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ABSTRACTBackground: Epigenetic markers are often quantified and related to disease in stored samples. While, effects of storage on stability of these markers have not been thoroughly examined. In this longitudinal study, we investigated the influence of storage time, material, temperature, and freeze-thaw cycles on stability of global DNA (hydroxy)methylation. Methods: EDTA blood was collected from 90 individuals. Blood (n = 30, group 1) and extracted DNA (n = 30, group 2) were stored at 4°C, −20°C and −80°C for 0, 1 (endpoint blood 4°C), 6, 12 or 18 months. Additionally, freeze-thaw cycles of blood and DNA samples (n = 30, group 3) were performed over three days. Global DNA methylation and hydroxymethylation (mean ± SD) were quantified using liquid chromatography–electrospray ionization–tandem mass spectrometry (LC-ESI-MS/MS) with between-run precision of 2.8% (methylation) and 6.3% (hydroxymethylation). Effects on stability were assessed using linear mixed models. Results: global DNA methylation was stable over 18 months in blood at −20°C and −80°C and DNA at 4°C and −80°C. However, at 18 months DNA methylation from DNA stored at −20°C relatively decreased −6.1% compared to baseline. Global DNA hydroxymethylation was more stable in DNA samples compared to blood, independent of temperature (p = 0.0131). Stability of global DNA methylation and hydroxymethylation was not affected up to three freeze – thaw cycles. Conclusion: Global DNA methylation and hydroxymethylation stored as blood and DNA can be used for epigenetic studies. The relevance of  small differences occuring during storage depend on the expected effect size and research question.

The scaphoid is the most common non-union site in the wrist. Fixation with vascularised or non-vascularised autograft is the gold standard when it comes to treating these non-unions. But, what can we offer if the autograft fails? Using osteoinductive proteins in difficult cases of long bone non-union yields good results. However, only a few studies have been published on their use for scaphoid non-union. In our study, five patients with an average age of 32 years (ranging from 21 to 44 years) with old non-union (more than 24 months) of the scaphoid were treated after autograft treatment had failed. The procedure consisted of reaming the non-union site, then adding bone autograft combined with BMP-7 (Osigraft®) in the defect and fixing it all with a screw or K-wire. Postoperative immobilisation was prescribed. Only one patient achieved bone union (20%) despite an average follow-up of 10 years (80–143 months). The average flexion-extension loss was 16.6° (0–30) relative to the contralateral side. The average strength deficit was 450 grams (0–2000) for pinch and 12.1kg (0–29) for grip compared to the contralateral side. Self-assessment questionnaires had an average PRWE at 28.9 (10.5–49) and an average QuickDASH at 28.6 (9.09–61.36). Our study could not demonstrate any real benefit of using BMP-7 for treating old scaphoid non-union despite an elevated cost. Further research is needed to look at other treatment approaches, for instance, the use of new scaffolds combining VEGF and BMP.

La formation médicale continue (FMC) est une obligation déontologique et légale en France. L’évaluation des pratiques professionnelles (EPP) a rejoint en 2004 l’obligation d’acquisition des connaissances pour devenir le développement professionnel continu (DPC) en 2009. Actuellement, le dispositif est complet : définition, organisation et validation. Mais l’obligation individuelle pour valider le DPC n’a jamais été appliquée. La recertification prévue par la loi de 2019 ne sera opérationnelle qu’en 2021, au plus tôt. Son pilier essentiel est le DPC. La mission de recertification qui a préparé la loi exclut toutes épreuves de vérification des connaissances. La recertification se fait par une valorisation du parcours professionnel comprenant, outre le DPC, une activité maintenue et régulière, une amélioration de la relation avec le patient, la prise en compte de la santé du médecin et l’absence d’évènements indésirables. L’Ordre veillant sur la compétence des médecins, c’est lui qui reçoit la validation du DPC, comme il recevra celle de la recertification.

