Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio

Cryopyrin-Associated Periodic Syndrome: An Update on Diagnosis and Treatment Response

Cryopyrin-associated periodic syndrome (CAPS) is a rare hereditary inflammatory disorder encompassing a continuum of three phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease. Distinguishing features include cutaneous, neurological, ophthalmologic, and rheumatologic manifestations. CAPS results from a gain-of-function mutation of the NLRP3 gene coding for cryopyrin, which forms intracellular protein complexes known as inflammasomes. Defects of the inflammasomes lead to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS. Diagnosis is often delayed and requires a thorough review of clinical symptoms. Remarkable advances in our understanding of the genetics and the molecular pathway that is responsible for the clinical phenotype of CAPS has led to the development of effective treatments. It also has become clear that the NLRP3 inflammasome plays a critical role in innate immune defense and therefore has wider implications for other inflammatory disease states

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

S

Evaluatie pilootproject leerlingenvervoer

status: accepte

Activity Participation and Perceptions on Informal Public Transport and Bus Rapid Transit in Dar es Salaam

This paper seeks to understand participation in out-of-home activities by inhabitants in Dar es Salaam, and their perceptions toward informal public transport (IPT) and bus rapid transit (BRT) in supporting these activities. Without fixed schedules, IPT (e.g., minibuses, motorcycles, and tricycles) is used as a means of transport for different trips. However, IPT is burdened by poor roads, traffic congestion, and high transport demand. Many developing cities are seeking to replace IPT with formal BRT lines. However, little is known in relation to the ability of IPT and BRT to support out-of-home activity participation of the inhabitants. This paper reports on a study in Dar es Salaam exploring the relative contribution of each type of service. The study took place before the opening of BRT, and encompasses focus group discussions, participatory geographical information systems, and questionnaires carried out in two study zones: one close to a BRT corridor and the other in a peri-urban location. The findings show that IPT was used to support participation in daily activities like work, education, shopping, and social matters; and was perceived to be flexible in providing access to both high and low density unplanned settlements. The BRT was viewed to benefit specific groups of people, especially individuals working in permanent offices in and around the city center, particularly professional workers. This paper sheds light on how the two systems were perceived by the local people and can inform policy makers about possible improvements in public transport systems to support activity participation of their inhabitants