75 results on '"J, Milet"'
Search Results
2. Intérêt de l'électrophorèse des isophosphatases alcalines chez l'insuffisant rénal hémodialysé
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N. Gillain, J. Milet, J.-M. Minon, M. Robin, and P. Cambier
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business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Medicine ,business ,Alkaline phosphatase isoenzymes ,Molecular biology - Abstract
Resume Le but de l'etude est d'etablir l'interet du profil des isophosphatases alcalines realise sur Hydrasys (Sebia) dans l'osteodystrophie renale. Cette procedure permet d'identifier un variant osseux, temoin d'une activite osteoblastique importante. Nous avons realise l'electrophorese et le dosage de la phosphatase osseuse par immunofluorescence (Ostase) chez 105 patients hemodialyses, traites par 1,25 (OH)2 vitamine D lorsque la PTH est superieure a 150 pg/ml. Le profil des isophosphatases de l'insuffisant renal est caracterise par une activite elevee des isoformes intestinales, hepatiques et macromoleculaires. On observe un variant osseux chez 10 % d'entre eux. La fraction osseuse estimee par electrophorese est bien correlee (r : 95) a l'Ostase. Parmi les 103 patients pour lesquels des examens radiologiques ont ete effectues avant et apres la realisation des analyses, on denombre 42 malades presentant des lesions caracteristiques d'hyperparathyroidie secondaire. La sensibilite, la specificite, la valeur predictive positive et la valeur predictive negative d'une anomalie a l'electrophorese est respectivement 31, 92, 72 et 65 %. La sensibilite, la specificite, la valeur predictive positive et la valeur predictive negative d'une valeur hors normes de l'Ostase est 14, 88, 46 et 58 % et celle d'une PTH superieure a 150 pg/ml, 25, 85, 59 et 58 %.
- Published
- 2004
3. Association of HLA-G 3' untranslated region polymorphisms with antibody response against Plasmodium falciparum antigens: preliminary results
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A, Sabbagh, D, Courtin, J, Milet, J D, Massaro, E C, Castelli, F, Migot-Nabias, B, Favier, N, Rouas-Freiss, P, Moreau, A, Garcia, and E A, Donadi
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HLA-G Antigens ,Polymorphism, Genetic ,Adolescent ,Plasmodium falciparum ,Antigens, Protozoan ,Linkage Disequilibrium ,Senegal ,Haplotypes ,Child, Preschool ,Antibody Formation ,Humans ,Malaria, Falciparum ,Child ,3' Untranslated Regions ,Genetic Association Studies - Abstract
Host and Plasmodium interactions result in highly variable clinical phenotypes, partly explained by the nature and level of anti-malarial antibody response. Human leukocyte antigen (HLA)-G can create a tolerogenic environment, allowing parasites to escape from anti-malarial immunity. We performed a family-based association study encompassing 483 Sereer individuals (261 children and their parents), and reported two independent signals at the HLA-G 3' untranslated region associated with antibody response to specific Plasmodium falciparum blood stage antigens, previously associated with malaria protection: (i) +3010G together with +3142C with total IgG and IgG1 against GLURP and (ii) +3196G with IgG3 against MSP2. While these results require further investigation, they suggest for the first time a role of HLA-G in the regulation of humoral immune response in malaria.
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- 2013
4. Evaluation of dual-energy X-ray absorptiometry for body-composition assessment in piglets and term human neonates
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Jacques Senterre, J. Milet, K Nyamugabo, J C Picaud, and Jacques Rigo
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musculoskeletal diseases ,Bone density ,Swine ,Birth weight ,Medicine (miscellaneous) ,chemistry.chemical_element ,Adipose tissue ,Gestational Age ,Calcium ,Sensitivity and Specificity ,Bone and Bones ,Absorptiometry, Photon ,Animal science ,Bone Density ,Suidae ,medicine ,Animals ,Humans ,Dual-energy X-ray absorptiometry ,Reproducibility ,Nutrition and Dietetics ,biology ,medicine.diagnostic_test ,Spectrophotometry, Atomic ,musculoskeletal, neural, and ocular physiology ,Body Weight ,Infant, Newborn ,Reproducibility of Results ,Anatomy ,musculoskeletal system ,biology.organism_classification ,Adipose Tissue ,Animals, Newborn ,chemistry ,Evaluation Studies as Topic ,Body Composition ,Composition (visual arts) ,human activities - Abstract
The reproducibility, accuracy, and precision of dual-energy X-ray absorptiometry (DXA) was assessed by scanning 13 piglets (1471-5507 g) in triplicate. In four piglets, fat content was increased with porcine lard around the abdomen; additional measurements were performed on these animals. Reproducibility in DXA measurements from the animals without added fat was 0.09% for body weight, 1.95% for bone mineral content (BMC), and 5.35% for fat content. DXA estimates of body weight, BMC, and fat content were significantly correlated with scale body weight, ash weight, chemical calcium, and chemical fat. Body weight was measured accurately but fat content was overestimated by DXA. Mean BMC estimated by DXA represented 48% of ash weight and 215% of calcium content. The precision of DXA was 0.23% for body weight, 10.99% for ash weight, and 4.44% for calcium content. The precision of DXA for fat content was poor. However, for measurements performed in piglets with > 250 g fat, the precision was 8.85%. Thirty appropriate-forgestational-age term human neonates (birth weight: 3188 +/- 217 g) were scanned once during the first week of life. BMC and fat content were 54 +/- 6 and 470 +/- 92 g, respectively, which corresponded to 26.4 +/- 2.6 g calcium and 427 +/- 82 g fat. These were close to the reference values previously determined by chemical analysis. This study suggests that DXA is accurate and reliable for measurement of calcium and fat contents in human neonates. Further refinements would be beneficial for determining fat content in preterm human infants.
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- 1996
5. Schistosoma haematobium infection affects Plasmodium falciparum-specific IgG responses associated with protection against malaria
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D, Courtin, A, Djilali-Saïah, J, Milet, V, Soulard, O, Gaye, F, Migot-Nabias, R, Sauerwein, A, Garcia, and A J F, Luty
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Male ,Adolescent ,Plasmodium falciparum ,Protozoan Proteins ,Antibodies, Protozoan ,Antigens, Protozoan ,Senegal ,Schistosomiasis haematobia ,Young Adult ,Immunoglobulin G ,Schistosoma haematobium ,Animals ,Humans ,Female ,Malaria, Falciparum ,Child ,Merozoite Surface Protein 1 - Abstract
We have previously shown that antibody responses directed to Plasmodium falciparum merozoite surface protein (MSP)-1, MSP-2 and glutamate-rich protein (GLURP) are associated with anti-malarial protection in residents of the Niakhar area of Senegal. In the same area, urinary schistosomiasis is frequent and we therefore assessed the possible influence of Schistosoma haematobium infection on these protective anti-malarial IgG responses. After adjustment for confounders, we found that the levels of IgG1 directed to MSP1 and GLURP were significantly lower in helminth carriers. The higher circulating levels of interleukin (IL)-10 present in the plasma of co-infected individuals were associated with decreased anti-plasmodial IgG responses, particularly of those directed to MSP-2. Our data thus reveal a modulation of P. falciparum-specific immune responses in the presence of a trematode helminth infection, potentially increasing infected individuals' risk of plasmodial infection or disease.
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- 2011
6. [Validation of the sentinel lymph node biopsy in breast cancer]
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V, Bleret, E, Lifrange, V, Ghuysen, J, Milet, V, Fridman, and C, Colin
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Adult ,Aged, 80 and over ,Sentinel Lymph Node Biopsy ,Lymphatic Metastasis ,Humans ,Breast Neoplasms ,Female ,Lymph Nodes ,Prospective Studies ,Middle Aged ,Aged - Abstract
Assessment of our experience and validation of the sentinel lymph node biopsy technique in breast cancer stage T0-T2N0M0 surgery.Identification and biopsy of the sentinel lymph node by the radio colloid method in a consecutive series of 205 patients undergoing surgery for breast cancer stage T0-T2N0M0 between October 1998 and January 2007, initially in association with a complete axillary lymph node dissection (learning curve), later in an elective way. Prospective recording of the data and analysis with an average follow-up of 50 months (3 to 102 months).Biopsy rate of the sentinel lymph node of 90%, false negative rate of the method 2.5%, axillary recurrence rate 0%.We confirm in this series that the sentinel lymph node biopsy technique is a reliable approach in our experience for the evaluation of the axillary lymph node status in breast cancer stage T0-T2N0M0.
- Published
- 2008
7. [Prolonged treatment with recombined growth hormone improves bone measures: study of body composition in 21 deficient adults on treatment]
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V, Beckers, J, Milet, and J J, Legros
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Adult ,Male ,Time Factors ,Adolescent ,Bone and Bones ,Hypopituitarism ,Absorptiometry, Photon ,Bone Density ,Humans ,Insulin-Like Growth Factor I ,Child ,Muscle, Skeletal ,Aged ,Hypophysectomy ,Minerals ,Human Growth Hormone ,Infant, Newborn ,Middle Aged ,Water-Electrolyte Balance ,Hormones ,Recombinant Proteins ,Adipose Tissue ,Body Composition ,Drug Evaluation ,Female ,Follow-Up Studies - Abstract
Adult growth hormone deficiency is characterized by changes in body composition: increase in total fat, decrease in lean mass and osteopenia, with a fall in Bone Mineral Content (BMC) and in Bone Mineral density (BMD) leading to a rise in risk of fracture. We have analyzed the changes in body composition in 21 adults treated from 9 to 78 months, by dual X-RAY absorptiometry (DEXA). We've demonstrated a gain in bone mass and density, particularly of axial skeleton; a latence of minimum 12 months has been necessary to objective these changes. The balance of fat and lean mass has been poorly modified by treatment except for the lean mass of the trunk, which is significantly increased. We think that the usual doses of rGH, based on IGF-1 level, are perhaps underestimated.
