Optimising the diagnosis and the treatment of iron overload diseases

International audienceA number of human disorders are related to chronic iron overload, either of genetic or acquired origin. The multi-organ damage produced by iron excess leads, in adults and in children, to severe clinical consequences, affecting both quality of life and life expectancy. The diagnosis is increasingly based on a non-invasive strategy, resorting to clinical, biological and imaging data. The treatment rests on either venesection or chelation therapy, depending on the etiology. Major advances in the fields of molecular biology, pharmacology, and biotechnology pave the road for key improvements in the diagnostic and therapeutic management of the patients

Physics and engineering of nuclear reactors at the "Ecole Nationale Supérieure de Physique de Grenoble" of the "Institut National Polytechnique de Grenoble"

International audienceIf the use of fossil fuels is to be limited to curtail greenhouse gas emissions, fission nuclear energy is, along with new renewable energies, one of the primary energy sources able to respond significantly to the increasing worldwide demand. In this context, it is necessary to design and evaluate new generations of nuclear reactors as defined by the Gen IV International Forum. The Energy and Nuclear Engineering (GEN) curriculum of the Ecole Nationale Supérieure de Physique de Grenoble (ENSPG), one of the nine engineering schools of the Grenoble Institute of Technology (INPG), includes a balanced blend of basic courses in energy, nuclear and thermal hydraulic engineering, together with the corresponding engineering sciences to cover the technological aspects. The objective is to train engineers who shall master not only nuclear engineering for the production of electricity but, more broadly, energy and nuclear technologies and their various application fields

Calibration and monitoring of the GENEPI neutron source for the MUSE IV experiment

Rapport intern

The Thorium Molten Salt Reactor : Moving on from the MSBR

A re-evaluation of the Molten Salt Breeder Reactor concept has revealed problems related to its safety and to the complexity of the reprocessing considered. A reflection is carried out anew in view of finding innovative solutions leading to the Thorium Molten Salt Reactor concept. Several main constraints are established and serve as guides to parametric evaluations. These then give an understanding of the influence of important core parameters on the reactor's operation. The aim of this paper is to discuss this vast research domain and to single out the Molten Salt Reactor configurations that deserve further evaluation.Comment: 11 pages, 8 figures, 6 table

Acupuncture facing up Evidence-Based Medicine (EBM) in Digestive Diseases

Introduction : Le but de ce travail est de faire la revue des indications de l’acupuncture, qui sont actuellement validées par l’EBM, dans les pathologies digestives. Matériel et méthode : Les bases de données Medline et Acudoc2 ont été interrogées, à partir de 1970, sur les études randomisées contrôlées (ECRs) et méta analyses, à l’aide du thésaurus MESH. Une interrogation complémentaire sur les mécanismes d’action de l’acupuncture a été faite en recherche fondamentale. Résultats : Ces publications dans le domaine des maladies digestives représentent 13 % de tous les ECRs, toutes pathologies confondues, et concernent 7 pathologies dont 6 en gastroentérologie et une en hépatologie. Il s’agit principalement de pathologies coliques et gastriques, à dominante fonctionnelle. Les études à partir de modèles animaux vont dans le sens de ces indications cliniques et montrent un effet favorable de l’acupuncture dans des atteintes hépatiques. Conclusion : L’EBM, dans un modèle adapté à l’acupuncture, pourrait être développée en pathologie digestive.Introduction: The aim of this work is to review the indications of acupuncture, which are now validated by EBM, in digestive diseases, Materials and methods: The Medline and Acudoc 2 databases were surveyed from 1970 about randomized controlled studies (RCTs) and meta-analysis, using the MESH thesaurus. A complementary question about the mechanisms of action of acupuncture was made in fundamental research. Results: These publications in the digestive diseases field account for 13% of all RCTs, all pathologies combined, and concern 7 diseases, including 6 in gastroenterology and one in hepatology. These are mainly colic and gastric diseases, predominantly functional. Studies from animal models go in the direction of these clinical indications and show a favorable effect of acupuncture in liver damage. Conclusion: The EBM, in a model adapted to acupuncture, could develop in digestive disorders

Analytical investigation and experimental application of the source modulation technique to measure ρ/βeff\rho/\beta_{eff}

In recent years great interest has been displayed, worldwide, for Accelerator Driven Sub critical reactors (ADS) to incinerate the minor actinides generated by the existing energy producing reactors. In sub critical systems, the effective neutron multiplication factor is lower than 1.0 and the neutrons otherwise required to maintain the chain reaction, can be put to other uses, in particular, the destruction of nuclear wastes such as minor actinides (MA). One of the major advantages of such ADS systems is that it can be operated with very high M.A content without jeopardizing the overall safety due to a small effective delayed neutron fraction, a small Doppler temperature coefficient and possibly also a large void coefficient depending on the chosen coolant. This enhanced safety however prerequisites at all time a sufficient subcriticality margin. Reliable reactivity monitoring techniques are hence required to achieve this goal. The MUSE-4 program is a series of low power experiments carried out at the CEA-Cadarache MASURCA facility to investigate the various methods leading to the measurement of the reactivity level and associated kinetic parameters such as the effective delayed neutron fraction. The aim of this paper is to present the results obtained with a method which directly gives the ratio, for a sub critical assembly, between the reactivity ρ and the effective delayed neutron fraction βeff. By combining these results to those obtained with the kp-method for the prompt neutron multiplication coefficient, we have access to the parameters which govern the prompt and the slow kinetics of a sub critical assembly. These parameters can be obtained without reference to any calibration measurement in critical configuration. It opens the way to the control of larger sub critical demonstrators which are operating with fuels which cannot be used in critical reactor, and, thanks to sub criticality, which are characterized by a deterministic safety

