Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

Background: Synovial tissue fibrosis is common in advanced OA with features including the presence of stress fiber-positive myofibroblasts and deposition of cross-linked collagen type-I. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. PRG4 is a ligand of the CD44 receptor. Our objective was to examine the role of PRG4-CD44 interaction in regulating synovial tissue fibrosis in vitro and in vivo. Methods: OA synoviocytes were treated with TGF-β ± PRG4 for 24h and α-SMA content was determined using immunofluorescence. Rhodamine-labeled rhPRG4 was incubated with OA synoviocytes ± anti-CD44 or isotype control antibodies and cellular uptake of rhPRG4 was determined following a 30-min incubation and α-SMA expression following a 24-h incubation. HEK-TGF-β cells were treated with TGF-β ± rhPRG4 and Smad3 phosphorylation was determined using immunofluorescence and TGF-β/Smad pathway activation was determined colorimetrically. We probed for stress fibers and focal adhesions (FAs) in TGF-β-treated murine fibroblasts and fibroblast migration was quantified ± rhPRG4. Synovial expression of fibrotic markers: α-SMA, collagen type-I, and PLOD2 in Prg4 gene-trap (Prg4GT) and recombined Prg4GTR animals were studied at 2 and 9 months of age. Synovial expression of α-SMA and PLOD2 was determined in 2-month-old Prg4GT/GT&Cd44−/− and Prg4GTR/GTR&Cd44−/− animals. Results: PRG4 reduced α-SMA content in OA synoviocytes (p \u3c 0.001). rhPRG4 was internalized by OA synoviocytes via CD44 and CD44 neutralization attenuated rhPRG4’s antifibrotic effect (p \u3c 0.05). rhPRG4 reduced pSmad3 signal in HEKTGF- β cells (p \u3c 0.001) and TGF-β/Smad pathway activation (p \u3c 0.001). rhPRG4 reduced the number of stress fiberpositive myofibroblasts, FAs mean size, and cell migration in TGF-β-treated NIH3T3 fibroblasts (p \u3c 0.05). rhPRG4 inhibited fibroblast migration in a macrophage and fibroblast co-culture model without altering active or total TGF-β levels. Synovial tissues of 9-month-old Prg4GT/GT animals had higher α-SMA, collagen type-I, and PLOD2 (p \u3c 0.001) content and Prg4 re-expression reduced these markers (p \u3c 0.01). Prg4 re-expression also reduced α-SMA and PLOD2 staining in CD44-deficient mice. Conclusion: PRG4 is an endogenous antifibrotic modulator in the joint and its effect on myofibroblast formation is partially mediated by CD44, but CD44 is not required to demonstrate an antifibrotic effect in vivo

Cleaning the carbon market! Market transparency and market efficiency in the EU ETS

International audienceThis paper revisits the informational efficiency of the EU ETS at a micro level, by introducing a novel time variant structural decomposition of variance. The new modelling introduces GARCH-like effects into a structural price modelling. With this, all variance components, including public information and price discreteness, can be estimated, for the first time, in a continuously updated setup that is free of sampling bias. The empirical findings report that although all variance components decrease in magnitude, this is primarily due to higher overall market liquidity that results in less price discovery per trade. On a proportional basis, though, the EU ETS appears to be increasingly inefficient prior to the introduction of MiFID II rules, with the situation reversing after their implementation. This is evidence that transparency is vital in rendering emission allowances a policy rather than a speculative instrument

Overview of challenges of residential nearly Zero Energy Buildings (nZEB) in Southern Europe

In times of great transition of the European construction sector to energy efficient and nearly zero energy buildings (nZEBs), a market observation containing qualitative and quantitative indications should help to fill out the enormous information gaps concerning the EU 2020 carbon targets. Next to the economic challenges, there are equally important factors that hinder renovating the existing residential building stock and adding newly constructed high performance buildings. Under these circumstances this paper summarizes the findings of a cross-comparative study of the societal and technical barriers of nZEBs implementation in 7 Southern European countries. The aim of the study was to enhance the understanding and provide and overview on future challenges of residential nZEBs in Southern Europe. The result presents an overview of challenges and provides recommendations based on available empirical evidence to further lower those barriers in the European construction sector. The paper finds that the most Southern European countries are poorly prepared for nZEBs implementation and especially for existing buildings. It is essential creating a common approach to further develop nZEBs concepts and definitions in adaptation with the climatic, societal and technical state of progress in Southern Europe. The paper provides suggestions for minimum energy efficiency and renewable energy thresholds to shift the identified gaps into opportunities for future development in deep renovation of buildings.2n

Soft tissue pseudotumours: A pictorial review with emphasis on MRI

Background: Several tumour-like conditions of the soft tissues may be encountered in clinical practice, or when patients undergo radiologic examinations. Al-though advances in cross sectional imaging (ultra-sound, MDCT and MRI) play a pivotal role in the correct evaluation of tumour-like lesions, a systematic approach is needed to achieve a definitive diagnosis or limit the differential diagnosis. Clinical history, physical examination and anatomic location are of paramount importance. Methods: In this pictorial essay we review some of the most frequent benign soft tissue conditions which may be mistaken for malignancy and thus lead to need-less referrals, unnecessary biopsies and great anxi-ety to the patients and their carers. Level of evidence: IV. © 2017, CIC Edizioni Internazionali s.r.l. All rights reserved

Normocortisolemic Cushing’s Syndrome Initially Presenting with Increased Glucocorticoid Receptor Numbers1

A girl who developed Cushingoid features in peripuberty, but was eucortisolemic, was previously reported to have markedly elevated lymphocyte glucocorticoid receptor sites per cell with normal binding affinity as a potential cause of her phenotype. Her circadian rhythm of cortisol and pituitary-adrenal axis were initially intact, but later proved to be dysregulated. The patient presented at age 10.8 yr with centripetal obesity, moon facies, buffalo hump, and purple striae, but no statural stunting, which is a cardinal sign of Cushing’s syndrome. At 11.5 yr she suffered a compression fracture of the L1 vertebra. That prompted treatment with the antiprogestin drug mifepristone (RU486), which was administered at high dose to achieve an antiglucocorticoid effect. From ages 13.75 yr through 15.5 yr, RU486 was administered in various intervals to suppress her Cushingoid features. Once RU486 was introduced, however, a consistent correlation over time between the Cushingoid features and glucocorticoid receptor sites per cell was no longer observed. However, the number of glucocorticoid receptor sites per cell tended to decrease in response to administering RU486. Ultimately, her Cushingoid phenotype proved to be transient.</jats:p