Potential for a large-scale newborn screening strategy for sickle cell disease in Mali: A comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood.

Sickle cell disease (SCD) is a life-threatening disease requiring reliable early diagnosis. We assessed the acceptability and diagnostic performances of two rapid diagnostic tests (RDTs) to identify SCD (HbSS, HbSC, HbS/ß-thalassaemia) or SCD carrier (HbS/HbC) in a pilot SCD newborn screening (NBS) strategy in Mali. All consenting delivering women were offered SCD NBS using cord blood sampling on two RDTs (SickleScan® and HemotypeSC®) compared to the high-performance liquid chromatography (HPLC) gold standard to detect SCD states. From April 2021 to August 2021, 4333 delivering women were eligible of whom 96.1% were offered NBS: 1.6% refused, 13.8% delivered before consenting and 84.6% consented; 3648 newborns were diagnosed by HPLC; 1.64% had SCD (0.63% HbSS, 0.85% HbSC, 0.16 HbS/ß-plus-thalassaemia); 21.79% were SCD carrier. To detect accurately SCD, SickleScan® had a sensitivity of 81.67% (95% confidence interval [CI]: 71.88-91.46) and a negative predictive value (NPV) of 99.69% (95% CI: 99.51-99.87); HemotypeSC® had a sensitivity of 78.33% (95% CI: 67.91-88.76) and a NPV of 99.64% (95% CI: 99.44-99.83). To detect SCD carrier: SickleScan® sensitivity was 96.10% (95% CI: 94.75-97.45) and NPV, 98.90% (95% CI: 98.51-99.29); HemotypeSC® sensitivity was 95.22% (95% CI: 93.74-96.70) and NPV, 98.66% (95% CI: 98.24-99.03). Routine SCD NBS was acceptable. Compared with HPLC, both RDTs had reliable diagnostic performances to exclude SCD-free newborns and to identify SCD carriers to be further confirmed. This strategy could be implemented in large-scale NBS programmes.

[Early Screening Of Sickle Cell Disease: Knowledge And Behaviors Of Pregnant Women And Health Workers In Burkina Faso]. / Depistage Precoce De La Drepanocytose : Connaissances Et Attitudes De Femmes Enceintes Et d'Agents De La Sante Au Burkina Faso.

OBJECTIVE: Early detection of sickle cell disease significantly reduces sickle cell mortality, but it is not practiced in Burkina Faso where the disease is responsible for significant early mortality. The objective of the study was to analyze the relationship between this finding and the knowledge and attitudes of pregnant women with hemoglobinopathy and health workers. MATERIALS AND METHODS: the study was cross-sectional and conducted in three health districts of Ouagadougou, Burkina Faso, from June 17 to July 31, 2019. Data were collected using a structured individual interview guide. RESULTS: 200 pregnant women with hemoglobinopathy and 50 active health workers had participated in the study. Most women defined sickle cell disease as a bone disease, did not know its transmission mode or the hemoglobin type of their child (ren); 95,4% had never heard of neonatal screening for sickle cell disease. Health workers had limited knowledge of sickle cell disease (16-87%), and only 30% offered neonatal screening to pregnant women with hemoglobinopathy. CONCLUSION: the awareness of the population and training health workers on sickle cell disease, supported by a policy of good access to screening tests, would improve the prognosis of sickle cell disease in Burkina Faso.

OBJECTIF: le dépistage précoce, stratégie ayant amélioré la survie des drépanocytaires, n'est pas pratiquée au Burkina Faso où la maladie est responsable d'une mortalité précoce importante. L'objectif de l'étude était d'analyser la relation entre ce constat et les connaissances et attitudes de femmes gestantes porteuses d'une hémoglobinopathie et des agents de santé. MATÉRIELS & MÉTHODES: l'étude était transversale et conduite dans trois districts sanitaires de Ouagadougou au Burkina Faso, du 17 juin au 31 juillet 2019. Les données étaient recueillies à l'aide d'un guide d'entretien individuel structuré. RÉSULTATS: 200 femmes enceintes porteuses d'une hémoglobinopathie et 50 agents de santé en activité avaient participé à l'étude. La majorité des femmes enquêtées définissait la drépanocytose comme une maladie des os, ne connaissaient pas son mode de transmission, ni le type d'hémoglobine de leur(s) enfant(s) ou n'avaient jamais entendu parler de dépistage néonatal de la drépanocytose. Les agents de santé avaient pour 16 à 87%, des connaissances limitées sur la drépanocytose, 30% seulement proposaient un dépistage néonatal aux femmes enceintes porteuses d'une hémoglobinopathie. CONCLUSION: l'information de la population et la formation des agents de santé sur la drépanocytose, soutenues par l'accès aux tests de dépistage améliorerait le pronostic de la drépanocytose au Burkina Faso.

