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Resume L’induction de tolerance orale realisee en centre specialise est une option de traitement des enfants allergiques a l’arachide. De frequents effets indesirables, parfois severes, ont ete rapportes. Objectif L’objectif principal est la description des effets indesirables au cours d’une induction de tolerance orale a l’arachide. L’objectif secondaire est la recherche de facteurs de risque d’effets indesirables. Methode Une etude observationnelle prospective, en vie reelle chez des enfants allergiques a l’arachide (4–17 ans), a ete conduite dans 3 centres pediatriques. L’induction de tolerance orale a ete realisee avec des produits du commerce ou de l’arachide nature. La dose d’entretien quotidienne de 500 mg (264 patients) ou de 300 mg (93 patients) de proteines d’arachide a ete atteinte en 12 a 18 mois. Les caracteristiques de patients et les effets secondaires ont ete colliges. Resultats Sur 357 enfants, 176 (49,3 %) ont presente des effets indesirables. Parmi eux, 154 ont presente 148 anaphylaxies, survenues en hopital de jour dans 69 % des cas (initiation ou montee de dose), 74 (20,7 %) ont eu recours a une injection d’adrenaline (84 % en hopital de jour), et 86 % d’entre eux ont poursuivi l’induction de tolerance orale, 27,5 % des patients ont abandonne dont la moitie par stress, degout ou lassitude. Des taux eleves d’immunoglobulines E specifiques pour Arachide globale et r Ara h2 sont associes (p Conclusion Nos resultats sont comparables a ceux de la litterature en termes de frequence, de nature d’effets indesirables et d’abandons. Des etudes sont necessaires pour preciser le phenotype des patients a risque d’effets indesirables, notamment les plus severes.

The hospital admission rate for anaphylaxis is increasing especially among the youngest children and food is the leading cause of anaphylaxis in children. In 2014, an emergency action plan for accidental food allergic reactions in children has been proposed to the medical community by the French Allergology Society. Since its publication, new information (dissemination of recommendations on the management of anaphylaxis, provision of a new dosage of 0.5 mg epinephrine in one of the autoinjector available in France, confirmation of the lack of evidence of the effectiveness of oral corticosteroids in anaphylaxis, experience gained on the use of the current action plan…) has led to an update of the initial emergency action plan. As a result, the “Allergy at school” working group, in conjunction with the task forces“Food allergy” working group of the French Allergology Society, supported by various learned societies, medical and patients’ associations, is proposing an update of the emergency action plan in case of allergic reaction in children and adolescents. The aim of this initiative is to harmonize current practices and to improve the quality of the management of allergic emergencies. The present manuscript combines a rationale on the contents of the emergency kit and the epinephrine autoinjectors.

Background and AimsThe YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Moreover, YAP/TAZ signaling plays a role in the progression of cancers and renal damage associated with diabetes. However, whether YAP/TAZ signaling is also implicated in diabetes-associated vascular complications is not known.MethodsThe effect of high glucose on YAP/TAZ signaling was firstly evaluated in vitro on endothelial cells cultured under static conditions or subjected to shear stress (either laminar or oscillatory flow). The impact of diabetes on YAP/TAZ signaling was additionally assessed in vivo in db/db mice.ResultsIn vitro, we found that YAP was dephosphorylated/activated by high glucose in endothelial cells, thus leading to increased endothelial inflammation and monocyte attachment. Moreover, YAP was further activated when high glucose was combined to laminar flow conditions. YAP was also activated by oscillatory flow conditions but, in contrast, high glucose did not exert any additional effect. Interestingly, inhibition of YAP reduced endothelial inflammation and monocyte attachment. Finally, we found that YAP is also activated in the vascular wall of diabetic mice, where inflammatory markers are also increased.ConclusionWith the current study we demonstrated that YAP signaling is activated by high glucose in endothelial cells in vitro and in the vasculature of diabetic mice, and we pinpointed YAP as a regulator of high glucose-mediated endothelial inflammation and monocyte attachment. YAP inhibition may represent a potential therapeutic opportunity to improve diabetes-associated vascular complications.

International audience; Lipoprotein(a) (Lp[a]) is the most common genetically inherited risk factor for cardiovascular disease. Many aspects of Lp(a) metabolism remain unknown. We assessed the uptake of fluorescent Lp(a) in primary human lymphocytes as well as Lp(a) hepatic capture in a mouse model in which endogenous hepatocytes have been ablated and replaced with human ones. Modulation of LDLR expression with the PCSK9 inhibitor alirocumab did not alter the cellular or the hepatic uptake of Lp(a), demonstrating that the LDL receptor is not a major route for Lp(a) plasma clearance. These results have clinical implications because they underpin why statins are not efficient at reducing Lp(a). (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