There are very few published studies describing the treatment of segmental bone defects of the forearm using the induced membrane technique. The objectives of this study were to evaluate the time to bone union, the function of the joints above and below the treated bone segment and the patients’ quality of life over the long-term. We performed a retrospective study in all patients treated by the induced membrane for a forearm bone defect over at 13-year period. Demographics, bone union, complications, functional outcomes and occupational status were collected. Six patients were included: 2 posttraumatic injuries, 1 osteomyelitis, 1 septic arthritis, 1 aseptic nonunion, 1 tumor. The average defect length was 64mm (48–110). All defects were treated with internal fixation. Bone graft was harvested from the iliac crest in two patients, the femur (using the Reamer Irrigator Aspirator technique) in three patients and the radius in one patient. Five patients achieved bone union after a mean of 4months (3–6). Three complications were observed: 1 radioulnar instability, 1 infection of the fixation device, 1 abscess. At an average 8½ years’ follow-up, the pain level on the VAS was 0.6 (0–3), the Mayo Elbow Performance Score was 98 (90–100), the Herzberg score was 108 (85.6–140) and the QuickDASH was 14.9 (2.7–35). All patients returned to work. Using the induced membrane technique avoids the complications associated with vascularized autograft and yields good functional outcome and quality of life.

La sinistralité en chirurgie viscérale constitue un sujet préoccupant et sa fréquence augmente régulièrement. Le but de cette étude est de réaliser au sein d’un groupe de 50 chirurgiens un état des lieux avec comparaison de 2 groupes francophones. Il s’agit d’une étude rétrospective descriptive réalisée depuis l’installation des 50 chirurgiens jusqu’au 31 décembre 2014. Les données principales répertoriées étaient le nombre, les motifs, les résultats des plaintes et les juridictions concernées. Quarante-trois chirurgiens ont participé à cette étude. Dans le groupe « français », 200 plaintes ont été analysées. Le nombre moyen de plainte était de 5,8 par chirurgien. Les interventions chirurgicales les plus exposées ont été la chirurgie bariatrique, la chirurgie colo-rectale et la chirurgie pariétale. Aucune faute n’a été retrouvée dans 69,5 % des cas. Quarante-six fautes ont été notées et représentent 23 % des plaintes). Les motifs principaux des plaintes étaient : infection nosocomiale, fistule anastomotique mauvaise prise en charge postopératoire, perforation d’un organe creux, complication neurologique périphérique, information préopératoire insuffisante. Quarante-quatre pour cent des plaintes ont été analysées par la commission de conciliation et d’indemnisation (CCI) et 43,5 % par le tribunal de grande instance (TGI). Dans le groupe « francophone », il a été retrouvé 13 plaintes dont seules 2 ont fait l’objet d’une indemnisation. Les chirurgiens français sont très exposés aux plaintes : pour le droit français, une maladresse est considérée comme une faute et le patient doit être informé en préopératoire de tout risque grave d’un acte médical. En Belgique, les complications exceptionnelles sont des aléas thérapeutiques. Le respect des recommandations données par la haute autorité de santé (HAS) et les sociétés savante et l’accréditation par l’HAS des chirurgiens français doivent permettre de diminuer les événements indésirables liés aux soins et la sinistralité.

Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders, is caused by mutations in the ABCC6gene encoding a putative efflux transporter ABCC6. It was recently shown that the absence of ABCC6-mediated adenosine triphosphate release from the liver and, consequently, reduced inorganic pyrophosphate levels underlie the pathogenesis of PXE. Given that tissue-nonspecific alkaline phosphatase (TNAP), encoded by ALPL, is the enzyme responsible for degrading inorganic pyrophosphate, we hypothesized that reducing TNAP levels either by genetic or pharmacological means would lead to amelioration of the ectopic mineralization phenotype in the Abcc6–/–mouse model of PXE. Thus, we bred Abcc6–/–mice to heterozygous Alpl+/–mice that display approximately 50% plasma TNAP activity. The Abcc6–/–Alpl+/–double-mutant mice showed 52% reduction of mineralization in the muzzle skin compared with the Abcc6–/–Alpl+/+mice. Subsequently, oral administration of SBI-425, a small molecule inhibitor of TNAP, resulted in 61% reduction of plasma TNAP activity and 58% reduction of mineralization in the muzzle skin of Abcc6–/–mice. By contrast, SBI-425 treatment of Enpp1mutant mice, another model of ectopic mineralization associated with reduced inorganic pyrophosphate, failed to reduce muzzle skin mineralization. These results suggest that inhibition of TNAP might provide a promising treatment strategy for PXE, a currently intractable disease.

