[The promise of omics in the precision medicine era]. / Les promesses des sciences omiques à l'ère de la médecine de précision.

The rise of omics technologies that simultaneously measure thousands of molecules in a complex biological sample represents the core of systems biology. These technologies have profoundly impacted biomarkers and therapeutic targets discovery in the precision medicine era. Systems biology aims to perform a systematic probing of complex interactions in biological systems. Powered by high-throughput omics technologies and high-performance computing, systems biology provides relevant, resolving, and multi-scale overviews from cells to populations. Precision medicine takes advantage of these conceptual and technological developments and is based on two main pillars: the generation of multimodal data and their subsequent modeling. High-throughput omics technologies enable the comprehensive and holistic extraction of biological information, while computational capabilities enable multidimensional modeling and, as a result, offer an intuitive and intelligible visualization. Despite their promise, translating these technologies into clinically actionable tools has been slow. In this contribution, we present the most recent multi-omics data generation and analysis strategies and their clinical deployment in the post-genomic era. Furthermore, medical application challenges of omics-based biomarkers are discussed.

Management of 35 critically ill hyperammonemic neonates: Role of early administration of metabolite scavengers and continuous hemodialysis.

Neurological involvement is frequent in inherited metabolic disease of the intoxication type. Hyperammonemic coma related to these diseases may cause severe neurological sequelae. Early optimal treatment is mandatory combining metabolite scavengers (MS) and sometimes continuous veno-venous hemodialysis (CVVHD). We aimed to describe the therapeutic management of hyperammonemia in neonates upon diagnosis of their metabolic disease and to compare neonates managed with MS alone or with both MS and CVVHD. We conducted a retrospective study including all neonates admitted for initial hyperammonemia to the pediatric intensive care unit of a Reference Center of Inherited Metabolic Diseases, between 2001 and 2012. The study included 35 neonates. Before admission, MS were initiated for 11 neonates. At admission, the median ammonia levels were 391 µmol/L and were significantly lower in neonates who received MS before admission. At admission, ammonia levels were 644 µmol/L in dialyzed and 283 µmol/L in non-dialyzed neonates. The median time to reach a 50% decrease of the initial ammonia levels was significantly shorter in dialyzed neonates; however, the normalization of ammonia levels was similar between dialyzed and non-dialyzed neonates. Hemodynamic disorders were more frequent in dialyzed neonates. CONCLUSION: MS represent an effective treatment for hyperammonemia and should be available in all pediatric units to avoid the need for CVVHD. Although CVVHD enhances the kinetics of toxic metabolite decrease, it is associated with adverse hemodynamic effects.

Transport properties of a Bentheim sandstone under deformation.

The mechanical and transport properties of a Bentheim sandstone are studied both experimentally and numerically. Three classical classes of loads are applied to a sample whose permeability is measured. The elasticity and the Stokes equations are discretized on unstructured tetrahedral meshes which precisely follow the deformations of the sample. Numerical results are presented, discussed, and compared to the available experimental data.

[Laboratory diagnosis and follow up of mucopolysaccharidoses]. / Diagnostic et suivi des mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) often raise diagnostic challenges, particularly in patients with progressive disease and relatively non-specific signs and symptoms. Early diagnosis improves management and enables to start specific treatment when available. Each type of MPS is associated with a deficiency of a lysosomal enzyme which catalyses the degradation of glycosaminoglycans (GAGs). The initial diagnosis Wis suggested by quantifying and identifying the accumulated metabolites. Diagnosis is then confirmed by assaying the deficient enzyme, allowing diagnosis in a large majority of cases. Indirect markers, which do not arise directly from the deficient metabolic pathway and vary in concentration depending on the degree of disease progression, are used to support a diagnosis of MPS and/or monitor the efficacy of the specific treatment. Identifying the underlying genic abnormality enables family studies to be carried out and perform prenatal diagnosis.

Antigen-bearing dendritic cells from the sublingual mucosa recirculate to distant systemic lymphoid organs to prime mucosal CD8 T cells.