In order to ensure the quality and the relevance of irradiation programs in the future Jules Horowitz Reactor (JHR), the French Alternative Energies and Atomic Energy Commission (CEA) has significantly increased its research and development effort in the field of in-pile instrumentation during the last decade. Major progress has been achieved in the capability to perform accurate in-pile measurements using reliable and updated techniques. A significant part of this effort has been conducted in the framework of the Joint Instrumentation Laboratory between the CEA and the Belgian Nuclear Research Centre (SCK $\cdot$ CEN). In order to improve measurement techniques for neutron flux assessment, a unique system for online measurement of fast neutron flux has been developed and recently qualified in-pile. The fast-neutron-detection-system (FNDS) has been designed to monitor accurately high-energy neutron flux (E > 1 MeV) in typical material testing reactor (MTR) conditions, where neutron flux levels can be as high as $10^{15}\,\,\text {N}\cdot \text {cm}^{-2}\cdot \text {s}^{-1}$ and are generally dominated by thermal neutrons. Moreover, the neutron flux is coupled with a high gamma flux of typically a few $10^{15} \gamma \cdot \text {cm}^{-2}\cdot \text {s}^{-1}$ , which can be highly disturbing for the online measurement of neutron fluxes. The patented FNDS system is based on two detectors allowing the simultaneous detection of both thermal- and fast-neutron flux. Thermal neutrons can be measured using a self-powered neutron detector or a 235U miniature fission chamber, while fast neutron detection requires a miniature fission chamber with a special fissile material presenting an energy threshold near 1 MeV, which can be 242Pu for MTR conditions. Fission chambers are operated in Campbelling mode for an efficient gamma rejection. FNDS also includes a specific software that processes measurements to compensate online the fissile material depletion and to adjust the sensitivity of the detectors, in order to produce a precise evaluation of both thermal and fast neutron flux even after long-term irradiation. FNDS has been validated through a two-step experimental program. A first set of tests was performed at BR2 reactor operated by SCK $\cdot$ CEN in Belgium. Two FNDS prototypes were operated in-pile during nearly 1000 h. These tests exhibited the consistency of the measurement of thermal to fast neutron flux ratio with Monte Carlo neutron and photon transport calculations, as well as the right compensation of fissile material depletion. This paper describes a second test recently completed at ISIS reactor operated by CEA in France. For this irradiation, FNDS signal was compared to reference thermal- and fast-neutron flux measurements using activation dosimeters analyzed under COFRAC Quality Certification. During this latter test, FNDS proved its ability to measure online the fast neutron flux with an overall accuracy better than 5%. FNDS is now operational and is assumed to be the first and unique acquisition system able to provide an online measurement of the fast neutron flux in MTR conditions. This system will be used to perform spectral neutron characterization of JHR channels, but it may also be implemented in future irradiation experiments, for a better and real-time evaluation of the fast neutron flux received by material and fuel samples.

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivo. Six nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [2H3]-leucine was assessed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (−28%), LDL-C (−67%), Lp(a) (−56%), apolipoprotein B100 (apoB100) (−53%), and apo(a) (−53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (−42%), but not significantly that of apoB100, compared with IgG1, respectively. In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.

Since many years, the Instrumentation, Sensors and Dosimetry laboratory at CEA Cadarache has been working to propose innovative and robust design of fission chambers. In this framework, few simulation tools like Chester or PyFc were developed to make detector prototyping and optimisation possible. Up to now, the code experimental validations are scarce mainly because of the lack of flexibility of regular fission chambers. In order to set up an experimental database for code validation, an innovative modular twin fission chamber, the CFTM, was designed. It allows to set with precision the inter-electrode gap, the filling gas pressure as well as the fissile deposit used. This detector was irradiated in Minerve zero power reactor in order to gather results for code validation. Thanks to a calibration procedure, a bank of experimental results is available for simulation validation.

The JSI TRIGA reactor features several in-core and ex-core irradiation facilities, each having different properties, such as neutron/gamma flux intensity, spectra and irradiation volume. A series of experiments and calculations was performed in order to characterise radiation fields in irradiation channel thus allowing users to perform irradiations in a well characterised environment. Since 2001 the reactor has been heavily used for radiation hardness studies for components used at accelerators such as the Large Hadron Collider (LHC) at CERN. Since 2010 it has been extensively used for testing of new detectors and innovative data acquisition systems and methods developed and used by the CEA. Recently, several campaigns were initiated to characterise the gamma field in the reactor and use the experimental data for improvement of the treatment of delayed gammas in Monte Carlo particle transport codes. In the future it is planned to extend the testing options by employing pulse mode operation, installation of a high energy gamma ray irradiation facility and allow irradiation of larger samples at elevated temperature.

The CEA MONACO v2 a multichannel acquisition system dedicated to neutron and gamma measurements. It is unique as it integrates all the following features in one module: automatic generation of saturation curves, automatic generation of pulse discrimination curves, detector pulse characterization using the embedded oscilloscope module, pulse mode acquisitions in count rate or pulse height analysis, fluctuation mode and current mode acquisitions. Sensors are plugged to a single connector and the implemented operating modes run constantly in parallel. Firsly designed for on line local neutron and gamma measurements with gaseous detectors in reactor experiments, the MONACO v2 system will also be available for self-powered detectors thanks to its wide current mode working range. After two years of development, CEA teams tested two MONACO v2 prototypes in the Slovenian TRIGA Mark II research reactor in 2018, using CEA miniature ion chambers and SPNDs. The system is now ready for industrialization to be available on the nuclear instrumentation market.

International audience

Introduction Chez les enfants ayant une allergie severe au lait de vache (LV) IgE-mediee (APLV-IgE), l’echec precoce d’une immunotherapie orale (ITO) au LV pourrait etre evite par l’adjonction d’omalizumab. L’objectif de cette etude etait d’evaluer en vie reelle l’efficacite et la tolerance de la phase initiale d’un protocole associant l’omalizumab a une ITO (oma-ITO), chez des enfants ayant une APLV-IgE en echec d’ITO classique. Methodes Les enfants en echec d’initiation d’ITO classique au LV cuit et ayant debute un protocole oma-ITO ont ete inclus. L’omalizumab avait debute 16 semaines avant l’initiation de l’ITO et poursuivi ensuite ; des tests de provocation orale (TPO) etaient realises tous les 1 a 2 mois pour augmenter la dose de LV avec un objectif final de 50 ml. L’efficacite etait jugee au TPO4 sur l’evolution de la dose cumulee toleree (DCT) de LV, des prick-tests (PT), des IgE specifiques (sIgE) et du ratio sIgG4/sIgE. Les administrations d’adrenaline lors des TPO et a domicile etaient egalement rapportees. Resultats Huit patients ayant debute un protocole oma-ITO depuis fevrier 2015 ont ete inclus. Entre les TPO1 et 4, la DCT mediane a progresse de 0,96 mg [0.64 ;15,04] a 160 mg [12,8 ;480] respectivement (facteur median 167 [0,64 ;480]). Entre les TPO1 et 4, les sIgE ont legerement diminue (476,0 kU/L [227,0 ;2048,0] vs 460,0 kU/L [97,2 ; 1482,0], respectivement, p = 0,0391) et le ratio IgG4/IgE a augmente (+ 103,5 % [1,8 ; 223,1 %]). Les PT n’ont pas evolue. Lors des 32 TPO realises au total, aucun n’a induit de reaction necessitant l’administration d’adrenaline. Conclusion La phase initiale du protocole oma-ITO est bien toleree et permet de debuter une ITO chez des enfants en echec d’ITO classique.

