bluuebunny/crossref_metadata_2025 huggingface dataset:
A85: Effect of Childhood‐Onset Systemic Lupus Erythematosus on Linear Height and Body Mass Index
Authors: Hersh Aimee O. , Son Mary Beth , von Scheven Emily
Published: March 2014

Background/Purpose:

To explore the relationship between childhood‐onset systemic lupus erythematosus (SLE) and anthropomorphic measures including linear height and body mass index (BMI).

Methods:

Cross‐sectional data were obtained from the CARRAnet registry, a United States pediatric rheumatology database. Subjects included in the database were diagnosed with SLE at ≤18 years of age and were ≤ age 21 at enrollment. Subject height and BMI at registry entry were recorded and compared with the US Centers for Disease Control and Prevention standardized growth charts for age and sex in order to obtain the appropriate percentiles. A history of renal disease was defined by a prior history of a renal biopsy. Chi squared testing was used to examine associations between height and BMI percentiles and history of renal disease and daily, chronic steroid use.

Results:

Data from 834 subjects were analyzed. Median age of onset was 12.3 years (range 0.88–17.32 years), median age at baseline was 15.5 years (range 3.1–20.4 years); 84% were female. Race/ethnicities included African American (35%), Caucasian (48%), Hispanic/Latino (27%), Asian (12%) and other (5%). The mean height percentile for the entire cohort was 40% (SD ± 30.6) with a median height percentile of 35% (range 1–100). Twenty one percent of the cohort (n = 174) had a height percentile of <10%. Mean height percentiles by age group at registry entry were as follows: <11 years (n = 67), 42%; 11–14 years (n = 159), 43% and >14 years (n = 608), 40%. In univariate analysis, height was not associated with a history of renal disease or long term daily steroid exposure. The mean BMI percentile was 69% (SD ± 38), median percentile was 78% (range 1–100). One‐third of the cohort (n = 276) had a BMI percentile of ≥90%. In univariate analysis, a BMI of ≥90% was associated with renal disease (p = 0.016) but not long term daily steroid exposure.

Conclusion:

In this large cohort of subjects with childhood‐onset SLE, average height was reduced and BMI was increased as compared to the general population. Longitudinal studies of this population are needed to assess change in height and BMI over time, and to determine the impact of age of disease onset, disease activity and treatment on these important anthropomorphic measures.
A93: Childhood Granulomatosis With Polyangiitis: Standardized Disease Assessment in 6 Czech Children
Authors: Böhm Marek , Nemcová Dana , Dallos Tomáš , Lád Václav , Suláková Terezie , Jancová Eva , Dolezalová Pavla
Published: March 2014

Background/Purpose:

Granulomatosis with polyangiitis is a rare primary systemic vasculitis affecting small blood vessels with predilection for the respiratory tract and kidneys. We describe clinical outcome of a small patient cohort as captured by the recently developed tools the Paediatric Vasculitis Activity Score (PVAS) and the Paediatric Vasculitis Damage Index (PVDI).

Methods:

A retrospective and prospective analysis of data gathered from 2006 to 2013 on patients fulfilling the EULAR/PRINTO/PRES criteria for GPA. Disease activity and damage items have been systematically recorded, data from the time of diagnosis and from the last follow‐up (F/U) are presented.

Results:

Characteristics of the 6 girls identified are summarized in the . The median F/U was 4 years. Disease manifestations were recorded under PVAS and PVDI sections with 6/9 and 8/10 systems affected with active disease or damage, respectively. General, ENT and pulmonary manifestations were observed in 4/6 patients. Nephritis developed in 2/6 patients. Cumulative damage was noted in all cases with ENT region most commonly affected. Persistent remission was achieved in one case with limited disease, in the other one subglottic stenosis caused an episode of airway obstruction and cerebral ischemia leading to apalic syndrome and later to death. Clinical inactivity on treatment was achieved in 2 girls.

Patient characteristics

Patient
1
2
3
4
5
6

Age at onset (years)
14
14
13
12
15
14

F/U (years)
5
2
5
5
3
0.2

ANCA
Atypical IF
c‐ANCA
p‐ANCA
Atypical IF
c‐ANCA
c‐ANCA

Treatment
CS, CP, MMF
CS, MTX
CS, MTX
CS, MTX, CP, AZA
CS, CP, MMF, RTX
CS, CP, RTX

PVAS category (section score)
Onset
F/U
Onset
F/U
Onset
F/U
Onset
F/U
Onset
F/U
Onset
F/U

General
0
0
3
0
1
0
0
0
3
0
2
N/A

Cutaneous
0
0
0
0
0
0
0
0
3
0
5
N/A

Mucous memb./Eyes
0
0
0
0
6
0
2
0
0
0
0
N/A

ENT
0
0
6
0
0
0
6
0
4
0
6
N/A

Chest
3
0
0
0
0
0
6
0
6
0
6
N/A

Renal
12
4
0
0
0
0
0
0
12
0
0
N/A

PVAS total
15
4
9
0
7
0
14
0
28
0
19
N/A

PVDI category (section score)
Onset
F/U
Onset
F/U
Onset
F/U
Onset
F/U
Onset
F/U
Onset
F/U

Musculoskeletal
0
0
0
0
0
0
0
0
0
2
0
N/A

Skin/Mucous memb.
0
0
0
0
0
0
0
1
0
0
1
N/A

Ocular
0
0
0
0
0
1
0
1
0
0
0
N/A

ENT
0
0
0
3
0
1
0
2
0
1
1
N/A

Chest
0
0
0
0
0
0
0
3
0
1
1
N/A

Renal
0
1
0
0
0
0
0
0
0
1
0
N/A

Nervous system
0
0
0
0
0
0
0
2
0
0
0
N/A

Other
0
1
0
1
0
0
0
3
0
0
1
N/A

PVDI total
0
2
0
4
0
2
0
12
0
5
4
N/A

F/U–follow‐up, N/A‐non–available, CS‐Corticosteroids, CP‐Cyclophosphamide, MTX‐Methotrexate, MMFMycophenolate mofetil, AZA‐Azathioprine, RTX‐Rituximab