Dépistage précoce de la drépanocytose: connaissances et attitudes de femmes enceintes et d'agents de la santé au Burkina Faso / Early screening of sickle cell disease: knowledge and behaviors of pregnant women and health workers in Burkina Faso

Objectif : le dépistage précoce, stratégie ayant amélioré la survie des drépanocytaires, n'est pas pratiquée au Burkina Faso où la maladie est responsable d'une mortalité précoce importante. L'objectif de l'étude était d'analyser la relation entre ce constat et les connaissances et attitudes de femmes gestantes porteuses d'une hémoglobinopathie et des agents de santé. Matériels & Méthodes : l'étude était transversale et conduite dans trois districts sanitaires de Ouagadougou au Burkina Faso, du 17 juin au 31 juillet 2019. Les données étaient recueillies à l'aide d'un guide d'entretien individuel structuré. Résultats : 200 femmes enceintes porteuses d'une hémoglobinopathie et 50 agents de santé en activité avaient participé à l'étude. La majorité des femmes enquêtées définissait la drépanocytose comme une maladie des os, ne connaissaient pas son mode de transmission, ni le type d'hémoglobine de leur(s) enfant(s) ou n'avaient jamais entendu parler de dépistage néonatal de la drépanocytose. Les agents de santé avaient pour 16 à 87%, des connaissances limitées sur la drépanocytose, 30% seulement proposaient un dépistage néonatal aux femmes enceintes porteuses d'une hémoglobinopathie. Conclusion: l'information de la population et la formation des agents de santé sur la drépanocytose, soutenues par l'accès aux tests de dépistage améliorerait le pronostic de la drépanocytose au Burkina Faso

Objective: Early detection of sickle cell disease significantly reduces sickle cell mortality, but it is not practiced in Burkina Faso where the disease is responsible for significant early mortality. The objective of the study was to analyze the relationship between this finding and the knowledge and attitudes of pregnant women with hemoglobinopathy and health workers. Materials and Methods: the study was cross-sectional and conducted in three health districts of Ouagadougou, Burkina Faso, from June 17 to July 31, 2019. Data were collected using a structured individual interview guide. Results: 200 pregnant women with hemoglobinopathy and 50 active health workers had participated in the study. Most women defined sickle cell disease as a bone disease, did not know its transmission mode or the hemoglobin type of their child (ren); 95,4% had never heard of neonatal screening for sickle cell disease. Health workers had limited knowledge of sickle cell disease (16-87%), and only 30% offered neonatal screening to pregnant women with hemoglobinopathy. Conclusion: the awareness of the population and training health workers on sickle cell disease, supported by a policy of good access to screening tests, would improve the prognosis of sickle cell disease in Burkina Faso.

[Platelet count in the steady state phase and clinical severity of sickle cell disease in a reference centre for sickle cell disease in Mali]. / Taux des plaquettes sanguines en phase intercritique et expressivité clinique de la drépanocytose dans un centre de référence de la drépanocytose au Mali.

Risk factors associated with complications occurring in sickle cell disease are not fully elucidated. The purpose of this study was to evaluate the existence of an association between the clinical severity of sickle cell disease and platelet count in the steady state phase in patients with sickle cell disease followed up at the Center for Research and Control of Sickle Cell Disease in Bamako, Mali. We conducted a retrospective review of 40 medical records of patients aged 5 to 42 years with sickle cell disease at the Center for Research and Control of Sickle Cell Disease in Bamako, Mali. Clinical severity of sickle cell disease was assessed according to the criteria of VOC and/or hospitalizations < 2 or ≥ 2 per year. Data entry was carried out using the Excel 2013 version. The statistical tests used were the Chi2, Student and Mac Nemar tests. Of the 40 patients, 82.5% had haemolytic phenotype and 17.5% hyperviscous phenotype; complications of sickle cell disease were more frequent in the haemolytic phenotype group (p < 0.05). There was a significant association between mean platelet count ≥ 450 G/L in the steady state phase and the annual number of CVOs ≥ 2 (p = 0.002). This study shows that mean platelet count ≥ 450 G/L in sickle cell patients in the steady state phase could be a risk factor for the frequent occurrence of CVO. It underlines the importance of conducting prospective studies focusing on both hyperplateletosis and platelet activation markers in larger sample sizes, as well as therapeutic trials involving platelet activation inhibitors, such as Crizanlizumab, a humanised anti-P-selectin monoclonal antibodies.

Estimating the risk of child mortality attributable to sickle cell anaemia in sub-Saharan Africa: a retrospective, multicentre, case-control study.