We report on the case of a young infant with chronic diarrhea that worsened and turned into hypovolemic shock with methemoglobinemia. We underline and discuss the main features of food protein-induced enterocolitis syndrome (FPIES). FPIES is a non-IgE-mediated food allergy involving tumor necrosis factor-alpha (TNF-α). Many triggering foods exist but cow's milk, as in the case reported herein, is one of the most frequent. It can start early or be delayed and start around the average age of 5 months. Symptoms are nonspecific with diarrhea and vomiting, but in the presence of methemoglobinemia, the diagnosis must be seriously considered. The oral food challenge remains the gold standard to confirm the diagnosis if there is still a doubt. Treatment of FPIES associates emergency treatment of acute dehydration with the prevention of relapses by avoiding the suspected protein.

Introduction L’allergie a la noisette est l’allergie alimentaire la plus repandue en Europe (EuroPrevall). L’immunotherapie par voie Orale (ITO) s’impose de plus en plus comme une alternative a l’eviction dans la strategie therapeutique. L’objectif de ce travail est de presenter les resultats d’une etude en cours sur l’ITO dans une population pediatrique allergique a la noisette. Methodes Le protocole d’ITO comporte au minimum 3 Tests de Provocation par voie Orale (TPO) a 6 mois d’intervalle chacun. A chaque TPO, le dosage des IgE specifiques de la noisette, de ses allergenes moleculaires (Cor a 1, 8, 9 et 14) et des IgG4 specifiques de la noisette est realise sur le Phadia 250 (Thermofisher Scientific) et le ratio IgG4/IgE pour l’extrait noisette est calcule. A ce jour, nous disposons des donnees completes pour 35 patients au 3e TPO (23 garcons/12 filles ; âge median : 10 ans). Les donnees du 3e TPO sont manquantes pour 30 patients (non inclus) : 9 sont en cours d’ITO, 2 ont mange plus de 5 g au 2e TPO (poursuite a domicile), 2 ont abandonne en raison d’effets indesirables (profils Cor a 9–14), 13 sont perdus de vue et 4 poursuivent l’ITO en cabinet de ville. Resultats Le ratio IgG4/IgE augmente de facon significative au cours de l’ITO (ratio median au 3e TPO = 59 versus 19 au 1er TPO) quel que soit le profil de sensibilisation (Cor a 1/Cor a 9-14). Tous les patients sauf un ont atteint la dose de 300 mg au 3e TPO. Parmi eux 8 patients ont atteint 1 g et 12 ont atteint 2 g ou plus. L’augmentation du ratio n’est pas significativement plus elevee chez les patients ayant atteint une dose de 2 g de noisette par rapport aux autres. A ce jour, 6 patients sont gueris et 2 patients ont abandonne apres le 3e TPO (pas d’augmentation des doses ingerees ni du ratio, profil Cor a 9–14). Conclusion Une augmentation significative du ratio IgG4/IgE est en faveur d’une reussite de l’ITO. A l’inverse, une absence d’augmentation est associee a l’abandon. Un profil de sensibilisation Cor a 1 apparait comme un facteur de bon pronostic. Ces resultats preliminaires sont a completer avec les patients en cours d’ITO afin de valider ces parametres comme marqueurs predictifs de reussite/d’echec de l’ITO.

Introduction Chez les enfants ayant une allergie severe au lait de vache (LV) IgE-mediee (APLV-IgE), l’echec precoce d’une immunotherapie orale (ITO) au LV pourrait etre evite par l’adjonction d’un traitement anti-IgE (omalizumab). L’objectif de cette etude etait d’evaluer l’efficacite et la tolerance de la phase initiale d’un protocole associant l’omalizumab a une ITO (oma-ITO), chez des enfants ayant une APLV-IgE en echec d’ITO classique. Methodes Les patients (âge Resultats Les 8 patients ayant debute un protocole oma-ITO entre fevrier 2015 et aout 2019 ont ete inclus. Entre les TPO1 et 4, la DCT mediane avait augmente pour tous les patients d’un facteur median de 156 [1,27 ; 250] soit DCT medianes passant respectivement de 0,03 ml [0,02 ; 0,47] a 5 ml [0,28 ; 15]. Entre les TPO1 et TPO4, les valeurs de PT et sIgE avaient diminue (respectivement − 15,0 % [− 80 ; 25] et − 14,3 % [− 14,29 ; 17,41]), et le ratio IgG4/IgE augmente (+ 55,2 % [13,8 ; 1455,6 %]). Lors des 32 TPO realises au total, aucun n’avait induit de reaction necessitant l’administration d’adrenaline. Conclusion La phase initiale du protocole oma-ITO est efficace et bien toleree. La poursuite du protocole apportera des donnees importantes sur l’interet de l’omalizumab en association a une ITO au LV.