Conclusion:

This small series of patients illustrates a variety of GPA outcomes. A standardized scoring of disease activity and damage enables systematic patient F/U and drives appropriate treatment decision‐making.
A103: Childhood Onset Takayasu Arteritis—Experience From a Tertiary Care Centre in South India
Authors: Kumar Sathish , Goel Ruchika , Danda Debashish , Surin Ajith Kumar , Bacon Paul A
Published: March 2014

Background/Purpose:

Takayasu Arteritis (TA) is a chronic granulomatous vasculitis of autoimmune etiology characterized by narrowing of aorta and its main branches. It is one of the rarest diseases but the third common cause of vasculitis in pediatric age group. Mortality in juvenile onset TA has been reported to range from 8% to 35%. The outcome of disease has improved recently with interdisciplinary treatment including immunosuppressants and cardiovascular interventional procedures. We aimed to study the clinical features, angiographic findings and outcome of children with TA referred to a single centre in South India over a 9 year period.

Methods:

Records of TA patients, with symptom onset prior to 16 years of age were studied. Disease Extent Index‐Takayasu (DEI.TAK), Indian Takayasu Arteritis Score 2010, and Takayasu Arteritis Damage Score (TADS) were calculated retrospectively using clinical information in electronic records. Cumulative incidence of sustained remission was estimated using Kaplan Meir curve

Results:

Forty patients with childhood onset TA with median age of onset of 12.5 (range 1–16) years presented at a median diagnostic delay of 11.3 (range 1–60) months. Commonest presenting features were hypertension, headache, malaise and fever. Pulse‐less disease was observed in 25 (62.5%) cases. Majority (n = 28) had active disease with raised inflammatory markers, high baseline DEI.TAK score of 10 (3–24) and high median TADS of 7 (3–14).

Of the 34 patients, followed up for 21.5 (range 3–192) months, remission was attained in 30, however cumulative sustained remission was achieved in only 29% of them at 5 years. Median period of sustained remission was 22.5 months (95% CI 17.1–26.8). New areas of vessel involvement were observed in 13 patients. Disease progression was arrested in majority (n= 20) with aggressive medical management and endovascular intervention. All 11 patients with an increment in TADS of ≥4 units during follow up had persistently active or relapsing disease. There was single case with fatality.

Conclusion:

Corticosteroids and immunosuppressive therapy were effective in the control of disease activity. Progression of damage was associated with persistent inflammation. Continued surveillance by clinical instruments and imaging is warranted.
A117: Demonstration of Antibodies to Multiple Citrullinated Epitopes in the Sera of Patients With Juvenile Idiopathic Arthritis
Authors: Feller Lance , Gilliam Brooke , Cleland Esperanza , Syed Reema H. , Pepmueller Peri H. , Moore Terry L.
Published: March 2014

Background/Purpose:

IgG anti‐cyclic citrullinated peptide (anti‐CCP) antibodies have been identified in the sera of juvenile idiopathic arthritis (JIA) patients and have been associated with more destructive disease. The identity of the target proteins of the citrullinated modification has remained elusive. We attempted to determine the prevalence and significance of different citrullinated epitopes.

Methods:

We evaluated serum from 96 patients with various subtypes of JIA for the presence of antideiminated (citrullinated) fibrinogen, anti‐citrullinated α‐enolase, anti‐citrullinated and native type II collagen, and anti‐vimentin (vim1–16 and vim 59–74) antibodies by enzyme‐linked immunosorbent assays. We correlated the presence of the antibodies with anti‐CCP and rheumatoid factor (RF) isotypes, erythrocyte sedimentation rate (ESR), and C‐reactive protein (CRP) levels.

Results:

31 JIA patients (32%) demonstrated reactivity to anti‐citrullinated fibrinogen, 23 (24%) to anti‐citrullinated type II collagen, 10 (10.5%) to anticitrullinated vimentin I‐16, 9 (9%) to anti‐citrullinated α‐enolase, and 7 (7.4%) to anti‐citrullinated vimentin 59–74 antibodies. One IgM RF positive JIA patient was positive for all 6 of the citrullinated autobodies assayed. The reactivity was higher in those JIA patients positive for IgM RF and IgG/IgM anti‐CCP antibodies.

Conclusion:

The study demonstrates that antibodies to multiple citrullinated epitopes are present in the sera of patients with JIA. A higher percentage of antibodies reacted with citrullinated fibrinogen and citrullinated type II collagen. The more widespread the positivity correlates with more severe disease.
A129: Unlike Fibroblast‐like Synoviocytes from Oligoarticular Juvenile Idiopathic Arthritis, Fibroblast‐like Synoviocytes From Polyarticular Subtype Do Not Display a Chondrocyte Phenotype
Authors: Brescia AnneMarie C. , Simonds Megan , McCahan Suzanne , Fawcett Paul T. , Rose Carlos D.
Published: March 2014

Background/Purpose:

Condylar bony hypertrophy is functionally detrimental for children with JIA. Through gene expression profiling, we have identified dysregulated TGFb‐signaling when fibroblast‐like synoviocytes (FLS) from persistent oligoarticular JIA was compared to controls (heatmap). JIA FLS have a chondrocyte phenotype and may contribute to bony hypertrophy. In the current work, we have expanded the study to determine if FLS from extended oligoarticular (ext) and polyarticular (poly) subtypes also display a chondrocyte phenotype.

