Autoimmune rheumatic disease IgG has differential effects upon neutrophil integrin activation that is modulated by the endothelium

The importance of neutrophils in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), is increasingly recognised. Generation of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs) by activated neutrophils are both thought to contribute to pathology; although the underlying mechanisms, particularly the effects of IgG autoantibodies upon neutrophil function, are not fully understood. Therefore, we determined whether purified IgG from patients with SLE or RA have differential effects upon neutrophil activation and function. We found that SLE- and RA-IgG both bound human neutrophils but differentially regulated neutrophil function. RA- and SLE-IgG both increased PMA-induced β1 integrin-mediated adhesion to fibronectin, whilst only SLE-IgG enhanced αMβ2 integrin-mediated adhesion to fibrinogen. Interestingly, only SLE-IgG modulated neutrophil adhesion to endothelial cells. Both SLE- and RA-IgG increased ROS generation and DNA externalisation by unstimulated neutrophils. Only SLE-IgG however, drove DNA externalisation following neutrophil activation. Co-culture of neutrophils with resting endothelium prevented IgG-mediated increase of extracellular DNA, but this inhibition was overcome for SLE-IgG when the endothelium was stimulated with TNF-α. This differential pattern of neutrophil activation has implications for understanding SLE and RA pathogenesis and may highlight avenues for development of novel therapeutic strategies

Identification of a Novel HIF-1α-α_{M}β_{2} Integrin-NET Axis in Fibrotic Interstitial Lung Disease

Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) particularly in the most severe form, idiopathic pulmonary fibrosis (IPF), although the underlying mechanisms remain unclear. Neutrophil function is modulated by numerous factors, including integrin activation, inflammatory cytokines and hypoxia. Hypoxia has an important role in inflammation and may also contribute to pulmonary disease. We aimed to determine how neutrophil activation occurs in ILD and the relative importance of hypoxia. Using lung biopsies and bronchoalveolar lavage (BAL) fluid from ILD patients we investigated the extent of hypoxia and neutrophil activation in ILD lungs. Then we used ex vivo neutrophils isolated from healthy volunteers and BAL from patients with ILD and non-ILD controls to further investigate aberrant neutrophil activation in hypoxia and ILD. We demonstrate for the first time using intracellular staining, HIF-1α stabilization in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous (+1.31-fold, p < 0.05) and phorbol 12-myristate 13-acetate (PMA)-induced (+1.65-fold, p < 0.001) neutrophil extracellular trap (NET) release, neutrophil adhesion (+8.8-fold, <0.05), and trans-endothelial migration (+1.9-fold, p < 0.05). Hypoxia also increased neutrophil expression of the αM (+3.1-fold, p < 0.001) and αX (+1.6-fold, p < 0.01) integrin subunits. Interestingly, NET formation was induced by αMβ2 integrin activation and prevented by cation chelation. Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. In conclusion, HIF-1α upregulation may augment neutrophil recruitment and activation within the lung interstitium through activation of β2 integrins. Our results identify a novel HIF-1α- αMβ2 integrin axis in NET formation for future exploration in therapeutic approaches to fibrotic ILD

MRI in multiple myeloma : a pictorial review of diagnostic and post-treatment findings

Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity. This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message aEuro cent Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. aEuro cent Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. aEuro cent Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. aEuro cent Combined morphological and functional MRI provides optimal bone marrow assessment for staging. aEuro cent Combined morphological and functional MRI is of considerable value in treatment follow-up

MMS observations of electron-scale filamentary currents in the reconnection exhaust and near the X line

© 2016. American Geophysical Union. All Rights Reserved.We report Magnetospheric Multiscale observations of macroscopic and electron-scale current layers in asymmetric reconnection. By intercomparing plasma, magnetic, and electric field data at multiple crossings of a reconnecting magnetopause on 22 October 2015, when the average interspacecraft separation was ~10km, we demonstrate that the ion and electron moments are sufficiently accurate to provide reliable current density measurements at 30ms cadence. These measurements, which resolve current layers narrower than the interspacecraft separation, reveal electron-scale filamentary Hall currents and electron vorticity within the reconnection exhaust far downstream of the X line and even in the magnetosheath. Slightly downstream of the X line, intense (up to 3μA/m2) electron currents, a super-Alfvénic outflowing electron jet, and nongyrotropic crescent shape electron distributions were observed deep inside the ion-scale magnetopause current sheet and embedded in the ion diffusion region. These characteristics are similar to those attributed to the electron dissipation/diffusion region around the X line

