CD47 fusion protein targets CD172a+ cells in Crohn’s disease and dampens the production of IL-1β and TNF

In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell–driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn’s disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX(3)CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(−)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD

Inappropriate Prescription of Proton Pump Inhibitors in a Community Setting

ABSTRACTBackground: Proton pump inhibitors (PPIs) are widely prescribed for gastrointestinal conditions, such as gastroesophageal reflux disease and dyspepsia, and for prevention of gastric ulcer. Although previous reportshave described inappropriate prescription of PPIs in the hospital setting, data from the community are lacking.Objective: To assess PPI prescriptions in the ambulatory setting.Methods: Patients presenting to the emergency department of a teaching hospital between June 2016 and March 2017 were prospectively assessed for use of a PPI at home. The appropriateness of PPI prescription wasevaluated on the basis of an interview with the patient and review of the medical record. The indication for PPI therapy was verified against current guidelines for the province of Quebec.Results: Over the 9-month study period, 2417 patients were screened, of whom 871 were included in the study. In relation to the Quebec guidelines, PPI prescription was inappropriate for 267 (30.7%) of the patients. When prescription of PPI for ulcer prevention in certain groups of patients (age ≥ 65 years and using acetylsalicylic acid or platelet aggregation inhibitors; age ≥ 75 years and using celecoxib) was re-classified as appropriate, the proportion of inappropriate PPI prescriptions declined to 20.3% (177/871).Conclusions: These findings suggest that inappropriate prescribing of PPIs remains problematic in the community setting in the province of Quebec.RÉSUMÉContexte : Les inhibiteurs de la pompe à protons (IPP) sont largement prescrits pour traiter les troubles gastro-intestinaux, comme le reflux gastro-oesophagien et la dyspepsie, et pour prévenir l’ulcère gastrique. Bienque des rapports antérieurs aient parlé de la prescription inadéquate des IPP dans les établissements de santé, il n’y a pas de données provenant de la communauté.Objectif : Évaluer la pertinence des prescriptions d’IPP dans un milieu ambulatoire.Méthodes : Les patients se présentant au service des urgences d’un hôpital universitaire entre juin 2016 et mars 2017 ont été évalués de façon prospective relativement à l’utilisation d’un IPP à la maison. La pertinence de la prescription d’un IPP a été jugée d’après une entrevue avec le patient et l’analyse du dossier médical. On a vérifié si l’indication pour un traitement par IPP respectait les lignes directrices actuelles du Québec.Résultats : Sur une période de neuf mois, 2 417 patients ont été évalués et 871 d’entre eux ont été admis à l’étude. Par rapport aux lignes directrices du Québec, la prescription d’IPP était inadéquate pour 267 (30,7 %) des patients. Or, si la prescription d’IPP pour prévenir l’ ulcère gastrique chez certains groupes de patients (âgés de 65 ans ou plus et prenant de l’acide acétylsalicylique ou un antiagrégant plaquettaire; âgés de 75 ans ou plus et prenant du célécoxib) était reclassée comme adéquate, la proportion de prescriptions d’IPP inadéquates reculait à 20,3 % (177/871).Conclusions : Ces résultats laissent croire que les prescriptions inadéquates d’IPP demeurent un problème dans le contexte communautaire au Québec

Reduced plasma dehydroepiandrosterone sulfate levels are significantly correlated with fatigue severity in patients with primary biliary cirrhosis.

Fatigue is a common debilitating complication of primary biliary cirrhosis (PBC), the pathophysiologic mechanism of which is poorly understood. Recently, the neuroactive steroid dehydroepinadrosterone sulfate (DHEAS) was reported to be implicated in Chronic Fatigue Syndrome in the absence of liver disease. The present study was undertaken to analyse fatigue scores and their relationship with disease severity and circulating levels of DHEAS as well as its precursors DHEA and pregnenolone in PBC patients with (n=15) or without fatigue (n=10) compared to control subjects (n=11). Fatigue was assessed using the fatigue impact scale (FIS) including cognitive, physical and psychosocial subclasses. Steroids were measured by radioimmunoassay or gas chromatography/mass spectrometry. Plasma concentrations of DHEAS were significantly reduced in PBC patients with fatigue as compared to controls, while those of its precursors DHEA and pregnenolone remained within the control range. Plasma levels of DHEAS in PBC patients were significantly correlated with fatigue severity as reflected by total FIS scores including total (rp=-0.42; p=0.018), as well as the cognitive (rp=-0.37; p=0.03), physical (rp=-0.48; p=0.006) and psychosocial (rp=-0.35; p=0.04) subclasses of fatigue scores. No correlation of fatigue scores was observed with indices of liver function. These findings suggest that reduced levels of the neurosteroid DHEAS may contribute to fatigue in patients with PBC; substitutive therapy using DHEAS or its precursor DHEA could be beneficial in the management of fatigue in patients with low levels of DHEAS

CD47 fusion protein targets CD172a+ cells in Crohn's disease and dampens the production of IL-1β and TNF.

In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(-)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe