A novel variant in the GNE gene in a Malian patient presenting with distal myopathy.

Background: GNE myopathy (GM) is a rare autosomal recessive disorder caused by variants in the GNE gene and characterized by progressive distal muscle weakness and atrophy. We report a novel variant in theGNE gene causing GM in a consanguineous Malian family. Case presentation: A 19-year-old male patient from a consanguineous family of Bambara ethnicity was seen for progressive walking difficulty and frequent falls. Neurological examination found distalmuscle weakness and atrophy and reduced tendon reflexes in four limbs. Electroneuromyography (ENMG) showed an axonal neuropathy pattern with reduced distal motor amplitudes. Charcot-Marie-Tooth (CMT) gene panel testing (Medical Neurogenetics LLC, Atlanta, GA) was negative. However, whole exome sequencing (WES) revealed a novel biallelic variant in GNE (c.1838G>A:p.Gly613Glu), segregating with the phenotype in the family. This variant is predicted to be pathogenic by several in silicoprediction tools including CADD= 29. Moreover, protein folding model showed major structural disruptions in the mutant protein. Conclusion: This study reports a novel variant in the GNE gene causing GM, the first molecularly diagnosed in sub-Saharan Africa (SSA). It highlights the diagnosis challenges in this region and broadens the genetic spectrum of this rare disease.

Preponderance of vaccine-preventable diseases hotspots in northern Ghana: a spatial and space-time clustering analysis from 2010 to 2014.

BACKGROUND: Vaccine-preventable diseases (VPDs) persist globally with a disproportionately high burden in Low and Middle-Income Countries (LMICs). Although this might be partly due to the failure to sustain vaccination coverage above 90% in some WHO regions, a more nuanced understanding of VPD transmission beyond vaccination coverage may unveil other important factors in VPD transmission and control. This study identified VPDs hotspots and explored their relationships with ecology, urbanicity and land-use variations (Artisanal and Small-scale Gold Mining (ASGM) activities) in Ghana. METHODS: District-level disease count data from 2010 to 2014 from the Ghana Health Service (GHS) and population data from the Ghana Population and Housing Census (PHC) were used to determine clustering patterns of six VPDs (Measles, Meningitis, Mumps, Otitis media, Pneumonia and Tetanus). Spatial and space-time cluster analyses were implemented in SaTScan using the discrete Poisson model. P-values were estimated using a combination of sequential Monte Carlo, standard Monte Carlo, and Gumbel approximations. RESULTS: The study found a preponderance for VPD hotspots in the northern parts of Ghana and northernmost ecological zones (Sudan Savannah and Guinea Savannah). Incidence of meningitis was higher in the Sudan Savannah ecological zone relative to: Tropical Rain Forest (p = 0.001); Semi Deciduous Forest (p < 0.0001); Transitional Zone (p < 0.0001); Coastal Savannah (p < 0.0001) and Guinea Savannah (p = 0.033). Except for mumps, which recorded a higher incidence in urban districts (p = 0.045), incidence of the other five VPDs did not differ across the urban-rural divide. Whereas spatial analysis suggested that some VPD hotspots (tetanus and otitis media) occur more frequently in mining districts in the southern part of the country, a Mann-Whitney U test revealed a higher incidence of meningitis in non-mining districts (p = 0.019). Pneumonia and meningitis recorded the highest (722.8 per 100,000) and least (0.8 per 100,000) incidence rates respectively during the study period. CONCLUSION: This study shows a preponderance of VPD hotspots in the northern parts of Ghana and in semi-arid ecoclimates. The relationship between ASGM activities and VPD transmission in Ghana remains blurred and requires further studies with better spatial resolution to clarify.

[Hospital epidemiology of psychiatric disorders in Mali]. / Épidémiologie hospitalière des troubles psychiatriques au Mali.