Methods:

Synovial fluid was obtained from our IRB‐approved repository. Appropriate samples from steroid‐naïve knee joints were identified by chart review and JIA subtype classification. Control samples were obtained from remnant synovial fluid/tissue obtained from orthopedic procedures performed on non‐arthritic joints. Both ext patients were on naprosyn and the first was also on methotrexate (mtx). Both poly patients were taking mtx and the first one was also taking naprosyn. Synovial fluid/tissue was plated in 6‐well plates with 15% FBS DMEM media and passaged 3–6 times to obtain a pure sample of FLS. We examined secreted proteins in the cell culture supernatants from JIA and control FLS using western blot and ELISA.

Results:

FLS from ext (O) secrete increased amounts of BMP4, BMP2, aggrecan, collagen II and COMP when compared to both FLS from controls (C) and from poly (P) (western blot). By ELISA, the ext samples (Oligo) secreted more BMP4 protein than the controls (Ctrl) (p = 0.012) and the poly (Poly) (p < 0.001). COMP was significantly more highly secreted by the ext than the controls (p = 0.038) and the poly (p < 0.001).

image

Conclusion:

Characterization of proteins expressed in cell culture media supernatants reveals that JIA FLS from oligoarticular subtype, either persistent or ext, but not from poly subtype, secrete chondrocyte differentiation markers. The difference more likely is related to differences in underlying disease pathogenesis between the subtypes rather than a medication effect since ¾ JIA patients were on mtx and no patients were on biologic agents at the time the synovial fluid was obtained. These characteristics may have implications for endochondral bone formation and local growth disturbances that are more prominent in oligoarticular than in poly JIA.
A141: Active Engagement of Teens with Juvenile Idiopathic Arthritis in Medical Education: What Do They Think Their Contribution Might Be?
Authors: Morin Marie‐Paule , Schneider Rayfel , Martimianakis Tina , Bowen Francois , Mylopoulos Maria
Published: March 2014

Background/Purpose:

The unique expertise and contributions to teaching of patients with chronic diseases is increasingly recognized and valued in medical education. Specifically in rheumatology, patient educators (also referred as patients partners) programs have been developed and shown to be effective for MSK exam teaching. To our knowledge, this educational strategy has never been adapted to pediatrics. We believe adolescents with juvenile idiopathic arthritis (JIA) might benefit from participation in such educational programs. Since little is known about how teens with JIA could actively be engaged in medical education, the main aim of the study was to explore and develop a detailed understanding of their perspective about potential contributions as patient educators.

Methods:

Using a qualitative approach, nineteen individual semi‐structured interviews were conducted with adolescents diagnosed with JIA. A purposeful critical case sampling was realized and participants were recruited at two tertiary pediatric hospitals. Consistent with qualitative research analysis, interviews were conducted until theme saturation. A thematic analysis of the transcripts was achieved using a constant comparative approach. In order to facilitate the data analysis, NVivo qualitative research software was utilized.

Results:

Motivational factors for teens' involvement and main barriers for engagement in patient partners programs were identified. Beyond teaching components of the pediatric musculoskeletal exam, adolescents brought to light other competencies, such as teaching of communication skills, which they valued as important elements to incorporate in the educational program. They also recognized their unique form of knowledge, referred as experiential knowledge, and expressed how it may complement the trainees' biomedical knowledge.

Conclusion:

Our work demonstrates that adolescents with juvenile idiopathic arthritis express a strong desire to be engaged as patient educators, manifest a clear understanding of what their potential contributions to the teaching might be and vocalize their desire to share with trainees their unique experiential knowledge. This study represents the first step toward the development of patient‐centered arthritis educational programs actively and effectively involving teens with JIA as teachers in medical education.
A143: Barriers to Referral to Pediatric Rheumatology among General Pediatricians in the Upper Midwest
Authors: Correll Colleen K. , Spector Logan G. , Zhang Lei , Binstadt Bryce A. , Vehe Richard K.
Published: March 2014

Background/Purpose:

Access to pediatric rheumatology (PR) care is limited. An average of 28 fellows graduate from PR training programs annually, and there are 224 board‐certified pediatric rheumatologists in the United States. Eleven states have no pediatric rheumatologist and 24 states have two or fewer. Furthermore, the mean distance to a certified pediatric rheumatologist is 60 miles. The impact that limited access to PR has on general pediatricians has not been studied.

Methods:

A web‐based survey was emailed to general pediatricians practicing in Minnesota (MN), North Dakota (ND), and South Dakota (SD). The email databases were obtained from the MN and ND state medical licensing boards and from the SD chapter of the American Academy of Pediatrics. The goal of the survey was to define barriers to access to PR care and the consequences of limited access. Basic descriptive analysis was performed and responses were summarized.

Results:

The overall response rate was 15.3% (93/609). Responders were younger than non‐responders (mean age 48 yo versus 53 yo, p = 0.0006) and had been in practice a shorter period of time (mean 22 y versus 27 y, p = 0.0051). Forty percent (37/92) of the clinics were urban, 40% (37/92) suburban, and 20% (18/92) rural. Twenty‐nine percent (27/92) of respondents' clinics were at least two hours by car from a pediatric rheumatologist, and 9% (8/92) were more than 6 hours away. Ninety‐two percent (85/92) had referred a patient to PR at least once, but 89% (83/93) had experienced a situation at least once in which they considered a referral to PR but ultimately did not. Reasons for not referring varied. When asked, “In cases in which you considered a PR referral but did not refer a patient to a pediatric rheumatologist, please indicate your reasons for doing so. (Select all that apply),” many had referred to other subspecialists instead: 29% (24/83) to pediatric infectious disease, 20% (17/83) to adult rheumatology, and 12% (10/83) to pediatric orthopedics, while 34% (28/83) managed the patient themselves. Although not a pre‐specified choice in the survey, 9% (3/32) of pediatricians added wait‐time as the reason for not referring to PR. Thirty‐five percent (32/60) had referred a pediatric patient to an adult rheumatologist, most commonly for distance (47%), while physician preference was never selected as a reason.