Autoantibodies of the IgG class against N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together over 5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-autoantibody seroprevalence with comparable immunoglobulin class and titer distribution across health and disease. The key question therefore is to understand the properties of these autoantibodies, also in healthy carriers, in order to assess secondary complications and possible contributions to neuropsychiatric disease. Here, we believe we provide for human NMDAR1-autoantibodies the first comprehensive analysis of their target epitopes and functionality. We selected sera of representative carriers, healthy or diagnosed with very diverse conditions, that is, schizophrenia, age-related disorders like hypertension and diabetes, or anti-NMDAR encephalitis. We show that all positive sera investigated, regardless of source (ill or healthy donor) and immunoglobulin class, provoked NMDAR1 internalization in human-induced pluripotent stem cell-derived neurons and reduction of glutamate-evoked currents in NR1-1b/NR2A-expressing Xenopus oocytes. They displayed frequently polyclonal/polyspecific epitope recognition in the extracellular or intracellular NMDAR1 domains and some additionally in NR2A. We conclude that all circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased blood–brain–barrier permeability.

Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context. We report a retrospective case control study comparing a CNI to belatacept switch in 17 patients with vascular damage and low eGFR to a control group of 18 matched patients with CNI continuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2–198 months). There was no difference between the two groups regarding eGFR at inclusion, and 3 months before inclusion. In the “CNI to belatacept switch group,” mean eGFR increased significantly from 23.5 ± 6.7 mL/min/1.73m2on day 0, to 30.4 ± 9.1 mL/min/1.73 m2on month 6 (p < 0.001) compared to the control group, in which no improvement was observed. These results were still significant on month 12. Two patients experienced biopsy-proven acute rejection. One was effectively treated without belatacept discontinuation. Two patients needed belatacept discontinuation for infection. In conclusion, the remplacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR.

Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context. We report a retrospective case control study comparing a CNIto belatacept switch in 17 patients with vascular damage and low eGFRto a control group of 18 matched patients with CNIcontinuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2–198 months). There was no difference between the two groups regarding eGFRat inclusion, and 3 months before inclusion. In the “CNIto belatacept switch group,” mean eGFRincreased significantly from 23.5 ± 6.7 mL/min/1.73m2on day 0, to 30.4 ± 9.1 mL/min/1.73 m2on month 6 (p < 0.001) compared to the control group, in which no improvement was observed. These results were still significant on month 12. Two patients experienced biopsy‐proven acute rejection. One was effectively treated without belatacept discontinuation. Two patients needed belatacept discontinuation for infection. In conclusion, the remplacement of CNIwith belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR. Replacement of calcineurin inhibitors with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR compared with an ongoing conventional strategy with calcineurin inhibitors.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0) >3 μg/L; group B had no change in TacER dose (TacER C07–12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0should be maintained >7 μg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended‐release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid‐free KTRswere randomized (1:1) after 4 mo: Group A had a 50% reduction in TacERdose with a targeted TacER trough level (C0) >3 μg/L; group B had no change in TacERdose (TacER C07–12 μg/L). The primary outcome was estimated GFRat 1 year. Of 300 patients, the intent‐to‐treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFRwas similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti‐HLAdonor‐specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0should be maintained >7 μg/L during the first year after transplantation in low‐immunological‐risk, steroid‐free KTRsreceiving a moderate dose of mycophenolic acid. This randomized clinical trial compares two different doses of extended‐released tacrolimus 4 months after kidney transplantation in stable steroid‐free recipients and shows that reduction of the tacrolimus dose increases the risk of acute rejection and the appearance of de novodonor‐specific antibodies.

