Aims/hypothesis Aggregation of islet amyloid polypeptide (IAPP) to form amyloid contributes to beta cell dysfunction in type 2 diabetes. Human but not non-amyloidogenic rodent IAPP induces islet macrophage proIL-1β synthesis. We evaluated the effect of IL-1 receptor antagonist (IL-1Ra) on islet inflammation and dysfunction in a mouse model of type 2 diabetes with amyloid formation. Methods Lean and obese male mice (A/a or A vy /A at the agouti locus, respectively) with or without beta cell human IAPP expression (hIAPP Tg/0 ) were treated with PBS or IL-1Ra (50 mg kg) from 16 weeks of age. Intraperitoneal glucose and insulin tolerance tests were performed after 8 weeks. Pancreases were harvested for histology and gene expression analysis. Results Aggregation of human IAPP was associated with marked upregulation of proinflammatory gene expression in islets of obese hIAPP Tg/0 mice, together with amyloid deposition and fasting hyperglycaemia. IL-1Ra improved glucose tolerance and reduced plasma proinsulin:insulin in both lean and obese hIAPP Tg/0 mice with no effect on insulin sensitivity. The severity and prevalence of islet amyloid was reduced by IL-1Ra in lean hIAPP Tg/0 mice, suggesting a feed-forward mechanism by which islet inflammation promotes islet amyloid at the early stages of disease. IL-1Ra limited Il1a, Il1b, Tnf and Ccl2 expression in islets from obese hIAPP Tg/0 mice, suggesting an altered islet inflammatory milieu. Conclusions/interpretation These data provide the first in vivo evidence-using a transgenic mouse model with amyloid deposits resembling those found in human islets-that IAPP-induced beta cell dysfunction in type 2 diabetes may be mediated by IL-1. Anti-IL-1 therapies may limit islet inflammation and dysfunction associated with amyloid formation.
Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette–Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.
Few patients who start with low clinical suspicion for AAV and have positive ANCA are subsequently diagnosed with AAV. Serial ANCA testing is common but is not supported by clear evidence, and rarely leads to change in management. Clarification of guidelines on effective ANCA ordering may reduce hospital laboratory costs.
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