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The objective of this study was to determine the effectiveness of MRP8/14 as a predictor of disease flare in patients with juvenile idiopathic arthritis (JIA) following the withdrawal of methotrexate (MTX) in a routine clinical setting. All MRP8/14 tests performed at a single centre in a 27-month period were considered for analysis. Patients were assessed against criteria for inactive disease and subsequent disease flare. Decisions on whether or not to stop treatment were recorded. MRP8/14 results were assessed in conjunction with clinical information. Clinicians were also surveyed to investigate if MRP8/14 influenced their decision to discontinue MTX where this was available at that time point. One hundred four cases met the inclusion criteria during the study period. Although there was no significant difference in flares between patients with an elevated or low MRP8/14 value, in those who stopped MTX (n = 22), no patients with a low MRP8/14 (≤ 4000 ng/ml) result flared (follow-up time 12 months). Clinicians reported that for patients with clinically inactive disease and an elevated MRP8/14 result (> 4000 ng/ml), none would advise withdrawal of MTX. Low MRP8/14 was interpreted favourably when considering stopping MTX treatment in patients with JIA. Implementation of MRP8/14 testing has changed clinical practice at this centre. However, the observation that some patients in our cohort who had an elevated MRP8/14 value did not flare after stopping MTX for non-disease-related reasons highlights the need for further biomarkers to predict the risk of flare off medication in JIA and aid clinicians in treatment decisions. Key Points• First study of serum MRP8/14 measurement in clinical practice to inform treatment decisions in patients with JIA.• No patients with a low MRP8/14 test result went on to suffer a disease flare in 12 months of follow follow-up.• Further biomarkers are needed to predict the risk of flare off medication in JIA and treatment decisions.

The use of technological devices has become natural, which is why technology seems to become a natural learning environment. Many studies show that technologically-rich learning environments improve learning outcomes. It has been shown that technological integration helps to create more authentic learning environments, in which students are more motivated to participate. Digital world has greater opportunities for communication, collaboration, and problem-solving and have more opportunities to expand and even amplify thinking, thus changing the role of students by building knowledge rather than reproducing information. Given the possible disadvantages of using digital devices permanently, it is important to find a good balance between constructively using digital technology and keeping it to avoid distraction and concentration. However, some research shows that electronic learning does not differ in effectiveness or efficiency from traditional learning. This chapter presents an in-depth and reasoned analysis of cognitive learning of university students using Web 2.0 tools.

In-service teachers have various emotional and motivational experiences that can influence their continuance intention towards online-only instruction during the COVID-19 pandemic, as a significant stress factor for their workplace. Derived from the Self-Determination Theory (SDT), Job Demands&ndash, Resources Model (JD&ndash, R), and Technology Acceptance Model (TAM), the present research model includes technological pedagogical knowledge (TPK) self-efficacy (SE), intrinsic (IM) and extrinsic (EM) work motivation, and occupational stress (OS) (i.e., burnout and technostress which have been examined in tandem) as key dimensions to explain the better continuance intention among in-service teachers to use online-only instruction (CI). Data for the research model were collected from 980 in-service teachers during the COVID-19 outbreak between April and May 2020. Overall, the structural model explained 70% of the variance in teachers&rsquo, CI. Motivational practices were directly and indirectly linked through OS with CI. The findings showed that IM has the most directly significant effect on teachers&rsquo, CI, followed by TPK-SE, and OS as significant, but lower predictors. IM was positively associated with TPK-SE and negatively associated with EM. The results offered valuable insights into how motivation constructs were related to OS and to a better understanding online instruction in an unstable work context, in order to support teachers in coping during working remotely.

Objective.Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response.Methods.S100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded.Results.Baseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133–440 ng/ml] and MTX (median 220, IQR 100–440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125–615) ng/ml versus 150 (IQR 87–233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150–624) ng/ml versus 151 (IQR 83–201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10.Conclusion.Responders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.

Objectives. In JIA there is an unmet need for biomarkers with which to identify patients who will respond well to MTX. The aim of this study was to define the prognostic value of baseline serum proteins and clinical variables in response to MTX to help inform the clinician at time of diagnosis whether the patient is likely to respond well to MTX. Methods. JIA patients were recruited into the Childhood Arthritis Response to Medication Study (CHARMS). Clinical data and venous blood were collected before administration of MTX and at followup. MRP8/14 and inflammatory cytokines were measured by ELISA and multiplex immunoassay, respectively. CRP and ESR were measured as part of routine clinical assessment. To explore which baseline factors might predict successful treatment, binary logistic regression models were fitted for outcome. Results. High disease activity (high serum MRP8/14, active joint count or physician’s score) pre-MTX was observed in a subgroup of patients with a better response to therapy. In a multivariable analysis, after accounting for MRP8/14 at baseline, no other factors were independently significantly associated with outcome. Patients with baseline MRP8/14 >3000 ng/ml were more likely to respond to MTX at ACR50 or better: odds ratio 16.07 (95% CI 2.00, 129.3). Conclusion. We have demonstrated that high levels of baseline serum MRP8/14 have prognostic value in predicting a subgroup of patients whose arthritis will improve on MTX. Routine collection of serum prior to the start of medication would be a valuable step in collaborative validation of such biomarkers.