The nuclear heating measurements in Material Testing Reactors (MTRs) are crucial for the study of nuclear materials and fuels under irradiation. The reference measurements of this nuclear heating are especially performed by a differential calorimeter including a graphite sample material and two calorimetric cells. Then these measurements are used for other experimental conditions in order to predict the nuclear heating and thermal conditions induced in the irradiation devices. This paper will present simulations with MCNP5 Monte-Carlo transport code (using ENDF/B-VI nuclear data library) to evaluate the nuclear heating inside the calorimeter during irradiation campaigns of the CARMEN-1P mock-up inside OSIRIS reactor periphery (MTR based on Saclay, France). The whole complete geometry of the sensor has been considered. The calculation method corresponds to a calculation in two steps. Consequently, we used as an input source in the model, the neutron and photon spectra calculated in various experimental locations tested during the irradiation campaign (H9, H10, H11, D9). After a description of the differential calorimeter sensor, the MCNP5 model used for the calculations of nuclear heating inside the calorimeter elements is introduced by two quantities: KERMA and energy deposition rate per mass unit. The Charged Particle Equilibrium (CPE) inside the calorimeter elements is studied. The contribution of prompt gamma and neutron is determined. A comparison between this total nuclear heating calculation and the experimental results in a graphite sample will be made. Then parametric studies performed on the influence of the various calorimeter components on the nuclear heating are presented and discussed. The studies of the influence of the nature of materials, the sensor jacket, the source type and the comparison of the results obtained for the two calorimetric cells leads to some proposals for the sensor improvement.

SUMMARY To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor–independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells., VISUAL ABSTRACT

We have monitored on-line the spectral characteristics of two lines of five multiplexed Fiber Bragg Gratings under high temperature and high neutron fluence (up to 670°C and 3×1019 nfast/cm2>1Mev). The gratings have been written using a femtosecond laser and the point-by-point technique onto pure silica core (PSC) single-mode fibers. This paper details the evolution of the Bragg wavelength shifts (BWS) during the irradiation conducted at the MIT Nuclear Research Reactor.

International audience

Background Cow's milk protein allergy (CMPA) represents one of the leading causes of food allergy in infants and young children. The immune reaction may be IgE mediated, non-IgE mediated, or mixed. IgE-mediated cow's milk protein allergy is revealed by immediate and acute symptoms which can be severe. The aim of this study is to report a one centre experience in the real life of testing children with IgE-mediated CMPA and try to identify predictive factor for follow-up challenges. Method Retrospective and monocentric study between September 1997 and February 2008. 178 infants diagnosed with IgE-mediated CMPA during breastfeeding weaning were included. Initial factors such as age, sex, skin prick tests (SPTs), specific IgE (sIgE), atopic dermatitis and types of reaction were noted. Between 12 and 24 months all infants have undergone at least one evaluation including SPT. Results At the food challenge, 138 (75.8%) infants were found tolerant. Results of the skin prick test (SPT) were statistically different according to the food challenge result (2.2 mm vs. 5.1 mm, p < 0.0001). It was the same result for sIgE for CM 2.0 ku/l vs. 11.5 ku/l � p < 0.0001 and for casein 1.0 ku/l vs. 16.0 ku/l � p = 0.0014. Conclusion This study confirms the practical interest of both SPT and sIgE in the evaluation of tolerance induction in IgE-mediated CMPA, but with no corresponding results. Sensitivity, specificity and probability curves of success for cow's milk challenge can be determined and have clinical utility.

Revue Francaise d'Allergologie - In Press.Proof corrected by the author Available online since jeudi 6 mars 2014

Nuclear heating is a key parameter which contributes to the thermal design and the quality of in-pile experiments performed in Material Testing Reactors (MTRs) for the study of nuclear materials and fuels under irradiation. Nuclear heating is typically measured in MTRs by radiometric calorimeters. However this kind of sensor has to be suited and improved in perspective of the new experimental conditions inside the channels of Jules Horowitz Reactor (JHR). In this paper, we study the responses of two non adiabatic differential calorimeter cells having the same geometric design, but different dimensions. These experimental works are carried out during a preliminary out-of-pile calibration operating procedure of these sensors which consists in simulating the sample heating by Joule effect. The influence of the imposed electrical power and of the forced cooling flow is determined on the sensor calibration curves. A more sensitive sensor leads to a quadratic calibration curve. This behavior difference of the two calorimetric configurations is explained by means of temperature and heat flux measurements performed with a new instrumented jacket.

Thermal neutron flux is one of the most important nuclear parameter to be measured on-line in Material Testing Reactors (MTRs). In particular two types of sensors with different physical operating principles are commonly used: self-powered neutron detectors (SPND) and fission chambers with uranium 235 coating. This work aims to compare on one hand the thermal neutron flux evaluation given by these two types of sensors and on the other hand to compare these evaluations with activation dosimeter measurements, which are considered as the reference for absolute neutron flux assessment. This study was conducted in an irradiation experiment, called CARMEN-1, performed during 2012 in OSIRIS reactor (CEA Saclay - France). The CARMEN-1 experiment aims to improve the neutron and photon flux and nuclear heating measurements in MTRs. In this paper we focus on the thermal neutron flux measurements performed in CARMEN-1 experiment. The use of fission chambers to measure the absolute thermal neutron flux in MTRs is not very usual. An innovative calibration method for fission chambers operated in Campbell mode has been developed at the CEA Cadarache (France) and tested for the first time in the CARMEN-1 experiment. The results of these measurements are discussed, with the objective to measure with the best accuracy the thermal neutron flux in the future Jules Horowitz Reactor.

