Etude du radon et du thoron par collection électrostatique et par spectrométrie gamma dans le cadre de l'expérience NEMO de décroissance double bêta

Ce travail s insère dans le cadre de l expérience NEMO cherchant à mettre en évidence une radioactivité extrêmement rare : la double désintégration bêta sans émission de neutrino et par suite d obtenir des informations sur la nature Dirac-Majorana et sur la masse du neutrino. La particularité de cette expérience actuellement en fin de prise de données au Laboratoire Souterrain de Modane est l extrême rareté du signal recherché (T1/2 > 1024 ans, quelques événements par an). Il s ensuit donc des conditions très contraignantes sur toutes les composantes du bruit de fond, et parmi celles-ci sur les niveaux de radon et de thoron. Après quelques rappels sur les propriétés du radon et du thoron et leur influence sur les données de l expérience NEMO, ce travail de thèse a porté sur la détection de ces gaz radioactifs par la technique de collection électrostatique des descendants sur la surface d une diode silicium et la détection des alpha émis. Nous avons montré que les rendements de détection sont fortement influencés par les conditions expérimentales et que le niveau de radon pouvait être contrôlé actuellement au niveau du mBq/m3. Une série des mesures de spectrométrie gamma nous a permis de comprendre l origine du bruit de fond du détecteur de radon, et ainsi d envisager dans l avenir un gain en sensibilité en augmentant le volume de détection et en effectuant une sélection très poussée des matériaux non radioactifs. Par contre, pour le thoron, qui n avait jamais été étudié jusqu à présent, les efficacités de détection sont très faibles à cause des périodes courtes mises en jeu. Un monitorage continu du thoron dans le gaz de NEMO est donc exclu, ce qui souligne l importance pour l expérience NEMO que le dispositif expérimental puisse contrôler son propre bruit de fond.This work is part of the NEMO (Neutrino Ettore Majorana Observatory) experiment that is looking for an extremely rare radioactivity: the double beta decay without neutrino emission. Such process could prove the Majorana nature of the neutrino and could give an estimation of its absolute mass. The particularity of this experiment, currently running in the Modane underground laboratory (LSM), is the extreme weak signal (for T1/2 ~ 1024 years, a few events per year). It requires therefore very stringent conditions on all components of the background among which the level of radon and thoron activity. After a reminding of the general properties of radon and thoron as well as their influence on the NEMO data, this thesis focuses on the detection of these radioactive gases using the technique of electrostatic collection. The radon and/or the thoron daughters are collected by an electrostatic field on the surface of a silicon diode, where their characteristic alphas are detected. We have shown that the detection efficiencies are strongly influenced by the experimental conditions and that sensitivity around 1 mBq/m3 can be achieved for the radon in a gas. A series of measures through low background gamma spectrometer allowed us to understand the origin of the radon background, and thus showing that better sensitivity could be obtained by increasing the detection volume and by carrying out a strict selection of non-radioactive materials. For the thoron gas, which had never been studied before, the detection efficiencies have been found very low as a consequence of the short periods involved. Therefore, a continuous monitoring of the level of thoron in the NEMO gas is excluded, which underlines the importance for the NEMO experimental device to be able to control its own background.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Factor VIII assays in treated hemophilia A patients

International audienceReplacement therapy with plasma-derived or recombinant FVIII (pdFVIII or rFVIII) concentrates is the standard of treatment in patients with hemophilia A. The reference method used for measuring factor VIII (FVIII:C) levels in patients treated by FVIII concentrates is the chromogenic substrate assay (CSA). However, the one-stage clotting assay (OSA) is predominantly used in current clinical practice, but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FVIII recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network) presents a review of the literature and proposals for the monitoring of FVIII:C levels in treated hemophilia A patients. The use of CSA calibrated with a plasma reference tested against the current FVIII WHO (World Health Organization) International Standard is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. OSA are adequate for the monitoring of patients treated with pdFVIII or with most of rFVIII concentrates. However, preliminary comparison with CSA is mandatory before measuring FVIII:C by OSA in patients treated by Refacto AF®. For rFVIII-EHL, OSA are only acceptable for Elocta®. Great caution is therefore required when measuring FVIII:C levels by OSA in patients substituted by other EHL-rFVIII. Indeed, most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients

Factor IX assays in treated hemophilia B patients

International audienceReplacement therapy with plasma-derived or recombinant FIX (pdFIX or rFIX) concentrates is the standard of treatment in patients with hemophilia B. The method predominantly used for measuring factor IX (FIX:C) levels is the one-stage clotting assay (OSA) but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FIX recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network), presents a review of the literature and proposals for the monitoring of FIX:C levels in treated hemophilia B patients. The use of OSA calibrated with a plasma reference tested against the current FIX WHO International Standard is recommended for the monitoring of patients treated with pdFIX or rFIX. Chromogenic substrate assays (CSA) are adequate for the monitoring of patients treated with Rixubis®, but data available for Benefix® are currently too limited. For extended half-life rFIX (EHL-rFIX), large discordances in the FIX:C levels measured were evidenced, depending on the method and reagents used. Great attention is therefore required for measuring FIX:C levels by OSA in patients substituted by EHL-rFIX. Commercial kits for CSA are not equivalent, and although potentially useful, they are not validated for all EHL-rFIX. Most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients

Preactivated Oxazaphosphorines Designed for Isophosphoramide Mustard Delivery as Bulk Form or Nanoassemblies: Synthesis and Proof of Concept

International audienceOxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several O- and S-alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4-hydroxy-IFO from these preactivated IFO analogues in plasma are reported

Multicentre evaluation of CK Prest ® for assaying plasma levels of factor IX fused with albumin (Idelvion ® )

International audienc

Preactivated Oxazaphosphorines Designed for Isophosphoramide Mustard Delivery as Bulk Form or Nanoassemblies: Synthesis and Proof of Concept

Oxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several <i>O-</i> and <i>S-</i>alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4-hydroxy-IFO from these preactivated IFO analogues in plasma are reported

SARS-CoV-2 neutralising antibody testing in Europe:Towards harmonisation of neutralising antibody titres for better use of convalescent plasma and comparability of trial data

We compared the performance of SARS-CoV-2 neutralising antibody testing between 12 European laboratories involved in convalescent plasma trials. Raw titres differed almost 100-fold differences between laboratories when blind-testing 15 plasma samples. Calibration of titres in relation to the reference reagent and standard curve obtained by testing a dilution series reduced the inter-laboratory variability ca 10-fold. The harmonisation of neutralising antibody quantification is a vital step towards determining the protective and therapeutic levels of neutralising antibodies