- Published
- 2002
8. Validation of dual, X-ray absorptiometry (DXA) for body composition assessment in piglets and in term human neonates
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J Senterre, J. Milet, J C Picaud, J. Rigo, K Nyamugabo, and Revues Inra, Import
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[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,business.industry ,[SDV.BDD] Life Sciences [q-bio]/Development Biology ,Dual x-ray absorptiometry ,Biology ,Nuclear medicine ,business ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology ,Term (time) - Published
- 1996
9. [Clinical case of the month. Value of a pentagastrin test in the early detection of thyroid medullary cancer]
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J J, Legros, V, Beckers, J, Milet, D, Denis, and C, Innocenti
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Calcitonin ,Carcinoma, Medullary ,Humans ,Female ,Pentagastrin ,Thyroid Neoplasms ,Aged ,Carcinoembryonic Antigen - Published
- 1995
10. Increased Parasellar Activity on Gallium SPECT is Not Specific for Active Cluster Headache
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J. Sianard-Gainko, J. Milet, V. Ghuysen, and Jean Schoenen
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Tomography, Emission-Computed, Single-Photon ,medicine.diagnostic_test ,business.industry ,Aura ,Incidence ,Migraine Disorders ,Cluster headache ,chemistry.chemical_element ,Cluster Headache ,Gallium Radioisotopes ,General Medicine ,medicine.disease ,Sensitivity and Specificity ,chemistry ,Migraine ,Positron emission tomography ,Cavernous sinus ,medicine ,Humans ,Sella Turcica ,Neurology (clinical) ,Gallium ,business ,Nuclear medicine - Abstract
We have performed Gallium SPECT head scans in 30 successive cluster headache (CH) patients and in 7 migraineurs without aura. Parasellar hyperactivity was judged as present in 81% of chronic CH patients, 54% of episodic CH patients in an active period, 56% of episodic CH patients in remission and 71% of migraineurs. No significant correlations were found between the SPECT images and the duration of the disease, of cluster periods or of remissions. Increased parasellar activity on Gallium SPECT is thus not specific for CH, nor for the active period of episodic CH. The method lacks reliability for investigation of putative cavernous sinus inflammation.
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- 1994
11. [Measurement of cerebral blood flow by radioactive xenon inhalation]
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J C, Depresseux, J, Milet, and J, Bonnal
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Adult ,Male ,Cerebrovascular Disorders ,Cerebrovascular Circulation ,Humans ,Female ,Middle Aged ,Xenon Radioisotopes ,Aged ,Cerebral Angiography ,Hydrocephalus - Published
- 1979
12. Control of diabetes: an attempt to formulate policy guidelines in a department of medicine
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Pierre Lefebvre, Alfred S. Luyckx, and J. Milet
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Gerontology ,Blood Glucose ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Control (management) ,Population ,Statistics as Topic ,Belgium ,Diabetes mellitus ,Physicians ,Internal Medicine ,Diabetes Mellitus ,Medicine ,Humans ,Diagnostic Errors ,education ,Quality of Health Care ,education.field_of_study ,Analysis of Variance ,Clinical Trials as Topic ,business.industry ,Computers ,Policy guidelines ,Human physiology ,medicine.disease ,Diabetes control ,Evaluation Studies as Topic ,Family medicine ,business - Abstract
Three hundred and twenty eight serial measurements of blood glucose (SMBG) performed in a Department of Medicine were rated by 7 experienced diabetes specialists. A statistical study showed considerable variation among the raters. Similarly, the ratings of the 7 physicians relative to the mean rating showed a great deal of individual variation. A highly satisfactory correlation was found between the mean rating of the 7 physicians and the M-value of Schlichtkrull as computed from 7 or 8 samples collected during the day. On the basis of these findings the degree of diabetes control for this population can be judged satisfactory, good or very good when the M-value is ⩽ 10. If the M-value is ⩾ 22, control is poor or very poor and major changes in the treatment program are indicated. Intermediate values, seen in one out of five cases, indicate the need for systematic consultation with a diabetes specialist.
- Published
- 1974
13. [Congenital hypothyroidism and its neonatal diagnosis]
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J P, Bourguignon, J, Milet, R, Schoos, P, Franchimont, and C, Lambotte
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Thyroid Hormones ,Thyroxine ,Hypothyroidism ,Congenital Hypothyroidism ,Infant, Newborn ,Humans ,Thyrotropin ,Triiodothyronine - Published
- 1979
14. [Complementary clinical relationship between blood volume determination and neuroradiologic exploration of the brain]
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J, Milet, J, Bernier, and J C, Depresseux
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Male ,Blood Volume ,Blood Volume Determination ,Brain ,Humans ,Arterial Occlusive Diseases ,Female ,Middle Aged ,Radionuclide Imaging ,Xenon Radioisotopes - Published
- 1980
15. [The concept of equilibration of diabetes in adults. Attempt at defining a policy in an internal medicine service]
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P, Lefebvre, J, Milet, and A, Luyckx
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Adult ,Blood Glucose ,Glycosuria ,Surveys and Questionnaires ,Diabetes Mellitus ,Methods ,Humans - Published
- 1973
16. IgG and IgM responses to the Plasmodium falciparum asexual stage antigens reflect respectively protection against malaria during pregnancy and infanthood.
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Gbaguidi MLE, Adamou R, Edslev S, Hansen A, Domingo ND, Dechavanne C, Massougbodji A, Garcia A, Theisen M, Milet J, Donadi EA, and Courtin D
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- Humans, Female, Pregnancy, Infant, Benin, Adult, Young Adult, Enzyme-Linked Immunosorbent Assay, Infant, Newborn, Pregnancy Complications, Parasitic prevention & control, Pregnancy Complications, Parasitic immunology, Cohort Studies, Plasmodium falciparum immunology, Malaria, Falciparum prevention & control, Malaria, Falciparum immunology, Immunoglobulin M blood, Immunoglobulin G blood, Antibodies, Protozoan blood, Antigens, Protozoan immunology
- Abstract
Background: Plasmodium falciparum malaria is a public health issue mostly seen in tropical countries. Until now, there is no effective malaria vaccine against antigens specific to the blood-stage of P. falciparum infection. Because the pathogenesis of malarial disease results from blood-stage infection, it is essential to identify the most promising blood-stage vaccine candidate antigens under natural exposure to malaria infection., Methods: A cohort of 400 pregnant women and their infants was implemented in South Benin. An active and passive protocol of malaria surveillance was established during pregnancy and infancy to precisely ascertain malaria infections during the follow-up. Twenty-eight antibody (Ab) responses specific to seven malaria candidate vaccine antigens were repeatedly quantified during pregnancy (3 time points) and infancy (6 time points) in order to study the Ab kinetics and their protective role. Abs were quantified by ELISA and logistic, linear and cox-proportional hazard model were performed to analyse the associations between Ab responses and protection against malaria in mothers and infants, taking into account socio-economic factors and for infants an environmental risk of exposure., Results: The levels of IgM against MSP1, MSP2 and MSP3 showed an early protective response against the onset of symptomatic malaria infections starting from the 18th month of life, whereas no association was found for IgG responses during infancy. In women, some IgG responses tend to be associated with a protection against malaria risk along pregnancy and at delivery, among them IgG3 against GLURP-R0 and IgG2 against MSP1., Conclusion: The main finding suggests that IgM should be considered in vaccine designs during infanthood. Investigation of the functional role played by IgM in malaria protection needs further attention., (© 2024. The Author(s).)
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- 2024
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17. Association of Endothelial Protein C Receptor (EPCR) rs867186 Gene Polymorphism With Increased Levels of Soluble EPCR and High Risk of Severe Malaria and Fatality in Beninese Children.
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Blankson SO, Dikroh L, Tettey P, Tornyigah B, Adamou R, Moussiliou A, Alao MJ, Amoussou A, Padounou C, Milet J, Mensah BA, Aniweh Y, Ndam NT, Roussilhon C, and Tahar R
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- Humans, Child, Endothelial Protein C Receptor genetics, Polymorphism, Genetic, Receptors, Cell Surface, Malaria, Cerebral
- Abstract
The endothelial protein C receptor (EPCR)-rs867186 G allele has been linked to high plasma levels of soluble EPCR (sEPCR) and controversially associated with either susceptibility or resistance to severe and cerebral malaria. In this study, quantitative enzyme-linked immunosorbent assay and sequencing were used to assess sEPCR levels and EPCR-rs867186 polymorphism in blood samples from Beninese children with different clinical presentations of malaria. Our findings show that sEPCR levels were higher at hospital admission than during convalescence and that EPCR-rs867186 G allele was associated with increased sEPCR plasma levels, malaria severity, and mortality rate (P < .001, P = .03, and P = .04, respectively), suggesting a role of sEPCR in the pathogenesis of severe malaria., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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18. Naturally acquired antibodies from Beninese infants promote Plasmodium falciparum merozoite-phagocytosis by human blood leukocytes: implications for control of asymptomatic malaria infections.
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Fall AKDJ, Kana IH, Dechavanne C, Garcia-Senosiain A, Guitard E, Milet J, Massougbodji A, Garcia A, Dugoujon JM, Migot-Nabias F, Theisen M, and Courtin D
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- Child, Infant, Animals, Humans, Merozoites, Plasmodium falciparum, Asymptomatic Infections, Longitudinal Studies, Phagocytosis, Leukocytes, Immunoglobulin G, Malaria, Malaria, Falciparum
- Abstract
Background: Immunoglobulin G (IgG) antibodies are thought to play important roles in the protection against Plasmodium falciparum (P. falciparum) malaria. A longitudinal cohort study performed in the Southern part of Benin, identified a group of infants who were able to control asymptomatic malaria infections (CAIG)., Methods: IgG antibodies against distinct merozoite antigens were quantified in plasma from Beninese infants. Functionality of these antibodies was assessed by the merozoite-phagocytosis assay using THP-1 cells and primary neutrophils as effector cells. Gm allotypes were determined by a serological method of haemagglutination inhibition., Results: Purified IgG from infants in CAIG promoted higher levels of merozoite-phagocytosis than did IgG from children who were unable to control asymptomatic infections (Ologit multivariate regression model, Coef. = 0.06, 95% CI 0.02;0.10, P = 0.002). High level of merozoite-phagocytosis activity was significantly associated with high levels of IgG against AMA1 (Coef. = 1.76, 95% CI 0.39;3.14, P = 0.012) and GLURP-R2 (Coef. = 12.24, 95% CI 1.35;23.12, P = 0.028). Moreover, infants of the G3m5,6,10,11,13,14,24 phenotype showed higher merozoite-phagocytosis activity (Generalized linear model multivariate regression, Coef. = 7.46, 95% CI 0.31;14.61, P = 0.041) than those presenting other G3m phenotypes., Conclusion: The results of the present study confirm the importance of antibodies to merozoite surface antigens in the control of asymptomatic malaria infection in Beninese infants. The study also demonstrated that G3m phenotypes impact the functional activity of IgG. This last point could have a considerable impact in the research of candidate vaccines against malaria parasites or other pathogens., (© 2022. The Author(s).)
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- 2022
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19. Fc Gamma Receptor IIIB NA1/NA2/SH Polymorphisms Are Associated with Malaria Susceptibility and Antibody Levels to P. falciparum Merozoite Antigens in Beninese Children.