Introduction Les IgE specifiques (IgEs) dirigees contre Ana o 3 (Alb 2S) sont un bon marqueur predictif de l’allergie a la noix de cajou (NC). En les combinant aux resultats des tests cutanes (TC) et au sexe des patients, van der Valk et al. ont etabli un score predictif de l’allergie a la NC (Allergy, 2014). L’objectif de cette etude est d’appliquer ce score a notre population de patients sensibilises a la NC afin de determiner son interet en pratique clinique pour guider la realisation d’un test de provocation par voie orale (TPO). Une correlation avec la severite des reactions allergiques a egalement ete recherchee. Methodes L’etude inclut 94 dosages d’IgEs Ana o 3 de 68 patients (sex-ratio = 1,7, âge median : 9 ans) realises entre 2015 et 2017. Cinq groupes ont ete realises sur la base de l’histoire clinique allergique a la NC. Le groupe 0 comprend les patients sensibilises non allergiques. Les groupes 1, 2 et 3 comprennent ceux ayant fait une reaction respectivement de grade 1, 2 ou 3 (aucun grade 4). Le groupe 4 comprend les patients sensibilises n’ayant jamais consomme de NC. Le score predictif a ete calcule pour chaque patient avec les IgEs Ana o 3, le sexe et le TC. Pour exemple, des scores de 3 et 8 sont associes a un risque de reaction lors du TPO de 26 et 97 % respectivement. Resultats Aucune reaction severe n’a ete observee pour des scores inferieurs a 4 (3 patients dans le groupe 0, 3 dans le groupe 1). Tous les patients ayant un score ≥ 8 sont allergiques. Les moyennes des scores par groupe augmentent avec la severite de la reaction (1,5 pour le groupe 0 et 7,6 dans le groupe 3), cependant, un score eleve n’est pas toujours associe a la severite de la reaction initiale. Conclusion Beaucoup d’evictions de la NC sont realisees apres la decouverte fortuite d’une sensibilisation. Ce score predictif permettrait de mieux guider la realisation du TPO dans cette population : le TPO pourrait etre evite chez les patients ayant un score eleve (≥ 8). A l’inverse, les patients avec des scores

Rationale Xanthomatosis associated with monoclonal gammopathy includes hyperlipidaemic xanthoma (HX), normolipidaemic xanthoma (NX) and necrobiotic xanthogranuloma (NXG). All three pathologies are characterized by skin or visceral lesions related to cholesterol accumulation, monoclonal immunoglobulin (MIg) and hypocomplementemia. The pathophysiology underlying NXG remains unknown although the involvement of MIg is suspected. Objective To provide further insights into the pathophysiology of NXG, we evaluated the plasma lipid phenotype, mechanisms involved in cellular cholesterol accumulation and role of MIg in an analysis of blood and plasma markers of inflammation in 16 patients with xanthomatosis [NXG (n = 8) and NX (n = 8)] associated with monoclonal IgG relative to the relevant controls. Results The lipid profile of patients with NXG was characterized by a low HDL-C phenotype and an abnormal distribution of HDL particles. Sera from patients with NXG induced cholesterol accumulation in human macrophages. This accumulation was due in part to a significant reduction in the HDL capacity to promote cholesterol efflux from macrophages, which was not found in the case of NX. The MIg of NXG and NX patients was tested positively by ELISA to recognize a large spectrum of lipoproteins. High plasma levels of pro-inflammatory cytokines (TNFα and IL-6), soluble cytokine receptors (sIL-6R, sTNFRI and sTNFRII), adhesion molecules (VCAM-1 and ICAM-1) and chemokines (MCP-1, IL-8 and MIP-1α) were observed in both patients with NXG and NX, revealing a specific xanthoma inflammatory signature which was inversely correlated with plasma levels of anti-inflammatory HDL. However, patients with NXG were distinguished by elevated levels of IL-15 and a marked increase in the rate of intermediate CD14++CD16+ monocytes. Conclusion This study revealed that NXG is characterized by impaired macrophage lipid homeostasis associated with a systemic inflammatory profile that may result from the interaction of MIg and lipoproteins.

Nuclear heating measurements in Material Testing Reactors (MTR) are crucial for the design of the experimental devices and the prediction of the temperature of the hosted samples. Nuclear heating in MTR materials (except fuel) is mainly due to the energy deposition by the photon flux. Therefore, the photon flux is a key input parameter for the computer codes which simulate nuclear heating and temperature reached by samples/devices under irradiation. In the Jules Horowitz MTR under construction at the CEA Cadarache, the maximal expected nuclear heating levels will be about 15 to 18 W g −1 and it will be necessary to assess this parameter with the best accuracy. An experiment was performed at the OSIRIS reactor to combine neutron flux, photon flux and nuclear heating measurements to improve the knowledge of the nuclear heating in MTR. There are few appropriate sensors for selective measurement of the photon flux in MTR even if studies and developments are ongoing. An experiment, called CARMEN-1, was conducted at the OSIRIS MTR and we used in particular a gas ionization chamber based on miniature fission chamber design to measure the photon flux. In this paper, we detail Monte-Carlo simulations to analyze the photon fluxes with ionization chamber measurements and we compare the photon flux calculations to the nuclear heating measurements. These results show a good accordance between photon flux measurements and nuclear heating measurement and allow improving the knowledge of these parameters.

In the framework of the Joint Instrumentation Laboratory (LCI), gathering resources from SCK-CEN (Belgium) and CEA (France), we are developing an optical sensor in order to accurately measure radiation-induced elongation of material placed in the core of a Material Testing Reactor (MTR). This extensometer displays common advantages of Fibre Optic (FO) sensors: high resolution, easy remote sensing and multiplexing, and also compact size which is of particular interest for in pile experiments with little room available. In addition, light weight reduces gamma heating hence limiting the thermal effect. In accordance with the specifications, the sensor has preferably two fixing points defining a gauge length of 10 to 15 mm (as a minimum). The diameter is less than 2 mm. Intense gamma and neutron irradiation as well as high temperatures are the most difficult environment conditions to withstand. Reactor radiation produces huge losses in common optical fibre. The losses can be limited by selecting the fibres (mainly with high purity silica core), the wavelength range (800–1200nm), and a measurement based on interferometry (largely insensitive to losses in the fibre thanks to the wavelength encoding of the useful signal). Heavy neutron — mainly — and gamma flux such as in MTR, also produce compaction of silica, resulting in a significant drift and preventing the use of commercial FO sensors in such environment. Knowing this issue we revised the basic scheme of Extrinsic Fabry Perot Interferometer (EFPI) in order to limit the effects of compaction. A first sensor prototype fixed on a stainless steel support was tested in the Smirnof test facility in the BR2 MTR in Mol (Belgium). The support was subject to a constant mechanical and thermal stress, and his dimensions were not supposed to vary. This test showed a very low drift of the revisited EPFI design under high irradiation field in comparison with a commercial EFPI. This result has to be confirmed with second generation sensors with an increased robustness. The other difficulty to face is high temperature. Fibre optics with metal coating allows safe operation under temperatures up to 400°C and even higher. But differential dilatation between silica and typical metallic material produces differential elongation in the range of 0.5 10–2 i.e 5000μe for an increase in temperature of 300–400°C. Such large elongation has to be considered carefully in the sensor design and its fixing on the sample. Laboratory tests with a second generation of adapted sensors demonstrated their good accuracy: less than 1% error over a displacement of 100μm (< 1 μm error), at room temperature. The displacement measured can reach 250μm (20000μe with a gauge length of 12.5 mm) or more. We are currently implementing metal-coated fibre and we are preparing the next in pile irradiation on the BR2 reactor scheduled for mid-2011. Other applications of the sensor can be considered.

