Journals
2014 EN
Guo Anran · Roso Martina · Modesti Michele
+2 more
Silicon oxycarbide (SiOC) fibers with different chemical compositions were successfully fabricated by electrospinning a mixture of polyvinylpyrrolidone (PVP) and commercially available polymethylsilsesquioxane (MK) or polymethylphenylsilsesquioxane (H44) preceramic polymers, followed by cross‐linking and pyrolysis at 1000°C in Argon. The influence of the processing procedure (solvent selection, cross‐linking catalyst and additives) on the morphology of the produced fibers was investigated. For the MK/isopropanol system, the introduction of 20 vol% N,N‐dimethylformamide (DMF) enabled to decrease the diameter of the as‐spun fibers from 2.72 ± 0.12 μm to 1.65 ± 0.09 μm. For the H44/DMF systems, beads‐free fibers were obtained by adding 50 vol% choloroform. After pyrolysis, the resultant SiOC fibers derived from MK and H44 resins possessed uniform morphology, with an average diameter of 0.97 ± 0.07 μm and 1.07 ± 0.08 μm, respectively. Due to their different chemical compositions, the MK‐derived and H44‐derived SiOC ceramic fibers could find different potential applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131 , 39836.
Journals
2014 EN
Pittarella Pamela · Antonioli Diego · Rizzi Manuela
+2 more
Mechanical properties of poly( d,l )lactic acid films enriched with Vitamin E and Vitamin E Acetate (5–40% w/w) were investigated. The addition of both formulations resulted in increased polymer Young's modulus and tensile strength. Human foreskin fibroblasts and murine pre‐osteoblasts were used to assess the biocompatibility of polymers. Pre‐osteoblasts adhesion and proliferation were strongly decreased by Vitamin E, whereas Vitamin E Acetate did not alter cell proliferation. Collagen deposition was lower onto Vitamin E blended polymers than onto native and Vitamin E Acetate blended ones. Fibroblasts adhesion and proliferation were increased by both Vitamin E and Vitamin E Acetate addition. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014 , 131 , 39970.
Journals
2014 EN
Smith Siobhán · Ní Gabhann Joan · McCarthy Eoghan
+13 more
Objective To examine the role of 17β‐estradiol in the regulation of the autoantigen tripartite motif–containing protein 21 (TRIM‐21) in patients with systemic lupus erythematosus (SLE). Methods Monocytes isolated from healthy control subjects and patients with SLE were stimulated with 17β‐estradiol and/or the estrogen receptor α (ERα) antagonist methyl‐piperidino‐pyrazole dihydrochloride. TRIM‐21, ERα, and CREMα expression was determined by real‐time polymerase chain reaction (PCR) analysis. MatInspector software was used to identify putative binding sites within the TRIM‐21 promoter. ERα binding to the TRIM‐21 gene promoter region in monocytes was analyzed by chromatin immunoprecipitation (ChIP) assay. TRIM‐21 and interferon regulatory factor 3 protein levels were analyzed by Western blotting. Results Real‐time PCR analysis demonstrated a role of estrogen in the regulation of TRIM‐21 expression in monocytes, which correlated positively with ERα gene expression in patients with SLE. Investigations into the human TRIM‐21 promoter revealed the presence of an estrogen response element, with ChIP assays confirming ERα binding to this site. Studies into estrogen‐induced TRIM‐21 expression revealed a hyperresponsiveness of SLE patients to 17β‐estradiol, which led to the enhanced levels of TRIM‐21 observed in these individuals. Conclusion Our results demonstrate a role of estrogen in the regulation of TRIM‐21 expression through an ERα‐dependent mechanism, a pathway that we observed to be overactive in SLE patients. Treatment of monocytes with an ERα antagonist abrogated estrogen‐induced TRIM‐21 expression and, as a consequence, decreased the expression of interleukin‐23. These findings identify TRIM‐21 as a novel ERα‐regulated gene and provide novel insights into the link between estrogen and the molecular pathogenesis of SLE.
Journals
2014 EN
Canna Scott W. · CostaReis Patrícia · Bernal William E.