Objective. The role of the adaptive immune system has not been explored in detail compared with the innate immune system in systemic JIA (sJIA) pathogenesis. The aim of this study was to examine the phenotype of circulating peripheral blood CD4 + T-cell subpopulations in a cross-sectional study of sJIA patients during disease remission on medication and during acute flare of the disease. Methods. Flow cytometry was used to examine the phenotype and cytokine production of IFNg-, IL-4and IL-17-producing CD4 + T cells in the peripheral blood of 10 sJIA patients with active disease, 9 sJIA with inactive disease, 14 JIA patients with oligoarticular onset, 10 adult control subjects and 10 agematched control subjects. In parallel, we examined the proportion of FoxP3 + Tregs. Results. IFNg- and IL-17-producing CD4 + T cells and IL-17-producing CD3 + CD4 T cells were present at higher proportions in the peripheral blood of sJIA patients, irrespective of their disease status. Our data also confirm the known increase of the proportions of IFNg-producing Th1 cells with increasing age and suggest an increase with age in the IL-17-producing CD4 + T-cell population. Conclusion. This study is the first to describe significantly higher proportions of Th1 and Th17 T helper cell subsets in the peripheral blood of sJIA patients. These proinflammatory cells may play a pathogenic role in sJIA. Our data also emphasize the importance of using paediatric age-matched control subjects when evaluating the T-cell cytokine profile in JIA.

Introduction Approximately 30 % of juvenile idiopathic arthritis (JIA) patients fail to respond to anti-TNF treatment. When clinical remission is induced, some patients relapse after treatment has been stopped. We tested the predictive value of MRP8/14 serum levels to identify responders to treatment and relapse after discontinuation of therapy. Methods Samples from 88 non-systemic JIA patients who started and 26 patients who discontinued TNF-blockers were analyzed. MRP8/14 serum levels were measured by in-house MRP8/14 ELISA and by Bühlmann Calprotectin ELISA at start of anti-TNF treatment, within 6 months after start and at discontinuation of etanercept in clinical remission. Patients were categorized into responders (ACRpedi ≥ 50 and/or inactive disease) and non-responders (ACRpedi

Regulatory FoxP3+CD4+ T cells (Treg) are vital for maintaining the balance between tolerance, adequate immune response, and autoimmunity. Despite this immunoregulatory role, it has been shown that Treg may also produce proinflammatory cytokines. Here we present a distinct population of Treg, defined by CD161 expression, as the major source of FoxP3+ Treg-derived proinflammatory cytokines. CD161+ Treg can be followed throughout development, from thymus and cord blood to healthy child and adult samples. CD161+ Treg display anergy, are suppressive in cocultures with conventional T cells (Tconv), and possess a predominantly demethylated Treg-specific demethylated region of the FOXP3 locus. In addition to the production of interleukin (IL) 17A, interferon γ, and IL-2, CD161+FoxP3+ cells share markers with Tconv, including expression of the transcription factors retinoic acid-related orphan receptor Cv2 (RORCv2) and T-cell-specific T-box transcription factor (Tbet). Expression of CD161 and enrichment for cytokine production are stable characteristics of CD161+ Treg upon both short- and longer-term culture in vitro. Additionally, CD161+ Treg are highly enriched within the inflammatory environment of childhood arthritis, suggesting a role in disease. Our data therefore demonstrate that CD161+FoxP3+ T cells are a novel Treg subset, found in health and disease, which display high proinflammatory potential but also exhibit hallmark Treg characteristics.

Item does not contain fulltext BACKGROUND: Analysis of myeloid-related protein 8 and 14 complex (MRP8/14) serum concentrations is a potential new tool to support the diagnosis of systemic-onset juvenile idiopathic arthritis (SJIA) in the presence of fever of unknown origin. OBJECTIVE: To test the ability of MRP8/14 serum concentrations to monitor disease activity in patients with SJIA and stratify patients at risk of relapse. METHODS: Serum concentrations of MRP8/14 in 52 patients with SJIA were determined by a sandwich ELISA. The monitoring of therapeutic regimens targeting interleukin 1 and tumour necrosis factor alpha, and methotrexate treatment was analysed and diagnostic power to predict flares was tested. RESULTS: MRP8/14 levels were clearly raised in active disease and decreased significantly in response to successful treatments. Serum concentrations of MRP8/14 increased significantly (p740 ng/ml predicted disease flares accurately (sensitivity 92%, specificity 88%). MRP8/14 levels correlated well with clinical disease activity, as assessed by physician's global assessment of disease activity (r=0.62), Childhood Health Assessment Questionnaire (r=0.56), active joint count (r=0.46) and with C-reactive protein (r=0.71) and erythrocyte sedimentation rate (r=0.72) (for all p

Background Methotrexate (MTX) is the first line of therapy for patients with juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). The mechanisms of action of MTX in childhood autoimmunity are not fully elucidated. The primary target sites of inflammation of JIA and JDM i.e. joint and muscle, respectively do not represent sites from which samples can be easily obtained to monitor inflammatory markers. In contrast peripheral blood is accessible and can be obtained at time of routine clinical screen. We hypothesized that changes in peripheral blood of patients would be informative in monitoring disease and understanding inflammatory pathways that are modulated by MTX.

