bluuebunny/crossref_metadata_2025_split huggingface dataset:
A125: Immunomodulatory Factors Produced by Mesenchymal Stem Cells After in vitro Priming with Danger Signals
Authors: Bukulmez Hulya , Bilgin Asuman , Bebek Gurkan , Caplan Arnold I. , Jones Olcay 
Published: March 2014

Background/Purpose:We have previously shown that pre‐exposure to IL‐1β augments the immunosuppressive activity of MSC using the mixed lymphocyte reaction as a readout assay. In this project, we studied the profiles of inflammatory cytokines secreted by MSCs at the protein level to identify biomarkers in in vitroprimed MSCs. The objective of this study was to determine the MSC response to “danger signals.”Methods:MSCs were isolated from a healthy donor and cultured as per a protocol published earlier by the Skeletal Research Center. After three passages, 200,000 cells per 35 mm culture dish were incubated in 2 ml DMEM with 10% fetal bovine serum at 37°C for 5 days until 90% confluent. The MSCs were then treated with LPS (10 μg/ml), IL‐1β (25 ng/ml), TNF‐α (50 ng/ml), or poly (I:C) (30 ng/ml) overnight (18 hours). Control and treatment groups were done in triplicate. The culture media were then collected and analyzed for secreted mediators using the RayBiotech® Human Cytokine Array (2000), as per the manufacturer's protocol. Chemiluminescense was detected using Kodak BioMax MR film, and was analyzed using the ImageJ program (rsbweb.nih.gov). Normalization and fold‐difference computations were then performed in MS Excel. Pathway analysis for biomarker detection was performed using the Ingenuity (ingenuity.com) program by the CWRU proteomics center.Results:There were clear distinctions in the patterns of inflammatory mediators produced by MSC upon exposure to LPS versus poly (I:C). LPS stimulated the production of mediators that affect mostly neutrophil chemotaxis and activation, including IL‐8 (1.8 fold), CXCL7 (2 fold), CXCL5 (2.4 fold), CXCL1 (1.6 fold). However, poly (I:C) induced mediators with activities on T cells and NK cells including IL‐15 (18 fold), IL‐4 (23 fold), TGF‐β3 (9.7 fold), CCL‐18 (4.6 fold). While poly (I:C) stimulated IL‐1β production (2.6 fold), LPS did not (0.7 fold), and neither agent increased TNF‐α significantly (1.3 and 2.1 fold). Interestingly, there was marked production of CCL1 (12 fold) upon exposure of MSC to IL‐1β but not to LPS (0.6 fold), TNF‐α (1.3) or poly (I:C) (2.1 fold).Conclusion:Priming MSC by TLRs ligands triggered different cytokine and chemokine expression profiles. These profile patterns may signify framework of the upcoming immune responses in the tissue. Accordingly, the candidate biomarkers for ongoing MSC immunomodulatory activities should include those for neutrophils versus those for T/NK cells. Furthermore, our results strongly suggest involvement of IL‐1β in MSCmediated activation of T‐regulatory cells by induction of the CCR‐8 ligand, CCL‐1. CCR‐8 is a known biomarker identifying CD4+ memory T‐cells enriched for FoxP3+ T‐regulatory cells and is involved in delivery of immunosuppression.
A137: Appropriateness of Rheumatology Lab Studies and Referrals among General Pediatricians
Authors: Correll Colleen K. , Spector Logan G. , Zhang Lei , Binstadt Bryce A. , Vehe Richard K. 
Published: March 2014

