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International audience; PET/MRI with 18F-FDG has demonstrated the advantages of simultaneous PET and MR imaging in head and neck cancer imaging, MRI allowing excellent soft-tissue contrast, while PET provides metabolic information. The aim of this study was to evaluate the added value of gadolinium contrast-enhanced sequences in the tumor delineation of head and neck cancers on 18F-FDG-PET/MR imaging.

Introduction : la sclérose en plaques est une pathologie inflammatoire démyélinisante chronique du système nerveux central. C’est une des causes les plus fréquentes de handicap non traumatique d’origine neurologique chez les sujets jeunes. Le diagnostic repose avant tout sur des éléments cliniques étayés par des arguments biologiques et d’imagerie. L’imagerie joue un rôle important pour le suivi de la maladie, car il peut exister des signes d’activité radiologique chez des patients asymptomatiques, nécessitant alors une adaptation du traitement. Jusque récemment, la recherche de ces signes d’activité passait par la réalisation d’une séquence T1 avec injection de gadolinium, à la recherche d’un rehaussement des lésions de sclérose en plaques, et par la comparaison des images pondérées en T2. Ces cinq dernières années, des études ont toutefois rapporté une accumulation de gadolinium dans les noyaux gris centraux cérébraux chez les patients ayant reçu des injections de gadolinium, sans conséquences cliniques démontrées en l’état actuel des connaissances. Il existe également des préoccupations environnementales croissantes en raison de rejets possibles de gadolinium dans l’environnement. Pour toutes ces raisons, il parait utile de rechercher des alternatives à l’utilisation du gadolinium. Notre étude a donc eu pour but d’évaluer, dans une population de patients SEP présentant une poussée clinique, si la présence d’une restriction du coefficient apparent de diffusion (CAD) des lésions cérébrales pouvait être utilisée comme marqueur de l’activité radiologique, se substituant ainsi à la prise de contraste visible sur les séquences T1 avec injection de gadolinium.Matériel et méthodes : nous avons mené une étude rétrospective monocentrique dans le service de neuroradiologie de l’hôpital Henri Mondor entre 2017 et 2019. Nous avons inclus d’une part des patients hospitalisés pour une poussée de sclérose en plaques ou un syndrome clinique isolé pour lesquels nous disposions d’une IRM cérébrale avec une séquence de diffusion réalisée dans les 2 mois suivant le début des symptômes. D’autre part, nous avons constitué un groupe de sujets contrôles suivis pour une SEP et sous traitement par Tysabri. Pour identifier les lésions en restriction de diffusion, nous avons appliqué à la cartographie paramétrique de CAD une méthode de post-traitement semi-automatique par seuillage disponible sur la console Advantage Window. Un seuil de CAD de 550 x 10-6 mm²/s a été utilisé. Nous avons ainsi pu classer les patients en deux groupes selon qu’ils présentaient ou non une lésion en restriction de diffusion sur leur imagerie. Nous avons ensuite recherché pour chaque patient la présence de signes classiques d’activité radiologique définis par l’apparition d’une nouvelle lésion T2 et/ou une prise de contraste après injection de gadolinium. Nous avons ainsi pu corréler la présence d’une restriction de diffusion à la présence d’un de ces signes d’activité. Enfin, nous avons calculé les performances diagnostiques de la restriction de diffusion pour (i) le diagnostic d’une poussée clinique (gold standard clinique), et (ii) le diagnostic d’activité radiologique (gold standard reposant sur les séquences injectées et la comparaison des images en pondération T2).Résultats : 134 patients présentant une poussée clinique ont été inclus ; 28 présentaient une restriction du CAD et 106 aucune restriction. 37 patients ont été inclus dans le groupe contrôle. Les groupes étaient comparables en termes d’âge et de sexe ratio. Parmi les 28 patients du groupe restriction, nous disposions d’une imagerie avec injection de gadolinium chez 27 patients. Parmi ces 27 patients, 24 patients présentaient au moins une lésion se rehaussant après injection (89%). Aucun patient du groupe contrôle ne présentait de restriction de diffusion. La sensibilité de la restriction de diffusion pour le diagnostic d’une poussée clinique était de 0,21 et sa spécificité de 1. Pour le diagnostic d’activité radiologique (basée sur l’imagerie avec injection de gadolinium comme référence), la sensibilité de la restriction de diffusion était de 0,44, sa spécificité de 0,95.Conclusion : notre étude confirme que la restriction de diffusion d’une lésion de SEP peut être considérée comme un biomarqueur spécifique d’activité. Sa faible sensibilité ne permet toutefois pas d’envisager en pratique de remplacer les séquences avec injection de gadolinium par la séquence de diffusion. Cette approche pourrait toutefois s’avérer utile dès lors que l’on identifierait une restriction du CAD chez un patient en poussée clinique : l’injection serait, d’après nos résultats, inutile dans ce contexte particulier.