Conclusion:

Pediatricians often refer children with possible rheumatic disease to specialists other than PR due to reasons of distance and wait‐time. Referral to adult rheumatologists occurs, but not based on pediatrician preference. These findings suggest that the PR workforce is inadequate to meet demand, at least in the Upper Midwest. Interventions are needed to improve access to care in PR.
A147: Engaging Patients and Families in the Pediatric Rheumatology Care and Outcomes Improvement Network
Authors: DeWitt Esi Morgan , Fricke Kay , Bergheger Lindsey , Griffin Nancy , Laxer Ronald M. , Jones Karla B. , Gottlieb Beth S. , Taylor Janalee , Mims Catherine C. , Robbins Lisa M. , Lovell Daniel J. , Noonan Laura
Published: March 2014

Background/Purpose:

The Pediatric Rheumatology Care and Outcomes Improvement Network (PR‐COIN) is a multi‐site quality improvement learning network that aims to improve outcomes for children and adolescents with juvenile idiopathic arthritis. In addition to addressing variations in care practices, PR‐COIN has incorporated guidance and tangible contributions from patients and families to its national organizational and governance structure to drive improvement in JIA outcomes. PR‐COIN aims to grow this initiative to bring care providers, patients and family members together as co‐producers in improving care and outcomes.

Methods:

Various methods supporting family engagement are employed. PR‐COIN teams invite interested parents at their respective clinical sites to bring the parent perspective and priorities into local improvement work. To assure a reliable structure, a parent engagement specialist was employed to develop a platform for bringing families and care providers together. National conference calls facilitated by the specialist establish relationships across site representatives and begin goal setting for this group. Parents contribute to shared decision making project efforts. PR‐COIN's public website encourages family awareness and involvement in the network's improvement efforts.

Results:

7 of 11 sites have welcomed parent contributions to their improvement efforts (e.g. focus groups, advisory activities, etc.). Parents and patients have participated in PR‐COIN's biannual conferences, sharing the family perspective and needs associated with JIA care. One parent brings a unique background and skillset as both a pediatrician with QI experience and the parent of a teen with JIA. This distinction prompted appointment to PR‐COIN's governing body. We incorporate patient perspectives into clinic process improvements (e.g. pain management, optimizing physical functioning), enhanced and refined PR‐COIN's Shared Decision Making tool, supporting stronger, more informed medication choice, and are developing best practices optimizing use of these materials in clinic. Finally our engaged parents are encouraging others to contribute ideas supportive of PR‐COIN structure, growth, strategy and improvement efforts.

Conclusion:

Parents and patients bring unique talents, insight and skills to the operation of quality improvement networks making efforts more relevant to the self‐identified needs of JIA families.
A155: Development of an Intensive Interdisciplinary Pediatric Pain Rehabilitation Program: Improving Pain, Functioning, and Psychological Outcomes
Authors: Hoffart Cara , Anderson Rawni , Wallace Dustin
Published: March 2014

Background/Purpose:

We examined functional, psychological, and pain‐related outcomes among children with amplified pain syndromes completing an intensive interdisciplinary pediatric pain rehabilitation program. We hypothesized that baseline psychological measures and disability would predict a longer treatment course.

Methods:

This outpatient program provides 5–6 hours of daily intensive physical and occupational therapy in addition to yoga, self‐regulation, and behavioral health intervention. All pain medications are discontinued, and no invasive therapeutic procedures are utilized. 30 patients (26 female) aged 11–18 with chronic musculoskeletal pain completed Functional Disability Inventory, 100mm Visual Analog Scale, PROMIS Anxiety, Depression, and PRCQ‐catastrophizing at baseline and the end of each week; 22 have completed a one‐month follow‐up, and 6 completed six‐month follow‐up. The mean program duration was 3.7 (SD 0.91) weeks, determined by achievement of functional goals. Analyses were conducted with SPSS and supplemented with hierarchical linear modeling (HLM7) for time‐series analyses of pain and functioning.

Results:

There is linear improvement in parent‐reported FDI (25.2 to 7.3, P < .001) and patient‐reported FDI (27.5 to 13.9, P < .001) between baseline and program end. Patient‐reported function showed additional significant gains at 1 and 6‐month follow‐up with FDI of 7.2 and 2.8, respectively (P < .001). Patient‐reported pain did not consistently change during the program (P = .975); however, longitudinal patterns demonstrated significant decrease in pain between program end and follow‐up (P < .001). Pain is significantly affected by conversion symptoms, which are associated with higher levels of pain (P = .005) but did not affect the pattern of pain resolution. Patient reported anxiety and depression decline significantly (P = 0.004 and P = 0.001, respectively) as does patient catastrophizing following treatment (P = .001). Duration of treatment correlated with baseline functional disability (FDI r = .664; P = .001), and presence of conversion symptoms (r = .548; P = .008).

image

Conclusion:

Children with amplified pain syndromes successfully restore and maintain function and improve pain without pharmacotherapy. Baseline functional disability and psychological factors correlate with treatment program duration. Prospective studies are warranted to determine long‐term efficacy and effectiveness of this interdisciplinary program.
A157: Macrophage Activation Syndrome‐like Illness Due to an Activating Mutation in NLRC4
Authors: Canna Scott , de Jesus Adriana Almeida , Deng Zuoming , Gouni Sushanth , Marrero Bernadette , Brooks Stephen , Dimattia Michael , Liu Yin , Huang Yan , Plass Nicole , Chapelle Dawn C. , Montealegre Gina , Benseler Susanne , Laxer Ronald M. , Goldbach‐Mansky Raphaela
Published: March 2014

Background/Purpose:

Macrophage Activation Syndrome (MAS) is a life‐threatening systemic inflammatory disorder of unknown etiology. While MAS has no known genetic basis, clinical similarity with a genetic disorder of impaired cytotoxicity known as primary Hemophagocytic Lymphohistiocytosis (HLH) has suggested shared pathogenesis. In contrast, other investigations have suggested innate immune dysregulation drives MAS.