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with hemiparesis during the aura. In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus. Recently, mutations in ATP1A2 on chromosome 1q23 encoding a Na+/K+ -ATPase subunit were identified in four families (FHM2). We now describe an FHM2 pedigree with a fifth ATP1A2 mutation coding for a G301R substitution. The phenotype was particularly severe and included hemiplegic migraine, seizure, prolonged coma, elevated temperature, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria. A mild crossed cerebellar diaschisis during an attack further supported the clinical evidence of a cerebellar deficit. This is the first report suggesting cerebellar involvement in FHM2. A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus. The study of this family suggests that the absence of cerebellar signs may not be a reliable indicator to clinically differentiate FHM2 from FHM1.

Standard management of Juvenile Idiopathic Arthritis (JIA) is heavily dependent on the use of methotrexate (MTX), which induces clinical benefit in about 65% of patients. We have previously demonstrated that children with high serum levels of MRP8/14 protein prior to starting MTX have a high chance of good response to MTX. However, among children whose MRP8/14 serum levels are moderate or low, prior to MTX, some respond well whilst others respond poorly to MTX. We have taken a proteomics approach to identify novel biomarkers present in serum prior to treatment that correlate with response or non response to MTX.

The nucleoside adenosine exerts regulatory functions prompting T cell anergy and preventing release of inflammatory cytokines. The main source of extracellular adenosine is AMP dephosphorylated by CD73. The resulting product can be taken up by the cell or further metabolized by ADA (Adenosine deaminase) expressed extracellularly when bound to the membrane via coupling to CD26 protein, a surrogate marker for ADA expression. We have shown that CD73 expression and its AMPase activity are reduced on JIA (juvenile idiopathic arthritis) SFMC (synovial fluid mononuclear cells), particularly on CD8+ T cells and CD19+ B cells; we hypothesise that this may lead to a defect in generation of anti inflammatory adenosine in JIA.

Background: Purinergic signaling is an important mechanism of immunomodulation. The ectoenzyme CD39 is a key regulator of extracellular ATP levels and catalyses hydrolysis of ATP to AMP. The A allele of the CD39 SNP rs10748643 is associated with both susceptibility to the autoimmune condition Crohn’s disease and low CD39 RNA transcript expression levels in HapMap transformed immune cell lines. Aim: To investigate the association between CD39 genetic polymorphism, protein expression and function in human healthy and autoimmune arthritis inflamed tissues. Results: We demonstrate increased CD39 protein on T cells in the human inflamed arthritis joint compared to peripheral blood. SNP rs10748643 AA individuals had a greatly reduced CD39 T cell expression and ATPase capacity compared to GG individuals (p

Background Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatological disease with an incidence of 1 in 1000. Methotrexate is the primary DMARD given to patients with JIA but approximately 30% of children fail to respond. The SPARKS CHARM study enrolls patients with JIA about to start MTX with the aim to discover predictors of response to MTX, to distinguish patients who will respond well to MTX from non-responders.

OBJECTIVES: Little is known about the mechanisms of efficacy of methotrexate (MTX) in childhood arthritis, or genetic influences upon response to MTX. The aims of this study were to use gene expression profiling to identify novel pathways/genes altered by MTX and then investigate these genes for genotype associations with response to MTX treatment. METHODS: Gene expression profiling before and after MTX treatment was performed on 11 children with juvenile idiopathic arthritis (JIA) treated with MTX, in whom response at 6 months of treatment was defined. Genes showing the most differential gene expression after the treatment were selected for single nucleotide polymorphism (SNP) genotyping. Genotype frequencies were compared between nonresponders and responders (ACR-Ped70). An independent cohort was available for validation. RESULTS: Gene expression profiling before and after MTX treatment revealed 1222 differentially expressed probes sets (fold change >1.7, P

Background Methotrexate (MTX) is the standard disease modifying therapy for children with juvenile idiopathic arthritis (JIA), inducing remission in ~65% of cases. There are currently no known predictors which classify who will successfully respond to MTX therapy nor those who will remain well following MTX withdrawal. Mechanisms of MTX action in JIA are at present unclear: genetic and gene expression profiling would provide novel insights into the biology of this therapy.

The nucleotidases CD39 and CD73 are responsible for the catabolism of pro-inflammatory ATP to AMP, and the consequent dephosphorylation of this nucleotide to regulatory adenosine. CD39 protein has previously been observed to be elevated (1) on JIA (Juvenile Idiopathic Arthritis) SFMC (synovial fluid mononuclear cells) with a correspondent increase in ATPase activity, while CD73 has been found decreased on JIA SFMC, potentially affecting the cells ability to synthesize suppressive adenosine.