International audience; Rare earth element (REE) concentrations were determined for 22 sites sampled during two water periods: high flow in winter and low flow in summer. Shale-normalized REE patterns of all samples displayed positive gadolinium (Gd) anomalies. They revealed a widespread contamination of anthropogenic Gd (Gdant) from waste water treatment plant (WWTP) outputs to catchment areas used for drinking water. No significant variations in Gdant were observed between the two flow water periods, but differences in the Gd anomalies were present. However, these differences seem to be associated rather with seasonal variations in the river flow rate than with the release of GdAnt from WWTPs. In proximity to WWTP discharges, strong GdAnt variations ranged from few nanograms per litre to more than 80 μg L-1 and rarely showed a repetitive pattern day after day during 14 days. These concentrations were diluted into the river stream and measured around 10 ng L-1 close to the catchment areas used for drinking water. A principal component analysis (PCA) using the GdAnt concentrations and some classical physicochemical parameters (pH, water temperature, total alkalinity (TA), total organic carbon (TOC), biochemical and chemical oxygen demand (BOD and COD), Cl-, NO3- and SO42-) allowed a site separation according to the level of Gd contamination, highlighting that the highest GdAnt concentrations were found in the north of the region Lorraine (France) where the population density is high and most of the MRI examinations are performed.

International audience; This article presents an overview of advanced magnetic resonance (MR) imaging techniques using contrast media in neuroimaging, focusing on T2*-weighted dynamic susceptibility contrast MR imaging and T1-weighted dynamic contrast-enhanced MR imaging. Image acquisition and data processing methods and their clinical application in brain tumors, stroke, dementia, and multiple sclerosis are discussed.

English Article NEW PHYTOL 325ED; Calcium (Ca2+)-permeable plasma membrane ion channels are critical to root hair elongation and signalling. Arabidopsis thaliana root hair plasma membrane contains a hyperpolarization-activated Ca2+ channel (HACC) conductance. Here, the co-residence of HACC with a depolarization-activated Ca2+ channel (DACC) conductance has been investigated. Whole-cell patch-clamping of apical plasma membrane has been used to study Ca2+ conductances and reveal the negative slope conductance typical of DACCs. Specific voltage protocols, Ba(2+)-permeation and inhibition by the cation channel blocker Gd3+ have been used to identify the DACC conductance. The Gd3+ sensitive DACC conductance was identified in only a minority of cells. DACC activity was quickly masked by the development of the HACC conductance. However, in the period between the disappearance of the negative slope conductance and the predominance of HACC, DACC activity could still be detected. A DACC conductance coexists with HACC in the root hair apical plasma membrane and could provide Ca2+ influx over a wide voltage range, consistent with a role in signalling.

In magnetic resonance imaging (MRI), cerebral blood volume (CBV) quantification is dependent on the MRI sequence and on the properties of the contrast agents (CAs). By using the rapid steady-state T1 method, we show the potential of gadolinium per (3,6-anhydro) α-cyclodextrin (Gd-ACX), a new MRI paramagnetic CA (inclusion complex of Gd3+ with per (3,6-anhydro)-α-cyclodextrin), for the CBV quantification in the presence of blood—brain barrier lesions. After biocompatibility and relaxivity experiments, in vivo experiments on rats were performed on a C6 tumor model with 0.05 mmol Gd-ACX/kg (1-weighted images, a signal enhancement of 170% appeared in vessels after injection, but not in the tumor (during the 1 h of observation), in contrast to the 90% signal enhancement obtained with Gd-DOTA (a clinical MRI CA) injected at a T1 isoefficient dose. This result shows the absence of Gd-ACX extravasation into the tumor tissue and its confinement to the vascular space. Fractional CBV values were found similar to Gd-ACX and Gd-DOTA in healthy brain tissue and in the contralateral hemisphere of tumor-bearing rats, whereas only Gd-ACX was appropriate for CBV quantification in tumor regions.

