Overview of the current use of levosimendan in France: a prospective observational cohort study

Abstract Background Following the results of randomized controlled trials on levosimendan, French health authorities requested an update of the current use and side-effects of this medication on a national scale. Method The France-LEVO registry was a prospective observational cohort study reflecting the indications, dosing regimens, and side-effects of levosimendan, as well as patient outcomes over a year. Results The patients included ( n = 602) represented 29.6% of the national yearly use of levosimendan in France. They were treated for cardiogenic shock ( n = 250, 41.5%), decompensated heart failure ( n = 127, 21.1%), cardiac surgery-related low cardiac output prophylaxis and/or treatment ( n = 86, 14.3%), and weaning from veno-arterial extracorporeal membrane oxygenation ( n = 82, 13.6%). They received 0.18 ± 0.07 µg/kg/min levosimendan over 26 ± 8 h. An initial bolus was administered in 45 patients (7.5%), 103 (17.1%) received repeated infusions, and 461 (76.6%) received inotropes and or vasoactive agents concomitantly. Hypotension was reported in 218 patients (36.2%), atrial fibrillation in 85 (14.1%), and serious adverse events in 17 (2.8%). 136 patients (22.6%) died in hospital, and 26 (4.3%) during the 90-day follow-up. Conclusions We observed that levosimendan was used in accordance with recent recommendations by French physicians. Hypotension and atrial fibrillation remained the most frequent side-effects, while serious adverse event potentially attributable to levosimendan were infrequent. The results suggest that this medication was safe and potentially associated with some benefit in the population studied

Le rôle du vermis cérébelleux dans les processus attentionnels : Étude de deux cas rarissimes avec Rhombecéphalosynapsis

National audienceLe rôle du vermis cérébelleux dans les processus attentionnels est très mal connu, la principale raison étant que ses lésions produisent des désordres cliniques importants dans lesquels les troubles attentionnels sont noyés. Il existe, cependant, des indices rares mais directs suggérant que le vermis fournit des influences modulatrices à des régions cérébrales impliquées dans des fonctions spécifiques. L'existence de connexions avec des aires impliquées dans l'attention (Middleton and Strick, 1998; Muggleton et al., 2003) appuie cette idée. Contrairement aux mouvements oculaires, l'orientation spatiale de l'attention n'est pas affectée par les lésions vermiennes (Machner et al., 2005; Yamaguchi et al., 1998; Golla et al., 2005), d'autres aspects de l'attention semblent touchés. Il s'agit surtout de la prise en compte des informations environnant une cible. En effet, les individus lésés manifestent une réactivité accrue à des cibles lorsque des distracteurs sont présents (Caston et al., 1998 ; Bobée et al., 2000 ; Michael et al., 2009), comme si ces derniers permettait de mieux appréhender les cibles. Il serait attendu, ainsi, que plus le nombre de distracteurs augmente, meilleure serait la détection d'une cible, et que l'absence de distracteurs n'affecte pas la performance. Nous avons directement testé cette hypothèse à l'aide d'un paradigme modifié de recherche visuelle auprès d'enfants normaux et de deux cas avec Rhombencéphalosynapsis (RS), une malformation congénitale rarissime caractérisée par l'absence de vermis et par une fusion médiane des hémisphères cérébelleux. Les deux cas sont d'autant plus rares que leurs fonctions intellectuelles sont intactes, contrairement à la très grande majorité de cas rapportés dans la littérature. Ce travail suggère que le vermis cérébelleux n'est pas impliqué dans les déplacements de l'attention dans l'espace, ni la recherche visuelle malgré la présence éventuelle de troubles oculomoteurs (Machner et al., 2005; Yamaguchi et al., 1998; Golla et al., 2005). Il semble impliqué dans la prise en compte des informations environnant une cible (Caston et al., 1998 ; Bobée et al., 2000 ; Michael et al., 2009). Ces conclusions sont d'autant plus valides que ces déficits semblent sélectifs, qu'ils sont présents dans les performances de deux cas ayant des pathologies identiques et spécifiquement concernant le vermis cérébelleux

Cognitive Decline and Reorganization of Functional Connectivity in Healthy Aging: The Pivotal Role of the Salience Network in the Prediction of Age and Cognitive Performances

Normal aging is related to a decline in specific cognitive processes, in particular in executive functions and memory. In recent years a growing number of studies have focused on changes in brain functional connectivity related to cognitive aging. A common finding is the decreased connectivity within multiple resting state networks, including the default mode network (DMN) and the salience network. In this study, we measured resting state activity using fMRI and explored whether cognitive decline is related to altered functional connectivity. To this end we used a machine learning approach to classify young and old participants from functional connectivity data. The originality of the approach consists in the prediction of the performance and age of the subjects based on functional connectivity by using a machine learning approach. Our findings showed that the connectivity profile between specific networks predicts both the age of the subjects and their cognitive abilities. In particular, we report that the connectivity profiles between the salience and visual networks, and the salience and the anterior part of the DMN, were the features that best predicted the age. Moreover, independently of the age of the subject, connectivity between the salience network and various specific networks (i.e., visual, frontal) predicted episodic memory skills either based on a standard assessment or on an autobiographical memory task, and short-term memory binding. Finally, the connectivity between the salience and the frontal networks predicted inhibition and updating performance, but this link was no longer significant after removing the effect of age. Our findings confirm the crucial role of episodic memory and executive functions in cognitive aging and suggest a pivotal role of the salience network in neural reorganization in aging

Endothelial Cells Activated by Extracellular Histones Promote Foxp3+ Suppressive Treg Cells In Vitro

International audienceHistones are widely recognized as pro-inflammatory mediators upon their release from the nucleus into the extracellular space. However, their impact on endothelial cell immunogenicity is unknown. Endothelial cells, Human Microvascular Endothelial cells 1 (HMEC1), have been exposed to recombinant histones in order to study their effect on the endothelial phenotype. We then studied the differentiation of CD4+-T lymphocytes subpopulations after three days of interaction with endothelial cells in vitro and observed that histone-treated endothelial cells differentiate a suppressive FoxP3+ T regulator subpopulation that expressed Human Leucocyte Antigen DR (HLA-DR) and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA4). Toll-Like Receptor 4 (TLR4) inhibition significantly decreased the expansion of these Treg cells. Moreover, blockade of Interleukin (IL)-6 and Intercellular Adhesion Molecule (ICAM)-1 in cocultures significantly decreased the expansion of Tregs, suggesting an IL-6 and ICAM-1 dependent pathway. Thus, beyond their inflammatory effects, extracellular histones may induce an increase of immunosuppressive Treg population via their action on endothelial cells. Further studies are needed to evaluate the impact on immunosuppression of an increase of peripheral suppressive Treg via endothelial cell activation by histones in vivo

Sex Differences in the Neural Correlates of Specific and General Autobiographical Memory

International audienceAutobiographical memory (AM) underlies the formation and temporal continuity over time of personal identity. The few studies on sex-related differences in AM suggest that men and women adopt different cognitive or emotional strategies when retrieving AMs. However, none of the previous works has taken into account the distinction between episodic autobiographical memory (EAM), consisting in the retrieval of specific events by means of mental time travel, and semantic autobiographical memory (SAM), which stores general personal events. Thus, it remains unclear whether differences in these strategies depend on the nature of the memory content to be retrieved. In the present study we employed functional MRI to examine brain activity underlying potential sex differences in EAM and SAM retrieval focusing on the differences in strategies related to the emotional aspects of memories while controlling for basic cognitive strategies. On the behavioral level, there was no significant sex difference in memory performances or subjective feature ratings of either type of AM. Activations common to men and women during AM retrieval were observed in a typical bilateral network comprising medial and lateral temporal regions, precuneus, occipital cortex as well as prefrontal cortex. Contrast analyses revealed that there was no difference between men and women in the EAM condition. In the SAM condition, women showed an increased activity, compared to men, in the dorsal anterior cingulate cortex, inferior parietal and precentral gyrus. Overall, these findings suggest that differential neural activations reflect sex-specific strategies related to emotional aspects of AMs, particularly regarding SAM. We propose that this pattern of activation during SAM retrieval reflects the cognitive cost linked to emotion regulation strategies recruited by women compared to men. These sex-related differences have interesting implications for understanding psychiatric disorders with differential sex prevalence and in which one of key features is overgenerality in AM

The Power Button Sign: A Newly Described Central Sulcal Pattern on Surface Rendering MR Images of Type 2 Focal Cortical Dysplasia

International audiencePURPOSE:To compare the occurrence of several central sulcus variants and to assess the reproducibility of a sulcal pattern named the power button sign (PBS) in patients with type 2 focal cortical dysplasia (FCD2) and healthy control subjects.MATERIALS AND METHODS:The local institutional review board approved the study, and written informed consent was waived for patients and was obtained from control subjects. Four readers reviewed three-dimensional (3D) T1-weighted magnetic resonance (MR) images in 37 patients (13 with negative MR imaging findings) with histologically proven FCD2 of the central region and 44 control subjects on the basis of a visual analysis of a 3D reconstruction of cortical folds. They searched for central sulcus variations (interruptions, side branches, and connections) and for a particular sulcal pattern, namely, the interposition of a precentral sulcal segment between the central sulcus and one of its hook-shaped anterior ascending branches (ie, PBS). Inter- and intraobserver reliability, specificity, and sensitivity were calculated.RESULTS:The central sulcus showed a greater number of side branches (P < .001) and was more frequently connected to the precentral sulcus (P < .001) in patients with FCD2 than in control subjects. The PBS was found in 23 (62%) of 37 total patients with FCD2, in six (46%) of 13 with negative MR imaging findings, and in only one control subject. Inter- and intraobserver rates were excellent (0.88 and 0.93, respectively) for the detection of PBS. FCD2 was located either in the depth of the ascending branch of the central sulcus (14 of 23, 61%) or in its immediate vicinity (nine of 23).CONCLUSION:Given its excellent reproducibility and specificity, the PBS, when present, could become a useful qualitative diagnostic MR criterion of FCD2 in the central region

The antiangiogenic 16K prolactin disturbs functional tumor neovascularization by affecting vessel maturation

16K hPRL, the antiangiogenic 16-kDa N-terminal fragment of human prolactin was shown to prevent tumor growth and metastasis by modifying tumor vessel morphology. Here we investigated the effect of 16K hPRL on tumor vessel maturation and on the related signaling pathways. We show that 16K hPRL treatment leads, in a murine B16-F10 tumor model, to a dysfunctional tumor vasculature with reduced pericyte coverage, and disruption of the PDGF-B/PDGFR-B, Ang/Tie2, and Delta/Notch pathways. In an aortic ring assay, 16K hPRL impairs endothelial cell and pericyte outgrowth from the vascular ring. In addition, 16K hPRL prevents pericyte migration to endothelial cells. This event was independent of a direct inhibitory effect of 16K hPRL on pericyte viability, proliferation, or migration. In endothelial cell-pericyte cocultures, we found 16K hPRL to disturb Notch signaling, this being the first time such an effect is observed with an endogenous antiangiogenic agent. These findings provide new insights into the mechanisms of 16K hPRL action and highlight its potential for use in anticancer therapy