Background/Purpose:Rheumatology lab tests are often of low diagnostic utility when ordered by primary care physicians, and may lead to erroneous referrals. No prior studies have investigated pediatricians' reasons for ordering these tests. We surveyed pediatricians in three states of the Upper Midwest regarding their ordering of rheumatology lab tests and reasons for referral to pediatric rheumatology (PR).Methods:A web‐based survey was emailed to general pediatricians practicing in Minnesota, North Dakota, and South Dakota. The rheumatology tests queried included antinuclear antibody (ANA), anti‐double‐stranded DNA antibody (anti‐dsDNA), rheumatoid factor (RF), anti‐citrullinated peptide antibodies (anti‐CCP), and HLA‐B27. Basic descriptive analysis was performed. Subgroup analysis was performed to assess the relationship between the pediatrician's experience with PR (defined as years since completion of residency training, whether or not the training program had a PR division, time spent in a PR clinic during training and completion of continued medical education focused on PR in the last three years) and the appropriateness of lab tests and PR referrals.Results:The response rate was 15.3% (93/609). Eighty‐nine percent (83/93) of the respondents had ordered ANA, for reasons including abnormal joint exam (72%), musculoskeletal (MSK) pain with a normal exam (52%), concern for juvenile idiopathic arthritis (JIA) (47%), rash (41%), concern for systemic lupus erythematosus (39%), fatigue (35%), and fever (35%). Fifty‐nine percent (54/92) had ordered anti‐dsDNA, and the distribution of reasons paralleled that of ANA. Seventy‐three percent (67/92) had ever ordered RF, most commonly for abnormal joint exam (67%), joint pain with a normal exam (60%), concern for JIA (42%), and fever (30%). Only 8% (7/92) had ordered anti‐CCP. Forty‐two percent (39/92) had ordered HLA‐B27, primarily for back pain (59%). Of those who had ever referred a patient to a pediatric rheumatologist, 44% (37/85) did so for a positive ANA of unclear significance, 14% (12/85) for positive RF of unclear significance, and 9% (8/85) for anti‐dsDNA of unclear significance. Positive HLA‐B27 and anti‐CCP were less common referral reasons. Subgroup analysis did not show significant differences between experience level and appropriateness of lab tests and referrals to PR.Conclusion:Inappropriate ordering of rheumatology lab tests with subsequent referral to PR is common among pediatricians in the Upper Midwest and likely elsewhere. The correctness of lab test utilization and referral to PR did not obviously improve with increased experience in PR. New educational interventions are needed to improve general pediatricians' understanding and utilization of rheumatology lab tests and to decrease unnecessary referrals to PR.
A139: Body Mass Index and Height Change Over Time in Childhood‐Onset Systemic Lupus Erythematosus Cohort
Authors: Harris Julia G. , Maletta Kristyn I. , Kuhn Evelyn M. , Olson Judyann C. 
Published: March 2014

Background/Purpose:Systemic lupus erythematosus (SLE) can lead to significant morbidity and mortality related to coronary artery disease. Obesity is an additional risk factor for cardiovascular disease that appears to be more prevalent in this population. Obesity in SLE has been linked to decreased health‐related quality of life, functional limitations, pain, fatigue, diabetes mellitus, and increased malignancies. In addition, growth retardation is an important aspect to consider in a child or adolescent that is exposed to corticosteroids. Growth failure has been a proposed addition to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) to modify this validated scale for childhood‐onset SLE (cSLE). There is limited data discussing change in growth parameters over time in cSLE patients, which our study sought to do.Methods:A retrospective chart review was performed on patients diagnosed with SLE prior to age 18 who were followed in the Children's Hospital of Wisconsin Rheumatology Clinic for at least one year between January 1999 and August 2012. Weight and height were collected two times per year. Body mass index (BMI; kg/m2) and percentiles of measurements for age were calculated based on sex‐specific growth references from the Centers for Disease Control and Prevention for patients 2 to 20 years old. Additional information collected included age of diagnosis, medication use, presence of lupus nephritis, and items of disease damage based on the SDI.Results:Analysis was performed on 75 patients with mean disease duration of 4.55 years. There were 685 growth for age percentile values recorded. Mean BMI percentage per age at diagnosis was 64.81 compared to 76.31 at the 610 follow‐up visits, which was statistically significant (p < 0.001). At diagnosis, 33.3% of patients were overweight (≥85–95% BMI for age), obese (≥95–99% BMI for age), or severely obese (≥99% BMI for age) versus 49.3% at last available follow‐up visit. Sixty‐eight percent of patients had at least one BMI measurement out of the normal range. Mean percent height for age at diagnosis was 64.21 versus 46.58 at follow‐up visits (p < 0.001). Eight of the seventy‐five patients had growth percentiles <5% at last follow‐up visit. imageConclusion:A majority of our cSLE population was overweight or obese during at least one time period. In addition, BMI statistically increased from diagnosis to follow‐up visits. Growth failure was present in greater than 10% of the population, and percent height for age statistically decreased after diagnosis as well. Interventions related to healthy living habits and medication adjustments should be made to address these important growth issues that can have long‐standing complications.
A146: Strategies for Assessment and Management of Severe Environmental Allergies at “Camp JRA”
Authors: Ostrov Barbara E. , Robbins Lisa 
Published: March 2014