Purpose: To assess the impact of gadolinium injection in Magnetic Resonance Imaging (MRI) to detect anastomotic recurrence after ileocaecal resection in Crohn’s disease (CD).Methods : The MRIs from 58 patients followed-up between 2007 and 2013 in Saint-Antoine Hospital for CD with ileocaecal resection were retrospectively reviewed by 3 radiologists in a two-step approach: without gadolinium injection and then after gadolinium injection. The patients were ranked M1 (no disease), M2 (probably no disease), M3 (I don’t know), M4 (probably ill), and M5 (certainly ill). The reference standard was established by a senior gastroenterologist with biological and endoscopic items.Results: By grouping M1+M2 and M4+M5, before injection sensitivity was 64%, specificity 85%, positive predictive value 81% and negative predictive value 70%. After injection, sensitivity was 64.3%, specificity 81.4%, positive predictive value 78%, and negative predictive value 69%. There was no significant change in the Receiver Operating Characteristic curves before and after injection (p=0.19, DeLong method).Before gadolinium injection, the Area Under Curve was 0,738 with a confidence interval (CI) of 95% between 0,606 and 0,845, and after injection of 0,775 with a CI of 95% between 0,646 and 0,874. Our results agreed with the reference standard in 70.6% of the cases before injection and 68.9% after. Gadolinium improved concordance in 3 cases and downgraded results in 4 cases.Conclusion: Gadolinium did not significantly improve the diagnosis of anastomotic recurrence after ileocaecal resection in CD.; Objectif : évaluer l’apport du gadolinium en Imagerie par Résonance Magnétique (IRM) pour chercher une récidive anastomotique après résection iléo-cæcale (RIC) chez les patients atteints de maladie de Crohn (MC).Méthode : Les entéro-IRM de 58 patients suivis de 2007 à 2013 à l’hôpital Saint-Antoine pour MC, opérés de RIC, ont été relues par 3 radiologues rétrospectivement en 2 temps : sans les séquences après injection, puis avec toutes les séquences. Les patients ont été classés : M1 non malade, M2 probablement non malade, M3 « je ne sais pas », M4 probablement malade, M5 certainement malade. Le critère de vérité était établi à partir de données cliniques, biologiques et endoscopiques par un médecin gastroentérologue senior.Résultats : En regroupant M1+M2 et M4+M5, avant injection la sensibilité était à 64%, la spécificité à 85%, la valeur prédictive positive à 81% et négative à 70%. Après injection, la sensibilité était 64%, la spécificité 81%, la valeur prédictive positive 78% et négative à 69%.Les courbes Receiver Operating Characteristics ne montraient pas de différence significative avant et après injection (p=0.19, méthode de DeLong). Avant injection, l’aire sous la courbe était de 0,738 avec un indice de confiance (IC) à 95% entre 0,606 et 0,845 et après injection de 0,775 avec un IC à 95% entre 0,646 et 0,874.Avant gadolinium l’IRM était concordante avec le critère de vérité dans 71% des cas et dans 69% après injection. Le gadolinium a amélioré le résultat dans 3 cas et l’a dégradé dans 4 cas.Conclusion : Le gadolinium n’a pas permis d’améliorer les résultats de l’entéro-IRM pour chercher une récidive anastomotique après RIC chez les patients atteints de MC.

International audience; Application of hydrodynamic mild shear stress to adherent Dictyostelium discoideum vegetative cells triggers active actin cytoskeleton remodeling resulting in net cell movement along the flow. The average cell speed is strongly stimulated by external calcium (Ca2+, K50%=22 microM), but the directionality of the movement is almost unaffected. This calcium concentration is ten times higher than the one promoting cell adhesion to glass surfaces (K50%=2 microM). Addition of the calcium chelator EGTA or the Ca2+-channel blocker gadolinium (Gd3+) transiently stops cell movement. Monitoring the evolution of cell-surface contact area with time reveals that calcium stimulates cell speed by increasing the amplitude of both protrusion and retraction events at the cell edge, but not the frequency. As a consequence, with saturating external calcium concentrations, cells are sensitive to very low shear forces (20 pN; sigma=0.1 Pa). Moreover, a null-mutant lacking the unique Gbeta subunit does not respond to external Ca2+ changes (K50%>1000 microM), although the directionality of the movement is comparable with that of wild-type cells. Furthermore, cells lacking the inositol 1,4,5-trisphosphate receptor (IP3-receptor) exhibit a markedly reduced Ca2+ sensitivity. Thus, calcium release from internal stores and calcium entry through the plasma membrane modulate cell speed in response to shear stress.

Purpose. To compare enhancement and contrast of FNH obtained with a triple arterial phase acquisition with a simple arterial phase acquisition; to determine the optimal arterial phase of FNH. Materials and Methods. Twenty patients (average age: 47 years; 20-60 years) with 30 FNH (simple phase group) were imaged with a conventional spoiled gradient echo acquisition and 15 patients (average age: 42 years; 20-66 years) with 20 FNH (triple phase group) were imaged with a triple arterial phase acquisition in parallel imaging, after the administration of gadolinium. Arterial enhancement of FNH, image quality,and respiratory artefacts were qualitatively graded. The ratio of lesion to parenchyma enhancement as well as relative enhancement of FNH were calculated. Type of phase obtained (angiographic, early arterial, late arterial and portal) were related. Mann-Whitney, Fisher et Chi-2 tests were used to compare differences. Results. One hundred per cent (20/20) of FNH of triple phase group and 73% (22/30) of FNH of simple phase group were intensely enhanced (p=0,042). Ten per cent (3/30) of FNH of simple phase group presented weak enhancement and MRI diagnosis could not have been made. The ratio of lesion to parenchyma enhancement was higher in triple phase group (p=0,004). There was no loss of image quality and no additionally respiratory artefacts in triple phase group. Optimal arterial phase of FNH was the early arterial phase. Conclusion. Triple arterial phase acquisition in parallel imaging resulted in higher arterial enhancement and better ratio of lesion to parenchyma enhancement than in simple arterial phase conventional acquisition.; Sujet. Comparer les paramètres du rehaussement artériel de l’HNF en IRM entre acquisition triple phase et simple phase ; et déterminer la phase artérielle optimale de l’HNF. Matériel et méthodes. Vingt patientes (âge moyen : 47 ans; 20-60 ans) avec 30 HNF ont eu une acquisition simple phase artérielle (groupe simple phase) et 15 patientes (42 ans; 20-66 ans) avec 20 HNF ont eu une acquisition triple phase artérielle avec technique d’acquisition parallèle (groupe triple phase) utilisant un chélate de Gadolinium standard. L’intensité du rehaussement artériel de l’HNF, la qualité de l’examen, la présence d’artéfacts respiratoires, le rehaussement lésionnel et le contraste lésionnel des HNF ont été comparés (test de Mann-Whitney, Fisher et Chi-2). Le type de phase acquis (angiographique, artériel précoce, artériel tardif et portal) était rapporté. Résultats. Cent pour cent (20/20) des HNF étaient rehaussées intensément dans le groupe triple phase contre 73% (22/30) dans le groupe simple phase (p=0,042). Dix pour cent (3/30) des HNF du groupe simple phase présentaient un rehaussement artériel faible ne permettant pas de conclure au diagnostic d’HNF en IRM. Le contraste lésionnel de l’HNF était significativement plus important dans le groupe triple phase que dans le groupe simple phase (p=0,004). Il n’y avait pas de perte de qualité image ou d’augmentation des artéfacts respiratoires dans le groupe triple phase. La phase artérielle optimale de l’HNF était la phase artérielle précoce. Conclusion. L’acquisition de trois phases artérielles en imagerie paral lèle améliore l’intensité du rehaussement artériel et le contraste lésionnel de l’HNF, comparativement à l’acquisition d’une seule phase artérielle en technique conventionnelle.