Proximity to Sports Facilities and Sports Participation for Adolescents in Germany

Objectives - To assess the relationship between proximity to specific sports facilities and participation in the corresponding sports activities for adolescents in Germany. Methods - A sample of 1,768 adolescents aged 11–17 years old and living in 161 German communities was examined. Distances to the nearest sports facilities were calculated as an indicator of proximity to sports facilities using Geographic Information Systems (GIS). Participation in specific leisure-time sports activities in sports clubs was assessed using a self-report questionnaire and individual-level socio-demographic variables were derived from a parent questionnaire. Community-level socio-demographics as covariates were selected from the INKAR database, in particular from indicators and maps on land development. Logistic regression analyses were conducted to examine associations between proximity to the nearest sports facilities and participation in the corresponding sports activities. Results - The logisitic regression analyses showed that girls residing longer distances from the nearest gym were less likely to engage in indoor sports activities; a significant interaction between distances to gyms and level of urbanization was identified. Decomposition of the interaction term showed that for adolescent girls living in rural areas participation in indoor sports activities was positively associated with gym proximity. Proximity to tennis courts and indoor pools was not associated with participation in tennis or water sports, respectively. Conclusions - Improved proximity to gyms is likely to be more important for female adolescents living in rural areas

The homocysteine controversy

Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions

Magnetic structure of Sm2IrIn8 determined by x-ray resonant magnetic scattering

The magnetic structure of the intermetallic antiferromagnet Sm2IrIn8 was determined using x-ray resonant magnetic scattering. Below T-N=14.2 K, Sm2IrIn8 has a commensurate antiferromagnetic structure with a propagation vector eta=(1/2,0,0). The Sm magnetic moments lie in the ab plane and are rotated roughly 18 degrees away from the a axis. The magnetic structure of this compound was obtained by measuring the strong dipolar resonant peak whose enhancement was of over 2 orders of magnitude at the L-2 edge. At the L-3 edge, both quadrupolar and dipolar features were observed in the energy line shape. The magnetic structure and properties of Sm2IrIn8 are found to be consistent with the general trend already seen for the Nd-, Tb-, and the Ce-based compounds from the RmMnIn3m+2n family (R=rare earth; M=Rh or Ir; m=1,2; n=0,1), where the crystalline electrical field effects determine the direction of magnetic moments and the T-N evolution in the series. The measured Neel temperature for Sm2IrIn8 is slightly suppressed when compared to the T-N of the parent cubic compound SmIn3.761

Attitudes towards chiropractic: an analysis of written comments from a survey of north american orthopaedic surgeons

<p>Abstract</p> <p>Background</p> <p>There is increasing interest by chiropractors in North America regarding integration into mainstream healthcare; however, there is limited information about attitudes towards the profession among conventional healthcare providers, including orthopaedic surgeons.</p> <p>Methods</p> <p>We administered a 43-item cross-sectional survey to 1000 Canadian and American orthopaedic surgeons that inquired about demographic variables and their attitudes towards chiropractic. Our survey included an option for respondants to include written comments, and our present analysis is restricted to these comments. Two reviewers, independantly and in duplicate, coded all written comments using thematic analysis.</p> <p>Results</p> <p>487 surgeons completed the survey (response rate 49%), and 174 provided written comments. Our analysis revealed 8 themes and 24 sub-themes represented in surgeons' comments. Reported themes were: variability amongst chiropractors (n = 55); concerns with chiropractic treatment (n = 54); areas where chiropractic is perceived as effective (n = 43); unethical behavior (n = 43); patient interaction (n = 36); the scientific basis of chiropractic (n = 26); personal experiences with chiropractic (n = 21); and chiropractic training (n = 18). Common sub-themes endorsed by surgeon's were diversity within the chiropractic profession as a barrier to increased interprofessional collaboration, endorsement for chiropractic treatment of musculoskeletal complaints, criticism for treatment of non-musculoskeletal complaints, and concern over whether chiropractic care was evidence-based.</p> <p>Conclusions</p> <p>Our analysis identified a number of issues that will have to be considered by the chiropractic profession as part of its efforts to further integrate chiropractic into mainstream healthcare.</p