Background/Purpose:Camp JRA (Juveniles Reaching Achievement) has been offering a week of fun, education, friendship, independence and support for 17 years to children with arthritis and related diseases. The number of campers has grown from 28 the first year to 120 maximum capacity for the past few years.Experienced Pediatric Rheumatology nurses and physicians provide hands‐on care in the “Med Shed” at Camp JRA. Medical information is completed by parents, pediatric rheumatologists and primary care providers. The senior medical staff review and verify the information. Over the past 5 years we identified that coping with environmental allergies consumed a disproportionate amount of time for the staff and we felt unprepared to optimally address these issues.We wish to share our strategy in addressing the growing concern about environmental sensitivities in a residential week long camp for children with rheumatic diseases.Mindfulness of drug allergies is standard of care in any environment where medications are given. Coping with food allergies has assumed a significant position in our hierarchy of medical responsibilities in the Med Shed, as well. We found ourselves struggling to manage the increasing complexity of this issue. We found that some campers had multiple allergies listed that had not been reported, and no details were provided. For many years, we have run a very organized medical camp, however, this issue confounded our care of these complex children.Methods:The emergence of the multiple allergies issue was a barrier to providing a confidently safe camp environment. New approaches were developed and implemented.

1. We developed new allergy history questionaire that triggered progression to further detailed information.

2. We consulted with our Pediatric Allergist to develop an algorithm for assessment of symptoms (Attached to poster).

3. We developed an Allergy Action Plan specific to each camper with allergy issues, approved in advance by parent and signed.

4. We developed a system for Epi‐pen storage: over the door holder with multiple clear pockets, with the Epi‐pen, the child's photo, the signed Allergy Action Plan.Results:We oriented all medical staff who worked in the Med‐Shed to the new system. When implemented at Camp JRA in July 2013 and we experienced no allergy response problems. Increasing allergy sensitivities in patients requires a proactive plan for residential camps. We have developed a model for assessing allergies and reaction preparedness. This plan has improved our confidence that we can provide safe rheumatologic AND allergy response care.Conclusion:The development of increasing allergy sensitivities and concerns by families and patients requires a proactive plan for residential camps of children with rheumatic disease. We hve developed a model for assessing allergies and reaction preparedness.
A150: Control of Cell Proliferation in Lupus Nephritis: The Role of miRNAs and HER2
Authors: Costa Reis Ana Patrícia , Russo Pierre , Gallucci Stefania , Sullivan Kathleen E. 
Published: March 2014