A set of seven caged gadolinium complexes were used as vectors for introducing the chelated Gd3+ ion into protein crystals in order to provide strong anomalous scattering for de novo phasing. The complexes contained multidentate ligand molecules with different functional groups to provide a panel of possible interactions with the protein. An exhaustive crystallographic analysis showed them to be nondisruptive to the diffraction quality of the prepared derivative crystals, and as many as 50% of the derivatives allowed the determination of accurate phases, leading to high-quality experimental electron-density maps. At least two successful derivatives were identified for all tested proteins. Structure refinement showed that the complexes bind to the protein surface or solvent-accessible cavities, involving hydrogen bonds, electrostatic and CH-π interactions, explaining their versatile binding modes. Their high phasing power, complementary binding modes and ease of use make them highly suitable as a heavy-atom screen for high-throughput de novo structure determination, in combination with the SAD method. They can also provide a reliable tool for the development of new methods such as serial femtosecond crystallography. © 2014 International Union of Crystallography.

In an effort towards the visualization of b-amyloid (Ab) plaques by T1-weighted magnetic resonance imaging for detection of Alzheimer’s disease, we report the synthesis and characterization of stable, noncharged Gd3? complexes of three different 1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a wellestablished marker of Ab plaques. The ligands L1, L2, and L3 differ in the nature and size of the spacer linking the macrocyclic chelator and the Pittsburgh compound B targeting moiety, which affects their lipophilicity, the octanol– water partition coefficients of the complexes ranging from -0.15 to 0.32. Given their amphiphilic behavior, the complexes form micelles in aqueous solution (critical micellar concentration 1.00–1.49 mM). The parameters determining the relaxivity, including the water exchange rate and the rotational correlation times, were assessed for the monomeric and the micellar form by a combined 17O NMR and 1H nuclear magnetic relaxation dispersion (NMRD) study. They are largely influenced by the aggregation state and the hydrophobic character of the linkers. The analysis of the rotational dynamics for the aggregated state in terms of local and global motions using the Lipari– Szabo approach indicates highly flexible, large aggregates. On binding of the complexes to human serum albumin or to the amyloid peptide Ab1–40 in solution, they undergo a fourfold and a twofold relaxivity increase, respectively (40 MHz). Proton relaxation enhancement studies confirmed moderate interaction of Gd(L1) and Gd(L3) with human serum albumin, with KA values ranging between 250 and 910 M-1. This work was financially supported by Fundação para a Ciência e a Tecnologia, Portugal (PhD grant SFRH/BD/ 46370/2008 to AFM) and Rede Nacional de RMN (project REDE/ 1517/RMN/2005) for the acquisition of the Varian VNMRS 600 NMR spectrometer in Coimbra and the French-Portuguese PESSOA project. This work was carried out in the frame of the European Actions TD1004 ‘‘Theragnostics Imaging and Therapy’’ and TD1007 ‘‘PET-MRI’’.

International audience; AIM: Our goal was to demonstrate the feasibility of pelvic magnetic resonance imaging (MRI) in the ewe. MATERIAL AND METHODS: Two ewes underwent a pelvic 3 Tesla MRI scan, under light anesthesia, with T2-weighted fast spin-echo images and T1-weighted spoiled gradient-echo images. Multiplan T1 weighted images were also obtained after the intravenous injection of a contrast product. One ewe was anestrous and the other one had undergone ovarian stimulation. RESULTS: No incident occurred during the examination. Both the uterus (with two horns) and the ovaries were identified. The intensity of the endometrial, myometrial and ovarian signals was similar to that encountered in women. The uterus and ovaries could be enhanced in both cases. Pelvic vasculature was also studied. In the case of hormonal stimulation, the endometrium was thicker, follicular growth was identified and enhancement seemed greater. CONCLUSION: MRI in the ewe is feasible and could be helpful in experimental gynecologic research, especially in uterus transplantation.