+4 more
Objective Hemophagocytes (HPCs) are activated macrophages that have engulfed other hematopoietic cells. Although HPCs are rarely identified in normal spleen tissue and bone marrow, an excess of these macrophages characterizes many cytokine storm syndromes, particularly macrophage activation syndrome and hemophagocytic lymphohistiocytosis. This study was undertaken to assess the functions of HPCs and their significance in acute inflammatory conditions. Methods HPCs were generated in wild‐type mice using repeated stimulation with Toll‐like receptor 9 (TLR‐9) and interleukin‐10 receptor blockade. RNA was extracted from HPCs that had been isolated by laser‐captured microdissection. Transcriptional profiles of the HPCs were then compared to those of resting splenic macrophages. In addition, bone marrow samples were obtained from a diverse cohort of patients in whom excess hemophagocytosis was identified by clinical bone marrow biopsy or aspiration. The bone marrow samples were analyzed by immunohistochemistry for markers of classic (CD64) or alternative (CD163 and CD206) macrophage activation. Results Differential gene expression and gene set enrichment analyses of murine HPCs identified up‐regulation of genes and gene sets associated with alternative activation of HPCs. Immunohistochemical analyses of HPCs in human bone marrow samples showed universal staining of HPCs for CD163, but rarely for CD206 or CD64. Conclusion Laser‐captured murine TLR‐9–induced HPCs had a transcriptional profile similar to that of alternatively activated macrophages. In addition, HPC expression of CD163 was confirmed in a uniquely diverse cohort of patients with hemophagocytic syndromes. Collectively, these data support the hypothesis that HPCs have both immunoregulatory and clean‐up functions.
Journals
2014 EN
Watanabe Duffy Karen N · Lee Jennifer · Guzman Jaime
+9 more
Background/Purpose: Previous studies of uveitis in Juvenile Idiopathic Arthritis (JIA) patients have reported prevalence and not incidence. The ReACCh Out cohort, a large inception cohort of newly diagnosed JIA patients provided the opportunity to prospectively ascertain the true incidence of new onset uveitis. The objectives of this study were to determine the overall incidence rate and its trajectory over time. Methods: ReACCh Out recruited newly diagnosed JIA patients between January 2005 and December 2010, from 16 Canadian centres across the country. Prospective data was collected every 6 months for the first 2 years, then yearly. Data was collected on numerous clinical and laboratory measures including the diagnosis of uveitis and its complications, determined by an ophthalmologist. A Poisson model was used to estimate the overall incidence rate. A Kaplan‐Meier plot was used to evaluate the time from diagnosis of JIA to the time of diagnosis of new onset uveitis. Results: 1104 patients with newly diagnosed (≤6 months) JIA with ≥1 follow‐up visit were reviewed. Patients were predominantly female (63%), age at diagnosis was 9.3 (3.9, 13.0) years. Time from diagnosis to enrollment was 0.3 (0, 1.6) months. Follow‐up to last visit or study end was 34.2 (21.5, 48) months. 23 patients whose uveitis status was not available, were excluded. 77 patients with new onset uveitis were identified during the study period. The overall incidence rate of new cases of uveitis following the diagnosis of JIA was 2.9% per year (95% confidence interval 2.3–3.6). Following the trajectory of new cases of uveitis over time, the incidence of new cases showed a slow decline over time (Figure ). Importantly, new cases of uveitis occurred as far out from diagnosis as the end of the study period. Kaplan‐Meier plots were also used to evaluate age at diagnosis of new onset uveitis and gender. Results support previously identified risk factors for uveitis including younger age (<5 years) and female gender. The frequency of uveitis occurred in the JIA patients in the following distribution according to subtype: oligoarthritis (43, 56%), polyarthritis RF negative (18, 23%), polyarthritis RF positive (1, 1%), psoriatic (4, 5%), ERA (1, 1%), systemic (1, 1%) and undifferentiated (9, 12%).Time (confidence intervals) from diagnosis of JIA to diagnosis of new onset uveitisConclusion: In a large inception cohort of newly diagnosed JIA patients followed prospectively, the overall incidence rate of new cases of uveitis was 2.9% per year. The slow decrease in incidence over time and the development of new cases of uveitis years later, highlight the importance of ongoing and long term surveillance.
Journals
2014 EN
GomezRamirez Oralia · Gibbon Michele · Berard Roberta A.