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Fall AKDJ, Courtin D, Adamou R, Edslev S, Hansen A, Domingo N, Christiansen M, Adu B, Milet J, Garcia A, Theisen M, Migot-Nabias F, and Dechavanne C
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- Infant, Child, Animals, Humans, Merozoites, Receptors, IgG genetics, Polymorphism, Genetic, Antigens, Protozoan genetics, Plasmodium falciparum genetics, Malaria, Falciparum genetics, Malaria genetics
- Abstract
This paper aimed to investigate the influence of polymorphisms in the FCGR2A gene encoding R131H FcgRIIA variants and in the FCGR3B gene (108G > C, 114C > T, 194 A > G, 233C > A, 244 G > A and 316G > A) encoding FcgRIIIB-NA1, -NA2 and -SH variants on malaria susceptibility and antibody responses against P. falciparum merozoite antigens in Beninese children. An active malaria follow-up was conducted in infants from birth to 24 months of age in Allada, Benin. FCGR3B exon 3 was sequenced and FCGR2A exon 4 was genotyped. Antibodies directed to GLURP and MSP3 were quantified by ELISA. Association studies were performed using mixed-effect models. Individual carriage of FCGR3B 194 AA genotype was associated with a high number of malaria infections and a low level of IgG1 against MSP3 and GLURP-R0. High parasitemia and increased malaria infections were observed in infants carrying the FCGR3B*05 108C-114T-194A-233C-244A-316A haplotype. A reduced risk of malaria infections and low parasitemia were related to the carriages of the FCGR3B 108C-114T-194G-233C-244G-316A (FCGR3B*06), FCGR3B 108C−114T−194G−233A−244A−316A (FCGR3B*03 encoding for FcgRIIIB-SH) haplotypes and FCGR3B 297 TT genotype. Our results highlight the impact of FCGR3B polymorphisms on the individual susceptibility to malaria and antibody responses against MSP3 and GLURP in Beninese children.
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- 2022
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20. Placental Malaria is Associated with Higher LILRB2 Expression in Monocyte Subsets and Lower Anti-Malarial IgG Antibodies During Infancy.
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Dechavanne C, Nouatin O, Adamou R, Edslev S, Hansen A, Meurisse F, Sadissou I, Gbaguidi E, Milet J, Cottrell G, Gineau L, Sabbagh A, Massougbodji A, Moutairou K, Donadi EA, Carosella ED, Moreau P, Remarque E, Theisen M, Rouas-Freiss N, Garcia A, Favier B, and Courtin D
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- Antibodies, Protozoan, Female, Humans, Immunoglobulin G blood, Infant, Infant, Newborn, Interleukin-10, Leukocyte Immunoglobulin-like Receptor B1 genetics, Leukocyte Immunoglobulin-like Receptor B1 immunology, Monocytes metabolism, Plasmodium falciparum, Pregnancy, Antimalarials, Malaria, Falciparum, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Placenta parasitology, Receptors, Immunologic genetics, Receptors, Immunologic immunology
- Abstract
Background: Placental malaria (PM) is associated with a higher susceptibility of infants to Plasmodium falciparum (Pf) malaria. A hypothesis of immune tolerance has been suggested but no clear explanation has been provided so far. Our goal was to investigate the involvement of inhibitory receptors LILRB1 and LILRB2, known to drive immune evasion upon ligation with pathogen and/or host ligands, in PM-induced immune tolerance., Method: Infants of women with or without PM were enrolled in Allada, southern Benin, and followed-up for 24 months. Antibodies with specificity for five blood stage parasite antigens were quantified by ELISA, and the frequency of immune cell subsets was quantified by flow cytometry. LILRB1 or LILRB2 expression was assessed on cells collected at 18 and 24 months of age., Findings: Infants born to women with PM had a higher risk of developing symptomatic malaria than those born to women without PM (IRR=1.53, p=0.040), and such infants displayed a lower frequency of non-classical monocytes (OR=0.74, p=0.01) that overexpressed LILRB2 (OR=1.36, p=0.002). Moreover, infants born to women with PM had lower levels of cytophilic IgG and higher levels of IL-10 during active infection., Interpretation: Modulation of IgG and IL-10 levels could impair monocyte functions (opsonisation/phagocytosis) in infants born to women with PM, possibly contributing to their higher susceptibility to malaria. The long-lasting effect of PM on infants' monocytes was notable, raising questions about the capacity of ligands such as Rifins or HLA-I molecules to bind to LILRB1 and LILRB2 and to modulate immune responses, and about the reprogramming of neonatal monocytes/macrophages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dechavanne, Nouatin, Adamou, Edslev, Hansen, Meurisse, Sadissou, Gbaguidi, Milet, Cottrell, Gineau, Sabbagh, Massougbodji, Moutairou, Donadi, Carosella, Moreau, Remarque, Theisen, Rouas-Freiss, Garcia, Favier and Courtin.)
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- 2022
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21. ICAM-1 Kilifi variant is not associated with cerebral and severe malaria pathogenesis in Beninese children.
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Blankson SO, Dadjé DS, Traikia N, Alao MJ, Ayivi S, Amoussou A, Deloron P, Ndam NT, Milet J, Basco LK, Aniweh Y, and Tahar R
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- Child, Humans, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 metabolism, Malawi, Plasmodium falciparum, Malaria, Cerebral, Malaria, Falciparum
- Abstract
Background: Cytoadhesion and sequestration of Plasmodium falciparum infected red blood cells (iRBC) in the microvasculature of vital organs are a major cause of malaria pathology. Several studies have provided evidence on the implication of the human host intercellular adhesion molecule-1 (ICAM-1) as a major receptor for iRBCs binding to P. falciparum erythrocyte membrane protein 1 (PfEMP1) in the development of severe and cerebral malaria. The genetic polymorphism K29M in the immunoglobulin-like domain of ICAM-1, known as ICAM-1
Kilifi , has been associated with either increased or decreased risk of developing cerebral malaria., Methods: To provide more conclusive results, the genetic polymorphism of ICAM-1Kilifi was assessed by PCR and sequencing in blood samples from 215 Beninese children who presented with either mild or severe malaria including cerebral malaria., Results and Conclusions: The results showed that in this cohort of Beninese children, the ICAM-1kilifi variant is present at the frequencies of 0.27, similar to the frequency observed in other African countries. This ICAM-1kilifi variant was not associated with disease severity in agreement with other findings from the Gambia, Tanzania, Malawi, Gabon, and Thailand, suggesting no evidence of a direct link between this polymorphism and the pathogenesis of severe and cerebral malaria., (© 2022. The Author(s).)- Published
- 2022
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22. Human leukocyte antigen (HLA)-F and -G gene polymorphisms and haplotypes are associated with malaria susceptibility in the Beninese Toffin children.
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Sonon P, Tokplonou L, Sadissou I, M'po KKG, Glitho SSC, Agniwo P, Ibikounlé M, Souza AS, Massaro JD, Gonzalez D, Tchégninougbo T, Ayitchédji A, Massougbodji A, Moreau P, Garcia A, Milet J, Sabbagh A, Mendes-Junior CT, Moutairou KA, Castelli EC, Courtin D, and Donadi EA
- Subjects
- 3' Untranslated Regions genetics, Alleles, Child, Child, Preschool, Female, Genotype, Humans, Immunoglobulin G genetics, Male, Plasmodium falciparum pathogenicity, Genetic Predisposition to Disease genetics, HLA-G Antigens genetics, Haplotypes genetics, Histocompatibility Antigens Class I genetics, Malaria, Falciparum genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Background: Little attention has been devoted to the role of the immunoregulatory HLA-E/-F/-G genes in malaria. We evaluated the entire HLA-E/-F/-G variability in Beninese children highly exposed to Plasmodium falciparum (P.f.) malaria., Methods: 154 unrelated children were followed-up for six months and evaluated for the presence and number of malaria episodes. HLA-E/-F/-G genes were genotyped using massively parallel sequencing. Anti P.f. antibodies were evaluated using ELISA., Results: Children carrying the G allele at HLA-F (-1499,rs183540921) showed increased P.f. asymptomatic/symptomatic ratio, suggesting that these children experienced more asymptomatic P.f. episodes than symptomatic one. Children carrying HLA-G-UTR-03 haplotype exhibited increased risk for symptomatic P.f. episodes and showed lower IgG2 response against P.f. GLURP-R2 when compared to the non-carriers. No associations were observed for the HLA-E gene., Conclusion: HLA-F associations may be related to the differential expression profiles of the encoded immunomodulatory molecules, and the regulatory sites at the HLA-G 3'UTR may be associated to posttranscriptional regulation of HLA-G and to host humoral response against P.f., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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23. Susceptibility to Plasmodium falciparum Malaria: Influence of Combined Polymorphisms of IgG3 Gm Allotypes and Fc Gamma Receptors IIA, IIIA, and IIIB.
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Fall AKDJ, Dechavanne C, Sabbagh A, Guitard E, Milet J, Garcia A, Dugoujon JM, Courtin D, and Migot-Nabias F
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- Benin, Female, GPI-Linked Proteins genetics, Genes, Immunoglobulin Heavy Chain, Genetic Association Studies, Genetic Predisposition to Disease, Host-Pathogen Interactions, Humans, Immunoglobulin Constant Regions, Immunoglobulin G blood, Infant, Infant, Newborn, Malaria, Falciparum diagnosis, Malaria, Falciparum immunology, Malaria, Falciparum parasitology, Male, Phenotype, Plasmodium falciparum immunology, Risk Assessment, Risk Factors, Immunoglobulin G genetics, Malaria, Falciparum genetics, Plasmodium falciparum pathogenicity, Polymorphism, Genetic, Receptors, IgG genetics
- Abstract
The binding of immunoglobulin (Ig) to Fc gamma receptors (FcgR) at the immune cell surface is an important step to initiate immunological defense against malaria. However, polymorphisms in receptors and/or constant regions of the IgG heavy chains may modulate this binding. Here, we investigated whether polymorphisms located in FcgR and constant regions of the heavy chain of IgG are associated with susceptibility to P. falciparum malaria. For this purpose, a clinical and parasitological follow-up on malaria was conducted among 656 infants in southern Benin. G3m allotypes (from total IgG3) were determined by a serological method of hemagglutination inhibition. FcgRIIA 131R/H and FcgRIIIA 176F/V genotypes were determined using the TaqMan method and FcgRIIIB NA1/NA2 genotypes were assessed by polymerase chain reaction using allele-specific primers. Association analyses between the number of malaria infections during the follow-up and polymorphisms in IgG G3m allotypes and FcgR were studied independently by zero inflated binomial negative regression. The influence of combinations of G3m allotypes and FcgRIIA/FcgRIIIA/FcgRIIIB polymorphisms on the number of P. falciparum infections, and their potential interaction with environmental exposure to malaria was assessed by using the generalized multifactor dimensionality reduction (GMDR) method. Results showed that individual carriage of G3m24 single allotype and of G3m5,6,10,11,13,14,24 phenotype was independently associated with a high risk of malaria infection. A risk effect for G3m6 was observed only under high environmental exposure. FcgRIIIA 176VV single genotype and combined carriage of FcgRIIA 131RH/FcgRIIIA 176VV/FcgRIIIB NA1NA2, FcgRIIA 131HH/FcgRIIIA 176FF/FcgRIIIB NA1NA1, FcgRIIA 131HH/FcgRIIIA 176VV/FcgRIIIB NA2NA2 and FcgRIIA 131HH/FcgRIIIA 176VV/FcgRIIIB NA1NA2 genotypes were related to a high number of malaria infections. The risk was accentuated for FcgRIIIA 176VV when considering the influence of environmental exposure to malaria. Finally, the GMDR analysis including environmental exposure showed strengthened associations with a malaria risk when FcgRIIA/FcgRIIIA/FcgRIIIB genotypes were combined to G3m5,6,11,24 and G3m5,6,10,11,13,15,24 phenotypes or G3m10 and G3m13 single allotypes. Our results highlight the relevance of studying IgG heavy chain and FcgR polymorphisms, independently as well as in combination, in relation to the individual susceptibility to P. falciparum infection. The intensity of individual exposure to mosquito bites was demonstrated to impact the relationships found., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Fall, Dechavanne, Sabbagh, Guitard, Milet, Garcia, Dugoujon, Courtin and Migot-Nabias.)
- Published
- 2020
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24. Mixed logistic regression in genome-wide association studies.
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Milet J, Courtin D, Garcia A, and Perdry H
- Subjects
- Bias, Computer Simulation, Genetics, Population, Genotype, Humans, Logistic Models, Malaria genetics, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide genetics, Principal Component Analysis, Sample Size, Time Factors, Genome-Wide Association Study
- Abstract
Background: Mixed linear models (MLM) have been widely used to account for population structure in case-control genome-wide association studies, the status being analyzed as a quantitative phenotype. Chen et al. proved in 2016 that this method is inappropriate in some situations and proposed GMMAT, a score test for the mixed logistic regression (MLR). However, this test does not produces an estimation of the variants' effects. We propose two computationally efficient methods to estimate the variants' effects. Their properties and those of other methods (MLM, logistic regression) are evaluated using both simulated and real genomic data from a recent GWAS in two geographically close population in West Africa., Results: We show that, when the disease prevalence differs between population strata, MLM is inappropriate to analyze binary traits. MLR performs the best in all circumstances. The variants' effects are well evaluated by our methods, with a moderate bias when the effect sizes are large. Additionally, we propose a stratified QQ-plot, enhancing the diagnosis of p values inflation or deflation when population strata are not clearly identified in the sample., Conclusion: The two proposed methods are implemented in the R package milorGWAS available on the CRAN. Both methods scale up to at least 10,000 individuals. The same computational strategies could be applied to other models (e.g. mixed Cox model for survival analysis).
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- 2020
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25. Schistosoma haematobium infection modulates Plasmodium falciparum parasite density and antimalarial antibody responses.
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Tokplonou L, Nouatin O, Sonon P, M'po G, Glitho S, Agniwo P, Gonzalez-Ortiz D, Tchégninougbo T, Ayitchédji A, Favier B, Donadi EA, Milet J, Luty AJF, Massougbodji A, Garcia A, Ibikounlé M, and Courtin D
- Subjects
- Animals, Antigens, Protozoan immunology, Antimalarials therapeutic use, Benin, Child, Child, Preschool, Coinfection parasitology, Cytokines blood, Enzyme-Linked Immunosorbent Assay, Female, Humans, Malaria, Falciparum complications, Male, Schistosomiasis haematobia complications, Schistosomiasis haematobia drug therapy, Antibodies, Protozoan blood, Antimalarials immunology, Malaria, Falciparum immunology, Plasmodium falciparum immunology, Schistosoma haematobium immunology, Schistosomiasis haematobia immunology
- Abstract
Aims: Schistosomiasis and malaria are endemic in sub-Saharan Africa where Schistosoma haematobium (Sh) and Plasmodium falciparum (Pf) coinfections are thus frequent. We explored the effect of Sh infection on antibody responses directed to Pf merozoite antigens and on malaria susceptibility in Beninese children., Methods and Results: A total of 268 children were followed during a malaria transmission season. Detection of Pf infection was performed by microscopy and rapid diagnostic tests. Sh infection was determined in urine by microscopy. Antimalarial antibody, cytokine and HLA-G concentrations were quantified by ELISA. The expression of HLA-G receptors by immune cells was assessed by flow cytometry. Children infected by Sh had higher concentrations of IgG1 directed to MSP3 and GLURP
R0 , IgG2 directed to GLURPR0 and IgG3 directed to MSP3, GLURPR0 and GLURPR2 and have lower Pf densities than those uninfected by Sh. No difference in cytokine and HLA-G concentrations was observed between Sh egg carriers and non-carriers., Conclusion: Schistosoma haematobium modulates host immune responses directed to Pf antigens. The absence of immune downregulation usually observed during helminth infections is surprising in our study. We hypothesize that the stage of Sh development could partly explain the immune pathways leading to increased antibody levels that favour better control of Pf parasitemia., (© 2020 John Wiley & Sons Ltd.)- Published
- 2020
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26. First genome-wide association study of non-severe malaria in two birth cohorts in Benin.
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Milet J, Boland A, Luisi P, Sabbagh A, Sadissou I, Sonon P, Domingo N, Palstra F, Gineau L, Courtin D, Massougbodji A, Garcia A, Deleuze JF, and Perdry H
- Subjects
- Benin epidemiology, Child, Preschool, Cohort Studies, Female, Genotype, Humans, Infant, Infant, Newborn, Malaria parasitology, Male, Carrier Proteins genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Malaria epidemiology, Malaria genetics, Quantitative Trait Loci
- Abstract
Recent research efforts to identify genes involved in malaria susceptibility using genome-wide approaches have focused on severe malaria. Here, we present the first GWAS on non-severe malaria designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Our study was performed on two cohorts of infants from southern Benin (525 and 250 individuals used as discovery and replication cohorts, respectively) closely followed from birth to 18-24 months of age, with an assessment of a space- and time-dependent environmental risk of exposure. Both the recurrence of mild malaria attacks and the recurrence of malaria infections as a whole (symptomatic and asymptomatic) were considered. Post-GWAS functional analyses were performed using positional, eQTL, and chromatin interaction mapping to identify the genes underlying association signals. Our study highlights a role of PTPRT, a tyrosine phosphatase receptor involved in STAT3 pathway, in the protection against both mild malaria attacks and malaria infections (p = 9.70 × 10
-8 and p = 1.78 × 10-7 , respectively, in the discovery cohort). Strong statistical support was also found for a role of MYLK4 (meta-analysis, p = 5.29 × 10-8 with malaria attacks), and for several other genes, whose biological functions are relevant in malaria infection. Results shows that GWAS on non-severe malaria can successfully identify new candidate genes and inform physiological mechanisms underlying natural protection against malaria.- Published
- 2019
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27. HLA-G expression during hookworm infection in pregnant women.
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Avokpaho E, d'Almeida TC, Sadissou I, Tokplonou L, Adamou R, Sonon P, Milet J, Cottrell G, Mondière A, Massougbodji A, Moutairou K, Donadi EA, Teixeira Mendes Junior C, Favier B, Carosella E, Moreau P, Rouas-Freiss N, Garcia A, and Courtin D
- Subjects
- Adult, Benin epidemiology, Female, HLA-G Antigens genetics, Hookworm Infections epidemiology, Hookworm Infections immunology, Humans, Pregnancy, Pregnancy Complications, Parasitic epidemiology, Prevalence, Young Adult, HLA-G Antigens metabolism, Hookworm Infections metabolism, Pregnancy Complications, Parasitic metabolism
- Abstract
Introduction: HLA-G plays a key role on immune tolerance. Pathogens can induce soluble HLA-G (sHLA-G) production to down-regulate the host immune response, creating a tolerogenic environment favorable for their dissemination. To our knowledge, no study has yet been conducted to assess the relationship between sHLA-G and geohelminth infections., Methods: The study was conducted in Allada, Southeastern Benin, from 2011-2014. The study population encompassed 400 pregnant women, included before the end of the 28th week of gestation and followed-up until delivery. At two antenatal care visits and at delivery, stool and blood samples were collected. Helminths were diagnosed by means of the Kato-Katz concentration technique. We used quantile regression to analyze the association between helminth infections and sHLA-G levels during pregnancy., Results: sHLA-G levels gradually increased during pregnancy and reached maximal levels at delivery. Prevalence of helminth infections was low, with a majority of hookworm infections. We found significantly more hookworm-infected women above the 80th quantile (Q80) of the distribution of the mean sHLA-G level (p < 0.03, multivariate quantile regression). Considering only women above the Q80 percentile, the mean sHLA-G level was significantly higher in hookworm-infected compared to uninfected women (p = 0.04)., Conclusion: High levels of sHLA-G were associated with hookworm infection in pregnant women. This result is consistent with the potential involvement of sHLA-G in immune tolerance induced by helminths during pregnancy., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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28. Blood lead level in infants and subsequent risk of malaria: A prospective cohort study in Benin, Sub-Saharan Africa.
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Garrison A, Khoshnood B, Courtin D, Milet J, Garcia A, Massougbodji A, Ayotte P, Cot M, and Bodeau-Livinec F
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- Africa South of the Sahara epidemiology, Benin epidemiology, Female, Follow-Up Studies, Humans, Incidence, Infant, Malaria parasitology, Male, Risk Assessment, Risk Factors, Lead blood, Malaria blood, Malaria epidemiology
- Abstract
Lead and malaria both present significant health risks to children in Sub-Saharan Africa. Previous studies have shown that high blood lead levels in children act as a protective factor against subsequent malaria incidence. The main objective of this study was to investigate associations between blood lead level and malaria outcomes prospectively in Beninese children from 12 to 24 months of age. Two-hundred and four children were assessed for lead at 12 months and closely followed until 24 months for malaria; when symptoms and parasite density were also recorded. Univariate and multivariate negative binomial and linear regression models tested associations between blood lead level quartile and total episodes of malaria (total symptomatic and asymptomatic episodes) and parasite density, respectively. Median blood lead level among children measured at 12 months was 56.50 (4.81-578) μg/L. During the 12-month follow-up, 172 (84.31%) children had at least one malaria episode. Univariate and multivariate negative binomial and linear regressions did not reveal significant associations between blood lead level quartile and malaria outcomes. Iron deficiency was not found to be an effect modifier. Results from this prospective child-cohort study investigating associations between blood lead level and malaria did not confirm results from previous cross-sectional studies. Further research is needed to further explore this relationship and other co-morbidities due to malaria and lead., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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29. High level of soluble human leukocyte antigen (HLA)-G at beginning of pregnancy as predictor of risk of malaria during infancy.
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d'Almeida TC, Sadissou I, Sagbohan M, Milet J, Avokpaho E, Gineau L, Sabbagh A, Moutairou K, Donadi EA, Favier B, Pennetier C, Baldet T, Moiroux N, Carosella E, Moreau P, Rouas-Freiss N, Cottrell G, Courtin D, and Garcia A
- Subjects
- Adult, Female, Humans, Infant, Male, Pregnancy, Proportional Hazards Models, Risk Assessment, Solubility, HLA-G Antigens chemistry, HLA-G Antigens metabolism, Malaria epidemiology
- Abstract
Placental malaria has been associated with an immune tolerance phenomenon and a higher susceptibility to malaria infection during infancy. HLA-G is involved in fetal maternal immune tolerance by inhibiting maternal immunity. During infections HLA-G can be involved in immune escape of pathogens by creating a tolerogenic environment. Recent studies have shown an association between the risk of malaria and HLA-G at both genetic and protein levels. Moreover, women with placental malaria have a higher probability of giving birth to children exhibiting high sHLA-G, independently of their own level during pregnancy. Our aim was to explore the association between the level of maternal soluble HLA-G and the risk of malaria infection in their newborns. Here, 400 pregnant women and their children were actively followed-up during 24 months. The results show a significant association between the level of sHLA-G at the first antenatal visit and the time to first malaria infection during infancy adjusted to the risk of exposure to vector bites (aHR = 1.02, 95%CI [1.01-1.03], p = 0.014). The level of sHLA-G is a significant predictor of the occurrence of malaria infection during infancy consistent with the hypothesis that mother sHLA-G could be a biomarker of malaria susceptibility in children.
- Published
- 2019
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30. Plasmodium falciparum merozoite surface antigen-specific cytophilic IgG and control of malaria infection in a Beninese birth cohort.
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Adamou R, Dechavanne C, Sadissou I, d'Almeida T, Bouraima A, Sonon P, Amoussa R, Cottrell G, Le Port A, Theisen M, Remarque EJ, Longacre S, Moutairou K, Massougbodji A, Luty AJF, Nuel G, Migot-Nabias F, Sanni A, Garcia A, Milet J, and Courtin D
- Subjects
- Benin, Enzyme-Linked Immunosorbent Assay, Female, Humans, Infant, Infant, Newborn, Longitudinal Studies, Male, Pregnancy, Surveys and Questionnaires, Antibodies, Protozoan blood, Antigens, Protozoan immunology, Immunoglobulin G blood, Malaria, Falciparum immunology, Plasmodium falciparum immunology, Protozoan Proteins immunology
- Abstract
Background: Substantial evidence indicates that cytophilic IgG responses to Plasmodium falciparum merozoite antigens play a role in protection from malaria. The specific targets mediating immunity remain unclear. Evaluating antibody responses in infants naturally-exposed to malaria will allow to better understand the establishment of anti-malarial immunity and to contribute to a vaccine development by identifying the most appropriate merozoite candidate antigens., Methods: The study was based on parasitological and clinical active follow-up of infants from birth to 18 months of age conducted in the Tori Bossito area of southern Benin. For 399 infants, plasma levels of cytophilic IgG antibodies with specificity for five asexual stage malaria vaccine candidate antigens were determined by ELISA in infants' peripheral blood at 6, 9, 12 and 15 months of age. Multivariate mixed logistic model was used to investigate the association between antibody levels and anti-malarial protection in the trimester following the IgG quantification. Moreover, the concentrations of merozoite antigen-specific IgG were compared between a group of infants apparently able to control asymptomatic malaria infection (CAIG) and a group of infants with no control of malaria infection (Control group (NCIG)). Protective effect of antibodies was also assessed after 15 months of malaria exposure with a Cox regression model adjusted on environmental risk., Results: Cytophilic IgG responses to AMA1, MSP1, MSP2-3D7, MSP2-FC27, MSP3 and GLURP R2 were associated with increasing malarial infection risk in univariate analysis. The multivariate mixed model showed that IgG1 and IgG3 to AMA1 were associated with an increased risk of malarial infection. However infants from CAIG (n = 53) had significantly higher AMA1-, MSP2-FC27-, MSP3-specific IgG1 and AMA1-, MSP1-, MSP2-FC27-, MSP3 and GLURP-R2-specific IgG3 than those from NCIG (n = 183). The latter IgG responses were not associated with protection against clinical malaria in the whole cohort when protective effect is assessed after 15 months of malaria exposition., Conclusion: In this cohort, merozoite antigen-specific cytophilic IgG levels represent a marker of malaria exposure in infants from 6 to 18 months of age. However, infants with resolution of asymptomatic infection (CAIG) seem to have acquired naturally immunity against P. falciparum. This observation is encouraging in the context of the development of multitarget P. falciparum vaccines.
- Published
- 2019
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31. Increased Risk of Malaria During the First Year of Life in Small-for-Gestational-Age Infants: A Longitudinal Study in Benin.
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Agbota G, Accrombessi M, Cottrell G, Martin-Prével Y, Milet J, Ouédraogo S, Courtin D, Massougbodji A, Garcia A, Cot M, and Briand V
- Subjects
- Adult, Benin epidemiology, Female, Humans, Infant, Infant, Newborn, Longitudinal Studies, Male, Mosquito Vectors, Pregnancy, Risk Factors, Infant, Small for Gestational Age, Malaria epidemiology
- Abstract
Background: According to the Developmental Origins of Health and Diseases paradigm, the fetal period is highly vulnerable and may have profound effects on later health. Few studies assessed the effect of small-for-gestational age (SGA), a proxy for fetal growth impairment, on risk of malaria during infancy in Africa., Methods: We used data from a cohort of 398 mother-child pairs, followed from early pregnancy to age 1 year in Benin. Malaria was actively and passively screened using thick blood smear. We assessed the effect of SGA on risk of malaria infection and clinical malaria from birth to 12 months, after stratifying on the infant's age using a logistic mixed regression model., Results: After adjustment for potential confounding factors and infant's exposure to mosquitoes, SGA was associated with a 2-times higher risk of malaria infection (adjusted odds ratio [aOR] = 2.16; 95% confidence interval [CI], 1.04-4.51; P = .039) and clinical malaria (aOR = 2.33; 95% CI, 1.09-4.98; P = .030) after age 6 months., Conclusion: Results suggest higher risk of malaria during the second semester of life in SGA infants, and argue for better follow-up of these infants after birth, as currently for preterm babies., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2019
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32. Erratum.
- Author
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Agbota G, Accrombessi M, Cottrell G, Martin-Prével Y, Milet J, Ouédraogo S, Courtin D, Massougbodji A, Garcia A, Cot M, and Briand V
- Published
- 2019
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33. Impact of Hemoglobin S Trait on Cell Surface Antibody Recognition of Plasmodium falciparum -Infected Erythrocytes in Pregnancy-Associated Malaria.
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Chauvet M, Tétard M, Cottrell G, Aussenac F, Brossier E, Denoyel L, Hanny M, Lohezic M, Milet J, Ndam NT, Pineau D, Roman J, Luty AJF, Gamain B, Migot-Nabias F, and Merckx A
- Abstract
Background: Sickle cell trait (HbAS) confers partial protection against malaria by reducing the adhesion of Plasmodium falciparum -infected erythrocytes to host receptors, but little is known about its potential protection against placental malaria., Methods: Using flow cytometry, we assessed the recognition of HbAA and HbAS VAR2CSA-expressing infected erythrocytes, by plasma from 159 Beninese pregnant women with either HbAA (normal) or HbAS. Using multivariate linear models adjusted for gravidity, parasite infection at delivery, glucose-6-phosphate dehydrogenase deficiency, and α-thalassemia carriage, we observed significantly reduced cell surface antibody binding of HbAS-infected erythrocytes by plasma from HbAS compared with HbAA women ( P < 10
-3 )., Results: The difference in cell surface antibody binding was only observed when infected erythrocytes and plasma were associated according to the same hemoglobin genotype. Similar levels of VAR2CSA-specific antibody were measured by enzyme-linked immunosorbent assay in the 2 groups, suggesting that the altered interaction between VAR2CSA and HbAS women's antibodies could reflect abnormal display of VAR2CSA on HbAS erythrocytes., Conclusions: Our data stress the need for assessments of erythrocyte disorders such as the sickle cell trait in a population group when studying immunological responses to P falciparum .- Published
- 2019
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34. Is Placental Malaria a Long-term Risk Factor for Mild Malaria Attack in Infancy? Revisiting a Paradigm.
- Author
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Bouaziz O, Courtin D, Cottrell G, Milet J, Nuel G, and Garcia A
- Subjects
- Adult, Female, Humans, Infant, Infant, Newborn, Male, Mothers, Parasitemia, Plasmodium falciparum isolation & purification, Pregnancy, Proportional Hazards Models, Risk Factors, Young Adult, Disease Susceptibility, Malaria, Falciparum complications, Placenta parasitology, Pregnancy Complications, Parasitic, Prenatal Exposure Delayed Effects parasitology
- Abstract
Background: Children born to mothers with placental malaria (PM) have been described as more susceptible to the occurrence of a first malaria infection. However, whether or not these children remain more at risk during infancy has never been explored. We aimed to determine if children born to mothers with PM are more susceptible to malaria and remain at higher risk between birth and 18 months., Methods: Five hundred fifty children were followed up weekly with control of temperature and, if >37.5°C, both a rapid diagnostic test for malaria and a thick blood smear were performed. Taking into account environmental risk of infection, the relationship between occurrences of malaria attacks from birth to 18 months was modeled using Cox models for recurrent events., Results: PM is not associated with an overall susceptibility to malaria but only with the delay of occurrence of the first malaria attack. Children born from mothers with PM tend to have an increased risk for the first malaria attack (hazard ratio [HR] = 1.33; P = .048) but not for subsequent ones (HR = 0.9; P = .46). Children who experienced 1 malaria attack were strongly at risk to develop subsequent infections independent of placental infection and environmental exposure., Conclusions: These results are consistent with the existence of an individual susceptibility to malaria unrelated to PM. From a public health point of view, protecting children born to infected placenta remains a priority, but seems insufficient to account for other frail children for whom a biomarker of frailty needs to be found., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2018
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35. APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis.
