C Beaumont

French Institute of Health and Medical Research, Lutetia Parisorum, Île-de-France, France

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Publications (186)923.56 Total impact

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    ABSTRACT: Iron-refractory iron-deficiency anaemia (IRIDA) is a rare autosomal-recessive disorder characterized by hypochromic microcytic anaemia, low transferrin saturation and inappropriate high levels of the iron hormone hepcidin. The disease is caused by variants in the transmembrane protease serine 6 (TMPRSS6) gene that encodes the type II serine protease matriptase-2, a negative regulator of hepcidin transcription. Sequencing analysis of the TMPRSS6 gene in 21 new IRIDA patients from 16 families with different ethnic origin reveal 17 novel mutations, including the most frequent mutation in Southern Italy (p.W590R). Eight missense mutations were analysed in vitro. All but the p.T287N variant impair matriptase-2 autoproteotylic activation, decrease ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation. Genotype-phenotype studies in IRIDA patients have been so far limited due to the relatively low number of described patients. Our genotype-phenotype correlation analysis demonstrates that patients carrying 2 nonsense mutations present a more severe anaemia and microcytosis and higher hepcidin levels than the other patients. We confirm that TMPRSS6 mutations are spread along the gene and that mechanistically they fully or partially abrogate hepcidin inhibition. Genotyping IRIDA patients help in predicting IRIDA severity and may be useful for predicting response to iron treatment.This article is protected by copyright. All rights reserved
    Human Mutation 08/2014; · 5.21 Impact Factor
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    P Zongo, A Ducrot, J-B Burie, C Beaumont
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    ABSTRACT: SUMMARY Salmonellosis is a foodborne disease of humans and animals caused by infection with Salmonella. The aim of this paper is to improve a deterministic model (DM) and an individual-based model (IBM) with reference to Salmonella propagation in flocks of laying hens taking into account variations in hens housed in the same cage and to compare both models. The spatio-temporal evolution, the basic reproduction number, R 0, and the speed of wave propagation were computed for both models. While in most cases the DM allows summary of all the features of the model in the formula for computation of R 0, slight differences between individuals or groups may be observed with the IBM that could not be expected from the DM, especially when initial environmental contamination is very low and some cages may get rid of bacteria. Both models suggest that the cage size plays a role on the risk and speed of propagation of the bacteria, which should be considered when designing new breeding systems.
    Epidemiology and infection. 08/2014;
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    ABSTRACT: In 90% of people with erythropoietic protoporphyria (EPP), the disease results from the inheritance of a common hypomorphic FECH allele, encoding ferrochelatase, in trans to a private deleterious FECH mutation. The activity of the resulting FECH enzyme falls below the critical threshold of 35%, leading to the accumulation of free protoporphyrin IX (PPIX) in bone marrow erythroblasts and in red cells. The mechanism of low expression involves a biallelic polymorphism (c.315-48T>C) localized in intron 3. The 315-48C allele increases usage of the 3' cryptic splice site between exons 3 and 4, resulting in the transcription of an unstable mRNA with a premature stop codon, reducing the abundance of wild-type FECH mRNA, and finally reducing FECH activity. Through a candidate-sequence approach and an antisense-oligonucleotide-tiling method, we identified a sequence that, when targeted by an antisense oligonucleotide (ASO-V1), prevented usage of the cryptic splice site. In lymphoblastoid cell lines derived from symptomatic EPP subjects, transfection of ASO-V1 reduced the usage of the cryptic splice site and efficiently redirected the splicing of intron 3 toward the physiological acceptor site, thereby increasing the amount of functional FECH mRNA. Moreover, the administration of ASO-V1 into developing human erythroblasts from an overtly EPP subject markedly increased the production of WT FECH mRNA and reduced the accumulation of PPIX to a level similar to that measured in asymptomatic EPP subjects. Thus, EPP is a paradigmatic Mendelian disease in which the in vivo correction of a common single splicing defect would improve the condition of most affected individuals.