L’autorisation de plein exercice professionnel demandé en France par des médecins, pharmaciens et chirurgiens-dentistes, dont le diplôme n’est pas français, est encadrée selon des modalités différentes en fonction de l’origine du diplôme et du métier concerné. Pour tous, elle requiert compétence et demande la maîtrise de la langue française. Pour les professionnels européens, la reconnaissance automatique est très prisée chez les chirurgiens-dentistes, elle représente environ 50 % des inscriptions annuelles ordinales, alors qu’elle n’est seulement que de 1 % pour les pharmaciens et d’environ 7,9 % pour les médecins. L’afflux actuel de demandes d’autorisation pour les médecins conduit à alléger les modalités d’une sélection qui restent cependant rigoureuses. Pour les diplômes hors Union européenne, la procédure actuelle de régularisation des seuls médecins comprend successivement un avis d’une commission régionale suivi d’une décision nationale. Une première recommandation, transitoire (le 31 mars 2023), a été de traiter rapidement les dossiers en souffrance en augmentant le nombre de jurys d’examen, en préparant leur travail pour le faciliter et en limitant le nombre d’examinateurs, ne retenant que des praticiens de la spécialité revendiquée. Une deuxième recommandation, souhaitée pérenne, concerne la procédure d’évaluation des médecins. Une hétérogénéité étant constatée entre l’avis et la décision, cette complexité est inutile, il faut supprimer l’étape régionale d’évaluation et ne conserver que l’étape de la commission nationale, ce qui est déjà le cas des deux autres professions. Pour le concours (liste A) et l’examen (liste B), les modalités actuelles sont satisfaisantes. L’évaluation conserve des épreuves écrites et pratiques pour tout diplômé hors Union européenne, elle prend en compte les besoins locaux qu’elle devrait recenser avec précision tout en considérant les situations locales acquises et pertinentes. Elle devrait préserver également les possibilités futures d’accès à l’exercice professionnel des étudiants français actuels et le recrutement de candidats d’exception.

Transplant recipients receiving a kidney from an extended‐criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNIto belatacept due to CNIintolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECDkidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR)<15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow‐up period. Among the remaining patients, renal function improved: The cGFRwas 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs. An early switch from calcineurin inhibitors (CNIs) to belatacept improves renal function in CNI‐intolerant graft recipients of kidneys from extended criteria donors.

Transplant recipients receiving a kidney from an extended‐criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow‐up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Nontuberculous mycobacteria (NTM) infection is a challenging diagnosis for clinicians in solid organ transplantation. Immune reconstitution inflammatory syndrome (IRIS) is so far unreported in this context. We report here the case of a renal transplant recipient who developed Mycobacterium kansasii–associated lymphadenitis complicated by IRIS while undergoing reduction of his immunosuppressive therapy. For IRIS, the patient required low-dose steroids and an increase in global immunosuppression, in association with NTM antibiotherapy.

Nontuberculous mycobacteria (NTM) infection is a challenging diagnosis for clinicians in solid organ transplantation. Immune reconstitution inflammatory syndrome (IRIS) is so far unreported in this context. We report here the case of a renal transplant recipient who developed Mycobacterium kansasii–associated lymphadenitis complicated by IRIS while undergoing reduction of his immunosuppressive therapy. For IRIS, the patient required low‐dose steroids and an increase in global immunosuppression, in association with NTM antibiotherapy. The authors report an original case of immune reconstitution inflammatory syndrome secondary to Mycobacterium kansasiilymphadenitis in a kidney transplant patient, highlighting the importance of its recognition to manage an immunosuppression regimen.

