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Digital ulcers (DUs) represent a severe and common complication occurring in patients affected by Systemic Sclerosis (SSc), with a consistent impact on the quality of life and often resulting in longer hospitalization than unaffected patients. Conventional treatment of SSc ulcers consists of both topical and systemic (oral or intravenous) pharmacological therapies. Several surgical options are also available, but there is overall a lack of official guidelines or recommendations. The aim of this study was to evaluate the efficacy of a novel local therapy based on polyurethane foam dressings, namely the Highly Hydrophilic Polyurethane Foam (HPF), in addition to the conventional pharmacological treatment, in a cohort of 41 SSc patients with at least one active ulcer. Our results showed that the addition of HPF to the conventional treatment based on systemic drugs induced i) a significant reduction in the number of active DUs (p=0.0034); ii) a significant reduction of the mean duration of ulcer-related hospitalization as compared with standard therapy (p=0.0001); iii) a significant improvement of patients' Quality of Life, as evaluated through the Scleroderma Health Assessment Questionnaire (SHAQ) (p=0.00011). Therefore, in our experience, the combined management of DUs can improve both the onset of new DUs and DU's healing thus leading to a better outcome.
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OBJECTIVE: To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi-IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0-9) and of CD20+ B cell infiltrate (on a scale of 0-4). B cell scores were validated by digital image analysis and B cell lineage-specific transcript analysis (RNA-Seq) in the early RA (n = 91) and TNFi-IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). RESULTS: Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage-specific transcripts. B cell-rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi-IR cohort (P = 0.025). B cell-rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti-citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell-rich patients were demonstrated in both cohorts. CONCLUSION: We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell-rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA.
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Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Linfocitos B , Sinovitis/complicaciones , Sinovitis/genética , Adulto , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Sinovitis/inmunologíaRESUMEN
Our aim was to identify subclinical right ventricular (RV) alterations in systemic lupus erythematosus (SLE) by combining standard and three-dimensional echocardiography (3DE). Fifty SLE patients without concomitant cardiac disease and 50 healthy controls, matched for age and gender, were enrolled. Disease damage was evaluated by inflammatory markers and SLE damage index. All patients underwent an echo-Doppler examination with 3DE assessment of RV function, RV septal and lateral longitudinal strain. The two groups had comparable body mass index and blood pressure. RV transversal middle diameter and pulmonary arterial pressure were significantly higher in SLE compared to controls. By 3DE, RV end-systolic volume ( p = 0.037) was greater, whereas stroke volume ( p = 0.023), ejection fraction ( p < 0.0001) and septal and lateral longitudinal strain (both p < 0.0001) were lower in SLE. SLE damage index ≥ 1 was negatively associated with tricuspid annular plane systolic excursion (TAPSE) ( p < 0.002), tricuspid E/A ratio ( p = 0.003), RV ejection fraction ( p < 0.05), lateral longitudinal strain ( p < 0.0001) and septal longitudinal strain ( p = 0.04). By separate multivariate models, after adjusting for age, C reactive protein and proBNP, SLE damage index was independently associated with TAPSE ( p = 0.009) and RV lateral longitudinal strain ( p = 0.007). In conclusion, a subclinical RV systolic dysfunction is detectable in SLE by 3DE, RV lateral wall strain being a key parameter. RV dysfunction is associated with cumulative disease damage.
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Ecocardiografía Tridimensional/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Lupus Eritematoso Sistémico/complicaciones , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/etiología , Adulto , Presión Sanguínea , Índice de Masa Corporal , Estudios de Casos y Controles , Ecocardiografía Doppler , Femenino , Humanos , Hipertensión Pulmonar/etiología , Masculino , Persona de Mediana Edad , Análisis de Regresión , Volumen Sistólico , Función Ventricular Derecha , Población BlancaRESUMEN
Dupuytren's disease is a connective tissue disorder of the hand causing excessive palmar fascial fibrosis with associated finger contracture and disability. The aetiology of the disease is heterogeneous, with both genetic and environmental components. The connective tissue is abnormally infiltrated by myofibroblasts that deposit collagen and other extracellular matrix proteins. We describe the clinical profile of Dupuytren's disease along with current therapeutic schemes. Recent findings on molecular and cellular parameters that are dysregulated in Dupuytren's disease, which may contribute to the onset of the disease, and the role of resident inflammation promoting fibrosis, are highlighted. We review recent literature focusing on non-myofibroblast cell types (stem cell-like cells), their pro-inflammatory and pro-fibrotic role that may account for abnormal wound healing response.
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OBJECTIVE: Mast cells may play a role in rheumatoid arthritis (RA), but activation of human mast cells in autoimmune settings has been little studied. Toll-like receptors (TLR) and Fcγ receptors (FcγR) are important receptors for cellular activation in the joint, but expression and stimulation of these receptors in human mast cells or the functional interplay between these pathways is poorly understood. Here, we analysed triggering of human mast cells via these receptors in the context of anti-citrullinated protein antibody-positive (ACPA+) RA. METHODS: RNA and protein expression of TLRs and FcγR was quantified using PCR and flow cytometry, respectively. Mast cells were stimulated with TLR ligands (including HSP70) combined with IgG immune complexes and IgG-ACPA. RESULTS: Human mast cells expressed TLRs and produced cytokines in response to TLR ligands. Both cultured and synovial mast cells expressed FcγRIIA, and triggering of this receptor by IgG immune complexes synergised with activation by TLR ligands, leading to two- to fivefold increased cytokine levels. Mast cells produced cytokines in response to ACPA immune complexes in a citrulline-specific manner, which synergised in the presence of HSP70. CONCLUSIONS: Our data show that synovial mast cells express FcγRIIA and that mast cells can be activated by IgG-ACPA and TLR ligands. Importantly, combined stimulation via TLRs and immune complexes leads to synergy in cytokine production. These findings suggest mast cells are important targets for TLR ligands and immune complexes, and that combined activation of mast cells via these pathways greatly enhances inflammation in synovial tissue of RA patients.
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Mastocitos/inmunología , Péptidos Cíclicos/inmunología , Receptores Toll-Like/biosíntesis , Complejo Antígeno-Anticuerpo/inmunología , Artritis Reumatoide/inmunología , Células Cultivadas , Citocinas/biosíntesis , Regulación de la Expresión Génica/inmunología , Humanos , Inmunoglobulina G/inmunología , Ligandos , Osteoartritis/inmunología , ARN Mensajero/genética , Receptores de IgG/inmunología , Membrana Sinovial/inmunología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunologíaRESUMEN
Eosinophils participate in the immune response against Helicobacter pylori, but little is known about their role in the gastritis associated to the infection. We recently demonstrated that the Hp(2-20) peptide derived from H. pylori accelerates wound healing of gastric mucosa by interacting with N-formyl peptide receptors (FPRs) expressed on gastric epithelial cells. The aim of the present study was to investigate whether eosinophils play a role in the repair of gastric mucosa tissue during H. pylori infection. Immuno-histochemistry and transmission electron microscopy were used to detect eosinophils in gastric mucosal biopsies. Eosinophil re-distribution occurred in the gastric mucosa of H. pylori-infected patients: their density did not change in the deep mucosal layer, whereas it increased in the superficial lamina propria just below the foveolar epithelium; eosinophils entered the epithelium itself as well as the lumen of foveolae located close to the area harboring bacteria, which in turn were also engulfed by eosinophils. The H. pylori-derived peptide Hp(2-20) stimulated eosinophil migration through the engagement of FPR2 and FPR3, and also induced production of VEGF-A and TGF-beta, two key mediators of tissue remodelling. We also demonstrate that Hp(2-20) in vivo induced eosinophil infiltration in rat gastric mucosa after injury brought about by indomethacin. This study suggests that eosinophil infiltrate could modulate the capacity of gastric mucosa to maintain or recover its integrity thereby shedding light on the role of eosinophils in H. pylori infection.
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Proteínas Bacterianas/metabolismo , Eosinófilos/metabolismo , Mucosa Gástrica/metabolismo , Gastritis/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Fragmentos de Péptidos/metabolismo , Receptores de Formil Péptido/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Estudios de Casos y Controles , Células Cultivadas , Quimiotaxis de Leucocito , Enfermedad Crónica , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Eosinófilos/microbiología , Eosinófilos/ultraestructura , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/ultraestructura , Gastritis/inmunología , Gastritis/microbiología , Gastritis/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Inmunohistoquímica , Indometacina , Masculino , Microscopía Electrónica de Transmisión , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Lipoxina/metabolismo , Transducción de Señal , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/inmunología , Úlcera Gástrica/metabolismo , Úlcera Gástrica/microbiología , Factor de Crecimiento Transformador beta/genética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Chronic rhinosinusitis is one of the most frequent chronic diseases in humans. Little is known about stimuli initiating tissue remodeling process that determines the morphological expression of the disease. N-formyl peptide receptors (FPRs) are innate immunity receptors important in tissue remodeling of gastric and intestinal epithelium. The expression and functions of FPRs in nasal epithelial cells were examined to evaluate whether they could be important in the remodeling of nasal mucosa. The aim of this study is to examine FPR expression in a nasal epithelial cell line (RPMI-2650) at mRNA and protein levels. To determine whether FPRs were functional, chemotaxis experiments were carried out. In addition the effects of FPRs agonists on the expression (PCR and ELISA) of VEGF-A and TGF-beta, two key mediators of tissue remodelling, were examined. Here we demonstrate that RPMI-2650 express FPR and FPRL2, but not FPRL1. fMLP, a bacterial product active on FPR, and uPAR(84-95), an inflammatory mediator agonist for FPRL2, stimulated migration of nasal epithelial cells. fMLP and uPAR(84-95) induce expression and secretion of VEGF-A and TGF-beta. Our results suggest a possible mechanisms initiating tissue remodeling observed during chronic rhinosinusitis. This study provides further evidence that FPRs play a more complex role in human pathophysiology than bacterial recognition.