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Hepatic encephalopathy (HE) is highly prevalent in patients with liver diseases. The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation. However, some data suggest altered functioning of the blood–brain barrier (BBB). Assessing BBB function is challenging in clinical practice and at the bedside. Protein-S-100 Beta (PS100-Beta) could be a useful peripheral marker of BBB permeability in HE. This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit (ICU) with decompensated cirrhosis with and without overt HE.

PAR2 activation in basal keratinocytes stimulates inflammation via the Ca2+-dependent production of mediators such as IL-1β, TNF-α, and TSLP. In this study, we investigated PAR2 calcium signaling and the consequent production of inflammatory mediators in differentiated human primary keratinocytes (DhPKs). Stimulation with the PAR2-activating peptide SLIGKV promoted Ca2+store depletion in both undifferentiated human primary keratinocytes and DhPKs. SLIGKV-evoked Ca2+store depletion did not trigger the store-operated Ca2+entry (i.e., SOCE) through ORAI1 in DhPKs compared with undifferentiated human primary keratinocytes. The inhibition of phospholipase C and the concomitant inhibition of TRPV1 and inositol triphosphate receptor in DhPKs abrogated the SLIGKV-evoked Ca2+store depletion; NF-κB activity; and the production of inflammatory mediators such as IL-1β, TNF-α, and TSLP. Taken together, these results indicate a key role for both InsP3R and TRPV1 in Ca2+internal stores in the PAR2-evoked Ca2+release and consequent skin inflammation in DhPKs. These findings may provide clues to understanding the pathological role of DhPKs in skin disorders in which PAR2 is known to be involved, such as atopic dermatitis, Netherton syndrome, and psoriasis.

Bien que l’hypophosphorémie soit rare dans la population générale, elle atteint deux à 3 % des patients hospitalisés et jusqu’à 28 % des patients de soins intensifs. Compte tenu du manque de connaissances sur l’impact de ce facteur, les pratiques cliniques concernant la recherche et le traitement de l’hypophosphorémie sont très hétérogènes. Pourtant, ses conséquences cliniques peuvent être graves. Mieux connaître les causes de l’hypophosphorémie, ses effets et son traitement pourrait permettre d’établir, dans les services de soins, une prise en charge documentée et homogène de ces situations.

Cutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.

La culture de neurones sensoriels animaux est un modèle in vitro couramment utilisé pour l’étude de l’inflammation neurogène, de la douleur ou du prurit. Cependant, cela pose des problèmes éthiques et d’extrapolation des résultats à l’homme. Depuis quelques années, des travaux ont mis en évidence la possibilité de différencier des iPS (cellules souches pluripotentes induites) ou des ES (cellules souches embryonnaires) en cellules ayant des caractéristiques de neurones sensoriels. Dans la plupart de ces travaux, ces neurones sont obtenus en deux étapes principales. Dans un premier temps, des cellules ES ou des iPS sont différenciées en cellules exprimant des marqueurs de précurseurs neuronaux et de la crête neurale. Puis dans un second temps, l’induction de la voie Wnt et/ou BMP permet la différenciation terminale. Nous avons cherché à savoir s’il était possible de différencier directement des cellules souches dérivées de la crête neurale en neurones sensoriels.

L’activation de PAR-2 dans les kératinocytes basaux renforce l’inflammation cutanée et le prurit par des mécanismes dépendants du calcium et la production de cytokines inflammatoires telles que la TSLP et le TNF-α. Cependant, dans la plupart des études, seuls les kératinocytes primaires issus de la couche basale de l’épiderme sont utilisés pour analyser le rôle de PAR-2 dans l’inflammation cutanée et le prurit. Nous avons étudié sur des cultures primaires de kératinocytes différenciés l’implication de PAR-2 sur la régulation des voies calciques et par conséquent, la modulation de gènes impliqués dans l’inflammation.

Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci:Agios: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Introduction:Fetal hemoglobin (HbF) expression is a major modulator of sickle cell disease (SCD) severity by decreasing the HbS polymerization. However, the distribution of HbF in red blood cells (RBC) is heterogeneous in SCD patients. In the hypothesis of an HbF “threshold” in RBCs for inhibiting the HbS polymerization, accurate measurement of the HbF content in each red blood cell (HbF/RBC) is mandatory. To this purpose we developed a new and accurate method allowing the direct measurement of HbF content per RBC. Thanks to it, as a proof of concept, we analyzed HbF distribution and content in RBC from SCD patients before and after 6 months of treatment by hydroxyurea (HU). To determine if a threshold of HbF/RBC could modulate SCD, we analyzed the associations between the %RBC reaching different thresholds of HbF (in picograms), and biological parameters and the incidence of severe VOC.