Introduction: in Mali, there are no data on the prevalence of mental disorders. The purpose of this study was to describe the clinical and epidemiological features of patients hospitalised in the Department of Psychiatry. Methods: we conducted a cross-sectional study in the Department of Psychiatry at the University Hospital of Point G between January 2014 and December 2018. Data were collected from the medical records of 1105 patients hospitalised for psychiatric disorders. Results: the average age of patients was 32.6 ± 11.1 years, ranging from 13 to 82 years. Male patients accounted for 83.8% (926/1105) of enrolled subjects, 53.2% (588/1105) were single, 18.8% (208/1105) were not employed and 28.2% (310/1105) had primary education. Seventy-four percent (818/1105) had a history of psychiatric disorders, 22.7% (251/1105) were born to consanguineous parents. Drug use was reported in 42.9% (474/1105) of cases, including tobacco 32.6% (361/1105), cannabis 26.0% (287/1105) and/or alcohol 15.6% (172/1105). The demand for care came from families in 87.5% (967/1105) of cases. Aggression was the most common reason for consultation (44.5%; 492/1105). In 67.8% (749/1105) of cases, the diagnosis was schizophrenia, schizotypic disorders or delusional disorders. The first use of care was traditional in 58.7% (649/1105) of cases. Conclusion: people hospitalised for psychiatric disorders from 2014 to 2018 were predominantly young and male with a history of psychiatric disorders. They mainly had schizophrenia, schizotypic disorders and delusional disorders.

Clinical and Genetic Aspects of Huntington's Disease in the Malian Population.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by mutation in the HTT gene and characterized by involuntary movements as well as cognitive and behavioral impairment. Since its first description 150 years ago, studies have been reported worldwide. However, genetically confirmed cases have been scarce in Africa. OBJECTIVE: To describe the clinical and genetic aspects of HD in the Malian population. METHODS: Patients with HD phenotype and their relatives were enrolled after obtaining consent. Symptoms were assessed using the Total Motor Scale (TMS) of the United Huntington's Disease Rating Scale (UHDRS) and the Mini-Mental State Examination (MMSE). Brain imaging and blood tests were performed to exclude other causes. DNA was extracted for HTT sequencing. RESULTS: Eighteen patients (13 families) with a HD phenotype were evaluated. A familial history of the disease was found in 84.6% with 55.5% of maternal transmission. The average length of the HTT CAG repeat was 43.6±11.5 (39-56) CAGs. The mean age at onset was 43.1±9.7years. Choreic movements were the predominant symptoms (100% of the cases) with an average TMS of 49.4±30.8, followed by cognitive impairment (average MMSE score: 23.0±12.0) and psychiatric symptoms with 22.2% and 44.4%, respectively. CONCLUSION: This is one of the largest HD cohorts reported in Africa. Increasing access to genetic testing could uncover many other HD cases and disease-modifying genetic variants. Future haplotype and psychosocial studies may inform the origin of the Malian mutation and the impact of the disease on patients and their relatives.

Descriptive study of cases of schizophrenia in the Malian population.

BACKGROUND: Schizophrenia is a relatively common disease worldwide with a point prevalence of around 5/1000 in the population. The aim of this present work was to assess the demographic, clinical, familial, and environmental factors associated with schizophrenia in Mali. METHODS: This was a prospective descriptive study on a series of 164 patients aged at least 12 years who came for a follow-up consultation at the psychiatry department of the University Hospital Center (CHU) Point G in Mali between February 2019 and January 2020 for schizophrenia spectrum disorder as defined by DSM-5 diagnostic criteria. RESULTS: Our results revealed that the male sex was predominant (80.5%). The 25-34 age group was more represented with 44.5%. The place of birth for the majority of our patients was the urban area (52.4%), which also represented the place of the first year of life for the majority of our patients (56.1%). We noted that the unemployed and single people accounted for 56.1 and 61% respectively. More than half of our patients 58.5% reported having reached secondary school level. With the exception of education level, there was a statistically significant difference in the distribution of demographic parameters. Familial schizophrenia cases accounted for 51.7% versus 49.3% for non-familial cases. The different clinical forms were represented by the paranoid form, followed by the undifferentiated form, and the hebephrenic form with respectively 34, 28 and 17.1%. We noted that almost half (48.8%) of patients were born during the cold season. Cannabis use history was not observed in 68.7% of the patients. The proportions of patients with an out-of-school father or an out-of-school mother were 51.2 and 64.2%, respectively. CONCLUSION: The onset of schizophrenia in the Malian population has been associated with socio-demographic, clinical, genetic and environmental characteristics.