+10 more
Background/Purpose: During a recent study we conducted to identify patients, parents, and clinicians' priorities in describing the course of juvenile idiopathic arthritis (JIA), parents expressed intense emotions related to the disease and its management even a decade after their children's diagnosis. Here we describe the predominant emotional experiences reported by parents and how they relate to different phases of the disease manifestation, treatments, and interactions with peers and healthcare providers. Methods: We analyzed focus group transcripts and reciprocal interview answers involving 9 experienced English‐speaking parents, 5 experienced French‐speaking parents and 8 novice parents (between 2 and 6 months since diagnosis). Their children were 2 to 16 years of age and had a variety of JIA subtypes and disease severity. Qualitative analysis included review of audio recordings to enrich transcripts (based on pauses, noises, and other non‐verbal cues), coding of emotional experiences by two investigators using a list of 69 emotion labels, coding verification by two other investigators, and analytical discussion and synthesis by our interdisciplinary team (to agree on what emotions were predominant at different stages of the disease, who or what were those emotions directed at, and how disease characteristics or parent background shaped them). Results: The time between onset and diagnosis was described by parents as a period of mounting anxiety, confusion and frustration with healthcare providers before a firm diagnosis was reached. The time shortly after diagnosis was described as a time of shock, disbelief, and fear during which parents often used denial as a coping mechanism; combined with feeling overwhelmed by a sea of information about the disease. Later in the disease course, at times of disease quiescence the predominant emotions were annoyance and worry about treatment side effects, and the fear of unpredictable flares. At times of increasing or ongoing symptoms the predominant emotions were admiration for the way their children coped with the disease, and frustration with peers and teachers that could not appreciate justification for the changes in the child's willingness to engage in physical activity and school work. This was also a time of frustration with increasing treatment and side effects. Throughout the disease parents felt a sense of powerlessness and that the disease was a “time‐consuming roller coaster.” The subtype of arthritis did not affect the range of emotions experienced, but influenced the proportion of time in quiescence or ongoing symptoms, and the intensity of treatments and side‐effects. Conclusion: The emotional experiences of parents of children with JIA can be conceptualized, as a parent put it, as roller coaster ride made of intensely emotional ups and downs. This is similar to the emotional turmoil faced by parents of children with other chronic illnesses, but JIA usually does not confront them with the chronic grief produced by progressive degenerative illnesses or the threat of imminent death.
Journals
2014 EN
Gibbon Michele · Tucker Lori B. · Feldman Debbie Ehrmann
+6 more
Background/Purpose: We implemented a novel knowledge translation (KT) initiative called the LEAP Ambassador Program to disseminate findings from the “Linking Exercise, Activity and Pathophysiology (LEAP) in Children with JIA study.” The main hypothesis of the study is that increased levels of physical activity will improve the outcomes (such as quality of life) of youth with juvenile idiopathic arthritis (JIA). The aim of this initiative is to inspire youth with JIA to be physically active through the creation of a community of athletes and youth with JIA, who model different levels of physical activity. Methods: The LEAP Ambassador program was developed by the LEAP study program manager and approved by the LEAP Steering Committee. Various levels of athletes, ranging from international, national, college/university level, and local LEAP study participants (youth with JIA, aged 8–16 years), were sought. Individuals agreeing to participate signed consent for use of their personal photo(s) and interview on the LEAP website ( www.leapjia.com ). Participants were asked to provide a photo of themselves involved in a sport or physical activity, and to answer 6 brief questions about their motivation to engage in sport/physical activities, in the face of disease flares and/or injuries. Each of the participating LEAP sites was encouraged to seek local LEAP ambassadors through their clinics and community connections, to ensure representation across the country. Results: To date, 15 LEAP ambassadors have been engaged in the program, including 3 international/national level athletes, 2 college/provincial level athletes and 10 youth with JIA. Different levels of physical activity and sports, including freestyle skiing, soccer, walking, horseback riding, speed skating, hockey, cycling and rowing, have been represented. The 10 youth with JIA who have agreed to be LEAP ambassadors come from across the country. Both English and Frenchspeaking ambassadors have been included. Conclusion: The LEAP ambassador program is a unique KT initiative aimed at developing a robust community across the country to support the research messages of the LEAP study, relating to the promotion of physical activity in youth with arthritis. A supportive network is being developed, in which athletes act as role models, inspiring youth with JIA to engage in physical activity, and the youth themselves encourage and motivate each other through shared experiences. Future plans include expansion of the program to include more athletes and youth with JIA, and increased use of social media to connect patients and athletes. An evaluation of the effectiveness of the program is also planned.