We show that the classification of glasses from “strong” to “fragile” can also be applied to spin glasses. Fragile, intermediate and strong behaviours would mean different universality classes and the strong limit would correspond to a lower critical dimension in the framework of the current scaling approach. While the class of a spin glass seems to be attached to the frozen in anisotropy of the interactions, there are experimental signs in glass-forming systems that a strong regime is the result of a cross-over from a more fragile high-temperature situation. The same fact can also be interpreted as a cross-over towards a more anisotropic state or as a restriction of space dimensionality.

Field analogs allow a better characterization of fracture networks to constrain naturally fractured reservoir models. In analogs, the origin, nature, geometry, and other attributes of fracture networks can be determined and can be related to the reservoir through the geodynamic history. In this article, we aim to determine the sedimentary and diagenetic controls on fracture patterns and the genetic correlation of fracture and diagenesis with tectonic and burial history. We targeted two outcrops of Barremian carbonates located on both limbs of the Nerthe anticline (southeastern France). We analyzed fracture patterns and rock facies as well as the tectonic, diagenetic, and burial history of both sites. Fracture patterns are determined from geometric, kinematic, and diagenetic criteria based on field and lab measurements. Fracture sequences are defined based on crosscutting and abutting relationships and compared with geodynamic history and subsidence curves. This analysis shows that fractures are organized in two close-to-perpendicular joint sets (i.e., mode I). Fracture average spacing is 50 cm (20 in.). Fracture size neither depends on fracture orientation nor is controlled by bed thickness. Neither mechanical stratigraphy nor fracture stratigraphy is observed at outcrop scale. Comparing fracture sequences and subsidence curves shows that fractures existed prior to folding and formed during early burial. Consequently, the Nerthe fold induced by the Pyrenean compression did not result in any new fracture initiation on the limbs of this fold. We assume that the studied Urgonian carbonates underwent early diagenesis, which conferred early brittle properties to the host rock. [ABSTRACT FROM AUTHOR]

High-dose methotrexate (MTX) is used in the treatment of proliferative diseases such as acute lymphoblastic leukemia. Therapeutic drug monitoring of plasma MTX is important to monitor efficacy and adverse events. The authors aimed to develop a liquid chromatography, electrospray ionization, tandem mass spectrometry (LC-ESI-MSMS)-based method to determine MTX in plasma for therapeutic drug monitoring and pharmacokinetic studies.

La pandémie de Covid-19 a frappé le monde de la transplantation en mars 2020. Rapidement, les équipes se sont organisées pour optimiser la prise en charge de leurs patients immunodéprimés et progresser dans la connaissance de cette nouvelle maladie. Pour ce faire, un registre français regroupant tous les patients transplantés d’organes solides ayant développé une infection à SARS Cov2 ont été recensés. De nombreux travaux réalisés à partir de ces données nous ont permis de décrire la maladie chez le transplanté, de caractériser ses facteurs de gravité clinique et biologique et d’en définir son pronostic. La mortalité des patients transplantés hospitalisés pour Covid-19 est de 23 % à 60jours et l’insuffisance rénale participe grandement au mauvais pronostic en sus des facteurs de risque classiques décrits dans la population générale. L’arrivée de la vaccination a été un grand soulagement mais les patients transplantés ont développé une moins bonne réponse vaccinale que les sujets immunocompétents les maintenant dans une situation à risque de maladie grave après un schéma vaccinal adapté. Des stratégies spécifiques ont dû être adoptées dans cette population particulièrement fragile (augmentation du nombre de doses de vaccin, injection d’anticorps monoclonaux). La collaboration des centres de transplantation français sous l’impulsion de la Société francophone de transplantation nous a permis de mener de nombreux projets collaboratifs qui ont été d’une grande utilité pour la prise en charge des patients.