Neuropsychiatric and socio-cultural aspects in a Malian family with spinocerebellar ataxia.

INTRODUCTION: Spino-cerebellar ataxia or SCA are dominant neurological diseases caused by mutations in several genes. According to social and cultural contexts, especially in populations with low education level, the advent of such diseases might generate other kinds of suffering beside those caused by the physical impairment and disability. The aim of this work was to determine the impact of this disease in patients and their relatives. METHODS: It was a qualitative approach carried out through semi-directive clinical interviews, neuropsychiatric observations and the administration of the Hamilton depression scale. RESULTS: The study included a polygamous family in which mothers had 10 and 12 maternities. Neurological manifestations concerned four children of the same siblings and the father in a subtle form. The mother of these children was designated as responsible for the transmission of the disease and presented a reaction depression. Irritability, anxiety and depression reactions were observed in two patients and an unaffected brother. The advent of the disease was associated to the hatching of a latent familial conflict related to the father's status that has been established only after four years. CONCLUSION: In a social and cultural setting of polygamy, the advent of dominant ataxia with anticipation might revive latent familial conflicts and have psychological and social repercussions on the affected individuals and their relatives.

INTRODUCTION: Les ataxies spinocérébelleuses dominantes ou SCA sont des maladies neurologiques causées par des mutations dans plusieurs gènes. En fonction des contextes socioculturels, surtout dans des populations à faible niveau éducatif, de telles pathologies sont susceptible d'engendrer d'autres types de souffrances en dehors de celles dues à l'atteinte physique et au handicap. Le présent travail a pour objectif de déterminer l'impact du vécu de cette maladie chez les patients ainsi que chez leurs parents. MÉTHODES: Il s'est agi d'une approche qualitative réalisée à travers des entretiens cliniques semi-directifs, des observations neuropsychiatriques et l'administration de l'échelle de dépression d'Hamilton. RÉSULTATS: L'étude a concerné une famille polygame dans laquelle les mères avaient eu 10 et 12 maternités. Les manifestations neurologiques ont concerné quatre enfants d'une même fratrie utérine et, de façon fruste, le père. La mère de ces enfants était désignée comme responsable de la transmission de la maladie et avait présenté une dépression réactionnelle. Des réactions d'irritabilité, d'anxiété et de dépression ont été observées chez deux patients et un frère non atteint. L'apparition de la maladie était associée à l'éclosion d'un conflit familial latent lié au statut du père qui n'a été établi que quatre années plus tard. CONCLUSION: Dans un contexte socioculturel de polygamie, le déclenchement d'une ataxie dominante avec notion d'anticipation est susceptible de raviver des conflits intrafamiliaux latents et de se répercuter sur la sphère psychologique et sociale des personnes affectées et de leur entourage.

Oral Hygiene: Knowledge and Practices of Students in Three Quranic Schools in Koutiala, Mali

Objective: To evaluate the knowledge, attitudes, and practices on oral hygiene (OH) of students of three Quranic schools of Koutiala, Mali. Material and Methods: It was carried out a descriptive prospective study with 300 students in three Quranic schools in the city of Koutiala, Mali. The data analyzed with the Epi Info 3.5.4 software. Results: The male sex was the most represented with 57.7% and the sex ratio = 0.73. The most represented age group was 8-12 with 52% with an average age of 17 years and minimum and maximum age of was 8 and 26 years. It was observed that 98.3% of students had a notion of knowledge about oral hygiene and this information was given by parents / elders in 60% of cases. They claimed that people who do not brush their teeth properly are the most likely to get tooth decay in 93.3% of cases. Regarding dental caries, 61.3% of students said that caries is transmitted by lack of oral hygiene; 33.3% of students said that using toothbrushes and having good oral hygiene are ways to avoid oral diseases. It was thought in 93.3% of cases that a good oral hygiene prevents oral diseases. The students brushed their teeth every day (98%) and they had a consultation with the dental surgeon in 8.7% of the cases. Conclusion: This study shows that students had knowledge of oral hygiene and preventive measures. Efforts should be made to promote, prevent, screen and manage oral diseases in Quranic schools while involving parents in the processes.