BACKGROUND: Many children with sickle cell disease living in sub-Saharan Africa die before reaching age 5 years. We estimate the child mortality associated with sickle cell anaemia using an indirect approach to overcome the absence of systematic screening at birth. METHODS: We did a retrospective, multicentre, case-control study in five countries in sub-Saharan Africa (Burkina Faso, Democratic Republic of the Congo, Côte d'Ivoire, Mali, and Senegal). Women with at least one child with a confirmed SS haemoglobin phenotype (sickle cell anaemia) and who had at least three (alive or deceased) children from the same father born more than 5 years ago were recruited at an outpatient consultation in a sickle cell disease care centre. Women who had children without sickle cell disease (control group) were recruited from the same area, with inclusion criteria of being a neighbour or relative of one of the mothers included in the study who had a child with sickle cell anaemia, having no child or other first-degree relative with major sickle cell syndrome, having at least three children (alive or deceased) born more than 5 years ago, and having a confirmed haemoglobin AA phenotype. During the mothers' interview, we collected data concerning the mortality of siblings from the same father of a child with sickle cell anaemia and characteristics of the family, such as age at the time of the survey and the level of education of both parents. Mortality rates were calculated for children younger than 1, 5, and 10 years using the Kaplan-Meier method after excluding the index children. We assumed, as per Mendel law, that in families who have a child with sickle cell anaemia and healthy heterozygous parents, 25% of children born on average have sickle cell anaemia. A multivariate Cox model was used to describe socioeconomic and geographical factors associated with mortality. FINDINGS: Between Sept 1, 2017, and Nov 30, 2020, 1563 women who had at least one child with sickle cell anaemia and 4972 women from the same neighbourhood who had children without sickle cell disease were assessed for eligibility. Of 1563 women, 248 were excluded because the genotype of the index child was SC or S ß-thalassaemia. 1315 families with cases of sickle cell anaemia and 1243 control families were included in the study. The median age of children (alive) was 14 years (IQR 8-20) in control families and 13 years (8-19) in families with cases of sickle cell anaemia. 5532 [50·6%] of 10 924 children were male. Mortality rates were 15·3% (95% CI 13·3-17·3) for children with sickle cell anaemia younger than 1 year, 36·4% (33·4-39·4) for those younger than 5 years, and 43·3% (39·3-47·3) for those younger than 10 years. Multivariate Cox survival analysis showed that belonging to a family with sickle cell anaemia (hazard ratio [HR] 2·23, 95% CI 1·96-2·54), living in the Democratic Republic of the Congo (HR 1·64, 1·34-2·01), having an older parent (father or mother age had similar effect; HR 1·12, 1·05-1·19 per 10 years of age), or a significantly higher global Multidimensional Poverty Index (HR 1·09, 1·03-1·14), independently increased the risk of mortality. Whereas, living in Senegal (HR 0·70, 95% CI 0·57-0·86) or having a mother with higher education (high school HR 0·66, 0·55-0·80 or advanced HR 0·41, 0·28-0·61) independently decreased the risk of mortality. INTERPRETATION: Although higher than in high-income countries and affected by non-specific socioeconomic factors, the estimated mortality in children with sickle cell anaemia living in sub-Saharan African cities was substantially lower than previous estimates, suggesting an improvement of sickle cell anaemia care in this setting. FUNDING: Fondation Pierre Fabre. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Diagnostic accuracy in field conditions of the sickle SCAN® rapid test for sickle cell disease among children and adults in two West African settings: the DREPATEST study.

BACKGROUND: Sickle cell disease (SCD) accounts for 5% of mortality in African children aged < 5 years. Improving the care management and quality of life of patients with SCD requires a reliable diagnosis in resource-limited settings. We assessed the diagnostic accuracy of the rapid Sickle SCAN® point-of-care (POC) test for SCD used in field conditions in two West-African countries. METHODS: We conducted a case-control study in Bamako (Mali) and Lomé (Togo). Known cases of sickle cell disease (HbSS, HbSC), trait (HbAS), HbC heterozygotes (HbAC) and homozygous (HbCC), aged ≥6 months were compared to Controls (HbAA), recruited by convenience. All subjects received both an index rapid POC test and a gold standard (high-performance liquid chromatography in Bamako; capillary electrophoresis in Lomé). Personnel conducting tests were blinded from subjects' SCD status. Sensitivity and specificity were calculated for each phenotype. Practicality was assessed by local healthcare professionals familiar with national diagnostic methods and their associated constraints. RESULTS: In Togo, 209 Cases (45 HbAS, 39 HbAC, 41 HbSS, 44 HbSC and 40 HbCC phenotypes) were compared to 86 Controls (HbAA). 100% sensitivity and specificity were observed for AA Controls and HbCC cases. Estimated sensitivity was 97.7% [95% confidence interval: 88.0-99.9], 97.6% [87.1-99.9%], 95.6% [84.8-99.5%], and 94.9% [82.7-99.4], for HbSC, HbSS, HbAS, and HbAC, respectively. Specificity exceeded 99.2% for all phenotypes. Among 160 cases and 80 controls in Mali, rapid testing was 100% sensitive and specific. Rapid testing was well accepted by local healthcare professionals. CONCLUSION: Rapid POC testing is 100% accurate for homozygote healthy people and excellent (Togo) or perfect (Mali) for sickle cell trait and disease patients. In addition to its comparable diagnostic performance, this test is cheaper, easier to implement, and logistically more convenient than the current standard diagnostic methods in use. Its predictive value indicators and diagnostic accuracy in newborns should be further evaluated prior to implementation in large-scale screening programs in resource-limited settings where SCD is prevalent.