Surcharges en fer rares d'origine génétique (caractérisation clinique, fonctionnelle, et biologique)

L'hémochromatose génétique liée au gène HFE (HG) se caractérise par une augmentation de la saturation de la transferrine plasmatique, qui entraîne une surcharge en fer. Ces anomalies sont dues à une sécrétion basse d'hepcidine, le régulateur principal du métabolisme du fer, et définissent le phénotype d'hepcidino déficience. De nouvelles formes de surcharges en fer ayant un phénotype similaire ont été identifiées. Les mécanismes moléculaires en sont parfois mal compris. L'objectif général de ce travail a été de caractériser sur le plan clinique, fonctionnel, et biologique, des surcharges en fer rares d'origine génétique ayant pour point commun un phénotype d'hepcidino-déficience. Nous avons d'abord analysé une cohorte de patients porteurs d'une HG, forme type de l'hepcidino-déficience, et montré que la transplantation hépatique normalisait le métabolisme du fer, montrant ainsi le rôle majeur du foie dans le phénotype d'hepcidino-déficience de l'HG. Nous avons ensuite caractérisé des surcharges en fer à saturation de la transferrine élevée liées à des anomalies de transport du fer : i) nous avons rapporté un cinquième cas de mutations du gène DMT1 et montré le caractère pathogène de la mutation p.Asn491Ser ; ii) nous décrivons un groupe de 12 patients qui présentent une mutation hétérozygote du gène TF, l'augmentation de la saturation de la transferrine ne semblant pas être en rapport avec une hepcidino-déficience, et l'existence de cofacteurs pouvant faciliter la surcharge en fer. Nous avons ensuite décrit l'impact de mutations du gène TFR2, qui sont responsables d'une hepcidino déficience dont l'expression clinique est hétérogène mais qui peut être très précoce. Nous avons alors, pour préciser les mécanismes liant les mutations du gène TFR2 à une diminution anormale de l'hepcidine, montré in vitro que les mutations p.Asn12Ile et p.Gly430Arg altèrent l'adressage cellulaire de TFR2 tandis que la mutation p.Arg768Pro altère son interaction avec la transferrine. N'ayant pu parvenir à induire l'expression d'hepcidine sous l'effet de la transferrine, au contraire de certaines équipes mais en accord avec d'autres, nous n'avons pu analyser l'impact des mutations sur la transduction du signal liant TFR2 et hepcidine. Nos résultats contribuent à préciser les mécanismes impliqués dans l'apparition de surcharges en fer rares à saturation élevée de la transferrine.HFE related hemochromatosis (HH) is characterized by an increased plasma transferrin saturation level, which causes iron overload. These anomalies are due to low hepcidin secretion, the key regulator of iron metabolism, and define the hepcidin deficiency phenotype. New forms of iron overload with similar phenotype were identified, but their molecular mechanisms remain unclear. The main objective of this work was to characterize the clinical, functional, and biological aspects of rare genetic iron overload with an hepcidin deficiency phenotype. We firstly analyzed a cohort of HH patients, archetype of hepcidin-deficiency and showed that liver transplantation cured the disease, demonstrating the major role of the liver in the phenotype. We then characterized iron overloads with high transferrin saturation related to abnormalities of iron transport: i) we reported a fifth case of patient with DMT1 gene mutations and demonstrated the pathogenicity of the mutation p.Asn491Ser; ii) we described 12 patients with heterozygous mutation of the TF gene, leading to serum transferrin decrease. The increase of transferrin saturation associated to the disease does not seem to be related to a hepcidin-deficiency, and the presence of cofactors may facilitate iron overload. We then described the impact of mutations in the TFR2 gene, which induce hepcidin-deficiency whose expression is heterogeneous but that can occur in young peoples. Then we tried to clarify in vitro the mechanisms linking mutations in the TFR2 gene to an abnormal decrease of hepcidin and showed that the p.Asn12Ile and p.Gly430Arg mutations alter the TFR2 protein intracellular trafficking while the p.Arg768Pro mutation alters its interaction with transferrin. Being unable to induce expression of hepcidin in response to transferrin, unlike some authors, but in agreement with others, we were not able to analyze the impact of mutations on signal transduction toward hepcidin. Our results help to clarify the mechanisms involved in the development of iron overload in rare high saturation of transferrin.RENNES1-Bibl. électronique (352382106) / SudocSudocFranceF