The curing process of epoxy affects the chemical structure of the final network so mechanical and physical properties of the polymeric matrix for a composite may be modified according to the polymerisation conditions. This paper describes the ambiguity in assignment of reference bands to follow the cure of poly‐epoxy reactive systems using a laboratory‐made system which allows the coupling of dielectric analysis and Fourier Transform Near Infrared Spectroscopy (FTNIR). The dielectric measurements were obtained using interdigitated electrode. In situmonitoring of extent of reaction was carried out from room temperature up to 160 °C using fibre‐optic FTNIR spectroscopy. For the DGEBA/MCDEA system the epoxy band at 6060 cm−1was chosen in preference to the band at 4530 cm−1as representative of the epoxy function evolution during polymerisation because a small unknown peak probably due to the hardener appears in the 4530 cm−1region. The bands at 4620 and 4680 cm−1assigned to aromatic combination bands and widely used as reference bands are not unique for this formulation hence the band at 5980 cm−1is used as reference. The Principal Components Analysis (PCA) shows clearly also that the bands at 4620 and 4680 cm−1vary during the polymerisation. Surprisingly, the band at 4530 cm−1is equivalent to the one at 6060 cm−1to calculate the conversion rate. It is probably due to the fact that the hardener band near 4530 cm−1follows the same behaviour as the epoxy band at 4530 cm−1.

Improved non-destructive instrumental approaches for grading fruit during post-harvest could be an efficient way to monitor stock in the apple industry. The objective of this study was to evaluate the ability of visible-near infrared (vis-NIR) spectroscopy in reflectance mode for classifying apples left on the shelf or stored in a cooled room. The ability of NIR spectroscopy to classify the duration of storage of three apple cultivars in two storage modalities was evaluated. A total of 450 fruit, sampled after 7, 14, 28, 60, 90 and 120 days of storage in a cooled room (CR) and 7, 14 and 28 days in shelflife (SL), has been studied. The classification of these modalities was analysed by factorial discriminant analysis (FDA) pooling the spectral data of all cultivars (global models) into a common data set. Then, the cultivar effect on the classification of the same modalities was analysed by processing data from each cultivar in separate factorial descriminant analyses. A preliminary analysis showed the genetic variability of spectral data due to the three apple cultivars. We show that vis-NIR spectroscopy allowed the correct classification of the fruits of each cultivar by more than 95%. The classification relied on both vis and NIR absorption bands: 500, 680, 1400 to 1700, 1850, 1950, 2200 and 2300 nm. We show that storage modalities of global modelscan be classified by more than 75% and 83% for fruits stored in a cooled room and shelf, respectively. Classification of the same storage modalities was improved by cultivar modelswith percentage of individuals correctly classified of 86% (Gala), 89% (Elstar) and 85% (Smoothee) for fruits stored in a cooled room and 95% (Gala), 98% (Elstar) and 95% (Smoothee) for fruits left in shelflife. We conclude that despite the slight increase of efficiency of the models when we considered each apple cultivar separately, global models applicable to a set of different cultivars presents a correct level of classification and could be usefull for some commercial applications.

Improved non-destructive instrumental approaches for grading fruit during post-harvest could be an efficient way to monitor stock in the apple industry. The objective of this study was to evaluate the ability of visible-near infrared (vis-NIR) spectroscopy in reflectance mode for classifying apples left on the shelf or stored in a cooled room. The ability of NIR spectroscopy to classify the duration of storage of three apple cultivars in two storage modalities was evaluated. A total of 450 fruit, sampled after 7, 14, 28, 60, 90 and 120 days of storage in a cooled room (CR) and 7, 14 and 28 days in shelflife (SL), has been studied. The classification of these modalities was analysed by factorial discriminant analysis (FDA) pooling the spectral data of all cultivars (global models) into a common data set. Then, the cultivar effect on the classification of the same modalities was analysed by processing data from each cultivar in separate factorial descriminant analyses. A preliminary analysis showed the genetic variability of spectral data due to the three apple cultivars. We show that vis-NIR spectroscopy allowed the correct classification of the fruits of each cultivar by more than 95%. The classification relied on both vis and NIR absorption bands: 500, 680, 1400 to 1700, 1850, 1950, 2200 and 2300 nm. We show that storage modalities of global models can be classified by more than 75% and 83% for fruits stored in a cooled room and shelf, respectively. Classification of the same storage modalities was improved by cultivar models with percentage of individuals correctly classified of 86% (Gala), 89% (Elstar) and 85% (Smoothee) for fruits stored in a cooled room and 95% (Gala), 98% (Elstar) and 95% (Smoothee) for fruits left in shelflife. We conclude that despite the slight increase of efficiency of the models when we considered each apple cultivar separately, global models applicable to a set of different cultivars presents a correct level of classification and could be usefull for some commercial applications.