Methods:

We performed detailed clinical, genetic, and immunologic evaluation of a patient with early onset, recurrent MAS‐like disease including whole exome sequencing and analyses of serum cytokines, whole blood transcription, and stimulated monocyte and macrophage responses. We subsequently tested the effects of a de novo mutation in transfection experiments with a monocytic cell line.

Results:

We identified a 7 year‐old female with recurrent episodes of fever, splenomegaly, transaminitis, pancytopenia, occasional evanescent rash, and massive hyperferritinemia since 6 months of age. Her Natural Killer cell function was normal, and she had no mutations in genes associated with HLH or hereditary periodic fever syndromes. Whole exome sequencing identified a de novo missense mutation in a highly conserved area in the nucleotide‐binding region of the inflammasome component NLRC4. Interleukin (IL)‐1b, Interferon a2, and particularly IL‐18 were elevated in the patient's peripheral blood even during clinical quiescence. The patient's monocytes produced more of a number of inflammatory cytokines in response to stimulation than controls, while monocyte‐derived macrophages specifically over‐produced IL‐1b and IL‐18. Transfection of THP1 monocytes with a plasmid bearing a mutant NLRC4 construct resulted in increased cell death and IL‐1b production versus a wild‐type plasmid. The patient showed short‐term clinical improvement and ability to wean steroids with recombinant IL‐1 receptor antagonist (IL‐1ra) therapy.

Conclusion:

While NLRP3 inflammasome hyperactivity has been implicated in the pathogenesis of a variety of autoinflammatory conditions, our data suggest that a mutation in the ADP binding domain of NLRC4 can result in MAS‐like disease. This mutation may destabilize NLRC4's auto‐inhibited conformation by altering ADP binding (), resulting in enhanced/spontaneous activation and pathogenic production of IL‐1b and IL‐18. NLRC4 hyperactivity represents a novel mechanism of MAS/HLH pathogenesis.
A160: Role of Interleukin‐1 in Abnormal Monocyte Phenotype in Systemic Onset Juvenile Idiopathic Arthritis
Authors: Zhang Yujuan , Macaubas Claudia , Gupta Saloni , Klein Clarissa , Pascual Virginia , Hay Arielle , Thompson Susan D. , Sandborg Christy I. , Ilowite Norman T. , Mellins Elizabeth D.
Published: March 2014

Background/Purpose:

Monocytes phenotype changes in different microenvironments: the proinflammatory M1, regulatory M2, and M2‐like phenotypes are each regulated by specific transcriptional factors (TFs). We have observed altered phenotypes in blood monocytes in systemic onset juvenile idiopathic arthritis (sJIA), including a decreased M1 cells, an increased mixed M1/M2 cells, and reduced secretion of IL‐1, despite an increased IL‐1b response to LPS (PMID 22281427). Here, we investigate whether these monocyte phenotypes are affected by IL‐1 blockade. We analyzed monocytes from RAPPORT (RAndomized Placebo Phase study Of Rilonacept in the Treatment of sJIA) patients to determine levels of TFs involved in monocyte polarization and expression of genes related to IL‐1 secretion, before and after treatment with Rilonacept, an IL‐1 trap.

Methods:

Subjects on the Rilonacept arm received active drug from week 0 for a total of 24 weeks; subjects on the placebo arm received placebo for 4 weeks, then Rilonacept for 20 weeks. Blood samples were obtained at week 0, 2, 4, 14 and 24. We used real time PCR to measure M1 associated genes: Interferon Regulatory factor (IRF) family IRF5, STAT1; M2 associated genes IRF4, STAT6, Kruppel‐Like Factor 4 (KLF4) and peroxisome proliferator‐activated receptor‐γ (PPAR‐γ); IL‐1 secretion related genes: RAB39, RAB27A, RAB27B, P2RX7, and IL‐1β. All TFs levels were normalized by the average levels of 3 housekeeping genes.

Results:

30 non‐paired RNA samples from 15 subjects were tested. Samples from subjects treated with Rilonacept for ≥10 weeks (Late RAPPORT) showed decreased expression of M2 genes, especially KLF4, compared to those untreated or treated for <10 weeks (Early RAPPORT) (Fig ), except for PPAR‐γ. Samples collected when there was clinical improvement also showed reduced KLF4 (Fig .). The expression of TFs following IL‐1 inhibition in sJIA patients is distinct from normal controls. Levels of IL‐1 secretion related genes, except for RAB27B, also were reduced in “Late RAPPORT” samples (Fig .).

imageimageimage

Conclusion:

IL‐1 blockade in sJIA is likely associated with changes in the activation profile and expression of IL‐1 secretion related genes in circulating monocytes. Monocytes phenotypes in treated subjects are not “normal” and likely reflect changes associated with compensated inflammation.
A168: Systemic Lupus Erythematosus In‐Hospital Mortality Risk Across Ages: A National Estimate
Authors: Lawson Erica F. , Trupin Laura , Hersh Aimee O. , Scheven Emily von , Yelin Edward H. , Yazdany Jinoos
Published: March 2014

Background/Purpose:

Systemic lupus erythematosus (SLE) mortality rates in the U.S. have improved dramatically over the past 50 years, with estimated 5‐year survival rates in childhood‐onset SLE (cSLE) increasing from <50% to >95%. However, current mortality risk for hospitalized individuals with SLE across all age groups has not been described. The goal of this study was to assess mortality risk among hospitalized children and adults with SLE, and to compare these rates to age‐ and sex‐specific all‐cause mortality, using a nationwide hospital discharge dataset.