Knowledge, Attitudes and Practices of Doctors and Dental Surgeons in Bamako on the Relationship Between Periodontal Diseases and Chronic Non-Communicable Diseases

Objective: To assess the level of knowledge, attitudes and practices of doctors and dentists in Bamako on the relationship between chronic non-communicable diseases and periodontal diseases. Material and Methods: A cross-sectional study of 420 physicians and dental surgeons was conducted from March to August 2016. Data analysis involved descriptive statistics (frequency distribution). All statistical analyses were performed using the Epi Info 3.5.4 Software. Results: The male sex was the most represented with 58% for a sex ratio of 1.3. The most represented age group was 30-40 years old (48.8%) with an average age of 33 ± 8.2 years. General practitioners were the most represented in 93.6% of cases. Physicians with no knowledge of periodontal disease accounted for 60% of all cases, and all dental surgeons reported knowledge of chronic noncommunicable conditions in 100% of cases. Physicians and dental surgeons rated their knowledge levels of periodontal disease and chronic disease as inadequate in 98% and 90% of cases, respectively. Examination of the oral cavity by the doctors was "sometimes" carried out in 66% of the cases and the non-demand of the clinical signs of the gingival bleeding (64%) and dental migration (80.5%). They did not make recommendations on oral hygiene in 61.7% of cases. Conclusion: This study shows shortcomings among doctors and dentists in Bamako on the relationship between periodontal diseases and chronic non-communicable diseases. Capacity building and multidisciplinary collaboration are needed to support people's health.

Does the survival motor neuron copy number variation play a role in the onset and severity of sporadic amyotrophic lateral sclerosis in Malians?

INTRODUCTION: Spinal muscular atrophy (SMA) and sporadic amyotrophic lateral sclerosis (SALS) are both motor neuron disorders. SMA results from the deletion of the survival motor neuron (SMN) 1 gene. High or low SMN1 copy number and the absence of SMN2 have been reported as risk factors for the development or severity of SALS. OBJECTIVE: To investigate the role of SMN gene copy number in the onset and severity of SALS in Malians. MATERIAL AND METHODS: We determined the SMN1 and SMN2 copy number in genomic DNA samples from 391 Malian adult volunteers, 120 Yoruba from Nigeria, 120 Luyha from Kenya and 74 U.S. Caucasians using a Taqman quantitative PCR assay. We evaluated the SALS risk based on the estimated SMA protein level using the Veldink formula (SMN1 copy number + 0.2 ∗ SMN2 copy number). We also characterized the disease natural history in 15 ALS patients at the teaching hospital of Point G, Bamako, Mali. RESULTS: We found that 131 of 391 (33.5%) had an estimated SMN protein expression of ≤ 2.2; 60 out of 391 (15.3%) had an estimated SMN protein expression < 2 and would be at risk of ALS and the disease onset was as early as 16 years old. All 15 patients were male and some were physically handicapped within 1-2 years in the disease course. CONCLUSION: Because of the short survival time of our patients, family histories and sample DNA for testing were not done. However, our results show that sporadic ALS is of earlier onset and shorter survival time as compared to patients elsewhere. We plan to establish a network of neurologists and researchers for early screening of ALS.

Non-motor signs in patients with Parkinson's disease at the University Hospital of Point "G", Mali.