Background/Purpose:miRNAS are responsible for post‐transcriptional gene silencing and typically regulate multiple targets. Our goal was to study the miRNA pattern of lupus nephritis (LN) in order to better understand its pathogenesis.Methods:A retrospective cohort study was performed on a large single‐center cohort of children exposed to anti‐Ro and/or anti‐La antibodies on whom prospective data has been collected since 1984. Inclusion criteria were: 1) first child born from a woman positive for anti‐Ro and/or anti‐La antibodies with a diagnosis of cutaneous lupus, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis or rheumatoid arthritis, 2) the mother underwent fetal echocardiography screening during pregnancy and/or the child had a postnatal ECG and 3) the child was ≥6 months old as of October 2013. We used Bayesian analysis for the association between prenatal use of AM and NLE.Results:A kidney LN miRNA signature was identified, which, according to Ingenuity pathway analysis, mainly reflected cell proliferation (p = 3.3E‐23‐0.049). miR‐26a, miR‐30b and miR‐4286 were significantly decreased in LN (p = 0.002; p = 0.005; p = 0.002). The levels of miR‐26a and miR‐30b were also decreased in the urine of LN patients when compared to controls (p = 0.03; p = 0.02). The genes significantly up‐regulated in the knockdowns of miR‐26a, miR‐30b and miR‐4286 when compared to controls were related to mitosis (p = 1.06E‐10). These results were validated by qRT‐PCR, including the increase on the expression of genes associated with cell cycle (CCNE2, E2F8, MAD2L1, MYBL1 and POLQ).Based on these results, we examined HER2 expression, a protein that regulates miR‐26a and miR‐30b levels in breast cancer cell lines. We found that it was highly increased in the glomeruli and tubular compartment of LN patients and not in other mesangioproliferative diseases. Moreover, the average of HER2+ cells in the glomeruli of NZM2410 mice was higher than in B6 or Balb/c mice (p < 0.0001; p = 0.009) and it was associated with proteinuria (p = 0.001). Finally, HER2 expression was increased in mesangial cells by α Ninterferon exposure (p = 0.02) and IRF‐1 transfection (p = 0.0009).Conclusion:The kidneys of LN patients have a miRNA pattern characterized by a significant decrease of miR‐26a, miR‐30b and miR‐4286, which is predicted to be associated with increased proliferation. In addition, miR‐26a and miR‐30b are also decreased in the urine of LN patients, which makes them interesting candidates as biomarkers. It was previously shown that trastuzumab, an antibody against HER2, produces therapeutic actions by up‐regulating miR‐26a and miR‐30b in breast cancer cell lines. Since we demonstrated that HER2 was highly increased in the kidneys of LN patients and NZM2410 mice, blocking HER2 may be a new promising pathway to decrease cell proliferation and damage in this disease.
A151: Pediatric Rheumatology Care and Outcomes Improvement Network Demonstrates Performance Improvement on Juvenile Idiopathic Arthritis Quality Measures
Authors: Harris Julia G. , DeWitt Esi Morgan , Laxer Ronald M. , Ardoin Stacy P. , Gottlieb Beth S. , Olson Judyann C. , Passo Murray H. , Weiss Jennifer E. , Lovell Daniel J. , Lee Tzielan C. , Vora Sheetal S. , Griffin Nancy , Stock Jason A. , Darbie Lynn M. , Bingham Catherine A. 
Published: March 2014

Background/Purpose:Pediatric Rheumatology Care and Outcomes Improvement Network (PR‐COIN) is a multi‐site learning network designed to improve outcomes of juvenile idiopathic arthritis (JIA) care. Teams collect point of care data on measures of process of care and outcomes of care for the purposes of analysis to guide improvement activities. Eleven North American pediatric rheumatology centers participate. This report illustrates our improvement in several JIA process quality measures (QMs).Methods:Process of care QMs targeted for improvement include measurement of: arthritis‐related pain, physician global assessment, joint count, health‐related quality of life, physical function, as well as screening for uveitis, medication toxicity, and tuberculosis per guidelines. Outcome measures for JIA include clinical inactive disease, clinical remission on and off medications, no or mild pain level, and optimal physical functioning. Network goals were determined for each process and outcome measure. Data are collected with IRB approval and informed consent, and the shared registry for data entry is the ACR's Rheumatology Clinical Registry. Site‐specific and aggregate data are analyzed and displayed monthly via statistical process control charts allowing PR‐COIN to track performance over time. Individual centers use established quality improvement methodology to reach and exceed pre‐determined goals.Results:Data from 5112 encounters for 1134 JIA patients have been collected since April 2011. QMs with performance meeting or exceeding initial goals include documentation of complete joint count and measurement of arthritis‐related pain. For PR‐COIN network as a collective unit, QMs improved in six processes—measurement of functional ability, completion of ongoing medication toxicity labs, documentation of complete joint count, medication counseling for newly prescribed DMARDs, documentation of annual medication counseling, and measurement of health‐related quality of life. All of these measures had a shift above the baseline mean, demonstrating special cause. In addition, five sites have demonstrated individual improvement in at least one process QM.Conclusion:PR‐COIN sites are collectively and individually demonstrating significant improvements in JIA process of care QMs. Quality improvement efforts in PR‐COIN are ongoing with the goal of improving the outcome for patients with JIA.
A177: Program Evaluation of the ACR/CARRA Inter‐Institutional Mentoring Program (AMIGO) in Pediatric Rheumatology
Authors: Muscal Eyal , Moorthy Lakshmi N. , Riebschleger Meredith P. , Eberhard Anne , Huttenlocher Anna , Klein‐Gitelman Marisa S. , Prahalad Sampath , Stevens Kelly Rouster , Schneider Rayfel , Nigrovic Peter A. 
Published: March 2014