    The American Journal of Human Genetics 03/2014; · 11.20 Impact Factor
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    ABSTRACT: Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders.
    Mammalian Genome 10/2013; · 2.42 Impact Factor
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    ABSTRACT: Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein. In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia. In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment. A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients. The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration; in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach.
    Haematologica 06/2013; 98(6):845-53. · 5.94 Impact Factor
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    ABSTRACT: Hepcidin, the key regulatory hormone of iron homeostasis, and iron carriers such as transferrin receptor1 (TFR1), divalent metal transporter1 (DMT1), and ferroportin (FPN) are expressed in kidney. Whether hepcidin plays an intrinsic role in the regulation of renal iron transport is unknown. Here, we analyzed the renal handling of iron in hemochromatosis Hepc(-/-) and Hjv(-/-) mouse models, as well as in phenylhydrazine (PHZ)-treated mice. We found a marked medullary iron deposition in the kidneys of Hepc(-/-) mice, and iron leak in the urine. The kidneys of Hepc(-/-) mice exhibited a concomitant decrease in TFR1 and increase in ferritin and FPN expression. Increased FPN abundance was restricted to the thick ascending limb (TAL). DMT1 protein remained unaffected despite a significant decrease of its mRNA level, suggesting that DMT1 protein is stabilized in the absence of hepcidin. Treatment of kidney sections from Hepc(-/-) mice with hepcidin decreased DMT1 protein, an effect confirmed in renal cell lines where hepcidin markedly decreased (55)Fe transport. In the kidneys of Hjv(-/-) mice exhibiting low hepcidin expression, the iron overload was similar to that in the kidneys of Hepc(-/-) mice. However, in PHZ mice, iron accumulation resulting from hemoglobin leak was detected in the proximal tubule. Thus, kidneys exhibit a tissue-specific handling of iron that depends on the extra iron source. Hepcidin may control the expression of iron transporters to prevent renal iron overload.Kidney International advance online publication, 24 April 2013; doi:10.1038/ki.2013.142.
    Kidney International 04/2013; · 8.52 Impact Factor
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    ABSTRACT: During the past 10 years, the knowledge of iron metabolism has been revolutionized by the discovery of the main regulatory hormone of body iron: hepcidin. Meanwhile, new formulations of intravenous iron have been developed and are already or readily available. In this article, we review the recent pathophysiological mechanisms underlying anemia of chronic disease or due to iron deficiency. We describe the various treatment modalities of iron deficiency anemia using oral or intravenous route and the emerging indications of treatment with iron. Finally, we discuss the situations in which iron supplementation may be harmful.
    La Revue de Médecine Interne. 01/2013; 34(1):26–31.
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  • Constance Delaby, Carole Beaumont
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    ABSTRACT: The characterization of hepcidin and of its role in iron metabolism in 2001 has entirely modified our understanding of the pathogenesis of iron-linked disorders. Clinical applications related to hepcidin are numerous, and involve iron-overload diseases, anemia, renal disease, chronic inflammation or cancer. Thus, new avenues have emerged from the discovery of this 25 amino acid peptide and numerous diagnostic and therapeutic tools have been developed and described in the past 10 years. In particular, various methods for accurate quantification of hepcidin in urine and serum have been published but development of a reliable assay is quite a challenging task because, in particular, of inherent properties of the peptide's structure and its low immunogenicity. Thus, the different methods described so far show high variability, in terms of quantitative value of hepcidin measured, specificity and sensitivity. Comparison of these methods has been recently described in a "Round Robin" study, in order to harmonise hepcidin assays and to improve and standardise the available detection/quantification tests. This article focuses on the molecular mechanisms of hepcidin regulation and reviews the various methods of hepcidin quantification, describing the advantages and limitations of each one of them.
    Annales de biologie clinique. 08/2012; 70(4):377-86.
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    ISAG 33rd Conference, Cairns, Australia; 07/2012
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    ABSTRACT: During the past 10years, the knowledge of iron metabolism has been revolutionized by the discovery of the main regulatory hormone of body iron: hepcidin. Meanwhile, new formulations of intravenous iron have been developed and are already or readily available. In this article, we review the recent pathophysiological mechanisms underlying anemia of chronic disease or due to iron deficiency. We describe the various treatment modalities of iron deficiency anemia using oral or intravenous route and the emerging indications of treatment with iron. Finally, we discuss the situations in which iron supplementation may be harmful.
    La Revue de Médecine Interne 05/2012; · 0.90 Impact Factor
  • C Beaumont, Z Karim
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    ABSTRACT: About 60% of body iron is associated with hemoglobin in circulating red blood cells and daily erythropoiesis requires about 25 to 30mg iron per day. This iron is provided by macrophages through recycling of heme iron following phagocytosis of senescent red blood cells and heme catabolism. Intestinal iron absorption (1 to 2mg per day) only compensates for daily iron losses. Hepcidin, a 25 amino-acid peptide synthesized in hepatocytes, secreted in plasma and rapidly removed in urines, is a negative regulator of both intestinal iron absorption and heme iron recycling by macrophages. Hepcidin synthesis is stimulated by iron or by inflammation (mostly by IL-6) and is repressed by iron deficiency and by all conditions that stimulate bone marrow erythropoiesis such as anemia, bleeding, hemolysis, dyserythropoiesis or erythropoietin injections. A defect in the activation of hepcidin normally triggered by iron excess is the underlying mechanism for all juvenile or adult forms of hemochromatosis whereas a defect in hepcidin repression is responsible for an iron deficiency iron refractory anemia (IRIDA). Reduced hepcidin filtration in renal insufficiency contributes to the associated anemia and stimulation of hepcidin synthesis by inflammation is a major determinant of the anemia of chronic disorders. New therapeutic perspectives are currently underway such as the development of agonists or antagonists of hepcidin or siRNA approaches aiming at reducing hepcidin synthesis. The validation of hepcidin assays in a near future will allow identifying the patients most likely to benefit from intravenous iron therapy.
    La Revue de Médecine Interne 05/2012; · 0.90 Impact Factor
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    ABSTRACT: Mutations of the TMPRSS6 gene, which encodes Matriptase-2, are responsible for iron-refractory iron-deficiency anemia. Matriptase-2 is a transmembrane protease that downregulates hepcidin expression. We report one frameshift (p.Ala605ProfsX8) and four novel missense mutations (p.Glu114Lys, p.Leu235Pro, p.Tyr418Cys, p.Pro765Ala) found in IRIDA patients. These mutations lead to changes in both the catalytic and noncatalytic domains of Matriptase-2. Analyses of the mutant proteins revealed a reduction of autoactivating cleavage and the loss of N-Boc-Gln-Ala-Arg-p-nitroanilide hydrolysis. This resulted either from a direct modification of the active site or from the lack of the autocatalytic cleavage that transforms the zymogen into an active protease. In a previously described transfection assay measuring the ability of Matriptase-2 to repress the hepcidin gene (HAMP) promoter, all mutants retained some, if not all, of their transcriptional repression activity. This suggests that caution is called for in interpreting the repression assay in assessing the functional relevance of Matriptase-2 substitutions. We propose that Matriptase-2 activity should be measured directly in the cell medium of transfected cells using the chromogenic substrate. This simple test can be used to determine whether a sequence variation leading to an amino acid substitution is functionally relevant or not.
