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Background Increased IL-17A production has been associated with more severe asthma, however the mechanisms whereby IL-17A may contribute to IL-13-driven pathology in asthma remain unclear. Objective We sought to gain mechanistic insight into how IL-17A can influence IL-13-driven responses. Methods The effect of IL-17A on IL-13-induced airway hyperresponsiveness (AHR), gene expression, mucus hypersecretion, and airway inflammation was assessed using in vivo models of IL-13-induced lung pathology and in vitro culture of murine fibroblast cell lines and primary fibroblasts, and human epithelial cell lines or primary human epithelial cells exposed to IL-13, IL-17A, or IL-13 and IL-17A. Results Compared to mice given intratracheal IL-13 alone, those exposed to IL-13 and IL-17A displayed augmented AHR, mucus production, airway inflammation and IL-13-induced gene expression. In vitro, IL-17A enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating influence of IL-17A on IL-13-induced responses, co-exposure to IL-13 inhibited IL-17A-driven antimicrobial gene expression in vivo and in vitro. Mechanistically, in both primary human and murine cells, IL-17A-driven elevation of IL-13-induced gene expression was associated with enhanced IL-13-driven STAT6 activation. Conclusions Our data suggest that IL-17A contributes to asthma pathophysiology by increasing the capacity of IL-13 to activate intracellular signaling pathways such as STAT6. These data represent the first mechanistic explanation of how IL-17A may directly contribute to the pathogenesis of IL-13-driven pathology.

AimsMyeloproliferative neoplasms (MPN) are a heterogeneous group of clonal proliferative bone marrow diseases characterised by extensive megakaryocytic hyperplasia and morphological atypia. Despite knowledge of genomic defects, the pathobiological processes driving these megakaryocytic abnormalities in MPN remain poorly explained. We have explored the proliferative, apoptotic and epigenetic profiles of megakaryocytes in human MPN.MethodsImmunohistochemical staining was performed on bone marrow trephine biopsies of 81 MPN (with and withoutJAK2V617FandCALRmutations) and 15 normal controls to assess the megakaryocytic expression of biomarkers associated with proliferation (Ki67), apoptosis (Bcl-XL, BNIP-3) and epigenetic regulation (EZH2, SUZ12).ResultsMyeloproliferative megakaryocytes showed significantly greater expression of proliferative Ki67 and anti-apoptotic Bcl-XL, reduced pro-apoptotic BNIP-3 and increased SUZ12 compared with controls. In essential thrombocythaemia, large-giant megakaryocytes with hyperlobated nuclei showed a trend towards a proliferative signature. In contrast, myelofibrotic megakaryocytes with condensed nuclear chromatin, and cases withCALRmutations, had significant reductions in pro-apoptotic BNIP-3.ConclusionsUncontrolled megakaryocytic expansion in MPN results from a combination of increased proliferation, attenuated apoptosis and defective epigenetic regulation withCALRmutations favouring apoptotic failure. The higher platelet counts reported to be seen in MPN withCALRmutations may be due to greater dysregulation of megakaryocyte apoptosis.

Background: Early discharge programmes in hospitals are encouraged to increase financial efficiency and bed availability, but standards of clinical care must not be compromised. Criteria for safe hospital discharge must be established and objective data are needed to assess how rapidly patients can achieve these discharge criteria. Methods: A prospective study was performed on 65 patients (mean age = 71 years) scheduled for primary total hip arthroplasty (THA). The Modified Barthel Index (MBI) was measured pre-operatively and postoperatively at set intervals to assess recovery of function after THA. A score of 90 out of a possible 100 was used as a discharge criterion and indicated that the patient was functionally independent for safe hospital discharge. In addition, a combined score for thigh flexion and extension isokinetic peak strength was recorded for each patient before and after surgery. The number and nature of comorbidities and complications were also recorded. Results:The length of hospital stay in this sample varied from 5 to 39 days. The MBI scores increased rapidly between days 3 and 5, then began to plateau from day 8 onwards. Based on the MBI, 58% of patients were fit for discharge at or before day 8. The remainder were fit for discharge from day 10 onwards (mean = 14.2 days). The latter group who required an extended hospital stay were older ( P = 0.003). had more identified comorbidities ( P = 0.01) and were weaker in their hip musculature prior to surgery ( P = 0.01). compared to those who were discharged by day 8. A logistic regression analysis indicated that the pre-operative MBI score and hip strength score were strong predictors of timing for hospital discharge. Conclusions: A clinical pathway with functional milestones laid out over 8 days would be an appropriate criterion for the discharge of the majority of patients. However, approximately 40% of the patients presented in this study required a longer hospital stay before the criteria for safe discharge could be achieved. These patients can be identified pre-operatively by screening their MBI and composite hip strength scores.