Cl−currents induced by cell swelling were characterized in an immortalized cell line (DC1) derived from rabbit distal bright convoluted tubule by the whole cell patch-clamp techniques and by125I−efflux experiments. Exposure of cells to a hypotonic shock induced outwardly rectifying Cl−currents that could be blocked by 0.1 mM 5-nitro-2-(3-phenylpropyl-amino)benzoic acid, 1 mM DIDS, and by 1 mM diphenylamine-2-carboxylate.125I−efflux experiments showed that exposure of the monolayer to a hypotonic medium increased125I−loss. Preincubation of cells with LaCl3or GdCl3prevented the development of the response. The addition of 10 μM adenosine to the bath medium activated outwardly rectifying whole cell currents similar to those recorded after hypotonic shock. This conductance was inhibited by the A1-receptor antagonist 8-cyclopentyl-1,3-diproxylxanthine (DPCPX), LaCl3, or GdCl3and was activated by GTPγS. The selective A1-receptor agonist N6-cyclopentyladenosine (CPA) mimicked the effect of hypotonicity on125I−efflux. The CPA-induced increase of125I−efflux was inhibited by DPCPX and external application of LaCl3or GdCl3. Adenosine also enhanced Mn2+influx across the apical membrane. Overall, the data show that DC1 cells possess swelling- and adenosine-activated Cl−conductances that share identical characteristics. The activation of both conductances involved Ca2+entry into the cell, probably via mechanosensitive Ca2+channels. The effects of adenosine are mediated via A1receptors that could mediate the purinergic regulation of the volume-sensitive Cl−conductance.

Previous studies using the patch-clamp technique demonstrated the presence of a small conductance Cl−channel in the apical membrane of respiratory gill cells in primary culture originating from sea bass Dicentrarchus labrax. We used the same technique here to characterize potassium channels in this model. A K+channel of 123 ± 3 pS was identified in the cell-attached configuration with 140 mM KCl in the bath and in the pipette. The activity of the channel declined rapidly with time and could be restored by the application of a negative pressure to the pipette (suction) or by substitution of the bath solution with a hypotonic solution (cell swelling). In the excised patch inside-out configuration, ionic substitution demonstrated a high selectivity of this channel for K+over Na+and Ca2+. The mechanosensitivity of this channel to membrane stretching via suction was also observed in this configuration. Pharmacological studies demonstrated that this channel was inhibited by barium (5 mM), quinidine (500 μM), and gadolinium (500 μM). Channel activity decreased when cytoplasmic pH was decreased from 7.7 to 6.8. The effect of membrane distension by suction and exposure to hypotonic solutions on K+channel activity is consistent with the hypothesis that stretch-activated K+channels could mediate an increase in K+conductance during cell swelling.

Previous studies performed on apical membranes of seawater fish gills in primary culture have demonstrated the existence of stretch-activated K+channels with a conductance of 122 pS. The present report examines the involvement of K+channels in ion transport mechanisms and cell swelling. In the whole cell patch-clamp configuration, K+currents were produced by exposing cells to a hypotonic solution or to 1 μM ionomycin. These K+currents were inhibited by the addition of quinidine and charybdotoxin to the bath solution. Isotopic efflux measurements were performed on cells grown on permeable supports using86Rb+as a tracer to indicate potassium movements. Apical and basolateral membrane86Rb effluxes were stimulated by the exposure of cells to a hypotonic medium. During the hypotonic shock, the stimulation of86Rb efflux on the apical side of the monolayer was inhibited by 500 μM quinidine or 100 μM gadolinium but was insensitive to scorpion venom [ Leirus quinquestriatus hebraeus (LQH)]. An increased86Rb efflux across the basolateral membrane was also reduced by the addition of quinidine and LQH venom but was not modified by gadolinium. Moreover, basolateral and apical membrane86Rb effluxes were not modified by bumetanide or thapsigargin. There is convincing evidence for two different populations of K+channels activated by hypotonic shock. These populations can be separated according to their cellular localization (apical or basolateral membrane) and as a function of their kinetic behavior and pharmacology.

International audience; Pathogenesis of peripartum cardiomyopathy (PPC) is still discussed. We report one case of PPC in which a cardiac magnetic resonance imaging analysis allowed to exclude some "classical" pathogenesis hypotheses. We would like to emphasize the benefits of cardiac MRI in the comprehension of the mechanism(s) involved in the genesis of PPC.

Stretch-sensitive ion channels are ubiquitous, yet evidence of their role in mechanotransduction remains scarce. The presence of stretch-inactivated cation channels in supraoptic neurons is consistent with the osmoreceptor potentials regulating vasopressin release. However, whether osmosensitivity depends on mechanical gating and ion flux through stretch-inactivated channels is unknown. Here we report that changes in channel open probability associated either with modification of pipette pressure or with external osmolality selectively result from variations in closed time. While channel mechanosensitivity and osmotically evoked changes in cell volume are not affected by gadolinium, similar concentrations of the lanthanide inhibit cation permeation through the single channels and macroscopic osmoreceptor potentials. Mechanotransduction through stretch-inactivated channels is therefore necessary for osmoreception in supraoptic neurons.