Methods:

Data derive from the 2011 National Inpatient Sample (NIS), the largest all‐payer inpatient health care database in the United States. The NIS contains all discharge data from more than 1,000 hospitals, which approximates a 20 percent stratified sample of all U.S. acute‐care non‐federal hospitals, including children's hospitals. All hospitalizations of non‐pregnant individuals age 5 years and older were included in the analysis. Lupus hospitalizations were identified by a discharge ICD‐9 diagnosis code of 710.0. We calculated age‐specific standardized mortality ratios (SMRs) to compare the risk of all‐cause in‐hospital mortality among individuals with SLE to the risk of in‐hospital mortality among all patients.

Results:

A total of 6,157,972 hospitalizations were included in the analysis, of which 39,635 carried a discharge diagnosis of SLE. Lupus hospitalizations included 242 hospitalizations of children age 5–14, 2,225 hospitalizations of youth age 15–24, and 4,610 hospitalizations of young adults age 25–34. Hospitalized individuals with SLE were younger (mean age 52 v. 61 years), more likely to be female (89% v. 53%), and less likely to be white (52% v. 71%). Among 148,507 deaths in the total sample, 709 carried a discharge diagnosis of SLE. There were no deaths among hospitalized children with SLE age 5–14, 14 deaths among youth age 15–24, and 54 deaths among young adults age 25–34. The SMR for hospitalizations of individuals with SLE was highest for ages 25–34 (2.3, 95% CI 1.7–3.0, Figure 1), followed by ages 15–24 (1.65, 95% CI 0.9–2.78), and 35–44 (1.4, 95% CI 1.1–1.9). Adults 45 or older with SLE did not have significantly elevated mortality risk.

image

Conclusion:

In this large national dataset, there were no in‐hospital deaths among children under age 15 with SLE, which supports previous findings that mortality rates in childhood‐onset SLE have improved significantly. However, across all ages, young adults with SLE had the greatest excess mortality risk. It is not known whether these young adults have recent‐onset SLE, or longstanding cSLE. Further work is needed to unravel whether this excess mortality results from disease severity, disease damage, poor health care transitions or other factors.
A174: JIA‐Associated SNPs From Non‐Coding Regions Are Located Within or Adjacent to Functional Genomic Elements of Human Neutrophils
Authors: Jarvis James N. , Jiang Kaiyu , Liu Tao , Buck Michael , Carrier Bradley , Chen Yanmin
Published: March 2014

Background/Purpose:

The recent completion of a large genome‐wide associate study (GWAS) for juvenile idiopathic arthritis (JIA) revealed multiple genomic regions conferring disease risk (Nature Genet 2013). However, as is typical of most GWAS, the majority of disease‐associated SNPs occurred in noncoding regions of the genome, either in intergenic regions or introns. This finding suggests, therefore, that disease risk for JIA resides in the control and coordination of transcription, rather than in malfunction of genetically‐altered proteins. This study was undertaken, therefore, to identify functional elements that might be associated with the identified, disease‐associated SNPs in polyarticular, RF‐negative JIA.

Methods:

We first generated a genome wide map of histone marks associated with enhancer elements in healthy adult neutrophils. Using chromatin immunoprecipitation/sequencing (ChIPseq) approaches, we mapped the histone marks associated with poised (H3K4me1+/H3K27ac−) or active (H3K4me1+/H3K27ac+) enhancers to the GRCh37/hg19 genome assembly. In addition, we performed paired‐end RNA sequencing on neutrophils from 5 children with newly diagnosed, untreated polyarticular, RF‐negative JIA and mapped reads to the same human genome assembly. These results were used to interrogate ENCODE and Roadmap Epigenomics data; we used the UCSC Genome browser to interrogate the 22 polyarticular JIA associated SNPs from non‐coding regions genome identified by Hicks et al (Nature Genet 2013) as conferring risk for polyarticular JIA.

Results:

Using the approach above, we ascertained that there are functional elements in neutrophil genomes in or adjacent to 13 of the 22 SNP regions identified by Hicks et al. Enhancer elements were the most frequently identified functional elements in this study, with 9 potentially active (H3K4me1+/H3K27ac+) and 3 additional potentially poised enhancers identified. We also identified 4 non‐coding transcripts within the SNP regions. Four of these regions (e.g., both of the SNPs around C5orf56‐IRF1) contained both non‐coding RNA transcripts and enhancer elements. It was also interesting to note abundant intronic transcription in other genes relevant to inflammation/immunity but not otherwise known to confer genetic risk e.g., CD36.

Conclusion:

Regions of known genetic risk for polyarticular JIA are rich with functional elements that are believed to regulate and coordinate transcription in human neutrophils. These data provide a new framework from which to understand genetic risk and disease pathogenesis in JIA, and suggest that transcriptional regulation and coordination may be a process that is fundamentally perturbed in this disease.
A175: Dysbiosis of the Enteric Microbiota in Pediatric Spondyloarthritis
Authors: Stoll Matthew L. , Kumar Ranjit , Morrow Casey , Lefkowitz Elliot
Published: March 2014

Background/Purpose:

Spondyloarthritis (SpA) affects 1% of the population in the United States. Studies have shown altered flora (dysbiosis) in a variety of inflammatory conditions, including inflammatory bowel disease. We hypothesized that we would identify dysbiosis in pediatric SpA.

