifestations, the most common presentation of severe malaria in this population (OR, 0.14; P =.03). Episodes of uncomplicated malaria and parasitemias (4800-205 050/microL) were identified in cases of homozygous HbC (HbCC), which indicates that P falciparum parasites are able to efficiently replicate within HbCC erythrocytes in vivo. These findings suggest that HbC does not protect against infection or uncomplicated malaria but can protect against severe malaria in the Dogon population of Bandiagara, Mali. The data also suggest that the protective effect associated with HbC may be greater than that of HbS in this population.

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.