- Author
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Cooper A, Ilboudo H, Alibu VP, Ravel S, Enyaru J, Weir W, Noyes H, Capewell P, Camara M, Milet J, Jamonneau V, Camara O, Matovu E, Bucheton B, and MacLeod A
- Subjects
- Africa South of the Sahara, Case-Control Studies, Genotype, Humans, Selection, Genetic, Trypanosoma brucei gambiense immunology, Trypanosoma brucei rhodesiense immunology, Alleles, Apolipoprotein L1 genetics, Disease Resistance, Genetic Predisposition to Disease, Kidney Diseases genetics, Trypanosomiasis, African genetics
- Abstract
Reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. In populations of African ancestry, two apolipoprotein-L1 (APOL1 ) variants with a recessive kidney disease risk, named G1 and G2, occur at high frequency. APOL1 is a trypanolytic protein that confers innate resistance to most African trypanosomes, but not Trypanosoma brucei rhodesiense or T.b. gambiense, which cause human African trypanosomiasis. In this case-control study, we test the prevailing hypothesis that these APOL1 variants reduce trypanosomiasis susceptibility, resulting in their positive selection in sub-Saharan Africa. We demonstrate a five-fold dominant protective association for G2 against T.b. rhodesiense infection. Furthermore, we report unpredicted strong opposing associations with T.b. gambiense disease outcome. G2 associates with faster progression of T.b. gambiense trypanosomiasis, while G1 associates with asymptomatic carriage and undetectable parasitemia. These results implicate both forms of human African trypanosomiasis in the selection and persistence of otherwise detrimental APOL1 kidney disease variants.
- Published
- 2017
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36. Heterozygous HbAC but not HbAS is associated with higher newborn birthweight among women with pregnancy-associated malaria.
- Author
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Tétard M, Milet J, Dechavanne S, Fievet N, Dorin-Semblat D, Elion J, Fairhurst RM, Deloron P, Tuikue-Ndam N, and Gamain B
- Subjects
- Africa, Western, Female, Genotype, Gestational Age, Hemoglobin A genetics, Heterozygote, Humans, Pregnancy, Prospective Studies, Birth Weight, Hemoglobin, Sickle genetics, Hemoglobins, Abnormal genetics, Malaria epidemiology, Malaria genetics, Pregnancy Complications, Parasitic epidemiology, Pregnancy Complications, Parasitic genetics
- Abstract
Pregnancy-associated malaria (PAM) is associated with poor pregnancy outcomes. Hemoglobin S (HbS) and hemoglobin C (HbC) mutations are frequently encountered in malaria-endemic areas of Africa, where they protect children from severe and uncomplicated Plasmodium falciparum malaria. However, scant epidemiological data exist on the impact of these Hb variants on PAM. A prospective cohort of 635 Beninese pregnant women was recruited before 24 weeks of gestational age and followed until the end of pregnancy. HbAA, HbAC, and HbAS genotypes were determined and tested for association with pregnancy outcomes and PAM indicators using linear and logistic multivariate models. Newborns from HbAC mothers had higher birthweights than those from HbAA mothers among women infected at any time during pregnancy (mean difference 182.9 g, p = 0.08), or during the first half of pregnancy (654.3 g, p = 0.0006). No such birthweight differences were observed between newborns from HbAS and HbAA mothers. HbAC and HbAS were not associated with other pregnancy outcomes or PAM indicators. In conclusion, HbAC but not HbAS is associated with an improved birth outcome in pregnant women with documented PAM. Higher-birthweight newborns from HbAC mothers may have a survival advantage that contributes to the natural selection of HbC in malaria-endemic areas.
- Published
- 2017
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37. Preferential expression of domain cassettes 4, 8 and 13 of Plasmodium falciparum erythrocyte membrane protein 1 in severe malaria imported in France.
- Author
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Argy N, Bertin GI, Milet J, Hubert V, Clain J, Cojean S, Houzé P, Tuikue-Ndam N, Kendjo E, Deloron P, and Houzé S
- Subjects
- Adult, Female, France, Humans, Male, Middle Aged, Plasmodium falciparum isolation & purification, Protozoan Proteins genetics, Real-Time Polymerase Chain Reaction, Severity of Illness Index, Young Adult, Gene Expression Profiling, Malaria, Falciparum parasitology, Malaria, Falciparum pathology, Plasmodium falciparum genetics, Protozoan Proteins biosynthesis
- Abstract
Objectives: Severe Plasmodium falciparum malaria (SM) involves cytoadhesion of parasitized red blood cells, mediated by P. falciparum erythrocyte membrane protein 1, which is encoded by var genes. Expression of var gene group A and B or encoding domain cassettes DC4, DC5, DC8 and DC13 has been implicated in SM in African children, but no data exist in the context of imported malaria. The aim of this study was to investigate var gene expression linked to clinical presentation and host factors in SM imported into France., Methods: Expression level of var gene groups A, B, C, var1, var2csa, var3 and var genes encoding DC4, DC5, DC8 and DC13 was measured by quantitative RT-PCR and expressed in transcript units. Seventy SM and 48 uncomplicated malaria (UM) P. falciparum cases were analysed according to disease severity, epidemiological characteristics (migrants or travellers) and anti-P. falciparum antibodies. Cluster analysis was performed to identify gene expression profiles., Results: Var1 and B/C expression were higher in UM than SM (0.66 (0-1.1) and 1.88 (1.3-2.4); p <0.04, respectively). Group C expression differed between migrants and travellers (0.21 (0-0.75) versus 0 (0-0); p 0.002). Group A differed in naive and pre-exposed patients (1.1 (0.7-1.5) versus 0.4 (0-1.1); p 0.01). Population clusters revealed increased expression from group A and B var genes, and DC4, DC8 and DC13 in SM., Conclusions: These results corroborate the implication of DC4, DC8 and DC13 in severe imported malaria cases as African children, and their expression depends of host factors., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2017
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38. Soluble human leukocyte antigen -G during pregnancy and infancy in Benin: Mother/child resemblance and association with the risk of malaria infection and low birth weight.
- Author
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d'Almeida TC, Sadissou I, Milet J, Cottrell G, Mondière A, Avokpaho E, Gineau L, Sabbagh A, Massougbodji A, Moutairou K, Donadi EA, Favier B, Carosella E, Moreau P, Rouas-Freiss N, Courtin D, and Garcia A
- Subjects
- Adolescent, Adult, Benin epidemiology, Female, Humans, Infant, Infant, Newborn, Malaria epidemiology, Pregnancy, Young Adult, Disease Susceptibility, HLA-G Antigens blood, Infant, Low Birth Weight, Malaria blood, Malaria etiology
- Abstract
Human leukocyte antigen (HLA) G is a tolerogenic molecule involved in the maternal-fetal immune tolerance phenomenon. Its expression during some infectious diseases leading to immune evasion has been established. A first study conducted in Benin has shown that the production of soluble HLA-G (sHLA-G) during the first months of life is strongly correlated with the maternal level at delivery and associated with low birth weight and malaria. However sHLA-G measurements during pregnancy were not available for mothers and furthermore, to date the evolution of sHLA-G in pregnancy is not documented in African populations. To extend these previous findings, between January 2010 and June 2013, 400 pregnant women of a malaria preventive trial and their newborns were followed up in Benin until the age of 2 years. Soluble HLA-G was measured 3 times during pregnancy and repeatedly during the 2 years follow-up to explore how sHLA-G evolved and the factors associated. During pregnancy, plasma levels of sHLA-G remained stable and increased significantly at delivery (p<0.001). Multigravid women seemed to have the highest levels (p = 0.039). In infants, the level was highest in cord blood and decreased before stabilizing after 18 months (p<0.001). For children, a high level of sHLA-G was associated with malaria infection during the follow-up (p = 0.02) and low birth weight (p = 0.06). The mean level of sHLA-G during infancy was strongly correlated with the mother's level during pregnancy (<0.001), and not only at delivery. Moreover, mothers with placental malaria infection had a higher probability of giving birth to a child with a high level of sHLA-g (p = 0.006). High sHLA-G levels during pregnancy might be associated with immune tolerance related to placental malaria. Further studies are needed but this study provides a first insight concerning the potential role of sHLA-G as a biomarker of weakness for newborns and infants., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2017
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39. Human Leukocyte Antigen-G: A Promising Prognostic Marker of Disease Progression to Improve the Control of Human African Trypanosomiasis.
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Gineau L, Courtin D, Camara M, Ilboudo H, Jamonneau V, Dias FC, Tokplonou L, Milet J, Mendonça PB, Castelli EC, Camara O, Camara M, Favier B, Rouas-Freiss N, Moreau P, Donadi EA, Bucheton B, Sabbagh A, and Garcia A
- Subjects
- Adult, Biomarkers blood, Disease Progression, Female, Haplotypes, Humans, Male, Prognosis, Trypanosoma brucei gambiense, Trypanosomiasis, African physiopathology, Trypanosomiasis, African prevention & control, HLA-G Antigens blood, Trypanosomiasis, African blood
- Abstract
Background: Human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense can be diagnosed in the early hemolymphatic stage (stage 1 [S1]) or meningoencephalitic stage (stage 2 [S2]). Importantly, individuals harbouring high and specific antibody responses to Tbg antigens but negative parasitology are also diagnosed in the field (seropositive [SERO]). Whereas some develop the disease in the months following their initial diagnosis (SERO/HAT), others remain parasitologically negative for long periods (SERO) and are apparently able to control infection. Human leucocyte antigen (HLA)-G, an immunosuppressive molecule, could play a critical role in this variability of progression between infection and disease., Methods: Soluble HLA-G (sHLA-G) was measured in plasma for patients in the SERO (n = 65), SERO/HAT (n = 14), or HAT (n = 268) group and in cerebrospinal fluid for patients in S1 (n = 55), early S2 (n = 93), or late S2 (n = 110). Associations between these different statuses and the soluble level or genetic polymorphisms of HLA-G were explored., Results: Plasma sHLA-G levels were significantly higher in HAT (P = 6 × 10
-7 ) and SERO/HAT (P = .007) than SERO patients. No difference was observed between the SERO/HAT and HAT groups. Within the HAT group, specific haplotypes (HG010102 and HG0103) displayed increased frequencies in S1 (P = .013) and late S2 (P = .036), respectively., Conclusions: These results strongly suggest the involvement of HLA-G in HAT disease progression. Importantly, high plasma sHLA-G levels in SERO patients could be predictive of subsequent disease development and could represent a serological marker to help guide therapeutic decision making. Further studies are necessary to assess the predictive nature of HLA-G and to estimate both sensitivity and specificity., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)- Published
- 2016
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40. Linseed oil presents different patterns of oxidation in real-time and accelerated aging assays.
