Inhibitor of DNA binding 1 as a secreted angiogenic transcription factor in rheumatoid arthritis

Abstract Introduction Rheumatoid arthritis (RA) is characterized by enhanced blood vessel development in joint synovium. This involves the recruitment of endothelial progenitor cells (EPCs), allowing for de novo vessel formation and pro-inflammatory cell infiltration. Inhibitor of DNA Binding 1 (Id1) is a transcription factor characteristic of EPCs that influences cell maturation. Method Enzyme-linked immunosorbant assay (ELISA) and polymerase chain reaction (PCR) were used to examine Id1 levels in synovial fluid (SF) and endothelial cells (ECs), respectively. Immunohistology was used to determine the expression of Id1 in synovial tissue (ST). Human dermal microvascular EC (HMVEC) migration and tube forming assays were used to determine if recombinant human Id1 (rhuId1) and/or RA SF immunodepleted Id1 showed angiogenic activity. We also utilized the RA ST severe combined immunodeficient (SCID) mouse chimera to examine if Id1 recruits EPCs to RA synovium. Results ST samples immunostained for Id1 showed heightened expression in RA compared to osteoarthritis (OA) and normal (NL) ST. By immunofluorescence staining, we found significantly more Id1 in RA compared to OA and NL vasculature, showing that Id1 expressing cells, and therefore EPCs, are most active in vascular remodeling in the RA synovium. We also detected significantly more Id1 in RA compared to OA and other arthritis SFs by ELISA, which correlates highly with Chemokine (C-X-C motif) ligand 16 (CXCL16) levels. In vitro chemotaxis assays showed that Id1 is highly chemotactic for HMVECs and can be attenuated by inhibition of Nuclear Factor κB and phosphoinositide 3-kinase. Using in vitro Matrigel assays, we found that HMVECs form tubes in response to rhuId1 and that Id1 immunodepleted from RA SF profoundly decreases tube formation in Matrigel in vitro. PCR showed that Id1 mRNA could be up-regulated in EPCs compared to HMVECs in response to CXCL16. Finally, using the K/BxN serum induced arthritis model, we found that EC CXCR6 correlated with Id1 expression by immunohistochemistry. Conclusions We conclude that Id1 correlates highly with CXCL16 expression, EPC recruitment, and blood vessel formation in the RA joint, and that Id1 is potently angiogenic and can be up-regulated in EPCs by CXCL16.http://deepblue.lib.umich.edu/bitstream/2027.42/110805/1/13075_2013_Article_4258.pd

A two-year participatory intervention project with owners to reduce lameness and limb abnormalities in working horses in Jaipur, India

Participatory methods are increasingly used in international human development, but scientific evaluation of their efficacy versus a control group is rare. Working horses support families in impoverished communities. Lameness and limb abnormalities are highly prevalent in these animals and a cause for welfare concern. We aimed to stimulate and evaluate improvements in lameness and limb abnormalities in horses whose owners took part in a 2-year participatory intervention project to reduce lameness (PI) versus a control group (C) in Jaipur, India.In total, 439 owners of 862 horses participated in the study. PI group owners from 21 communities were encouraged to meet regularly to discuss management and work practices influencing lameness and poor welfare and to track their own progress in improving these. Lameness examinations (41 parameters) were conducted at the start of the study (Baseline), and after 1 year and 2 years. Results were compared with control horses from a further 21 communities outside the intervention. Of the 149 horses assessed on all three occasions, PI horses showed significantly (P<0.05) greater improvement than C horses in 20 parameters, most notably overall lameness score, measures of sole pain and range of movement on limb flexion. Control horses showed slight but significantly greater improvements in four parameters, including frog quality in fore and hindlimbs.This participatory intervention succeeded in improving lameness and some limb abnormalities in working horses, by encouraging changes in management and work practices which were feasible within owners’ socioeconomic and environmental constraints. Demonstration of the potentially sustainable improvements achieved here should encourage further development of participatory intervention approaches to benefit humans and animals in other contexts

Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis

Abstract Background Inhibitor of DNA binding 1 (Id1) is a nuclear protein containing a basic helix-loop-helix (bHLH) domain that regulates cell growth by selective binding and prevention of gene transcription. Sources of Id1 production in rheumatoid arthritis synovial tissue (RA ST) and its range of functional effects in RA remain to be clarified. Methods We analyzed Id1 produced from synovial fibroblasts and endothelial cells (ECs) with histology and real-time polymerase chain reaction (RT-PCR). Fibroblast supernatants subjected to differential centrifugation to isolate and purify exosomes were measured for Id1 by enzyme-linked immunosorbent assay (ELISA). Western blotting of Id1-stimulated ECs was performed to determine the kinetics of intracellular protein phosphorylation. EC intracellular signaling pathways induced by Id1 were subsequently targeted with silencing RNA (siRNA) for angiogenesis inhibition. Results By PCR and histologic analysis, we found that the primary source of Id1 in STs is from activated fibroblasts that correlate with inflammatory scores in human RA ST and in joints from K/BxN serum-induced mice. Normal (NL) and RA synovial fibroblasts increase Id1 production with stimulation by transforming growth factor beta (TGF-β). Most of the Id1 released by RA synovial fibroblasts is contained within exosomes. Endothelial progenitor cells (EPCs) and human dermal microvascular ECs (HMVECs) activate the Jnk signaling pathway in response to Id1, and Jnk siRNA reverses Id1-induced HMVEC vessel formation in Matrigel plugs in vivo. Conclusions Id1 is a pleotropic molecule affecting angiogenesis, vasculogenesis, and fibrosis. Our data shows that Id1 is not only an important nuclear protein, but also can be released from fibroblasts via exosomes. The ability of extracellular Id1 to activate signaling pathways expands the role of Id1 in the orchestration of tissue inflammation.http://deepblue.lib.umich.edu/bitstream/2027.42/134552/1/13075_2016_Article_984.pd

The SOS Pilot Study: a RCT of routine oxygen supplementation early after acute stroke—effect on recovery of neurological function at one week

Mild hypoxia is common after stroke and associated with poor long-term outcome. Oxygen supplementation could prevent hypoxia and improve recovery. A previous study of routine oxygen supplementation showed no significant benefit at 7 and 12 months. This pilot study reports the effects of routine oxygen supplementation for 72 hours on oxygen saturation and neurological outcomes at 1 week after a stroke

Preliminary Jitter Stability Results for the Large UV/Optical/Infrared (LUVOIR) Surveyor Concept Using a Non-Contact Vibration Isolation and Precision Pointing System

The need for high payload dynamic stability and ultra-stable mechanical systems is an overarching technology need for large space telescopes such as the Large Ultraviolet / Optical / Infrared (LUVOIR) Surveyor concept. The LUVOIR concept includes a 15-meter-diameter segmented-aperture telescope with a suite of serviceable instruments operating over a range of wavelengths between 100nm to 2.5 um. Wavefront error (WFE) stability of less than 10 picometers RMS of uncorrected system WFE per wavefront control step represents a drastic performance improvement over current space-based telescopes being fielded. Through the utilization of an isolation architecture that involves no mechanical contact between the telescope and the host spacecraft structure, a system design is realized that maximizes the telescope dynamic stability performance without driving stringent technology requirements on spacecraft structure, sensors or actuators. Through analysis of the LUVOIR finite element model and linear optical model, the wavefront error and Line-Of-Sight (LOS) jitter performance is discussed in this paper when using the Vibration Isolation and Precision Pointing System (VIPPS) being developed cooperatively with Lockheed Martin in addition to a multi-loop control architecture. The multi-loop control architecture consists of the spacecraft Attitude Control System (ACS), VIPPS, and a Fast Steering Mirror on the instrument. While the baseline attitude control device for LUVOIR is a set of Control Moment Gyroscopes (CMGs), Reaction Wheel Assembly (RWA) disturbance contribution to wavefront error stability and LOS stability are presented to give preliminary results in this paper. CMG disturbance will be explored in further work to be completed

Amniotic fluid embolism incidence, risk factors and outcomes: a review and recommendations