In this study, 33 patients were randomly assigned to receive desflurane (D) or isoflurane (I) for acoustic neuroma surgery. The time from end of the procedure to spontaneous breathing, extubation, eye-opening, hand-squeezing to command, and ability to state name, birthdate and phone number were recorded. The Steward recovery score was also recorded every five minutes during the first 20 minutes postoperatively and then every 10 to 15 minutes.Groups were similar regarding patient characteristics, depth of anaesthesia, sufentanil total dose, anaesthesia duration (D: 349.1 ±19.1 min; I: 349.2±22.9 min), haemodynamic/respiratory parameters, and surgical conditions (assessed by a bleeding score). The emergence time in the D group was significantly faster than the I group (D: 14.9±2.4 min vs I: 29.2±2.4 min for eye-opening). Full recovery also occurred earlier in the D group (D: 22.1±3.1 min vs I: 37.6±4.0 min, P<0.005 for stating name). Steward recovery scores were also better during the first postoperative hour in the D group (D: 40 min vs I: 90 min, P<0.005 for 100% of patients with Steward score of 6).The results indicate that desflurane is associated with similar operating conditions and faster postoperative recovery following acoustic neuroma surgery. The faster recovery following desflurane may be desirable after long surgical procedures, enabling the patient's full cooperation and facilitating early diagnosis of any potential neurological deficit.

We verify in the rational quaternionic case a conjecture of C. Liebendörfer relating the degrees of abelian subvarieties of certain polarized abelian varieties to the (quaternionic) heights of their defining equations.We verify in the rational quaternionic case a conjecture of C. Liebendörfer relating the degrees of abelian subvarieties of certain polarized abelian varieties to the (quaternionic) heights of their defining equations.

We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI50, cont) or short-term (3 hours; TSI50, short) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI50, cont. In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL. (Blood. 2005;106:717-720)

We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI50, cont) or short-term (3 hours; TSI50, short) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR677C>T, MTHFR1298A>C), methionine synthase (MTR2756A>G), methionine synthase reductase (MTRR66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS2R3R), and the reduced folate carrier (RFC80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR1298AC variant or the MTRR66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI50, cont. In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL. (Blood. 2005;106:717-720)

While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems it has also been observed that this alkaloid can have beneficial effects. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states we review the possibility to design new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.

We have examined the properties of nicotinic acetylcholine receptors in embryonic chick retinal ganglion cells. Ganglion cells, identified according to morphological and physiological criteria, displayed spontaneous or induced action potentials. In 9499 cells acetylcholine pulses evoked responses. In current clamp mode, acetylcholine provoked membrane depolarization and triggered action potentials. Under voltage clamp conditions, acetylcholine evoked inward currents that were readily blocked by d-tubocurarine. Antagonists specific for homomeric (-bungarotoxin) and heteromeric (dihydro--erythroidine) receptors revealed that ganglion cells express multiple functional receptor subtypes. These findings demonstrate that ACh modulates the electrical activity of these cells and is likely to mediate synaptic transmission. The presence of multiple receptor subtypes may contribute to processing and transmission of information in the retina.

Dry and dense snow avalanches are considered as dry granular flows. Theirinteraction with dams is the main objective of this paper. We studied howvarying the dam height could shorten a granular avalanche run-out thanksto a set of simple laboratory experiments carried out on different scales.Shortening the run-out was expected to depend on two effects: (i) storageof the granular material upstream of the dam, and (ii) local energy dissipations.A scaling law is highlighted. As suggested by dimensional arguments, thecontribution of the local energy dissipation was shown to be more dominantthan the storage effects.