INTRODUCTION: Despite significant progress in the field of scientific research on Parkinson's disease (PD), the prevalence and pathophysiology of its non-motor signs remains less understood than the classic motor signs of bradykinesia, rigidity, tremor and postural instability. Data covering this topic are rare in Africa, and almost non-existent in sub-Saharan Africa. Thus, this study aims to highlight the frequency of certain non-motor signs in PD patients followed in the Department of Neurology of the University Hospital Point "G", Bamako, Mali. METHODOLOGY: This is a retrospective and descriptive study from January 2012 to November 2013. We identified records of patients with dopamine-responsive idiopathic Parkinson's disease, and quantified associated non-motor symptoms. Data were analyzed with Epi-Info 2000 version 3.5.5. RESULT: During this period we reviewed 60 patient charts of which 68.3% were men. The average age of patients was 66.51 ranging from 25 to 94 years.Non-motor symptoms were present in 90% of cases, including sensitive disorders in 76.7%, dysautonomia in 73.3%, and psycho-behavioral disorders, including sleep disorders, in 81.7%. CONCLUSION: At the end of this study, we observed an important place for non-motor signs in the clinical manifestation of PD patients in general.

Socio-cultural adaptation and standardization of Dubois' five words testing in a population of normal subject in Mali, West Africa.

INTRODUCTION: Dubois' five words testing (5WT) is a verbal memory test that depends on many parameters. The aim of this study is to adapt Dubois' 5WT to the Malian socio-cultural conditions to (i) determine performances of normal subjects to the 5WT and (ii) provide reference scores of the 5WT. METHODS: A sample of 276 normal subjects aged ≥ 50 years (154 males and 122 females; 144 literates and 132 illiterates) were enrolled from February 2008 to January 2009. Subjects with a history of symptoms likely to modify cognitive functions and those who were found disabled under Lawton's four simplified item test were excluded. RESULTS: The learning score in illiterates was 1.51 in Dubois' 5WT and 4.90 in the modified 5WT. The mean value of the modified 5WT total score was 9.71. Majority (90.22%) of the subjects scored the maximum (10). The modified 5WT reduced with both the age (p < 0.006) and education level (p < 0.04). CONCLUSION: Our results show that Dubois' 5WT is influenced by culture and the socio-educative level in French. Its adaptation to the socio-cultural context could prove useful and efficient in countries with a low literacy rate and a diverse cultural background.

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

BACKGROUND: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. METHODS: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. RESULTS: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. CONCLUSION: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.

Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations.

BACKGROUND: The full-length (L-) variant of caspase-12 is believed to predispose to sepsis. It has been replaced in the genome of most human populations by the (S-) variant, which leads to premature termination of translation. Strikingly, the L-allele is still widely prevalent in African populations, presumably due to a counterbalancing selective force specific to this continent, for which malaria is a prime candidate. METHODS: We investigated associations between caspase-12 genotype and malarial parameters in three West-African populations, in studies encompassing immunological, clinical and obstetric data. RESULTS: The caspase-12 L-allele was found at frequencies of 11-34%. Plasmodium falciparum-stimulated mononuclear cells from S/L heterozygote donors produced stronger interferon-gamma and interleukin-10 responses than S/S homozygotes (p = 0.011 and p = 0.023 in uninfected and infected donors respectively). Nevertheless, we found no association between caspase-12 genotype and either the presentation of severe malaria or individual clinical parameters in sick children. Amongst pregnant women, the caspase-12 genotype did not influence peripheral or placental malaria infection, or basic obstetric parameters. Interestingly, perinatal mortality was more frequent in children of both S/S and L/L than S/L mothers, independent of placental P. falciparum-infection. CONCLUSION: We find little clinical or epidemiological evidence that malaria has contributed to the persistence of functional caspase-12 in Africa, suggesting either that alternative selective forces are at work or that genetic drift underlies its current global distribution.

Early interferon-gamma response against Plasmodium falciparum correlates with interethnic differences in susceptibility to parasitemia between sympatric Fulani and Dogon in Mali.