Hemoglobin C Trait Provides Protection From Clinical Falciparum Malaria in Malian Children.

BACKGROUND: Hemoglobin C trait, like hemoglobin S trait, protects against severe malaria in children, but it is unclear whether hemoglobin C trait also protects against uncomplicated malaria. We hypothesized that Malian children with hemoglobin C trait would have a lower risk of clinical malaria than children with hemoglobin AA. METHODS: Three hundred children aged 0-6 years were enrolled in a cohort study of malaria incidence in Bandiagara, Mali, with continuous passive and monthly active follow-up from June 2009 to June 2010. RESULTS: Compared to hemoglobin AA children (n = 242), hemoglobin AC children (n = 39) had a longer time to first clinical malaria episode (hazard ratio [HR], 0.19; P = .001; 364 median malaria-free days vs 181 days), fewer episodes of clinical malaria, and a lower cumulative parasite burden. Similarly, hemoglobin AS children (n = 14) had a longer time to first clinical malaria episode than hemoglobin AA children (HR, 0.15; P = .015; 364 median malaria-free days vs 181 days), but experienced the most asymptomatic malaria infections of any group. CONCLUSIONS: Both hemoglobin C and S traits exerted a protective effect against clinical malaria episodes, but appeared to do so by mechanisms that differentially affect the response to infecting malaria parasites.

Extensive genomic variability of knops blood group polymorphisms is associated with sickle cell disease in Africa.

Sickle cell disease (SCD) is a multisystem disorder characterized by chronic hemolytic anemia, vaso-occlusive crises, and marked variability in disease severity. Patients require transfusions to manage disease complications, with complements, directed by complement regulatory genes (CR1) and its polymorphisms, implicated in the development of alloantibodies. We hypothesize that CR1 polymorphisms affect complement regulation and function, leading to adverse outcome in SCD. To this end, we determined the genomic diversity of complement regulatory genes by examining single nucleotide polymorphisms associated with Knops blood group antigens. Genomic DNA samples from 130 SCD cases and 356 control Africans, 331 SCD cases and 497 control African Americans, and 254 Caucasians were obtained and analyzed, utilizing a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) assay. Analyzing for ethnic diversity, we found significant differences in the genotypic and allelic frequencies of Sl1/Sl2 (rs17047661) and McCa/b (rs17047660) polymorphisms between Africans, African Americans, and Caucasians (P < 0.05). The homozygote mutant variants had significantly higher frequencies in Africans and African Americans but were insignificant in Caucasians (80.2% and 59.6% vs 5.9% for Sl1/2; and 36% and 24% vs 1.8% for McCa/b). With SCD, we did not detect any difference among cases and controls either in Africa or in the United States. However, we found significant difference in genotypic (P < 0.0001) and allelic frequencies (P < 0.0001) of Sl1/Sl2 (rs17047661) and McCa/b (rs17047660) polymorphisms between SCD groups from Africa and the United States. There was no difference in haplotype frequencies of these polymorphisms among or between groups. The higher frequency of CR1 homozygote mutant variants in Africa but not United States indicates a potential pathogenic role, possibly associated with complicated disease pathophysiology in the former and potentially protective in the latter. The difference between sickle cell groups suggests potential genetic drift or founder effect imposed on the disease in the United States, but not in Africa, and a possible confirmation of the ancestral susceptibility hypothesis. The lower haplotype frequencies among sickle cell and control populations in the United States may be due to the admixture and the dilution of African genetic ancestry in the African American population.

Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease.

Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803) in healthy control and sickle cell disease (SCD) populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali), 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2%) and allelic frequencies (48.7% versus 42.1% versus 19.8%) of the homozygote mutant variant of the CD209 (snp 309A/G) gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002) and allelic frequencies (39.7% versus 48.7%; p = 0.02) of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19) or allelic (p = 0.72) frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups.

Stable malaria incidence despite scaling up control strategies in a malaria vaccine-testing site in Mali.