Journals
2014 EN
Croia Cristina · Astorri Elisa · MurrayBrown William
+8 more
Objective To examine whether the B cell tropic γ‐herpesvirus Epstein‐Barr virus (EBV) is aberrantly expressed in its latent and lytic forms within ectopic lymphoid structures (ELS) in the salivary glands of patients with Sjögren's syndrome (SS), and to investigate the relationship between EBV dysregulation, B cell activation, in situ differentiation of autoreactive plasma cells, disease‐specific autoantibody production, and cytotoxicity. Methods Latent and lytic EBV infection in the salivary glands of 28 patients with SS and 38 patients with nonspecific chronic sialadenitis (NSCS), characterized for the presence or absence of ELS, was investigated by reverse transcription–polymerase chain reaction, in situ hybridization, and immunohistochemical/immunofluorescence staining. Glandular versus synovial production of anti−Ro 52, anti–citrullinated protein antibodies (ACPAs), and anti–EBV peptide antibodies was analyzed in situ or in vivo in human SS/SCID and human rheumatoid arthritis/SCID mouse chimeras. Results EBV dysregulation within inflammatory infiltrates was observed exclusively in ELS+ SS salivary gland tissue, as revealed by latent EBV infection and lytic EBV infection in B cells and plasma cells, respectively. Conversely, epithelial latent membrane protein 2A expression was observed in both patients with SS and patients with NSCS. Importantly, perifollicular plasma cells displaying Ro 52 immunoreactivity were frequently infected by EBV. Furthermore, ELS‐containing SS salivary gland tissue that was transplanted into SCID mice supported the production of anti–Ro 52/anti–La 48 and anti‐EBV antibodies but not ACPAs. Analysis of CD4+ and CD8+ T cell localization and granzyme B expression demonstrated that the persistence of EBV in ELS‐containing SS salivary glands was associated with follicular exclusion of CD8+ T cells and impaired CD8‐mediated cytotoxicity. Conclusion Active EBV infection is selectively associated with ELS in the salivary glands of patients with SS and appears to contribute to local growth and differentiation of disease‐specific autoreactive B cells.
Journals
2014 EN
Benhamou Ygal · Bellien Jeremy · Armengol Guillaume
+16 more
Objective To assess the role of Toll‐like receptors (TLRs) in antiphospholipid antibody (aPL)–mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS). Methods Forty‐eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild‐type (WT) and TLR‐knockout mice. Results APS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium‐dependent flow‐mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima‐media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro‐oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor α levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR‐2 and TLR‐4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin‐1 receptor–associated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist‐stimulated cell‐surface expression of TLR‐2 and TLR‐4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium‐dependent relaxation and increased TF expression in WT mice but not in TLR‐2– or TLR‐4–knockout mice. Conclusion This translational study supports the notion that TLR‐2 and TLR‐4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.
Journals
2014 EN
Battié Michele C. · OrtegaAlonso Alfredo · Niemelainen Riikka
+4 more
Objective Lumbar spinal stenosis is one of the most commonly diagnosed spinal disorders in older adults. Although the pathophysiology of the clinical syndrome is not well understood, a narrow central canal or intervertebral foramen is an essential or defining feature. The aim of the present study was to estimate the magnitude of genetic versus environmental influences on central lumbar spinal stenosis and to investigate disc degeneration and stature or bone development as possible genetic pathways. Methods A classic twin study with multivariate analyses considering lumbar level and other covariates was conducted. The study sample comprised 598 male twins (147 monozygotic and 152 dizygotic pairs), 35–70 years of age, from the population‐based Finnish Twin Cohort. The primary phenotypes were central lumbar stenosis as assessed qualitatively on magnetic resonance imaging (MRI) and quantitatively measured dural sac cross‐sectional area. Additional phenotypes (to examine possible genetic pathways) included disc bulging and standing height, as an indicator of overall skeletal size or development. Results The heritability estimate (h 2 ) for qualitatively assessed central lumbar spinal stenosis on MRI was 66.9% (95% confidence interval [95% CI] 56.8, 74.5). The broad‐sense heritability estimate for dural sac cross‐sectional area was 81.2% (95% CI 74.5, 86.1), with a similar magnitude of genetic influences across lumbar levels (h 2 = 72.4–75.6). The additive genetic correlation of quantitatively assessed stenosis and disc bulging was extremely high. There was no indication of shared genetic influences between stenosis and stature. Conclusion Central lumbar spinal stenosis and associated dural sac dimensions are highly genetic, and disc degeneration (bulging) appears to be one pathway through which genes influence spinal stenosis.