Objectives To identify key determinants of plasma endogenous CETP activity and threshold value of plasma CETP activity associated with high cardiovascular risk. Methods Endogenous plasma CETP activity was measured in a total of 1403 individuals. Results Multivariate analysis revealed that 23.5% of endogenous CETP activity variability was explained by plasma LDL-C (12.0%), HDL-C (6.4%) and TG (4.4%) whereas sex and BMI accounted together for only 0.7% of its variability. Scoring patients for cardiovascular risk on the basis of their plasma lipid levels (TC, TG, LDL-C and HDL-C), revealed that patients with high cardiovascular risk (score ≥3) displayed a mean endogenous plasma CETP activity above 34%. Conclusion Plasma CETP activity represents a potent indicator of cardiovascular risk in patients with metabolic disorders since it integrates major independent risk factors.

Since 2012, clinical trials dedicated to proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies (mAbs) have unambiguously demonstrated robust reductions not only in low-density lipoprotein (LDL) cholesterol (LDL-C) but also in lipoprotein (a) [Lp(a)] levels. The scientific literature published prior to those studies did not provide any evidence for a link between PCSK9 and Lp(a) metabolism. More recent investigations, either in vitro or in vivo, have attempted to unravel the mechanism(s) by which PCSK9 mAbs reduce circulating Lp(a) levels, with some showing a specific implication of the LDL receptor (LDLR) in Lp(a) clearance whereas others found no significant role for the LDLR in that process. This elusive pathway appears clearly distinct from that of the widely prescribed statins that also enhance LDLR function but do not lower circulating Lp (a) levels in humans. So how does PCSK9 inhibition with mAbs reduce Lp(a)? This still remains to be established.

Neutron and gamma flux levels are key parameters in nuclear research reactors. In Material Testing Reactors, such as the future Jules Horowitz Reactor, under construction at the French Alternative Energies and Atomic Energy Commission (CEA Cadarache, France), the expected gamma flux levels are very high (nuclear heating is of the order of 20 W/g at 100 MWth). As gamma rays deposit their energy in the reactor structures and structural materials it is important to take them into account when designing irradiation devices. There are only a few sensors which allow measurements of the nuclear heating [12]; a recent development at the CEA Cadarache allows measurements of the gamma flux using a miniature ionization chamber (MIC) [3]. The measured MIC response is often compared with calculation using modern Monte Carlo (MC) neutron and photon transport codes, such as TRIPOLI-4 and MCNP6. In these calculations only the production of prompt gamma rays in the reactor is usually modelled thus neglecting the delayed gamma rays. Hence calculations and measurements are usually in better accordance for the neutron flux than for the gamma flux. In this paper we study the contribution of delayed gamma rays to the total MIC signal in order to estimate the systematic error in gamma flux MC calculations. In order to experimentally determine the delayed gamma flux contributions to the MIC response, we performed gamma flux measurements with CEA developed MIC at three different research reactors: the OSIRIS reactor (MTR — 70 MWth at CEA Saclay, France), the TRIGA MARK II reactor (TRIGA — 250 kWth at the Jozef Stefan Institute, Slovenia) and the MARIA reactor (MTR — 30 MWth at the National Center for Nuclear Research, Poland). In order to experimentally assess the delayed gamma flux contribution to the total gamma flux, several reactor shut down (scram) experiments were performed specifically for the purpose of the measurements. Results show that on average about 30 % of the MIC signal is due to the delayed gamma rays. In this paper we describe experiments in each of the three reactors and how we estimate delayed gamma rays with MIC measurements. The results and perspectives are discussed.

International audience; In the field of nuclear research, the measurement and knowledge of nuclear heating are of crucial importance to carry out accurate studies of the accelerated ageing of materials and the behavior of nuclear fuels under irradiation with precisely imposed temperature conditions. Nuclear heating can be quantified with a differential calorimeter by using in-pile temperature measurements and the preliminary out-of-pile calibration curves of each calorimetric cell. This paper focuses on experimental studies of two new calorimetric cell prototypes developed to test the influence of the Joule effect heating of specific cell body areas on the out-of-pile-calibration curves. The calibration curves are determined, discussed for different applied internal/external thermal conditions, and compared to irradiation data obtained with the CARMEN-1P type calorimeter used in the OSIRIS reflector.