BACKGROUND: The recent decline in malaria incidence in many African countries has been attributed to the provision of prompt and effective anti-malarial treatment using artemisinin-based combination therapy (ACT) and to the widespread distribution of long-lasting, insecticide-treated bed nets (LLINs). At a malaria vaccine-testing site in Bandiagara, Mali, ACT was introduced in 2004, and LLINs have been distributed free of charge since 2007 to infants after they complete the Expanded Programme of Immunization (EPI) schedule and to pregnant women receiving antenatal care. These strategies may have an impact on malaria incidence. METHODS: To document malaria incidence, a cohort of 400 children aged 0 to 14 years was followed for three to four years up to July 2013. Monthly cross-sectional surveys were done to measure the prevalence of malaria infection and anaemia. Clinical disease was measured both actively and passively through continuous availability of primary medical care. Measured outcomes included asymptomatic Plasmodium infection, anaemia and clinical malaria episodes. RESULTS: The incidence rate of clinical malaria varied significantly from June 2009 to July 2013 without a clear downward trend. A sharp seasonality in malaria illness incidence was observed with higher clinical malaria incidence rates during the rainy season. Parasite and anaemia point prevalence also showed seasonal variation with much higher prevalence rates during rainy seasons compared to dry seasons. CONCLUSIONS: Despite the scaling up of malaria prevention and treatment, including the widespread use of bed nets, better diagnosis and wider availability of ACT, malaria incidence did not decrease in Bandiagara during the study period.

Endothelin-1 but not Endothelial Nitric Oxide Synthase Gene Polymorphism is Associated with Sickle Cell Disease in Africa.

Sickle cell disease shows marked variability in severity and pathophysiology among individuals, probably linked to differential expression of various adhesion molecules. In this study, we investigated the differential distribution, genomic diversity and haplotype frequency of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) polymorphisms, recently implicated as important in modification of disease severity. One hundred and forty five sickle cell disease patients (HbSS) and 244 adult and pediatric controls, without sickle cell disease (HbAA), were recruited from Mali. Genotypic analysis of the functionally significant eNOS variants (T786C, G894T and intron 4) and endothelin-1 (G5665T) was carried out with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Our results show that the wild type alleles are the most frequent for all eNOS variants between cases and controls. Allelic and genotypic frequencies of eNOS polymorphic groups are not significantly different between cases and controls (P > 0.05). In addition, there is no association between eNOS variants and sickle cell disease, contrary to published reports. On the other hand, we report that endothelin-1 (G5665T) mutant variant had the lowest allelic frequency, and is significantly associated with sickle cell disease in Africa (P < 0.05). Similarly, haplotype frequencies were the same between cases and controls, except for the haplotype combining all mutant variants (T, C, 4a; P = 0.01). eNOS polymorphic variants are less frequent, with no significance with sickle cell disease in Africa. On the other hand, endothelin-1 is associated with sickle cell disease, and has the capacity to redefine pathophysiology and possibly serve as modulator of disease phenotype.

Sickle cell disease in sub-Saharan Africa: stakes and strategies for control of the disease.

PURPOSE OF REVIEW: In the late 1990s publications on cohorts of sickle cell disease (SCD) patients, followed since birth, showed that the life expectancy of SCD patients in developed countries could approach that of those without SCD, when managed appropriately. Between 2005 and 2008, SCD was declared as a public health priority issue worldwide. In 2006, the WHO recommended that African states should include the fight against SCD in their health policies. Nevertheless, there are, as of yet, no data on effective strategies to implement SCD control in these countries. This review discusses the stakes and proposes strategies for SCD management and research in sub-Saharan Africa. RECENT FINDINGS: This work is a review of the recent literature on the burden of SCD in sub-Saharan Africa; on approaches that resulted in improved survival and comfort for SCD patients in developed countries; and, in contrast, on the inadequacies of most issues relating to the fight against SCD in Africa. SUMMARY: Multiple constraints require an organization based on a network of health professionals working in sickle cell referral centers with specific missions of research, communication, teaching, establishment of guidelines for diagnosis, treatment, and prevention, and the centers of competence that will focus primarily on the screening, diagnosis, and management of SCD patients favoring equity in access to care.

Genetics of low spinal muscular atrophy carrier frequency in sub-Saharan Africa.

