Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche(1,2). Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor alpha (PPAR-alpha)(3), and lowered PPAR-a activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.Peer reviewe

The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitisA and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitisB in perforated diverticulitis (NTR2037)

Background: Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy. The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis). Methods/Design: In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and powe

Permanent work disability in patients ≤50 years old after percutaneous coronary intervention and coronary artery bypass grafting (the CRAGS study)

Abstract Background: The aim of this study was to investigate the incidence of permanent working disability (PWD) in young patients after percutaneous or surgical coronary revascularization. Methods and Results: The study included 1035 consecutive patients ≤50 years old who underwent coronary revascularization [910 and 125 patients in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) groups, respectively] between 2002 and 2012 at 4 Finnish hospitals. The median follow-up time was 41 months. The overall incidence of PWD was higher after CABG compared to PCI (at 5 years, 34.8 vs. 14.7%, P < 0.001). Freedom from PWD in the general population aged 45 was 97.2% at 4 years follow-up. Median time to grant disability pension was 11.6 months after CABG and 24.4 months after PCI (P = 0.018). Reasons for PWD were classified as cardiac (35.3 vs. 36.9%), psychiatric (14.7 vs. 14.6%), and musculoskeletal (14.7 vs. 15.5%) in patients undergoing CABG vs. PCI. Overall freedom from PWD was higher in patients without major adverse cardiac and cerebrovascular event (MACCE) (at 5 years, 85.6 vs. 71.9%, P < 0.001). Nevertheless, rate of PWD was high also in patients without MACCE and patients with preserved ejection fraction during follow-up. Conclusions: Although coronary revascularization confers good overall survival in young patients, PWD is common especially after CABG and mostly for cardiac reasons even without occurrence of MACCE. Supportive measures to preserve occupational health are warranted concomitantly with coronary revascularization at all levels of health care