    Human Mutation 05/2012; 33(9):1388-96. · 5.21 Impact Factor
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    ABSTRACT: Anemia is common in critically ill patients, due to inflammation and blood loss. Anemia can be associated with iron deficiency and low serum hepcidin levels. However, iron administration in this setting remains controversial because of its potential toxicity, including oxidative stress induction and sepsis facilitation. The objective of this work was to determine the efficacy and toxicity of iron administration using a mouse model mimicking critical care anemia as well as a model of acute septicemia. Prospective, randomized, open label controlled animal study. University-based research laboratory. C57BL/6 and OF1 mice. Intraperitoneal injection of zymosan inducing generalized inflammation in C57BL/6 mice, followed in our full model by repeated phlebotomies. A dose equivalent to 15 mg/kg of ferric carboxymaltose was injected intravenously on day 5. To assess the toxicity of iron in a septicemia model, OF1 mice were simultaneously injected with iron and different Escherichia coli strains. To investigate the effect of iron on oxidative stress, we measured reactive oxygen species production in the blood using luminol-amplified chemiluminescence and superoxide dismutase 2 messenger RNA levels in the liver. These markers of oxidative stress were increased after iron administration in control mice but not in zymosan-treated mice. Liver catalase messenger RNA levels decreased in iron-treated control mice. Iron administration was not associated with increased mortality in the septicemia model or in the generalized inflammation model. Iron increased hemoglobin levels in mice fed with a low iron diet and subjected to phlebotomies and zymosan 2 wks after treatment administration. Adverse effects of intravenous iron supplementation by ferric carboxymaltose seem to be minimal in our animal models. Furthermore, iron appears to be effective in correcting anemia, despite inflammation. Studies of efficacy and safety of iron in critically ill patients are warranted.
    Critical care medicine 05/2012; 40(7):2141-8. · 6.37 Impact Factor
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    ABSTRACT: Investigating persistent hyperferritinaemia without apparent iron overload is challenging. Even when inflammation, cirrhosis, Still's disease, fatty liver and malignancy are excluded, there remains a group of patients with unexplained hyperferritinaemia for whom rare forms of haemochromatosis (ferroportin disease) are a consideration. Preliminary results suggest that abnormal percentage glycosylation of serum ferritin is seen in some cases of genetically determined hyperferritinaemia. Serum ferritin is normally 50-81% glycosylated, but low glycosylation (20-42%) prevails in hereditary hyperferritinaemia cataract syndrome. This contrasts with hyperglycosylation (>90%) associated with the benign hyperferritinaemia related to missense L ferritin (p.Thr30Ile) mutation. Here, we describe two novel missense L ferritin variants also associated with hyperglycosylation, p.Gln26Ile and p.Ala27Val. Ferritin glycosylation, a comparatively simple measurement, can identify patients for DNA sequencing as hyperglycosylation (>90%) is associated with benign hyperferritinaemia and mutant L ferritin chain.
    Annals of Clinical Biochemistry 04/2012; 49(Pt 3):302-5. · 1.92 Impact Factor
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    ABSTRACT: Iron deficiency is the most frequent cause of hypochromic microcytic anemia in children, but other causes, some of them requiring specific management, may be involved. Checking the iron-status is absolutely mandatory. When iron-status parameters are low, inadequate intake, malabsorption, blood loss, and abnormal iron utilization must be tested. In absence of iron deficiency, α- and β-globin and heme biosynthetic gene status must be checked. Assessing the iron stock level is difficult, because there is an overlap between the values observed in iron-replete and iron-deprived patients, so that at least 2 iron-status parameters must be below normal for diagnosing iron deficiency. Furthermore, inflammation may also mimic some characteristics of iron deficiency. Diagnosing iron deficiency leads to prescribing iron supplementation with follow-up at the end and 3 months after cessation of treatment. When iron stores are not replete at the end of treatment, compliance and dosage must be reevaluated and occult bleeding sought. The latter is also required when the iron store decreases 3 months after cessation of iron replacement.