Near InfraRed (NIR) spectroscopy was used to monitor in situ a polyurethane synthesis during a RIM process. Univariate and multivariate analysis of transmittance spectra were used to calculate the reaction extent. A very good agreement was observed between multivariate analysis (PCA), univariate (Beer-Lambert) analysis and kinetic predictions. It was demonstrated that, in this case, PCA methods can provide a good estimation of the reaction extent versus time, without time-consuming calibration. The spectral range of PCA has to be carefully chosen.

Near InfraRed (NIR) spectroscopy was used to monitor in situa polyurethane synthesis during a RIM process. Univariate and multivariate analysis of transmittance spectra were used to calculate the reaction extent. A very good agreement was observed between multivariate analysis (PCA), univariate (Beer‐Lambert) analysis and kinetic predictions. It was demonstrated that, in this case, PCA methods can provide a good estimation of the reaction extent versus time, without time‐consuming calibration. The spectral range of PCA has to be carefully chosen.

We have developed a new approach to study the molecular organization of salivary mucus and salivary mucins using confocal fluorescence recovery after photobleaching (confocal-FRAP). MUC5B mucin, its reduced subunit and T-domains were prepared from saliva and fluorescently labelled. The translational self-diffusion coefficients were determined up to 3.6mg/ml by confocal-FRAP. The results suggest that, in solutions of purified MUC5B mucin, at concentrations at which the hydrodynamic domains overlap, the intermolecular interactions are predominantly due to dynamic entanglements, and there was no evidence of specific self-association of MUC5B mucin, or of its subunits, or T-domains. The analysis of the salivary mucus gel also showed no specific interactions with the purified MUC5B components, but it was much less permeable than expected from its MUC5B content. The saliva was completely permeable to microspheres of 207nm diameter, but showed size-dependent effects on the diffusion of larger microspheres (499nm and 711nm diameter). From these analyses the salivary mucus was shown to be both permeable and dynamic, and with the characteristics of a semi-dilute transient network at physiological concentration. Comparison of the results from saliva and purified MUC5B mucin solutions showed that the network properties of saliva were equivalent to a solution of purified MUC5B mucin of 10–20 times higher concentration. This showed that saliva has additional structure and organization not present in the purified MUC5B mucin and suggests there are other interactions and/or components within saliva that combine with MUC5B to produce its complete properties.

A search for pair-produced charged Higgs bosons was performed in the high energy data collected by the DELPHI detector at LEP II at centre-of-mass energies from 189 GeV to 202 GeV. The three different final states, τντν, cs̄c̄sand cs̄τνwere considered. New methods were applied to reject wrong hadronic jet pairings and for the tau identification, where a discriminator based on tau polarisation and polar angles was used. No excess of data compared to the expected Standard Model processes was observed and the existence of a charged Higgs boson with mass lower than 71.5 GeV/c2is excluded at the 95% confidence level.

Epilepsy is one of the most frequent neurological diseases and although most patients nowadays respond well to anti-epileptic drugs (AED), 30 - 40% of them still present seizures despite treatment with 2 or more AED. This illustrates the need for discovery and testing of new molecules designed for specific brain targets. Several voltage-gated Na+ channel gene mutations were shown to be associated with genetic and hereditary epilepsy. Thus, while it is noteworthy that some currently available AED act through Na+ channels, the identified mutations in Na+ channel genes strongly support the development of new Na+ channel blockers used as AED. This review focuses on the pathophysiology of epilepsy and particularly on insight gained from the identification of mutations in idiopathic epilepsy (IE). All of the IE mutations identified concern genes coding for ion channels, suggesting a possible role of these integral membrane proteins in epileptogenesis. The recent identification of mutations in genes encoding the α1, α2 and β1 subunits of the voltage-gated Na+ channel (SCN1A, SCN2A, SCN1B) and their association with febrile seizures (FS) further illustrates the contribution of these channels in epilepsy. Modes of action of AED supposed to act through the voltage-gated Na+ channels are examined in an attempt to propose alternative routes to discover new active compounds.