Methods:

Patients were children with enthesitisrelated arthritis. Controls were either healthy children from the community or subjects seen in our clinic and diagnosed with non‐inflammatory causes of joint pain. Stool specimens were collected at home and shipped overnight via commercial carrier. Purified DNA underwent PCR amplification using primers designed to the conserved region flanking the variable IV region from the 16S rDNA gene. The PCR products were run on the miSeq. Analysis was performed with the Quantitative Insight into Microbial Ecology (QIIME) suite. Pairwise comparisons of individual taxa were performed with the Mann‐Whitney U‐test, and multiple‐group comparisons were performed with the non‐parametric Kruskal‐Wallis test. Nominal data was evaluated with the Chi‐Squared or Fisher's exact test.

Results:

28 children with SpA age (median, range) 14, 7–18 and 13 controls age 13, 5–17 were included. 3 of the subjects had IBD. 21 patients and no controls were on immunosuppressive therapy. The SpA patients had significantly less faecalibacterium (11% vs 4.8%, p = 0.006) and a non‐significant increase in bacteroides (19% vs 11%, p = 0.216). Additionally, akkermansia was present in low quantities in most patients, but was relatively abundant (>2%) in 0/13 controls compared to 8/28 patients (p = 0.040.) Principal coordinates analysis (PCoA; Figure ) demonstrated that while most of the patients clustered with the controls, 10 patients formed their own cluster. Phylogenetic tree analysis (Figure ) likewise demonstrated a small cluster of 10 subjects (9 patients and 1 control) who formed their own cluster separate from other subjects, 8 of whom corresponded to the indicated cluster from the PCoA. These 8 subjects demonstrated significantly increased bacteroides (p < 0.001) and decreased faecalibacterium (p = 0.022) compared to the remainder of the subjects. In contrast, none the patients in this cluster, compared to 8/20 who clustered with the controls, had elevated levels of akkermansia (p = 0.005, Chi‐Squared).

Output of Principal Coordinates Analysis (PCoA) of 16S sequencing data. Spondyloarthritis patients are shown in blue, controls in red.

image

Output of unweighted Pair Group Method with Arithmetic Mean (UPGMA) analysis of 16S sequencing data. Controls are indicated with asterisks.

image

Conclusion:

We demonstrate decreased faecalibacterium among patients with SpA, consistent with a suspected anti‐inflammatory effect of f. prausnitzii. We also introduce akkermansia as a possible pathogenetic species in a subset of SpA patients.
The cranial nerve skywalk: A 3D tutorial of cranial nerves in a virtual platform
Authors: Richardson‐Hatcher April , Hazzard Matthew , Ramirez‐Yanez German
Published: March 2014

Visualization of the complex courses of the cranial nerves by students in the health‐related professions is challenging through either diagrams in books or plastic models in the gross laboratory. Furthermore, dissection of the cranial nerves in the gross laboratory is an extremely meticulous task. Teaching and learning the cranial nerve pathways is difficult using two‐dimensional (2D) illustrations alone. Three‐dimensional (3D) models aid the teacher in describing intricate and complex anatomical structures and help students visualize them. The study of the cranial nerves can be supplemented with 3D, which permits the students to fully visualize their distribution within the craniofacial complex. This article describes the construction and usage of a virtual anatomy platform in Second Life™, which contains 3D models of the cranial nerves III, V, VII, and IX. The Cranial Nerve Skywalk features select cranial nerves and the associated autonomic pathways in an immersive online environment. This teaching supplement was introduced to groups of pre‐healthcare professional students in gross anatomy courses at both institutions and student feedback is included. Anat Sci Educ 7: 469–478. © 2014 American Association of Anatomists.
How do digits emerge? – mathematical models of limb development
Authors: Iber Dagmar , Germann Philipp
Published: March 2014

The mechanism that controls digit formation has long intrigued developmental and theoretical biologists, and many different models and mechanisms have been proposed. Here we review models of limb development with a specific focus on digit and long bone formation. Decades of experiments have revealed the basic signaling circuits that control limb development, and recent advances in imaging and molecular technologies provide us with unprecedented spatial detail and a broader view of the regulatory networks. Computational approaches are important to integrate the available information into a consistent framework that will allow us to achieve a deeper level of understanding, and that will help with the future planning and interpretation of complex experiments, paving the way to in silico genetics. Previous models of development had to be focused on very few, simple regulatory interactions. Algorithmic developments and increasing computing power now enable the generation and validation of increasingly realistic models that can be used to test old theories and uncover new mechanisms. Birth Defects Research (Part C) 102:1–12, 2014. © 2014 Wiley Periodicals, Inc.
Coming together is a beginning: The making of an intervertebral disc
Authors: Chan Wilson C. W. , Au Tiffany Y. K. , Tam Vivian , Cheah Kathryn S. E. , Chan Danny
Published: March 2014