    Archives de Pédiatrie 03/2012; 19(3):295-304. · 0.36 Impact Factor
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    ABSTRACT: Only a few studies based on small cohorts have been carried out on iron status in anorexia nervosa (AN) patients. The aim of this study was to evaluate the role of hepcidin in hyperferritinemia in AN adolescents. Twenty-seven adolescents hospitalized for AN in the pediatric inpatient unit of Ambroise Paré Academic Hospital were enrolled in the study. The control group comprised 11 patients. Hematologic variables and markers of iron status, including serum hepcidin, were measured before and after nutritional rehabilitation. The mean age of patients was 14.4 y. Except for 2 AN patients and 1 control patient, all patients presented normal hemoglobin, vitamin B-12, and folate concentrations. Markers of inflammation and cytokines were normal throughout the study. None of the muscular lysis markers were elevated. Most AN patients had normal serum iron concentrations on admission. Serum ferritin concentrations were significantly higher in patients than in control subjects (198 compared with 49 μg/L, respectively; P < 0.001). The median hepcidin concentration was significantly higher in AN patients than in the control group (186.5 compared with 39.5 μg/L, respectively; P = 0.002). There was a highly significant correlation between ferritinemia and serum hepcidin concentrations (P < 0.0001). After nutritional rehabilitation, a significant reduction was observed (P = 0.004) in serum ferritin. Serum hepcidin analyzed in a smaller number of patients also returned to within the normal range. Hepcidin and ferritin concentrations were higher in the serum of AN patients, without any evidence of iron overload or inflammation. These concentrations returned to normal after nutritional rehabilitation. These results suggest that nutritional stress induced by malnourishment in the hepatocyte could be yet another mechanism that regulates hepcidin.
    American Journal of Clinical Nutrition 03/2012; 95(3):548-54. · 6.50 Impact Factor
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    ABSTRACT: Iron deficiency is the most frequent cause of hypochromic microcytic anemia in children, but other causes, some of them requiring specific management, may be involved. Checking the iron-status is absolutely mandatory. When iron-status parameters are low, inadequate intake, malabsorption, blood loss, and abnormal iron utilization must be tested. In absence of iron deficiency, α- and β-globin and heme biosynthetic gene status must be checked. Assessing the iron stock level is difficult, because there is an overlap between the values observed in iron-replete and iron-deprived patients, so that at least 2 iron-status parameters must be below normal for diagnosing iron deficiency. Furthermore, inflammation may also mimic some characteristics of iron deficiency. Diagnosing iron deficiency leads to prescribing iron supplementation with follow-up at the end and 3 months after cessation of treatment. When iron stores are not replete at the end of treatment, compliance and dosage must be reevaluated and occult bleeding sought. The latter is also required when the iron store decreases 3 months after cessation of iron replacement.
    Archives de Pédiatrie. 03/2012; 19(3):295–304.
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    C. BEAUMONT, J.-B. BURIE, A. DUCROT, P. ZONGO
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    ABSTRACT: We propose a mathematical spatial and age structured model to describe the spatial spread of Salmonella among laying hens in industrial hen houses. We provide a mathematical study of traveling pulses of infection and describe a minimal speed property for such a problem. The dependence with respect to some heterogeneities of the medium is also discussed. Finally, based on biological data, the parameters of the model are estimated to provide some information on the propagation speed of the bacteria.
    SIAM Journal on Applied Mathematics 01/2012; 72(4):1113-1148. · 1.58 Impact Factor

Publication Stats

6k Citations
923.56 Total Impact Points

Institutions

  • 2002–2014
    • French Institute of Health and Medical Research
      • • Unit of Biotherapies of Genetic Diseases and Cancers
      • • Centre de Recherche Biomédicale Bichat-Beaujon U773
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Université Paris Descartes
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2008–2012
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Cardiff University
      • Department of Medical Biochemistry and Immunology
      Cardiff, WLS, United Kingdom
  • 1997–2011
    • French National Institute for Agricultural Research
      • • Laboratoire de Génétique Cellulaire
      • • Département de Génétique Animale
      Lutetia Parisorum, Île-de-France, France
  • 1981–2011
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2009
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
    • Hospital General Universitario de Alicante
      Alicante, Valencia, Spain
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      Lutetia Parisorum, Île-de-France, France
  • 2008–2009
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 2007–2009
    • Paris Diderot University
      • Centre de recherche biomédicale Bichat, Beaujon (CRB3) UMR-S 773
      Lutetia Parisorum, Île-de-France, France
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2006
    • Université du Havre
      El Havre, Upper Normandy, France
  • 2002–2003
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1985
    • St Louis University Hospital
      San Luis, Missouri, United States