Objective— The physiological function of the ATP–binding cassette G1 (ABCG1) transporter in humans is not yet elucidated, as no genetic disease caused by ABCG1 mutations has been documented. The goal of our study was, therefore, to investigate the potential role(s) of ABCG1 in lipid metabolism in humans. Methods and Results— Here we report that among the 104 polymorphisms present in the ABCG1 gene, the analysis of the frequent functional rs1893590 and rs1378577 single nucleotide polymorphisms located in the regulatory region of ABCG1 in the Regression Growth Evaluation Statin Study population revealed that both ABCG1 single nucleotide polymorphisms were significantly associated with plasma lipoprotein lipase (LPL) activity. Moreover, we observed that plasma LPL activity was modestly reduced in Abcg1 −/− mice as compared with control mice. Adipose tissue and skeletal muscle are the major tissues accounting for levels and activity of plasma LPL in the body. However, beyond its lipolytic action in the plasma compartment, LPL was also described to act locally at the cellular level. Thus, macrophage LPL was reported to promote foam cell formation and atherosclerosis in vivo. Analysis of the relationship between ABCG1 and LPL in macrophages revealed that the knockdown of ABCG1 expression (ABCG1 knockdown) in primary cultures of human monocyte–derived macrophages using small interfering RNAs led to a marked reduction of both the secretion and activity of LPL. Indeed, LPL was trapped at the cell surface of ABCG1 knockdown human monocyte–derived macrophages, likely in cholesterol-rich domains, thereby reducing the bioavailability and activity of LPL. As a consequence, LPL–mediated lipid accumulation in human macrophage foam cells in the presence of triglyceride-rich lipoproteins was abolished when ABCG1 expression was repressed. Conclusion— We presently report that ABCG1 controls LPL activity and promotes lipid accumulation in human macrophages in the presence of triglyceride-rich lipoproteins, thereby suggesting a potential deleterious role of macrophage ABCG1 in metabolic situations associated with high levels of circulating triglyceride-rich lipoproteins together with the presence of macrophages in the arterial wall.

Objective To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspecies to promote key steps of the reverse cholesterol transport pathway. Methods The capacity of HDL particles to mediate cellular free cholesterol efflux and selective hepatic uptake of cholesteryl esters was evaluated throughout postprandial phase (0–8h) following consumption of a standardised mixed meal before and after treatment for 6 weeks with atorvastatin alone (10mg/d) and subsequently with combination torcetrapib/atorvastatin (60/10mg/d) in 16 patients displaying low HDL-C levels ( Results The larger HDL2b and HDL2a subfraction displayed a superior capacity to mediate cellular free cholesterol efflux via both SR-BI and ABCG1-dependent pathways than smaller HDL3 subspecies. CETP inhibition specifically enhanced the capacity of HDL2b subfraction for both SR-BI and ABCG1 dependent efflux. However, only the SR-BI-dependent efflux to HDL2b subspecies can be further enhanced during postprandial lipemia following CETP inhibition. Concomitantly, postprandial lipemia was associated with a reduced capacity of total HDL particles to deliver cholesteryl esters to hepatic cells in a drug independent manner. Conclusion CETP inhibition specifically improves postprandial SR-BI and ABCG1-dependent efflux to larger HDL2b subspecies. In addition, CETP inhibition improves HDL-CE delivery to hepatic cells and maintains an efficient direct return of cholesteryl esters to the liver during postprandial lipemia.

The effects of nuclear radiations on conventional thermocouples (type K, C and N) mainly used in irradiation experiments may create significant drifts of the signals. In order to solve these difficulties, the Commissariat a l'Energie Atomique has started to develop and qualify in laboratory conditions a miniature device, which combines a noise thermometer and thermocouples, for a future application in a research reactor. In this paper, a particular approach of a combined noise thermometer-thermocouples is described. Present measurements, based on a correlation and comparison method, are realized in laboratory at 300°C which represents the mean temperature in materials irradiation experiments. Referred measurement uncertainties are lower than ±1.5°C corresponding to the accuracy tolerance of conventional thermocouples at this temperature.

Optimizing the life cycle of nuclear systems under safety constraints requires high-performance experimental programs to reduce uncertainties on margins and limits. In addition to improvement in modeling and simulation, innovation in instrumentation is crucial for analytical and integral experiments conducted in research reactors.Significant efforts have been made recently to improve in-pile instrumentation for the benefit of material testing reactors. The quality of nuclear research programs obviously relies on an excellent knowledge of their experimental environment, which constantly calls for better online determination of neutron and gamma flux. But the combination of continuously increasing scientific requirements and new experimental domains—brought, for example, by Generation-IV programs—also necessitates major innovations for in-pile measurements of temperature, dimensions, pressure, or chemical analysis in innovative mediums.To face these challenges, the CEA (French Nuclear Energy Commiss...

Introduction L’induction de tolerance par voie orale (ITO) a l’arachide, a montre des resultats prometteurs ces dernieres annees dans la prise en charge de l’allergie a l’arachide. Nous avons realise une etude monocentrique pediatrique cherchant a evaluer l’efficacite et la tolerance d’un protocole d’ITO a l’arachide adapte a la vie reelle. Methodes Consommation quotidienne de doses croissantes d’arachide, avec des aliments du commerce contenant de l’arachide, selon un tableau d’equivalence de doses, pour varier la source d’arachide et eviter la lassitude. L’augmentation de dose est determinee par la dose cumulee reactogene (DCR) ou toleree (DCT) lors du test de provocation orale (TPO) initial. Realisation d’un TPO tous les 6 mois, pour determiner une nouvelle DCR ou DCT et poursuivre l’augmentation de la dose d’arachide consommee quotidienne (DACQ) sans depasser 80 % de cette DCR/DCT. L’efficacite a ete evaluee sur l’augmentation de la DACQ, et la tolerance sur les accidents allergiques presentes et un questionnaire de satisfaction. Le profil immunologique (test cutane [TC] a l’arachide, ratio IgG4/IgE specifiques de l’arachide) de chaque enfant est mesure initialement, puis a chaque TPO. Resultats Cent trente enfants allergiques a l’arachide de 2,5 a 17,5 ans ont suivi ce protocole. Cent dix-sept sur 130 (90 %) ont augmente significativement leur DACQ d’une mediane de 16 mg a 337,5 mg d’arachide sur 10,5 mois (en mediane), p Discussion/Conclusion Notre protocole d’ITO a l’arachide apparait efficace, securise, adapte a la vie reelle, et satisfaisant pour la plupart des patients.