Effector T cells are described to be primed in the lymph nodes draining the site of immunization and to recirculate to effector sites. Sublingual immunization generates effector T cells able to disseminate to the genital tract. Herein, we report an alternative mechanism that involves the recirculation of antigen-bearing dendritic cells (DCs) in remote lymphoid organs to prime T cells. Sublingual immunization with a muco-adhesive model antigen unable to diffuse through lymphatic or blood vessels induced genital CD8 T cells. The sublingual draining lymph nodes were not mandatory to generate these lymphocytes, and antigen-bearing DCs from distant lymph nodes and spleen were able to prime specific CD8 T cells in a time- and dose-dependent manner. This study demonstrates, for the first time, that antigen-bearing DCs originating from the site of immunization recirculate to distant lymphoid organs and provides insights into the mechanism of distant CD8 T-cell generation by sublingual immunization.

B cell and T cell immunity in the female genital tract: potential of distinct mucosal routes of vaccination and role of tissue-associated dendritic cells and natural killer cells.

The female genital mucosa constitutes the major port of entry of sexually transmitted infections. Most genital microbial pathogens represent an enormous challenge for developing vaccines that can induce genital immunity that will prevent their transmission. It is now established that long-lasting protective immunity at mucosal surfaces has to involve local B-cell and T-cell effectors as well as local memory cells. Mucosal immunization constitutes an attractive way to generate systemic and genital B-cell and T-cell immune responses that can control early infection by sexually transmitted pathogens. Nevertheless, no mucosal vaccines against sexually transmitted infections are approved for human use. The mucosa-associated immune system is highly compartmentalized and the selection of any particular route or combinations of routes of immunization is critical when defining vaccine strategies against genital infections. Furthermore, mucosal surfaces are complex immunocompetent tissues that comprise antigen-presenting cells and also innate immune effectors and non-immune cells that can act as 'natural adjuvants' or negative immune modulators. The functions of these cells have to be taken into account when designing tissue-specific antigen-delivery systems and adjuvants. Here, we will discuss data that compare different mucosal routes of immunization to generate B-cell and T-cell responses in the genital tract, with a special emphasis on the newly described sublingual route of immunization. We will also summarize data on the understanding of the effector and induction mechanisms of genital immunity that may influence the development of vaccine strategies against genital infections.

[Stroke and cornea verticillata revealing Fabry's disease in a female]. / Accident vasculaire cérébral ischémique et cornée verticillée révélant une maladie de Fabry chez une femme.

INTRODUCTION: Fabry's disease is a X-linked lysosomal storage disorder caused by an alpha-galactosidase A deficiency responsible for the accumulation of glycosphingolipids. Males are more severely and frequently affected than females. We report the case of a female who presented a stroke revealing Fabry's disease. CASE REPORT: An 53-year-old woman, with cardiovascular risk factors and two previous transient ischemic attacks, was admitted with a brutal right hemiparisia. Cerebral MRI showed multiple white matter lesions in the cerebral hemispheres with multiple lacunar infarcts and ectatic vessels, cardiac echography revealed a hypertrophic concentric cardiomyopathy, and slit-lamp examination demonstrated a cornea verticillata. The sequencing of the alpha-galactosidase gene (GLA) revealed the c.150_151del mutation responsible for a loss of function. DISCUSSION: As in the present case, ophthalmological examination is very useful to determine Fabry's disease as a cause of young onset stroke. Females may be affected by X-linked disease, as the Fabry's disease. Fabry's disease among females is mainly characterized by the involvement of the nervous and cardiovascular systems. The specific treatment is based on an enzyme replacement therapy by recombinant enzyme with cardiovascular benefit. Despite the presence of cardiovascular risk factors, this case demonstrates the importance of thorough standardized investigations including ophthalmological examination of young patients with stroke.

Molecular characterization of MPS IIIA, MPS IIIB and MPS IIIC in Tunisian patients.

Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the heparan sulfate degradation, with sulfamidase (SGSH), α-N-acetylglucosaminidase (NAGLU), acetyl-coenzyme A: α-glucosaminide N-acetyltransferase (HGSNAT), and N-acetylglucosamine-6-sulfatase (GNS) being deficient respectively in MPS IIIA, MPS IIIB, MPS IIIC and MPS IIID. Mutation screening using PCR reaction/sequencing analysis on genomic DNA fragments was performed in seven Tunisian index cases with MPS IIIA, three with MPS IIIB and two with MPS IIIC. QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) analysis was developed for the detection of genomic deletions and duplications in the SGSH gene. These approaches allowed the identification of 11 mutations, 8 of them were novel including a mutation involving the start codon (p.Met1?), one small duplication (p.Leu11AlafsX22), one small deletion (p.Val361SerfsX52) and a large deletion of exon 1 to exon 5 in the SGSH gene, one missense mutation (p.Pro604Leu) and one nonsense mutation (p.Tyr558X) in the NAGLU gene and, finally, one missense mutation (p.Trp627Cys) and one nonsense mutation (p.Trp403X) in the HGSNAT gene.

From computed microtomography images to resistivity index calculations of heterogeneous carbonates using a dual-porosity pore-network approach: influence of percolation on the electrical transport properties.

Standard reservoir evaluations are based on Archie's law relating the average water saturation to the average electrical resistivity by R(ind) = S(w)(-2). However, especially in the case of complex heterogeneous carbonates, deviation from Archie's law is observed and generally attributed to factors affecting the percolation or disconnectedness of the different phases (wetting films, microporosity, macropores) assuring electrical conductance. Pore-network models (PNM's) in combination with high-resolution computed microtomography (µ-CT) constitute a very effective tool to investigate the influence of the geometry and topology of the porous media on the spatial distribution of the conductive phase, and therefore on the shape of the resistivity index curve. An extended version of the classical PNM applicable to dual-porosity systems is presented. It combines the classical pore-network modeling applied on the macroporous space with the macroscopic properties of the microporous phase, supposing that the two pore systems act in parallel. Three-dimensional images provide information on the connectedness of the microporous phase, which is then included in the simulations. Electrical behavior of sandstone and two carbonates presenting distinct resistivity index curves were simulated and compared to measurements. Both Archie and "non-Archie" behavior were correctly reproduced, and the curve shape was explained considering percolation of the different phases.

Plasma carnitine is associated with fatigue in chronic hepatitis C but not in the irritable bowel syndrome.

BACKGROUND: Fatigue is an important determinant of altered quality of life in patients affected by chronic hepatitis C or the irritable bowel syndrome (IBS). AIM: In this study, we aimed at determining the contributory role of plasma levels of leptin and carnitine on fatigue in chronic hepatitis C and IBS. METHODS: We enrolled 81 patients with chronic hepatitis C, 42 with IBS and 44 healthy subjects. Fatigue was evaluated using the Fatigue Impact Scale questionnaire. Body composition was assessed through impedance analysis. Plasma carnitine and leptin were measured. RESULTS: Fatigue scores were significantly more elevated in patients with chronic hepatitis C and IBS than in healthy subjects. Patients with chronic hepatitis C but not IBS, had significant lower plasma levels of total and free carnitine adjusted for fat mass compared with healthy subjects. In patients with chronic hepatitis C and not with IBS, fatigue scores were negatively correlated with plasma levels of carnitine. Levels of free carnitine were significantly and independently associated with the severity of fatigue in patients with chronic hepatitis C [OR=2.019, P=0.02, CI 95% (1.01-1.23)]. CONCLUSIONS: In patients with chronic hepatitis C, the severity of fatigue is associated with a low level of carnitine, suggesting that an oral supplementation may be effective to relieve fatigue in chronic hepatitis C. The underlying mechanism of fatigue in IBS does not seem to involve carnitine.

Development and implementation of a novel assay for L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) in cell lysates: L-2-HGDH deficiency in 15 patients with L-2-hydroxyglutaric aciduria.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphocyte lysates has hitherto been unavailable. We developed an L-2-HGDH enzyme assay in cell lysates based on the conversion of stable-isotope-labelled L-2-hydroxyglutarate to 2-ketoglutarate, which is converted into L-glutamate in situ. The formation of stable isotope labelled L-glutamate is therefore a direct measure of L-2-HGDH activity, and this product is detected by liquid chromatography-tandem mass spectrometry. A deficiency of L-2-HGDH activity was detected in cell lysates from 15 out of 15 L-2-HGA patients. Therefore, this specific assay confirmed the diagnosis unambiguously affirming the relationship between molecular and biochemical observations. Residual activity was detected in cells derived from one L-2-HGA patient. The L-2-HGDH assay will be valuable for examining in vitro riboflavin/FAD therapy to rescue L-2-HGDH activity.

Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature.

Enzyme replacement therapy (ERT) has been used to treat Fabry disease - a progressive lysosomal storage disorder - since 2001. Two preparations of the enzyme alpha-galactosidase A are available in Europe: agalsidase alpha, produced in a human cell line, and agalsidase beta, produced in Chinese hamster ovary cells. To review critically the published evidence for the clinical efficacy of these two enzyme preparations. A systematic literature search was undertaken to identify open or randomised controlled trials published on Fabry disease since 2001. Eleven trials fulfilled the criteria for inclusion in this review, of a total of 586 references on Fabry disease. To date, no direct comparisons exists between the two available enzyme preparations. Significant clinical benefits compared with placebo, however, have been demonstrated with ERT, with positive effects on the heart, kidneys, nervous system and quality of life. The quality of most of these publications was less than optimal. Further prospective studies are required to confirm the long-term clinical benefits of ERT. More studies are also needed on the effects of ERT in women and on the use of ERT early in the course of Fabry disease, to prevent organ damage. Large national and international outcomes databases will also be invaluable in evaluating treatment effects and safety.

Early diagnosis of mucopolysaccharidosis III A with a nonsense mutation and two de novo missense mutations in SGSH gene.

An early presentation of heparan N-sulphatase (SGSH) deficiency (mucopolysaccharidosis IIIA, MPS IIIA) with a prominent and isolated hepato-splenomegaly is described. Molecular analysis detected a nonsense mutation (Y40X) and two de novo missense mutations (E300V; Q307P).

[Hereditary sideroblastic anemia: a rare diagnosis]. / Anémie sidéroblastique héréditaire: une maladie rare.

Hereditary sideroblastic anemia is a very rare disease recessive and X-linked that affect heme biosynthesis by deficit or decreased of delta aminolevulinic acid synthase (ALAS) activity. We report a case of a six-month-old boy, admitted in the hospital for anemic syndrome. The hemogram showed anemia (hemoglobin: 4.5 g/dL), frankly hypochronic microcytic and a regenerated (mean corpuscular hemoglobin concentration: 26 g/dL, mean cell volume: 53 fl, reticulocytes: 10 x 10(9)/L) with red cells morphologic disorders in smears (anisopoikylocytosis) without attack of the other lineages; white blood cells: 11 x 10(9)/L (neutrophils: 64% and lymphocytes: 35%); platelets: 350 x 10(9)/L. Examination of bone marrow showed an important erythroid hyperplasia (about 69%) with dyserythropoiesis. Perls stain revealed intense siderosis with 90% of ringed sideroblasts and a large number of siderocytes. Exploration of ALAS2 and ABC7 genes on the DNA of the infant was not found abnormalities. Treatment with pyridoxine corrects moderately the anemia. By the way, we proposed to remind that iron deficiency, inflammatory syndrome and thalassemia are the common microcytic anemia. However, it's mandatory to explore other causes if diagnosis is not solved.

The molecular basis of succinic semialdehyde dehydrogenase deficiency in one family.

Succinic semialdehyde dehydrogenase (SSADH) deficiency has predominantly neurological consequences, affecting psychomotor, speech and language development. Recently, two clinical reviews summarized the features of this disease and their relative frequency [Neurology 60 (2003) 1413; Ann. Neurol. 54 (2003) S73]. The molecular genetics of SSADH deficiency is still being explored. We describe the molecular basis of this defect in a Tunisian female child presenting with a mild phenotype. A small scale deletion in exon 10 of the gene led to a frameshift that predicts premature termination of the resulting putative protein. The parents were shown to be heterozygotes for this deletion, supporting its causative role.

Integration esthetique d'une prothese partielle amovible a chassis metallique

L'objectif primordial du traitement d'un edentement partiel est de retablir la fonction occlusale; mais dans le cas ou l'edentement est borde par une dent anterieure notre objectif sera aussi de retablir l'esthetique. A travers un cas clinique; nous allons discuter l'apport d'un attachement axial sur les deux plans esthetique et fonctionnel ainsi que les cles de reussite de ce traitement prothetique qui doit repondre imperativement aux regles regissant la realisation des protheses composites