The intervertebral disc (IVD) is a complex fibrocartilaginous structure located between the vertebral bodies that allows for movement and acts as a shock absorber in our spine for daily activities. It is composed of three components: the nucleus pulposus (NP), annulus fibrosus, and cartilaginous endplate. The characteristics of these cells are different, as they produce specific extracellular matrix (ECM) for tissue function and the niche in supporting the differentiation status of the cells in the IVD. Furthermore, cell heterogeneities exist in each compartment. The cells and the supporting ECM change as we age, leading to degenerative outcomes that often lead to pathological symptoms such as back pain and sciatica. There are speculations as to the potential of cell therapy or the use of tissue engineering as treatments. However, the nature of the cells present in the IVD that support tissue function is not clear. This review looks at the origin of cells in the making of an IVD, from the earliest stages of embryogenesis in the formation of the notochord, and its role as a signaling center, guiding the formation of spine, and in its journey to become the NP at the center of the IVD. While our current understanding of the molecular signatures of IVD cells is still limited, the field is moving fast and the potential is enormous as we begin to understand the progenitor and differentiated cells present, their molecular signatures, and signals that we could harness in directing the appropriate in vitro and in vivo cellular responses in our quest to regain or maintain a healthy IVD as we age. Birth Defects Research (Part C) 102:83–100, 2014. © 2014 Wiley Periodicals, Inc.
A novel peptide to disrupt the interaction of BST‐2 and Vpu
Authors: Mi Zeyun , Wang Xin , He Yang , Li Xiaoyu , Ding Jiwei , Liu Hongyun , Zhou Jinming , Cen Shan
Published: March 2014

Bone marrow stromal cell antigen 2 (BST‐2) inhibits the release of HIV‐1 and other enveloped viruses from the cell surface. HIV‐1 Vpu binds to BST‐2 through an interaction between transmembrane domains (TMD) of the two proteins and induces the downregulation of cell surface BST‐2, thereby counteracting its antiviral activity. In this study, we designed and prepared a modified peptide BST2‐TM‐P1, which include the sequence of BST‐2 TMD, keeping its property competing with BST‐2 to bind with Vpu. Biological assay results indicate BST2‐TM‐P1 could increase the BST‐2 level at the cell surface in Vpu dependent manner and significantly inhibit the replication of HIV‐1 virion. Our studies indicate that blocking the interaction of Vpu and BST‐2 is an effective way to combat HIV‐1 infection. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 280–287, 2014.
Opportunities and challenges of next-generation DNA sequencing for breast units
Authors: Pilgrim S M , Pain S J , Tischkowitz M D
Published: March 2014

Background

The aim of this review is to introduce the topic of next-generation DNA sequencing, a new technology that is being introduced into clinical practice, and to explain the potential impact for breast cancer surgeons and the wider breast cancer multidisciplinary team.

Methods

The PubMed database was used to identify relevant studies relating to breast cancer genetics. This evidence was then used to provide context and background information to demonstrate how next-generation sequencing (NGS) might change breast cancer practice.

Results

With NGS, breast cancer clinicians will know whether their patients carry high-risk mutations in genes, such as BRCA1 or BRCA2, before the start of treatment. This could alter treatment decisions; for instance, more women might opt for mastectomy instead of breast-conserving surgery, or for bilateral rather than unilateral surgery.

Conclusion

The introduction of NGS will have a significant impact on breast cancer services in the near future. Speed of testing will improve in regions of the world where NGS is adopted in place of conventional sequencing, and, as costs decrease, genetic testing will also become accessible and realistic in less well funded health economies. This will create opportunities to improve patient treatment and challenges for the breast cancer multidisciplinary team.
Person‐Group Value Congruence and Subjective Well‐Being in Students from Argentina, Bulgaria and Finland: The Role of Interpersonal Relationships
Authors: Sortheix Florencia M. , Lönnqvist Jan‐Erik
Published: March 2014

The present study examined the relations between personal values, value congruence, interpersonal relationships and subjective well‐being in psychology/education and business students from Argentina (N = 275), Bulgaria (N = 182) and Finland (N = 148). Regression analyses showed, first, that there were no direct relations between higher order value priorities and life satisfaction (LS), positive affect (PA) or negative affect (NA). Second, objective value‐congruence (VC)—the similarity between individual and group values—was positively related to LS and PA, and negatively related to NA. Most importantly, the effects of VC on LS, NA and PA were partially mediated by good interpersonal relationships. Our results show that interpersonal relationships are facilitated by sharing values similar to those of one's fellow students. More generally, personal values per se appear not to be associated with subjective well‐being, more important is how these values fit into the social context. Copyright © 2014 John Wiley & Sons, Ltd.
Unravelling offending in schizophrenia: Factors characterising subgroups of offenders
Authors: van Dongen Josanne , Buck Nicole , Van Marle Hjalmar
Published: March 2014

Background

Previous studies have led to suggestions that there are at least three sub‐types of offenders with schizophrenia, but these have not previously been examined simultaneously in one sample.

Aims

The aims of this study were to investigate categorisation of offenders with psychosis as early or late starters or late first offenders, and test the hypotheses that, compared with non‐offenders with psychosis, early starters would be characterised by low educational or occupational achievement, negative childhood experiences and early substance use, whereas positive psychotic symptoms would characterise late starters or late first offenders.

Methods

A retrospective file study was conducted, yielding 97 early starters, 100 late starters and 26 late first offenders identified from a specialist inpatient forensic mental health assessment service and 129 non‐offenders identified from general psychiatric services in the same geographic region, all with schizophreniform psychoses.

Results

We found little difference between early and later starters in terms of measured antecedents, but substance misuse was up to 20 times less likely among late first offenders. Persecutory and/or grandiose delusions were more strongly associated with each offender group compared with non‐offenders, most so with late first offenders.

Conclusions

Our findings underscore the importance of treating delusions – for safety as well as health. Childhood antecedents may be less important indicators of offender sub‐types among people with psychosis than previously thought. When patients present with grandiose or persecutory delusions over the age of 35 years without co‐morbid substance misuse disorders, but with a history of childhood neglect and low educational achievement, particular care should be taken to assess risk of violence. Copyright © 2014 John Wiley & Sons, Ltd.