OBJECTIVE: Spinal muscular atrophy (SMA) is one of the most common severe hereditary diseases of infancy and early childhood in North America, Europe, and Asia. SMA is usually caused by deletions of the survival motor neuron 1 (SMN1) gene. A closely related gene, SMN2, modifies the disease severity. SMA carriers have only 1 copy of SMN1 and are relatively common (1 in 30-50) in populations of European and Asian descent. SMN copy numbers and SMA carrier frequencies have not been reliably estimated in Malians and other sub-Saharan Africans. METHODS: We used a quantitative polymerase chain reaction assay to determine SMN1 and SMN2 copy numbers in 628 Malians, 120 Nigerians, and 120 Kenyans. We also explored possible mechanisms for SMN1 and SMN2 copy number differences in Malians, and investigated their effects on SMN mRNA and protein levels. RESULTS: The SMA carrier frequency in Malians is 1 in 209, lower than in Eurasians. Malians and other sub-Saharan Africans are more likely to have ≥3 copies of SMN1 than Eurasians, and more likely to lack SMN2 than Europeans. There was no evidence of gene conversion, gene locus duplication, or natural selection from malaria resistance to account for the higher SMN1 copy numbers in Malians. High SMN1 copy numbers were not associated with increased SMN mRNA or protein levels in human cell lines. INTERPRETATION: SMA carrier frequencies are much lower in sub-Saharan Africans than in Eurasians. This finding is important to consider in SMA genetic counseling in individuals with black African ancestry.

Survenue du VIH et du VHB dans une cohorte d'enfants drepanocytaires transfuses au Complexe Pediatrique de Bangui

Objectif : Evaluer les risques d'infection par le VIH et le VHB au cours des transfusions chez l'enfant drepanocytaire a Bangui. Cadre et Methode : L'etude; prospective; s'est deroulee au Complexe Pediatrique de Bangui d'octobre 2008 au mois d'aout 2009. Elle a porte sur 98 enfants drepanocytaires ages de 18 mois a 18 ans ; apres consentement des parents. Une evaluation clinique et des tests serologiques pour la recherche du VIH et de l'antigene HBs ont ete realises avant et apres transfusion sanguine lors d'un suivi en hospitalisation et en ambulatoire. Resultats : Parmi les 98 patients recrutes dont 35 (35;7) garcons; soixante quatre (65) d'entre eux etaient ages de moins de 5 ans et la quasi-totalite (99) etait porteur d'hemoglobine SS. Le paludisme; retrouve chez 58;2 des patients; occupait le 1er rang parmi les pathologies associees. Lors des transfusions realisees; six (6) des enfants ont ete contamines par le VIH; et 14 (14;3) par le VHB. Un nombre de transfusion superieur ou egal a 3 chez un meme enfant etait significativement associe a la transmission du virus de l'hepatite B. Conclusion : Ce risque de contamination recommande le renforcement de la communaute pour des soins essentiels de base aux patients atteints de drepanocytose

Extensive ethnogenomic diversity of endothelial nitric oxide synthase (eNOS) polymorphisms.

Nitric oxide (NO) is highly reactive, produced in endothelial cells by endothelial NO synthase (eNOS) and has been implicated in sickle cell pathophysiology. We evaluated the distribution of functionally significant eNOS variants (the T786C variant in the promoter region, the Glu298Asp variant in exon 7, and the variable number of tandem repeats (VNTR) in intron 4) in Africans, African Americans and Caucasians. The C-786 variant was more common in Caucasians than in Africans and African Americans. Consistent with other findings, the Asp-298 variant had the highest frequency in Caucasians followed by African Americans, but was completely absent in Africans. The very rare intron 4 allele, eNOS 4c, was found in some Africans and African Americans, but not in Caucasians. eNOS 4d allele was present in 2 Africans. These findings suggest a consistent and widespread genomic diversity in the distribution of eNOS variants in Africans, comparative to African Americans and Caucasians.

[Reference values of neonatal erythrocyte and leukocyte count in Bamako, Mali]. / Valeurs de Référence érythrocytaires et leucocytaires chez le Nouveau-né à Bamako, Mali.

Reference values for blood cell count are not established at birth in Mali. This study aimed to determine reference values for erythrocyte and leukocyte at birth in Bamako. Blood was collected from the umbilical cord immediately following its clamping and studied for complete blood cell count in 481 newborns with a birth weight > 2500g, Apgar score ≤ 7 at 5 or 10 minutes, without abnormal hemoglobin mutations and whose mothers were willing in Bamako, Mali. Other than the median and mean values, 2.5 and 97.5 percentiles were calculated. The findings suggest that the normal reference values following a timely clamping of the umbilical cord were (mean ± 1SD and range): RBC = 4,00 ± 0,46.1012/L (3,13 - 4,89), Hb = 14,12 ± 1,49 g/dL (11,20 - 17,00), Hct = 40,27 ± 4,71% (31,62 - 50,18), MCV = 101 ± 5 fl (91 - 112), MCHC = 35,37 ± 2,16 pg/cellule (30,70 - 39,59), MCH = 35,06 ± 0,93 g/dL (33,40 - 36,90), RDW = 17,79 ± 7,33% (15,50 - 20,39), Reticulocytes (109/L) = 133,081 ± 29,95 (66,62 - 200,86), GB (109/L) = 13,24 ± 7,23 (7,20 - 23,70), PMN (109/L) = 7,16 ± 4,70 (3,07 - 14,22), PME (109/L) = 0,28 ± 0,26 (0 - 0,98), PMB(109/L) = 0,05 ± 0,09 (0 - 0,31), Lymphocytes (109/L) = 4,49 ± 2,45 (1,96 - 9,42), Monocytes (109/L) = 1,06 ± 0,73 (0,21 - 2,54), myelocytes = 1.43 ± 1.51%, erythroblasts = 4.52 ± 7.83%. It should be noted that male babies had a lower neutrophil count than female newborns. By taking into account these results when interpreting the blood cell count in Malian newborn infants, costly misdiagnoses should be considerably decreased in a population struggling with low incomes.