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Douny C, Razanakolona R, Ribonnet L, Milet J, Baeten V, Rogez H, Scippo ML, and Larondelle Y
- Subjects
- Food Preservation, Oxidation-Reduction drug effects, Temperature, Aniline Compounds analysis, Antioxidants pharmacology, Linseed Oil chemistry, Peroxides analysis
- Abstract
This study aimed at verifying if the hypothesis that one day at 60°C is equivalent to one month at 20°C could be confirmed during linseed oil aging for 6months at 20°C and 6days at 60°C using the "Schaal oven stability test". Tests were conducted with linseed oil supplemented or not with myricetin or butyl-hydroxytoluene as antioxidants. Oxidation was evaluated with the peroxide and p-anisidine values, as well as the content in conjugated dienes and aldehydes. All four indicators of oxidation showed very different kinetic behaviors at 20 and 60°C. The hypothesis is thus not verified for linseed oil, supplemented or not with antioxidant. In the control oil, the conjugated dienes and the peroxide value observed were respectively of 41.8±0.8 Absorbance Unit (AU)/g oil and 254.3±5.8meq.O2/kg oil after 6months at 20°C. These values were of 18.2±1.3AU/g oil and 65.2±20.3meq.O2/kg after 6days at 60°C., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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41. Acquisition of natural humoral immunity to P. falciparum in early life in Benin: impact of clinical, environmental and host factors.
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Dechavanne C, Sadissou I, Bouraima A, Ahouangninou C, Amoussa R, Milet J, Moutairou K, Massougbodji A, Theisen M, Remarque EJ, Courtin D, Nuel G, Migot-Nabias F, and Garcia A
- Abstract
To our knowledge, effects of age, placental malaria infection, infections during follow-up, nutritional habits, sickle-cell trait and individual exposure to Anopheles bites were never explored together in a study focusing on the acquisition of malaria antibody responses among infants living in endemic areas.Five hundred and sixty-seven Beninese infants were weekly followed-up from birth to 18 months of age. Immunoglobulin G (IgG), IgG1 and IgG3 specific for 5 malaria antigens were measured every 3 months. A linear mixed model was used to analyze the effect of each variable on the acquisition of antimalarial antibodies in 6-to18-month old infants in univariate and multivariate analyses. Placental malaria, nutrition intakes and sickle-cell trait did not influence the infant antibody levels to P. falciparum antigens. In contrary, age, malaria antibody levels at birth, previous and present malaria infections as well as exposure to Anopheles bites were significantly associated with the natural acquisition of malaria antibodies in 6-to18-month old Beninese infants. This study highlighted inescapable factors to consider simultaneously in an immuno-epidemiological study or a vaccine trial in early life.
- Published
- 2016
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42. Plasmodium falciparum infection and age influence parasite growth inhibition mediated by IgG in Beninese infants.
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Adamou R, Chénou F, Sadissou I, Sonon P, Dechavanne C, Djilali-Saïah A, Cottrell G, Le Port A, Massougbodji A, Remarque EJ, Luty AJ, Sanni A, Garcia A, Migot-Nabias F, Milet J, and Courtin D
- Subjects
- Age Factors, Animals, Antibodies, Protozoan blood, Antigens, Protozoan blood, Benin, Enzyme-Linked Immunosorbent Assay, Erythrocytes parasitology, Female, Humans, Immunoglobulin G blood, Infant, Infant, Newborn, Malaria, Falciparum blood, Malaria, Falciparum parasitology, Male, Metallothionein 3, Nerve Tissue Proteins blood, Antibodies, Protozoan immunology, Antigens, Protozoan immunology, Antimalarials immunology, Merozoites immunology, Plasmodium falciparum growth & development, Plasmodium falciparum immunology
- Abstract
Antibodies that impede the invasion of Plasmodium falciparum (P. falciparum) merozoites into erythrocytes play a critical role in anti-malarial immunity. The Growth Inhibition Assay (GIA) is an in vitro measure of the functional capacity of such antibodies to limit erythrocyte invasion and/or parasite growth. Up to now, it is unclear whether growth-inhibitory activity correlates with protection from clinical disease and there are inconsistent results from studies performed with GIA. Studies that have focused on the relationship between IgGs and their in vitro parasite Growth Inhibition Activity (GIAc) in infants aged less than two years old are rare. Here, we used clinical and parasitological data to precisely define symptomatic or asymptomatic infection with P. falciparum in groups of infants followed-up actively for 18 months post-natally. We quantified the levels of IgG1 and IgG3 directed to a panel of candidate P. falciparum vaccine antigens (AMA-1, MSP1, 2, 3 and GLURP) using ELISA and the functional activity of IgG was quantified using GIA. Data were then correlated with individuals' infection status. At 18 months of age, infants harbouring infections at the time of blood sampling had an average 19% less GIAc than those not infected (p=0.004, multivariate linear regression). GIAc decreased from 12 to 18 months of age (p=0.003, Wilcoxon matched pairs test). Antibody levels quantified at 18 months in infants were strongly correlated with their exposure to malarial infection, however GIAc was not correlated with malaria infectious status (asymptomatic and symptomatic groups). In conclusion, both infection status at blood draw and age influence parasite growth inhibition mediated by IgG in the GIA. Both factors must be taken into account when correlations between GIAc and anti-malarial protection or vaccine efficacy have to be made., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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43. Genome-wide association study of antibody responses to Plasmodium falciparum candidate vaccine antigens.
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Milet J, Sabbagh A, Migot-Nabias F, Luty AJ, Gaye O, Garcia A, and Courtin D
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- Adolescent, Antibodies, Protozoan biosynthesis, Antibodies, Protozoan immunology, Antigens, Protozoan chemistry, Child, Chromosome Mapping, Chromosomes, Human immunology, Female, Genome-Wide Association Study, Humans, Immunoglobulin G biosynthesis, Immunoglobulin G genetics, Malaria, Falciparum immunology, Malaria, Falciparum parasitology, Malaria, Falciparum prevention & control, Male, Merozoite Surface Protein 1 chemistry, Merozoite Surface Protein 1 immunology, Plasmodium falciparum chemistry, Protozoan Proteins chemistry, Protozoan Proteins immunology, Senegal, Antibodies, Protozoan genetics, Antigens, Protozoan immunology, Chromosomes, Human chemistry, Genetic Loci, Malaria Vaccines therapeutic use, Malaria, Falciparum genetics, Plasmodium falciparum immunology
- Abstract
We conducted a genome-wide association study (GWAS) of antibody responses directed to three Plasmodium falciparum vaccine candidate antigens (MSP1, MSP2 and GLURP) previously associated with different patterns of protection against malaria infection in Senegalese children. A total of 174 950 single-nucleotide polymorphisms (SNPs) were tested for association with immunoglobulin G1 (IgG1) responses directed to MSP1 and to GLURP and with IgG3 responses to MSP2 FC27 and to MSP2 3D7. We first performed a single-trait analysis with each antibody response and then a multiple-trait analysis in which we analyzed simultaneously the three immune responses associated with the control of clinical malaria episodes. Suggestive associations (P<1 × 10(-4)) were observed for 25 SNPs in MSP1 antibody response analysis or in multiple-trait analysis. According to the strength of their observed associations and their functional role, the following genes are of particular interest: RASGRP3 (2p22.3, P=7.6 × 10(-6)), RIMS1 (6q13, P=2.0 × 10(-5)), MVB12B (9q33.3, P=8.9 × 10(-5)) and GNPTAB (12q23.2, P=7.4 × 10(-5)). Future studies will be required to replicate these findings in other African populations. This work will contribute to the elucidation of the host genetic factors underlying variable immune responses to P. falciparum.
- Published
- 2016
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44. Immunoglobulin response to Plasmodium falciparum RESA proteins in uncomplicated and severe malaria.
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Badaut C, Guyonnet L, Milet J, Renard E, Durand R, Viwami F, Sagbo G, Layla F, Deloron P, Bonnefoy S, and Migot-Nabias F
- Subjects
- Antibodies, Protozoan blood, Benin epidemiology, Child, Child, Preschool, Cross-Sectional Studies, Cytokines blood, Cytokines immunology, Female, Humans, Immunoglobulin G blood, Immunoglobulin G immunology, Infant, Malaria, Falciparum epidemiology, Male, Recombinant Proteins immunology, Antibodies, Protozoan immunology, Malaria, Falciparum immunology, Plasmodium falciparum immunology, Protozoan Proteins immunology
- Abstract
Background: The three members of the ring-infected erythrocyte surface antigen (RESA) proteins family share high sequence homologies, which impair the detection and assignment to one or another protein of some pathogenic processes inherent to Plasmodium falciparum malaria. The present study was intended to determine if the antibody and inflammatory responses of children living in a malaria-endemic area varied depending on the RESA-1, RESA-2 or RESA-3 proteins and the severity of the disease, two groups of severe and uncomplicated malaria cases being considered., Methods: Two synthetic peptides representing predicted B cell epitopes were designed per RESA protein, all located outside of the 3' and 5' repetition blocks, in order to allow an antibody detection specific of each member of the family. Recombinant rRESA-1B and rRESA-3B proteins were also engineered. Two groups of Beninese children admitted to hospital in 2009 for either uncomplicated or severe malaria were compared for their plasma levels of IgG specifically recognizing each recombinant RESA protein or synthetic peptide, and for their plasma inflammatory cytokine levels (IFN-γ, TNF-α and IL-10), taking into account host and parasite genetic factors., Results: The absence of IgG cross-reactivity between rRESA proteins and their protein carrier as well as between each RESA peptide and a non-epitopic RESA control peptide validated the use of the engineered recombinant proteins and peptides for the measurement of plasma IgG. Taking into account age, fever duration and parasitaemia, a multiple logistic regression performed on children clustered according to their antibody responses' profiles concluded to an increased risk of severe malaria for P2 (representative of RESA-1) responders (P = 0.007). Increased IL-10 plasma levels were found in children harbouring multiclonal P. falciparum infections on the basis of the T1526G resa2 gene polymorphism (P = 0.004)., Conclusions: This study provided novel tools to dissect the seroreactivity against the three members of the RESA protein family and to describe its relation to protection against malaria. It suggested the measurement of plasma antibodies raised against specific peptides to serve as predictive immunologic markers for disease severity. Lastly, it reinforced previous observations linking the T1526G resa2 gene mutation to severe malaria.
- Published
- 2015
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45. Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G.