International audience; Gd(III)-containing metallostar contrast agents are gaining increased attention, because their architecture allows for a slower tumbling rate, which, in turn, results in larger relaxivities. So far, these metallostars find possible applications as blood pool contrast agents. In this work, the first example of a tissue-selective metallostar contrast agent is described. This RGD-peptide decorated Ru(II)(Gd(III))(3)metallostar is synthesized as an α(v)β(3)-integrin specific contrast agent, with possible applications in the detection of atherosclerotic plaques and tumor angiogenesis. The contrast agent showed a relaxivity of 9.65 s(-1) mM(-1), which represents an increase of 170%, compared to a low-molecular-weight analogue, because of a decreased tumbling rate (τ(R) = 470 ps). The presence of the MLCT band (absorption 375-500 nm, emission 525-850 nm) of the central Ru(II)(Ph-Phen)(3)-based complex grants the metallostar attractive luminescent properties. The (3)MLCT emission is characterized by a quantum yield of 4.69% and a lifetime of 804 ns, which makes it an interesting candidate for time-gated luminescence imaging. The potential application as a selective MRI contrast agent for α(v)β(3)-integrin expressing tissues is shown by an in vitro relaxometric analysis, as well as an in vitroT(1)-weighted MR image.

International audience; Vessel size index (VSI), a parameter related to the distribution of vessel diameters, may be estimated using two MRI approaches: (i) dynamic susceptibility contrast (DSC) MRI following the injection of a bolus of Gd-chelate. This technique is routinely applied in the clinic to assess intracranial tissue perfusion in patients; (ii) steady-state susceptibility contrast with USPIO contrast agents, which is considered here as the standard method. Such agents are not available for human yet and the steady-state approach is currently limited to animal studies. The aim is to compare VSI estimates obtained with these two approaches on rats bearing C6 glioma (n = 7). In a first session, VSI was estimated from two consecutive injections of Gd-Chelate (Gd(1) and Gd(2)). In a second session (4 hours later), VSI was estimated using USPIO. Our findings indicate that both approaches yield comparable VSI estimates both in contralateral (VSI{USPIO} = 7.5 ± 2.0 µm, VSI{Gd(1)} = 6.5 ± 0.7 µm) and in brain tumour tissues (VSI{USPIO} = 19.4 ± 7.1 µm, VSI{Gd(1)} = 16.6 ± 4.5 µm). We also observed that, in the presence of BBB leakage (as it occurs typically in brain tumours), applying a preload of Gd-chelate improves the VSI estimate with the DSC approach both in contralateral (VSI{Gd(2)} = 7.1 ± 0.4 µm) and in brain tumour tissues (VSI{Gd(2)} = 18.5 ± 4.3 µm) but is not mandatory. VSI estimates do not appear to be sensitive to T(1) changes related to Gd extravasation. These results suggest that robust VSI estimates may be obtained in patients at 3 T or higher magnetic fields with the DSC approach.

International audience; Touch is detected through receptors located in the skin and the activation of channels in sensory nerve fibres. Epidermal keratinocytes themselves, however, may sense mechanical stimulus and contribute to skin sensation. Here, we showed that the mechanical stimulation of human keratinocytes by hypo-osmotic shock releases adenosine triphosphate (ATP) and increases intracellular calcium. We demonstrated that the release of ATP was found to be calcium independent because emptying the intracellular calcium stores did not cause ATP release; ATP release was still observed in the absence of external calcium and it persisted on chelating cytosolic calcium. On the other hand, the released ATP activated purinergic receptors and mobilized intracellular calcium stores. The resulting depletion of stored calcium led to the activation of capacitative calcium entry. Increase in cytosolic calcium concentration was blocked by the purinergic receptor blocker suramin, phospholipase C inhibitor and apyrase, which hydrolyses ATP. Collectively, our data demonstrate that human keratinocytes are mechanically activated by hypo-osmotic shock, leading first to the release of ATP, which in turn stimulates purinergic receptors, resulting in the mobilization of intracellular calcium and capacitative calcium entry. These results emphasize the crucial role of ATP signalling in the transduction of mechanical stimuli in human keratinocytes.

International audience; OBJECTIVES: To compare 2 cardiac magnetic resonance (CMR) techniques for the evaluation of the prognostic significance of microvascular damage after non ST-segment elevation myocardial infarction (NSTEMI). MATERIALS AND METHODS: CMR was performed at 3T in 61 patients within the week following their first NSTEMI. A first-pass saturation-recovery gradient-echo perfusion sequence was started during the infusion of contrast material to evaluate the extent of microvascular obstruction (MO) during the first 2 minutes after injection (MO(

International audience; Perfusion magnetic resonance imaging (MRI) offers relative safety (no ionizing radiation), high spatial/temporal resolution, multi-orientation imaging capability, and relative low cost when compared with sophisticated techniques, such as positron emission tomography (PET). Several methods have been recently proposed to image perfusion. Some techniques mimic conventional nuclear medicine principles, but use radioactively inert tracers. Other approaches directly use blood as an endogenous natural tracer. Such methods are totally noninvasive, and offer original insights, for instance by monitoring variations in blood oxygenation in human brain cortex during activation tasks. These methods are presented and compared. Emphasis is given on advantages and drawbacks, and potential clinical applications.