<p>Abstract</p> <p>Background</p> <p>Amniotic fluid embolism (AFE) is a rare but severe complication of pregnancy. A recent systematic review highlighted apparent differences in the incidence, with studies estimating the incidence of AFE to be more than three times higher in North America than Europe. The aim of this study was to examine population-based regional or national data from five high-resource countries in order to investigate incidence, risk factors and outcomes of AFE and to investigate whether any variation identified could be ascribed to methodological differences between the studies.</p> <p>Methods</p> <p>We reviewed available data sources on the incidence of AFE in Australia, Canada, the Netherlands, the United Kingdom and the USA. Where information was available, the risk factors and outcomes of AFE were examined.</p> <p>Results</p> <p>The reported incidence of AFE ranged from 1.9 cases per 100 000 maternities (UK) to 6.1 per 100 000 maternities (Australia). There was a clear distinction between rates estimated using different methodologies. The lowest estimated incidence rates were obtained through validated case identification (range 1.9-2.5 cases per 100 000 maternities); rates obtained from retrospective analysis of population discharge databases were significantly higher (range 5.5-6.1 per 100 000 admissions with delivery diagnosis). Older maternal age and induction of labour were consistently associated with AFE.</p> <p>Conclusions</p> <p>Recommendation 1: Comparisons of AFE incidence estimates should be restricted to studies using similar methodology. The recommended approaches would be either population-based database studies using additional criteria to exclude false positive cases, or tailored data collection using existing specific population-based systems.</p> <p>Recommendation 2: Comparisons of AFE incidence between and within countries would be facilitated by development of an agreed case definition and an agreed set of criteria to minimise inclusion of false positive cases for database studies.</p> <p>Recommendation 3: Groups conducting detailed population-based studies on AFE should develop an agreed strategy to allow combined analysis of data obtained using consistent methodologies in order to identify potentially modifiable risk factors.</p> <p>Recommendation 4: Future specific studies on AFE should aim to collect information on management and longer-term outcomes for both mothers and infants in order to guide best practice, counselling and service planning.</p

Risk Compensation Is Not Associated with Male Circumcision in Kisumu, Kenya: A Multi-Faceted Assessment of Men Enrolled in a Randomized Controlled Trial

Three randomized controlled trials (RCTs) have confirmed that male circumcision (MC) significantly reduces acquisition of HIV-1 infection among men. The objective of this study was to perform a comprehensive, prospective evaluation of risk compensation, comparing circumcised versus uncircumcised controls in a sample of RCT participants.Between March 2004 and September 2005, we systematically recruited men enrolled in a RCT of MC in Kenya. Detailed sexual histories were taken using a modified Timeline Followback approach at baseline, 6, and 12 months. Participants provided permission to obtain circumcision status and laboratory results from the RCT. We evaluated circumcised and uncircumcised men's sexual behavior using an 18-item risk propensity score and acquisition of incident infections of gonorrhea, chlamydia, and trichomoniasis. Of 1780 eligible RCT participants, 1319 enrolled (response rate = 74%). At the baseline RCT visit, men who enrolled in the sub-study reported the same sexual behaviors as men who did not. We found a significant reduction in sexual risk behavior among both circumcised and uncircumcised men from baseline to 6 (p<0.01) and 12 (p = 0.05) months post-enrollment. Longitudinal analyses indicated no statistically significant differences between sexual risk propensity scores or in incident infections of gonorrhea, chlamydia, and trichomoniasis between circumcised and uncircumcised men. These results are based on the most comprehensive analysis of risk compensation yet done.In the context of a RCT, circumcision did not result in increased HIV risk behavior. Continued monitoring and evaluation of risk compensation associated with circumcision is needed as evidence supporting its' efficacy is disseminated and MC is widely promoted for HIV prevention

Symptomatic and Asymptomatic Neurological Complications of Infective Endocarditis: Impact on Surgical Management and Prognosis

International audienceObjectives:Symptomatic neurological complications (NC) are a major cause of mortality in infective endocarditis (IE) but the impact of asymptomatic complications is unknown. We aimed to assess the impact of asymptomatic NC (AsNC) on the management and prognosis of IE.Methods: From the database of cases collected for a population-based study on IE, we selected 283 patients with definite left-sided IE who had undergone at least one neuroimaging procedure (cerebral CT scan and/or MRI) performed as part of initial evaluation.Results Among those 283 patients, 100 had symptomatic neurological complications (SNC) prior to the investigation, 35 had an asymptomatic neurological complications (AsNC), and 148 had a normal cerebral imaging (NoNC). The rate of valve surgery was 43% in the 100 patients with SNC, 77% in the 35 with AsNC, and 54% in the 148 with NoNC (p<0.001). In-hospital mortality was 42% in patients with SNC, 8.6% in patients with AsNC, and 16.9% in patients with NoNC (p<0.001). Among the 135 patients with NC, 95 had an indication for valve surgery (71%), which was performed in 70 of them (mortality 20%) and not performed in 25 (mortality 68%). In a multivariate adjusted analysis of the 135 patients with NC, age, renal failure, septic shock, and IE caused by S. aureus were independently associated with in-hospital and 1-year mortality. In addition SNC was an independent predictor of 1-year mortality.Conclusions The presence of NC was associated with a poorer prognosis when symptomatic. Patients with AsNC had the highest rate of valve surgery and the lowest mortality rate, which suggests a protective role of surgery guided by systematic neuroimaging results