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Gineau L, Luisi P, Castelli EC, Milet J, Courtin D, Cagnin N, Patillon B, Laayouni H, Moreau P, Donadi EA, Garcia A, and Sabbagh A
- Subjects
- Genetics, Population, Haplotypes, Humans, Immune Tolerance, Linkage Disequilibrium, Polymorphism, Genetic, HLA-G Antigens genetics, HLA-G Antigens immunology, Regulatory Elements, Transcriptional, Selection, Genetic
- Abstract
Human leukocyte antigen-G (HLA-G) has well-recognized immunosuppressive properties modulating the activity of many immune system cells, and polymorphisms observed at the HLA-G 5' upstream regulatory region (5'URR) may influence gene transcriptional regulation. In this study, we characterized the sequence variation and haplotype structure of the HLA-G 5'URR in worldwide populations to investigate the evolutionary history of the HLA-G promoter and shed some light into the mechanisms that may underlie HLA-G expression control. A 1.4-kb region, encompassing the known HLA-G regulatory elements, was sequenced in three African populations from Senegal, Benin and Congo, and data were combined with those available in the literature, resulting in a total of 1411 individuals from 21 worldwide populations. High levels of nucleotide and haplotype diversities, excess of intermediate-frequency variants and reduced population differentiation were observed at this locus when compared with the background genomic variation. These features support a strong molecular signature of balancing selection at HLA-G 5'URR, probably as a result of the competing needs to maintain both a maternal-fetal immune tolerance and an efficient host immune response to invading pathogens during human evolution. An extended analysis of a 300-kb region surrounding HLA-G revealed that this region is not involved in a hitchhiking effect and may be the direct target of selection.
- Published
- 2015
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46. Worldwide genetic variation at the 3' untranslated region of the HLA-G gene: balancing selection influencing genetic diversity.
- Author
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Sabbagh A, Luisi P, Castelli EC, Gineau L, Courtin D, Milet J, Massaro JD, Laayouni H, Moreau P, Donadi EA, and Garcia A
- Subjects
- Africa, Americas, Asia, Base Sequence, Ethnicity genetics, Europe, Female, Gene Frequency, Humans, INDEL Mutation, Immune Tolerance genetics, Linkage Disequilibrium, Male, Polymorphism, Genetic, Sequence Analysis, DNA, 3' Untranslated Regions genetics, HLA-G Antigens genetics, Haplotypes genetics
- Abstract
The HLA-G (human leukocyte antigen-G) molecule plays a pivotal role in immune tolerance by inhibiting different cell subsets involved in both innate and adaptive immunity. Besides its primary function in maintaining the maternal-fetal tolerance, HLA-G has been involved in a wide range of pathological conditions where it can be either favorable or detrimental to the patient, depending on the nature of the pathology. Although several studies have demonstrated the utmost importance of the 3' untranslated region (3'UTR) in the HLA-G expression profile, limited data exist on the sequence variability of this gene region in human populations. In this study, we characterized the genetic diversity and haplotype structure of the HLA-G 3'UTR by resequencing 444 individuals from three sub-Saharan African populations and retrieving data from the 1000 Genomes project and the literature. A total of 1936 individuals representing 21 worldwide populations were combined and jointly analyzed. Our data revealed a high level of nucleotide diversity, an excess of intermediate frequency variants and an extremely low population differentiation, strongly supporting a history of balancing selection at this locus. The 14-bp insertion/deletion polymorphism was further pointed out as the likely target of selection, emphasizing its potential role in the post-transcriptional regulation of HLA-G expression.
- Published
- 2014
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47. Haptoglobin (HP) and Haptoglobin-related protein (HPR) copy number variation, natural selection, and trypanosomiasis.
- Author
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Hardwick RJ, Ménard A, Sironi M, Milet J, Garcia A, Sese C, Yang F, Fu B, Courtin D, and Hollox EJ
- Subjects
- Alleles, Apolipoprotein L1, Apolipoproteins genetics, Comparative Genomic Hybridization, Congo, Gene Duplication, Gene Frequency, Genetic Association Studies, Genetics, Population, Haplotypes, Humans, In Situ Hybridization, Fluorescence, Lipoproteins, HDL genetics, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Trypanosoma brucei gambiense isolation & purification, Trypanosomiasis, African epidemiology, Antigens, Neoplasm genetics, DNA Copy Number Variations, Haptoglobins genetics, Selection, Genetic, Trypanosomiasis, African genetics
- Abstract
Haptoglobin, coded by the HP gene, is a plasma protein that acts as a scavenger for free heme, and haptoglobin-related protein (coded by the HPR gene) forms part of the trypanolytic factor TLF-1, together with apolipoprotein L1 (ApoL1). We analyse the polymorphic small intragenic duplication of the HP gene, with alleles Hp1 and Hp2, in 52 populations, and find no evidence for natural selection either from extended haplotype analysis or from correlation with pathogen richness matrices. Using fiber-FISH, the paralog ratio test, and array-CGH data, we also confirm that the HPR gene is copy number variable, with duplication of the whole HPR gene at polymorphic frequencies in west and central Africa, up to an allele frequency of 15 %. The geographical distribution of the HPR duplication allele overlaps the region where the pathogen causing chronic human African trypanosomiasis, Trypanosoma brucei gambiense, is endemic. The HPR duplication has occurred on one SNP haplotype, but there is no strong evidence of extended homozygosity, a characteristic of recent natural selection. The HPR duplication shows a slight, non-significant undertransmission to human African trypanosomiasis-affected children of unaffected parents in the Democratic Republic of Congo. However, taken together with alleles of APOL1, there is an overall significant undertransmission of putative protective alleles to human African trypanosomiasis-affected children.
- Published
- 2014
- Full Text
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48. Association of HLA-G 3' untranslated region polymorphisms with antibody response against Plasmodium falciparum antigens: preliminary results.
- Author
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Sabbagh A, Courtin D, Milet J, Massaro JD, Castelli EC, Migot-Nabias F, Favier B, Rouas-Freiss N, Moreau P, Garcia A, and Donadi EA
- Subjects
- Adolescent, Child, Child, Preschool, Haplotypes genetics, Humans, Linkage Disequilibrium genetics, Malaria, Falciparum immunology, Senegal, 3' Untranslated Regions genetics, Antibody Formation immunology, Antigens, Protozoan immunology, Genetic Association Studies, HLA-G Antigens genetics, Plasmodium falciparum immunology, Polymorphism, Genetic
- Abstract
Host and Plasmodium interactions result in highly variable clinical phenotypes, partly explained by the nature and level of anti-malarial antibody response. Human leukocyte antigen (HLA)-G can create a tolerogenic environment, allowing parasites to escape from anti-malarial immunity. We performed a family-based association study encompassing 483 Sereer individuals (261 children and their parents), and reported two independent signals at the HLA-G 3' untranslated region associated with antibody response to specific Plasmodium falciparum blood stage antigens, previously associated with malaria protection: (i) +3010G together with +3142C with total IgG and IgG1 against GLURP and (ii) +3196G with IgG3 against MSP2. While these results require further investigation, they suggest for the first time a role of HLA-G in the regulation of humoral immune response in malaria., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2013
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49. HLA-G 3' UTR-2 haplotype is associated with Human African trypanosomiasis susceptibility.
- Author
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Courtin D, Milet J, Sabbagh A, Massaro JD, Castelli EC, Jamonneau V, Bucheton B, Sese C, Favier B, Rouas-Freiss N, Moreau P, Donadi EA, and Garcia A
- Subjects
- Adolescent, Adult, Alleles, Child, Child, Preschool, Congo, Female, Gene Frequency, Humans, Linkage Disequilibrium, Male, Polymorphism, Genetic, Young Adult, 3' Untranslated Regions, Genetic Predisposition to Disease, HLA-G Antigens genetics, Haplotypes, Trypanosomiasis, African genetics
- Abstract
Trypanosoma brucei gambiense (Tbg) is responsible for the chronic form of Human African trypanosomiasis (HAT), classically lasting for years. Clinical evolution of HAT cases seems to be complex and reports on asymptomatic carriers and spontaneous cure have been published recently, strengthening the likely existence of the phenomenon of human trypanotolerance. Host's genetic factors could be involved in both the control of infection levels and the mortality rates, as clearly shown in experimental models, but also in human. Although genes directly involved in immune response are important candidates, genes implicated in the regulation of immunity, such as HLA-G, could also play a critical role. A candidate gene association study was previously conducted in the Democratic Republic of Congo using a family-based sample including 106 families (n=353). All individuals, from the Yansi ethnic group, were born in the area and had been exposed to the risk of infection since birth. We sequenced the HLA-G 3' untranslated region (UTR) and performed a family based association analysis of the 14 polymorphisms identified (14-bp insertion/deletion plus 13 SNPs). Three polymorphisms, 14-bp insertion/deletion and SNPs located at the +3003 and +3196 positions were associated to HAT (FBAT p=0.008, p=0.015 and p=0.022, respectively). HLA-G 3'UTR haplotypes were significantly associated with HAT (HBAT, global p=0.0026). UTR-2 haplotype (including 14-pb insertion and G allele at position +3196) was over-transmitted to the affected offspring (HBAT p=0.003) at the expense of UTR-4 haplotype, which was under-transmitted (HBAT p=0.013). These results are the first to report an association between polymorphisms in HLA-G and variable risks to develop HAT and suggest the involvement of the HLA-G molecule on HAT susceptibility., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
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50. Association of HLA-G 3'UTR polymorphisms with response to malaria infection: a first insight.
- Author
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Garcia A, Milet J, Courtin D, Sabbagh A, Massaro JD, Castelli EC, Migot-Nabias F, Favier B, Rouas-Freiss N, Donadi EA, and Moreau P
- Subjects
- Adolescent, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Predisposition to Disease, HLA-G Antigens immunology, Haplotypes, Humans, Malaria, Falciparum immunology, Male, Polymorphism, Single Nucleotide, 3' Untranslated Regions, HLA-G Antigens genetics, Malaria, Falciparum genetics
- Abstract
Malaria represents one of the most important causes of mortality and morbidity in Africa. Variability in clinical presentation is partly due to host genetic polymorphisms. Among them, human leukocyte antigen (HLA) class I and class II alleles may be responsible for malaria susceptibility; however less is known about the possible role of non classical HLA molecules. Among them, HLA-G is a tolerogenic molecule with immunomodulatory properties, which differs from classical HLA class I molecules by its lower genetic diversity, tissue expression and function. Although primarily associated with maternal-fetal tolerance, HLA-G is now known to be involved in a wide range of physiopathological conditions, such as tumor, autoimmunity, transplantation, inflammation and viral infection by suppressing the function of various immune cells. In this work, we present the first evidence of an association between HLA-G 3'UTR polymorphisms and malaria infection. More precisely, we showed that HLA-G polymorphisms are associated with asymptomatic infection through two parasitological phenotypes, the intensity of Plasmodium falciparum infection and the mean level of parasite density. The allele+3187G and its haplotype (UTR-1, 14bp-Del/3001C/3003T/3010G/3035C/3052C/3142C/3187G/3196C) was associated with lower level of infection under a dominant model, and the haplotype UTR-3 (Del/3001C/3003T/3010C/3035C/3152C/3142G/3187A/3196C) was associated with high levels of infection under a recessive model. In conclusion, although further investigations are on the way to better address the possible involvement of the HLA-G molecule in the control of P. falciparum infection, this work presents the first evidence of an association between HLA-G polymorphisms and malaria infection. Further investigations are on the way to take into account the particularities of African populations., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
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