uPARAP/Endo180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion

The uptake and lysosomal degradation of collagen by fibroblasts constitute a major pathway in the turnover of connective tissue. However, the molecular mechanisms governing this pathway are poorly understood. Here, we show that the urokinase plasminogen activator receptor–associated protein (uPARAP)/Endo180, a novel mesenchymally expressed member of the macrophage mannose receptor family of endocytic receptors, is a key player in this process. Fibroblasts from mice with a targeted deletion in the uPARAP/Endo180 gene displayed a near to complete abrogation of collagen endocytosis. Furthermore, these cells had diminished initial adhesion to a range of different collagens, as well as impaired migration on fibrillar collagen. These studies identify a central function of uPARAP/Endo180 in cellular collagen interactions

Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality:a cluster-randomized clinical trial (TRIAGE III)

Abstract Background Risk stratification of patients in the emergency department can be strengthened using prognostic biomarkers, but the impact on patient prognosis is unknown. The aim of the TRIAGE III trial was to investigate whether the introduction of the prognostic and nonspecific biomarker: soluble urokinase plasminogen activator receptor (suPAR) for risk stratification in the emergency department reduces mortality in acutely admitted patients. Methods The TRIAGE III trial was a cluster-randomized interventional trial conducted at emergency departments in the Capitol Region of Denmark. Eligible hospitals were required to have an emergency department with an intake of acute medical and surgical patients and no previous access to suPAR measurement. Three emergency departments were randomized; one withdrew shortly after the trial began. The inclusion period was from January through June of 2016 consisting of twelve cluster-periods of 3-weeks alternating between intervention and control and a subsequent follow-up of ten months. Patients were allocated to the intervention if they arrived in interventional periods, where suPAR measurement was routinely analysed at arrival. In the control periods suPAR measurement was not performed. The main outcome was all-cause mortality 10 months after arrival of the last patient in the inclusion period. Secondary outcomes included 30-day mortality. Results The trial enrolled a consecutive cohort of 16,801 acutely admitted patients; all were included in the analyses. The intervention group consisted of 6 cluster periods with 8900 patients and the control group consisted of 6 cluster periods with 7901 patients. After a median follow-up of 362 days, death occurred in 1241 patients (13.9%) in the intervention group and in 1126 patients (14.3%) in the control group. The weighted Cox model found a hazard ratio of 0.97 (95% confidence interval, 0.89 to 1.07; p = 0.57). Analysis of all subgroups and of 30-day all-cause mortality showed similar results. Conclusions The TRIAGE III trial found no effect of introducing the nonspecific and prognostic biomarker suPAR in emergency departments on short- or long-term all-cause mortality among acutely admitted patients. Further research is required to evaluate how prognostic biomarkers can be implemented in routine clinical practice. Trial registration clinicaltrials.gov, NCT02643459. Registered 31 December 2015

Beneficial effects of ramipril on left ventricular end-diastolic and end-systolic volume indexes after uncomplicated invasive revascularization are associated with a reduction in cardiac events in patients with moderately impaired left ventricular function and no clinical heart failure

AbstractOBJECTIVESWe sought to assess the effect of ramipril on left ventricular (LV) volumes, and the clinical significance thereof, in patients with moderate LV dysfunction and no clinical heart failure undergoing invasive revascularization for chronic stable angina.BACKGROUNDIt is unsettled whether treatment with an angiotensin-converting enzyme inhibitor has an impact on LV volumes in this patient group, and, if so, whether this is associated with the clinical outcome.METHODSA total of 133 patients with a left ventricular ejection fraction (LVEF) between 0.30 and 0.50 and no clinical heart failure undergoing invasive revascularization for chronic stable angina were randomized to receive ramipril 10 mg once daily or placebo and were followed for a median of 33 months with echocardiography at baseline and 3, 12 and 24 months postoperatively.RESULTSRepeated measures analysis of all time points showed that ramipril significantly reduced the end-diastolic volume index (EDVI) (p = 0.032) and end-systolic volume index (ESVI) (p = 0.006) as compared with placebo. Ramipril also reduced the incidence of the triple composite end point of cardiac death, acute myocardial infarction or development of heart failure (p = 0.046). Cox regression analysis, controlling for baseline LVEF and assignment to ramipril, revealed: 1) that increases in EDVI and ESVI up to three months predicted an increasing risk of a future adverse clinical outcome; and 2) that the benefit with ramipril on clinical outcome was partly dependent on a reduction in LV volumes.CONCLUSIONSEven in this patient group, LV dilation may supervene and lead to an adverse clinical outcome. Ramipril reduces the postoperative increase in LV volumes and may thereby improve clinical outcome