Background/Purpose:In pediatric rheumatology, the small size of many academic programs translates into limited mentoring options for early career physicians. To address this “mentorship gap,” in 2011 the American College of Rheumatology (ACR) and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) joined together to develop AMIGO, the ACR/CARRA Mentoring Interest Group, that now includes greater than half of pediatric rheumatology fellows and junior faculty in the US and Canada. We report ongoing program evaluation encompassing pilot (2011) and full roll‐out (2012, 2013) phases of the AMIGO project.Methods:Mentees and mentors participating in the AMIGO project were surveyed via online questionnaire to determine dynamics of contact and perceived benefit. The entire pediatric rheumatology community was surveyed in 2011 to determine the state of mentoring and career development, with a repeat survey planned for early 2014. We tabulated the active dyads as of January 2014.Results:As recently reported, detailed evaluation of the pilot phase 17 months after initial roll‐out found that 19 of 20 pilot AMIGO dyads were still functioning, with substantial benefit noted by mentees in career guidance, scholarship, and job satisfaction. Benefits reported by mentors included improvement of their mentoring skills and development of their academic portfolios. Both mentees and mentors reported improved connectedness to the wider pediatric rheumatology community. 83 additional dyads were matched prior to 2012 and 2013 ACR meetings. Comparison of these 17‐month pilot results to a December 2013/January 2014 survey of all active AMIGO participants is ongoing. A questionnaire administered to the whole pediatric rheumatology community in 2011 (n = 135 respondents, including an estimated 64–70% response rate among fellows and junior faculty) found that approximately 60% of fellows and junior faculty had a career development mentor. We will assess whether the AMIGO program has had a global impact upon the mentoring culture in pediatric rheumatology by collecting community‐wide survey data in 2014 and then comparing to 2011 data.Conclusion:The 2011 AMIGO pilot program has confirmed the feasibility of a North American inter‐institutional mentoring program in pediatric rheumatology. Participants identified benefits to both mentees and mentors in multiple domains, most prominently in career guidance, a core goal of the program. Ongoing program evaluation will determine how much of this benefit has been sustained after participation was opened to the whole community, and whether the program has had a measureable impact on the overall state of mentoring in pediatric rheumatology.
Engineering of a bispecific affibody molecule towards HER2 and HER3 by addition of an albumin‐binding domain allows for affinity purification and in vivo half‐life extension
Authors: Malm Magdalena , Bass Tarek , Gudmundsdotter Lindvi , Lord Martin , Frejd Fredrik Y. , Ståhl Stefan , Löfblom John 
Published: March 2014

AbstractEmerging strategies in cancer biotherapy include the generation and application of bispecific antibodies, targeting two tumor‐associated antigens for improved tumor selectivity and potency. Here, an alternative format for bispecific molecules was designed and investigated, in which two Affibody molecules were linked by an albumin‐binding domain (ABD). Affibody molecules are small (6 kDa) affinity proteins and this new format allows for engineering of molecules with similar function as full‐length bispecific antibodies, but in a dramatically smaller size (around eight‐fold smaller). The ABD was intended to function both as a tag for affinity purification as well as for in vivo half‐life extension in future preclinical and clinical investigations. Affinity‐purified bispecific Affibody molecules, targeting HER2 and HER3, showed simultaneous binding to the three target proteins (HER2, HER3, and albumin) when investigated in biosensor assays. Moreover, simultaneous interactions with the receptors and albumin were demonstrated using flow cytometry on cancer cells. The bispecific Affibody molecules were also able to block ligand‐induced phosphorylation of the HER receptors, indicating an anti‐proliferative effect. We believe that this compact and flexible format has great potential for developing new potent bispecific affinity proteins in the future, as it combines the benefits of a small size (e.g. improved tissue penetration and reduced cost of goods) with a long circulatory half‐life.