International audience; This study aimed at combining an iron-based, steady-state, vessel size index magnetic resonance imaging (VSI MRI) approach, and a gadolinium (Gd)-based, dynamic contrast-enhanced MRI approach (DCE MRI) to characterize tumoral microvasculature. Rats bearing an orthotopic glioma (C6, n=14 and RG2, n=6) underwent DCE MRI and combined VSI and DCE MRI 4 h later, at 2.35 T. Gd-DOTA (200 mumol of Gd per kg) and ultrasmall superparamagnetic iron oxide (USPIO) (200 micromol of iron per kg) were used for DCE and VSI MRI, respectively. C6 and RG2 gliomas were equally permeable to Gd-DOTA but presented different blood volume fractions and VSI, in good agreement with histologic data. The presence of USPIO yielded reduced K(trans) values. The K(trans) values obtained with Gd-DOTA in the absence and in the presence of USPIO were well correlated for the C6 glioma but not for the RG2 glioma. It was also observed that, within the time frame of DCE MRI, USPIO remained intravascular in the C6 glioma whereas it extravasated in the RG2 glioma. In conclusion, VSI and DCE MRI can be combined provided that USPIO does not extravasate with the time frame of the DCE MRI experiment. The mechanisms at the origin of USPIO extravasation remain to be elucidated.

International audience; This study aimed at combining an iron-based, steady-state, vessel size index magnetic resonance imaging (VSI MRI) approach, and a gadolinium (Gd)-based, dynamic contrast-enhanced MRI approach (DCE MRI) to characterize tumoral microvasculature. Rats bearing an orthotopic glioma (C6, n=14 and RG2, n=6) underwent DCE MRI and combined VSI and DCE MRI 4 h later, at 2.35 T. Gd-DOTA (200 mumol of Gd per kg) and ultrasmall superparamagnetic iron oxide (USPIO) (200 micromol of iron per kg) were used for DCE and VSI MRI, respectively. C6 and RG2 gliomas were equally permeable to Gd-DOTA but presented different blood volume fractions and VSI, in good agreement with histologic data. The presence of USPIO yielded reduced K(trans) values. The K(trans) values obtained with Gd-DOTA in the absence and in the presence of USPIO were well correlated for the C6 glioma but not for the RG2 glioma. It was also observed that, within the time frame of DCE MRI, USPIO remained intravascular in the C6 glioma whereas it extravasated in the RG2 glioma. In conclusion, VSI and DCE MRI can be combined provided that USPIO does not extravasate with the time frame of the DCE MRI experiment. The mechanisms at the origin of USPIO extravasation remain to be elucidated.

International audience; In this paper, we provide an update on cation channels in nucleated chicken erythrocytes. Patch-clamp techniques were used to further characterize the two different types of cation channels present in the membrane of chicken red blood. In the whole-cell mode, with Ringer in the bath and internal K+ saline in the pipette solution, the membrane conductance was generated by cationic currents, since the reversal potential was shifted toward cations equilibrium when the impermeant cation NMDG was substituted to small cations. The membrane conductance could be increased by application of mechanical deformation or by the addition of agonists of the cAMP-dependent pathway. At the unitary level, two different types of cationic channels were revealed and could account for the cationic conductance observed in whole-cell configuration. One of them belongs to the family of stretch-activated cationic channel showing changes in activity under conditions of membrane deformation, whereas the second one belongs to the family of the cAMP activated cationic channels. These two channels could be distinguished according to their unitary conductances and drug sensitivities. The stretch-activated channel was sensitive to Gd(3+) and the cAMP-dependent channel was sensitive to flufenamic acid. Possible role of these channels in cell volume regulation process is discussed.

Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain. Upon interaction with Ca2+, they exhibit high and reversible relaxivity changes in buffered solution or in a model of the brain extracellular medium. These efficient Ca2+ magnetic resonance imaging sensors might open new perspectives in functional molecular imaging.

International audience; Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N'',N''-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.

International audience; Luminescent hybrid nanoparticles with a paramagnetic Gd2O 3 core were applied as contrast agents for both in vivo fluorescence and magnetic resonance imaging. These hybrid particles were obtained by encapsulating Gd2O3 cores within a polysiloxane shell which carries organic fluorophores and carboxylated PEG covalently tethered to the inorganic network. Longitudinal proton relaxivities of these particles are higher than the positive contrast agents like Gd-DOTA which are commonly used for clinical magnetic resonance imaging. Moreover these particles can be followed up by fluorescence imaging. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in lungs and liver.

International audience; MR and CT imaging techniques provide both morphological data and functional data. MR and recently CT perfusion have substantially modified the treatment of acute stroke. CT perfusion offers new opportunities to improve the management strategy in vasospasm after subarachnoid hemorrhage. Both are also helpful for the diagnosis of brain tumors and the assessment of treatment effects.