In the final objective of elaborating an optical sensor of dimensional change in a nuclear testing reactor, we present extreme high level irradiation tests, up to 1.3 1020 nfast/cm2 and 16 GGy, conducted on high purity silica and hollow core photonic bandgap (PBG) fibers. These tests are performed in the OSIRIS reactor at CEA Saclay. We measure continuously radiation induced absorption (RIA), at 3 optical wavelengths: 980 nm, 1064 nm and 1310 nm. The evolution with the time of the spectral dependency over larger wavelength range is also reported. As well as reporting RIA up to higher dose than presented before, we demonstrate here the excellent superiority of hollow core PBG fibers over their conventional counterparts in term of radiation resistance up to over 1020nfast/cm2 and 10 GGy. We also report some optical time domain reflectometry (OTDR) measurements that probe the irradiated parts of the fibers and show a back scattering peak which appears, widens spatially then duplicates. We provide an interpretation based on the change of silica when it turns to metamict phase.

Many irradiation experiments performed in research reactors are used to assess the effects of nuclear radiations on material or fuel sample properties, and are therefore a crucial stage in most qualification and innovation studies regarding nuclear technologies. However, monitoring these experiments requires accurate and reliable instrumentation. Among all measurement systems implemented in irradiation devices, temperature—and more particularly high-temperature (above 1000°C)—is a major parameter for future experiments related, for example, to the Generation IV International Forum (GIF) Program or the International Thermonuclear Experimental Reactor (ITER) Project. In this context, the French Commissariat a l’Energie Atomique (CEA) develops and qualifies innovative in-pile instrumentation for its irradiation experiments in current and future research reactors. Logically, a significant part of these research and development programs concerns the improvement of in-pile high-temperature measurements. This article describes the development and qualification of innovative high-temperature thermocouples specifically designed for in-pile applications. This key study has been achieved with technical contributions from the Thermocoax Company. This new kind of thermocouple is based on molybdenum and niobium thermoelements, which remain nearly unchanged by thermal neutron flux even under harsh nuclear environments, whereas typical high-temperature thermocouples such as Type C or Type S are altered by significant drifts caused by material transmutations under the same conditions. This improvement has a significant impact on the temperature measurement capabilities for future irradiation experiments. Details of the successive stages of this development are given, including the results of prototype qualification tests and the manufacturing process.

We report on the case of a young infant with chronic diarrhea that worsened and turned into hypovolemic shock with methemoglobinemia. We underline and discuss the main features of food protein-induced enterocolitis syndrome (FPIES). FPIES is a non-IgE-mediated food allergy involving tumor necrosis factor-alpha (TNF-α). Many triggering foods exist but cow's milk, as in the case reported herein, is one of the most frequent. It can start early or be delayed and start around the average age of 5 months. Symptoms are nonspecific with diarrhea and vomiting, but in the presence of methemoglobinemia, the diagnosis must be seriously considered. The oral food challenge remains the gold standard to confirm the diagnosis if there is still a doubt. Treatment of FPIES associates emergency treatment of acute dehydration with the prevention of relapses by avoiding the suspected protein.

The nuclear heating measurements in Material Testing Reactors (MTRs) are crucial for the study of nuclear materials and fuels under irradiation. The reference measurements of this nuclear heating are especially performed by a differential calorimeter including a graphite sample material. Then these measurements are used for other materials, other geometries, or other experimental conditions in order to predict the nuclear heating and thermal conditions induced in the irradiation devices. This paper will present new simulations with MCNP Monte-Carlo transport code to determine the gamma heating profile inside the calorimeter. The whole complex geometry of the sensor has been considered. We use as an input source in the model, the photon spectra calculated in various positions of CARMEN-1 irradiation program in OSIRIS reactor. After a description of the differential calorimeter device, the MCNP modeling used for the calculations of radial profile of nuclear heating inside the calorimeter elements will be introduced. The obtained results of different simulations will be detailed and discussed in this paper. The charged particle equilibrium inside the calorimeter elements will be studied. Then we will focus on parametric studies of the various components of the calorimeter. The influence of source type will be also took into account. Moreover the influence of the material used for the sample will be described.

International audience; The Fukushima-Daiichi nuclear disaster showed that the need for safety must always prevail. This paper discusses the development of remote monitoring technologies to improve Nuclear Power Plants (NPPs) safety, in operation (Pressurized Water Reactors), under construction (the EPR reactors, i.e. the GEN 3 PWR), or for any other next generations of reactors. At Fukushima, the total loss of electrical power supplies has quickly led most of the instrumentation inoperative and the operator (TEPCO) with no way to monitor the status and the evolution of the accident. To overcome these important drawbacks, advantage can be taken from the considerable potential of distributed sensing technologies based on both "Optical Fiber Sensors" (Raman, Brillouin, and Rayleigh Reflectometries) and long-length "Self Powered Neutron Detectors" (SPNDs). The goal consists in inquiring about the status of the third barrier of confinement and to define possible mitigation strategies in case of severe accident, namely: i) reactor pressure vessel breakthrough and corium relocation outside the vessel, ii) concrete basemat erosion and iii) corium cooling. Such monitoring should consist in "sensing cables" embedded in concrete basemat below the reactor vessel and interrogated from a rear base where operators can work safely. In this context, DISCOMS, which stands for "DIstributed Sensing for COrium Monitoring and Safety", is a five-year project, managed by the French National Research Agency (ANR), dealing with the NPP safety improvement, from normal situation to severe accidents. Monitoring phases include reactor vessel breaching, corium flow, along with post-accidental period (corium cooling ex-vessel). Thus, optical fibers selected for their resistance to ionizing radiations and long length SPNDs, both judiciously deployed within the reactor concrete basemat, and the structures around it, will provide a useful real-time or on-demand monitoring, in normal operation, and more important in accidental and post-accidental situations.