Les valeurs de référence de l'hémogramme ne sont pas établies à la naissance au Mali. Cette étude détermine les valeurs de référence érythrocytaires et leucocytaires du nouveau-né à Bamako. Le sang du cordon ombilical a été prélevé après clampage sans délai et étudié pour les paramètres érythrocytaires et leucocytaires chez 481 nouveau-nés à terme avec un poids de naissance > 2500g, un score d'Apgar ≥ 7 à 5 ou 10 minutes, sans mutant de l'hémoglobine et dont les mamans étaient consentantes, à Bamako, Mali. Outre les valeurs médianes et moyennes, les percentiles 2,5 et 97,5 ont été calculés. Les valeurs considérées comme normes de référence locales après un clampage sans délai du cordon ombilical (moyenne ± 1SD et extrêmes) sont : GR = 4,00 ± 0,46.1012/L (3,13 ­ 4,89), Hb = 14,12 ± 1,49 g/dL (11,20 ­ 17,00), Ht = 40,27 ± 4,71% (31,62 ­ 50,18), VGM = 101 ± 5 fl (91 ­ 112), TCMH = 35,37 ± 2,16 pg/cellule (30,70 ­ 39,59), CCMH = 35,06 ± 0,93 g/dL (33,40 ­ 36,90), IDR = 17,79 ± 7,33% (15,50 ­ 20,39), Réticulocytes (109/L) = 133,081 ± 29,95 (66,62 ­ 200,86), GB (109/L) = 13,24 ± 7,23 (7,20 ­ 23,70), PNN (109/L) = 7,16 ± 4,70 (3,07 ­ 14,22), PE (109/L) = 0,28 ± 0,26 (0 ­ 0,98), PB (109/L) = 0,05 ± 0,09 (0 ­ 0,31), Lymphocytes (109/L) = 4,49 ± 2,45 (1,96 ­ 9,42), Monocytes (109/L) = 1,06 ± 0,73 (0,21 ­ 2,54), myélocytes = 1,43 ± 1,51%, érythroblastes = 4,52 ± 7,83%. A noter un taux des polynucléaires neutrophiles plus bas chez le garçon que chez la fille. Ces valeurs diffèrent de celles rapportées pour d'autres populations. La prise en compte de ces résultats dans l'interprétation de l'hémogramme du nouveau-né au Mali, devrait éviter des erreurs de diagnostic et des explorations par excès chez une population à faibles revenues.

Valeurs de reference des erythrocytes et des leucocytes chez le nouveau-ne a Bamako; Mali

Les valeurs de reference de l'hemogramme ne sont pas etablies a la naissance au Mali. Cette etude determine les valeurs de reference erythrocytaires et leucocytaires du nouveau-ne a Bamako. Le sang du cordon ombilical a ete preleve apres clampage sans delai et etudie pour les parametres erythrocytaires et leucocytaires chez 481 nouveau-nes a terme avec un poids de naissance 2500g; un score d'Abgar ? 7 a 5ou 10 minutes; sans mutant de l'hemoglobine et dont les mamans etaient consentantes; a Bamako; Mali. Outre les valeurs medianes et moyennes; les percentiles 2;5 et 97;5 ont ete calcules. Les valeurs considerees comme normes de reference locales apres un clampage sans delai du cordon ombilical (moyenne _///} 1SD et extremes) sont : GR = 4;00 _///} 0;46.1012/L (3;13 - 4;89); Hb = 14;12 _///} 1;49 g/dL (11;20 - 17;00); Ht = 40;27 _///} 4;71 (31;62 - 50;18); VGM = 101 _///} 5 fl (91 - 112); TCMH = 35;37 _///} 2;16 pg/cellule (30;70 - 39;59); CCMH = 35;06 _///} 0;93 g/dL (33;40 - 36;90); IDR = 17;79 _///} 7;33 (15;50 - 20;39); Reticulocytes (109/L) = 133;081 _///} 29;95 (66;62 - 200;86); GB (109/L) = 13;24 _///} 7;23 (7;20 - 23;70); PNN (109/L) = 7;16 _///} 4;70 (3;07 - 14;22); PE (109/L) = 0;28 _///} 0;26 (0 - 0;98); PB (109/L) = 0;05 _///} 0;09 (0 - 0;31); Lymphocytes (109/L) = 4;49 _///} 2;45 (1;96 - 9;42); Monocytes (109/L) = 1;06 _///} 0;73 (0;21 - 2;54); myelocytes = 1;43 _///} 1;51; erythroblastes = 4;52 _///} 7;83. A noter un taux des polynucleaires neutrophiles plus bas chez le garcon que chez la fille. Ces valeurs different de celles rapportees pour d'autres populations. La prise en compte de ces resultats dans l'interpretation de l'hemogramme du nouveau-ne au Mali; devrait eviter des erreurs de diagnostic et des explorations par exces chez une population a faibles revenues