International audience; To date, intravenous immunoglobulin (IvIg) has more often been considered as a safe medication. However, with the wider use of IvIg, severe side effects have also been reported to occur in IvIg-treated patients, notably aseptic meningitis. Other neurological complications have more rarely been described in patients receiving IvIg therapy, e.g. stroke or acute encephalopathy. We recently observed a case which is of particular interest, as the patient with steroid-refractory polyarteritis nodosa developed cranial pachymeningitis related to IvIg therapy. To our knowledge, this is the first reported case of cranial pachymeningitis complicating IvIg therapy. Our findings emphasize the importance of recognizing IvIg-related neurological complications in IvIg-treated patients. As cranial pachymeningitis is a fibrosing process, both recognition and management at an early stage are required to prevent definite neurological impairment in patients.

International audience

International audience; BACKGROUND: Recent studies have demonstrated magnetic resonance (MR) capabilities in evaluating renal morphology and function in patients with urinary obstruction. The objective of this report is to support the introduction of dynamic MR renography on any MR equipment. METHODS: A custom-made device of vials filled with different concentrations of gadolinium was studied by combinations of T1-weighted gradient-echo sequences and coils. We compared the capabilities of two coils (phased array vs. standard body), the properties of dynamic sequences, and the effects of increasing concentrations of gadolinium on signal intensity. In a second section, we designed MR urography plug-ins of Image J (DICOM image software) for the analysis of dynamic studies. RESULTS: Optimized gradient-echo sequences acquired with a phased array body coil produced acceptable quality images with a linear relation between signal intensity and the lowest concentrations of gadolinium. In vitro measurements showed loss of linearity above 8 mmol/L. CONCLUSION: Theoretical calculation and data from the literature suggest that the gadolinium dose to the patient should not exceed one-fourth of the usual one (0.025 mmol/kg). Postprocessing using Image J software and the specifically designed plug-ins was validated. The collection of plug-ins is now available on the Internet.

International audience; The effect of gadolinium ions on the sarcoplasmic reticulum (SR) calcium release channel/ryanodine receptor (RyR1) was studied using heavy SR (HSR) vesicles and RyR1 isolated from rabbit fast twitch muscle. In the [(3)H]ryanodine binding assay, 5 microM Gd(3+) increased the K(d) of the [(3)H]ryanodine binding of the vesicles from 33.8 nM to 45.6 nM while B(max), referring to the binding capacity, was not affected significantly. In the presence of 18 nM[(3)H]ryanodine and 100 microM free Ca(2+), Gd(3+) inhibited the binding of the radiolabeled ryanodine with an apparent K(d) value of 14.7 microM and a Hill coefficient of 3.17. In (45)Ca(2+) experiments the time constant of (45)Ca(2+) efflux from HSR vesicles increased from 90.9 (+/- 11.1) ms to 187.7 (+/- 24.9) ms in the presence of 20 microM gadolinium. In single channel experiments gadolinium inhibited the channel activity from both the cytoplasmic (cis) (IC(50) = 5.65 +/- 0.33 microM, n(Hill) = 4.71) and the luminal (trans) side (IC(50) = 5.47 +/- 0.24 microM, n(Hill) = 4.31). The degree of inhibition on the cis side didn't show calcium dependency in the 100 microM to 1 mM Ca(2+) concentration range which indicates no competition with calcium on its regulatory binding sites. When Gd(3+) was applied at the trans side, EGTA was present at the cis side to prevent the binding of Gd(+3) to the cytoplasmic calcium binding regulatory sites of the RyR1 if Gd(3+) accidentally passed through the channel. The inhibition of the channel did not show any voltage dependence, which would be the case if Gd(3+) exerted its effect after getting to the cis side. Our results suggest the presence of inhibitory binding sites for Gd(3+) on both sides of the RyR1 with similar Hill coefficients and IC(50) values.

To characterize Ca2+transport in newborn rat cortical collecting duct (CCD) cells, we used nifedipine, which in adult rat distal tubules inhibits the intracellular Ca2+concentration ([Ca2+]i) increase in response to hormonal activation. We found that the dihydropyridine (DHP) nifedipine (20 μM) produced an increase in [Ca2+]ifrom 87.6 ± 3.3 nM to 389.9 ± 29.0 nM in 65% of the cells. Similar effects of other DHP (BAY K 8644, isradipine) were also observed. Conversely, DHPs did not induce any increase in [Ca2+]iin cells obtained from proximal convoluted tubule. In CCD cells, neither verapamil nor diltiazem induced any rise in [Ca2+]i. Experiments in the presence of EGTA showed that external Ca2+was required for the nifedipine effect, while lanthanum (20 μM), gadolinium (100 μM), and diltiazem (20 μM) inhibited the effect. Experiments done in the presence of valinomycin resulted in the same nifedipine effect, showing that K+channels were not involved in the nifedipine-induced [Ca2+]irise. H2O2also triggered [Ca2+]irise. However, nifedipine-induced [Ca2+]iincrease was not affected by protamine. In conclusion, the present results indicate that 1) primary cultures of cells from terminal nephron of newborn rats are a useful tool for investigating Ca2+transport mechanisms during growth, and 2) newborn rat CCD cells in primary culture exhibit a new apical nifedipine-activated Ca2+channel of capacitive type (either transient receptor potential or leak channel).