INTRODUCTION: Interethnic differences in susceptibility to malaria provide a unique opportunity to explore immunological correlates of protection. The Fulani of Sahelian Africa are known for their reduced susceptibility to Plasmodium falciparum, compared with surrounding tribes, yet the immunology underlying this is still poorly understood. METHODS AND RESULTS: Here, we show that mononuclear cells from Fulani elicit >10-fold stronger interferon (IFN)-gamma production following a 24-h in vitro coincubation with asexual parasites than cells from sympatric Dogon. This response appears to be specific for P. falciparum among a panel of other human pathogens and is independent of the lower number of regulatory T cell counts present in Fulani. IFN-gamma responses in both tribes were inversely correlated with peripheral parasite density as quantified by nucleic acid sequenced-based amplification, but responses of Fulani remained significantly stronger than those of Dogon after adjustment for concurrent parasitemia, suggesting that hard-wired immunological differences underlie the observed protection. CONCLUSIONS: These results underscore the value of early IFN-gamma responses to P. falciparum as a correlate of anti-parasite immunity, not only in this setting but also in the wider context of malaria, and support the development of malaria vaccines aimed at inducing such responses.

Caspase-12 and the inflammatory response to Yersinia pestis.

BACKGROUND: Caspase-12 functions as an antiinflammatory enzyme inhibiting caspase-1 and the NOD2/RIP2 pathways. Due to increased susceptibility to sepsis in individuals with functional caspase-12, an early-stop mutation leading to the loss of caspase-12 has replaced the ancient genotype in Eurasia and a significant proportion of individuals from African populations. In African-Americans, it has been shown that caspase-12 inhibits the pro-inflammatory cytokine production. METHODOLOGY/PRINCIPAL FINDINGS: We assessed whether similar mechanisms are present in African individuals, and whether evolutionary pressures due to plague may have led to the present caspase-12 genotype population frequencies. No difference in cytokine induction through the caspase-1 and/or NOD2/RIP2 pathways was observed in two independent African populations, among individuals with either an intact or absent caspase-12. In addition, stimulations with Yersinia pestis and two other species of Yersinia were preformed to investigate whether caspase-12 modulates the inflammatory reaction induced by Yersinia. We found that caspase-12 did not modulate cytokine production induced by Yersinia spp. CONCLUSIONS: Our experiments demonstrate for the first time the involvement of the NOD2/RIP2 pathway for recognition of Yersinia. However, caspase-12 does not modulate innate host defense against Y. pestis and alternative explanations for the geographical distribution of caspase-12 should be sought.

Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.

Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.

TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.

Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.

Assessing malaria burden during pregnancy in Mali.

Malaria infection during pregnancy is associated with adverse consequences including low birth weight (LBW) and maternal anemia, particularly in primigravidae and secundigravidae. In preparation for a clinical trial of the efficacy of chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) containing prevention regimens during pregnancy, we conducted a one-year cross sectional study in Koro and Bandiagara, Mali using an assessment methodology developed by the Centers for Disease Control and Prevention (CDC) to generate basic data on malarial burden during pregnancy. Two hundred and sixty-one and 192 women were enrolled in Koro and Bandiagara, respectively. Rates of placental parasitemia were 17.1 and 42.3% in Koro and Bandiagara, respectively, despite high (70-80%) use of preventive medication (mainly CQ). Low gravidity (1st and 2nd pregnancies) was associated with peripheral (p<0.001) and placental (p<0.001) malaria only in Bandiagara, whereas it was associated with low birth weight in both sites (p<0.001 in Koro and p=0.002 in Bandiagara). First and second pregnancies were the most important characteristics associated with placental malaria (RR=2.78, 95%CI 1.81-4.29) and (ARR=2.06, 95%CI 1.03-4.15) and low birth weight (RR=4.26, 95%CI 2.50-7.27) and (ARR=4.51, 95%CI 2.55-8.00). Birth during the rainy season was associated with placental infection in univariate analysis. Characteristics such as younger age, having fever during pregnancy, and unmarried status were associated with low birth weight only in univariate analysis and singleton premature delivery and low gravidity were associated with low birth weight in both univariate and multivariate analysis. Data from this assessment demonstrated the high burden of malaria during pregnancy in Mali. Results had been used by researchers as local reference data and by ministry of health for to stop recommending CQ prophylaxis. The methodology could be used by other malaria-endemic countries to direct their national malaria program efforts.