Filariasis attenuates anemia and proinflammatory responses associated with clinical malaria: a matched prospective study in children and young adults.

BACKGROUND: Wuchereria bancrofti (Wb) and Mansonella perstans (Mp) are blood-borne filarial parasites that are endemic in many countries of Africa, including Mali. The geographic distribution of Wb and Mp overlaps considerably with that of malaria, and coinfection is common. Although chronic filarial infection has been shown to alter immune responses to malaria parasites, its effect on clinical and immunologic responses in acute malaria is unknown. METHODOLOGY/PRINCIPAL FINDINGS: To address this question, 31 filaria-positive (FIL+) and 31 filaria-negative (FIL-) children and young adults, matched for age, gender and hemoglobin type, were followed prospectively through a malaria transmission season. Filarial infection was defined by the presence of Wb or Mp microfilariae on calibrated thick smears performed between 10 pm and 2 am and/or by the presence of circulating filarial antigen in serum. Clinical malaria was defined as axillary temperature ≥37.5°C or another symptom or sign compatible with malaria infection plus the presence of asexual malaria parasites on a thick blood smear. Although the incidence of clinical malaria, time to first episode, clinical signs and symptoms, and malaria parasitemia were comparable between the two groups, geometric mean hemoglobin levels were significantly decreased in FIL- subjects at the height of the transmission season compared to FIL+ subjects (11.4 g/dL vs. 12.5 g/dL, p<0.01). Plasma levels of IL-1ra, IP-10 and IL-8 were significantly decreased in FIL+ subjects at the time of presentation with clinical malaria (99, 2145 and 49 pg/ml, respectively as compared to 474, 5522 and 247 pg/ml in FIL- subjects). CONCLUSIONS/SIGNIFICANCE: These data suggest that pre-existent filarial infection attenuates immune responses associated with severe malaria and protects against anemia, but has little effect on susceptibility to or severity of acute malaria infection. The apparent protective effect of filarial infection against anemia is intriguing and warrants further study in a larger cohort.

[Epidermal Tuberculosis in an orphan living with HIV in the Pediatric Unit of Bangui (Central African Republic)]. / Tuberculose cutanee chez un orphelin vivant avec le VIH au complexe pediatrique de Bangui (Republique Centrafricaine).

We report the case of ulceration of the anterior chest region in a non BCG vaccinated adolescent. Tuberculosis confirmations has been made by the isolation of M. tuberculosis from the pus culture in Löwenstein-Jensen medium. Topography and chronology of the clinical manifestations argue in favour of scrofuloderma. For technical reasons, we were not able to distinguish scrofuloderma from the gum. The use of the single standard regime of tuberculosis treatment according to the immunological status has provided a healing of skin injury in children living with HIV. In addition, this observation emphasises the medical interest to implement systematic vaccination against tuberculosis and to ensure effective control of the disease, particularly in orphans.

Nous rapportons le cas d'une ulcération de la région antérieure du thorax chez un adolescent non vacciné par le BCG. L'étiologie tuberculeuse a été prouvée par l'isolement de M. tuberculosis à la culture du pus sur milieu de Löwenstein Jensen. La topographie et la chronologie des manifestations cliniques plaident en faveur d'un scrofuloderme. Cependant, les moyens d'investigation disponibles n'ont pu mettre en évidence de foyer infectieux contigu de sorte qu'il n'a pas été possible de discriminer le scrofuloderme du gomme. La mise en route du seul régime standard de traitement de la tuberculose, au regard du niveau d'immunocompétence, a permis d'obtenir une cicatrisation de la lésion cutanée chez cet adolescent atteint de VIH. En outre, cette observation souligne l'intérêt non seulement de vacciner contre la tuberculose mais d'en assurer le contrôle de l'efficacité par la suite; notamment chez les orphelins.