Scottish Rite Hospital

BACKGROUND: We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS: We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS: All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS: Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Mechanical properties of cortical and cancellous bone from eight human subjects were determined using an ultrasonic transmission technique. Raw computerized tomography (CT) values obtained from scans of the bones in water were corrected to Hounsfield units. The correlations between CT numbers and mechanical property estimated from cortical bone were found to be low (r2 < 0.2), while these relationships for cancellous bone were found to be higher (r2 > 0.6). These results suggest that CT values may be useful in predicting mechanical properties only for cancellous bone. Poor correlations were found between modulus in the radial or circumferential direction and modulus in the superior-inferior direction for cortical bone, whereas good correlations were found between modulus in the anterior-posterior direction or medial-lateral direction and modulus in the S-I direction for cancellous bone. These results indicate that modulus in the radial or circumferential direction could not be predicted from modulus in the S-I direction for cortical bone, but could be predicted for cancellous bone. The predictive capabilities of linear and power models evaluated for cancellous bone alone were approximately equal. However, the power function gives a better fit of data at the low and high density values. The specific relationships, depending on the types of bone, that predict elastic modulus from density and CT numbers were suggested for human cortical and cancellous bone. These specific correlations may help a number of researchers develop more accurate models; however, these hypotheses should be proven by further study.

BACKGROUND: While early spinal fusion may halt progressive deformity in young children with scoliosis, it does not facilitate lung growth and, in certain children, it can result in thoracic insufficiency syndrome. The purpose of this study was to determine pulmonary function at intermediate-term follow-up in patients with scoliosis who underwent thoracic fusion before the age of nine years. METHODS: Patients who had thoracic spine fusions before the age of nine years with a minimum five-year follow-up underwent pulmonary function testing. Forced vital capacity, forced expiratory volume in one second, and maximum inspiratory pressure were measured and compared with age-matched normal values. Patients with neuromuscular disease, skeletal dysplasias, or preexisting pulmonary disease were excluded, while those with rib malformations were included. The relationships between forced vital capacity and age at the time of surgery, length of follow-up, extent of the fusion, proximal level of the fusion, and revision surgery were studied. RESULTS: Twenty-eight patients underwent evaluation. Twenty patients had congenital scoliosis, three had idiopathic scoliosis, three had scoliosis associated with neurofibromatosis, one had congenital kyphosis, and one had syndromic scoliosis. Seventeen patients had one spinal surgery, while eleven had additional procedures. The average age of the patients was 3.3 years at the time of surgery and 14.6 years at the time of follow-up. The average extent of the thoracic spine fused was 58.7%. The average forced vital capacity was 57.8% of age-matched normal values, and the average forced expiratory volume in one second was 54.7%. The forced vital capacity was <50% of normal in twelve of the twenty-eight patients, and two required respiratory support, implying that substantial restrictive lung disease was present. With the numbers studied, no significant correlation could be detected between the age at the time of fusion or the length of follow-up and pulmonary function. The extent of the spine fused correlated with the forced vital capacity (p = 0.01, r = -0.46). Fusions in the proximal aspect of the spine were found to be associated with diminished pulmonary function as eight of twelve patients with a proximal fusion level of T1 or T2 had a forced vital capacity of <50%, but only four of sixteen patients with a fusion beginning caudad to T2 had a forced vital capacity of <50% (p = 0.0004, r = 0.62). CONCLUSIONS: Patients with proximal thoracic deformity who require fusion of more than four segments, especially those with rib anomalies, are at the highest risk for the development of restrictive pulmonary disease. Pulmonary function tests should be performed for all patients who have an early fusion. The pursuit of alternative procedures to treat early spinal deformity is merited.

Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to alpha-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a heretofore unappreciated vascular mechanism contributing to the pathogenesis of DMD.

We reviewed 40 spinal fusions done prior to Risser stage I for idiopathic and paralytic scoliosis to evaluate postoperative curve progression. The 39 patients who had posterior fusion alone had progressive angulation and rotation of the spine over the postoperative follow-up period. The more immature the patient, the greater the resultant progression. This progression is an inevitable consequence of continued anterior spinal growth in the presence of a posterior fusion, and occurs without pseudarthrosis or hardware failure. Younger patients may require anterior and posterior fusion to achieve stable correction.

We performed a prospective study to determine whether flexible flatfoot in children can be influenced by treatment. One hundred and twenty-nine children who had been referred by pediatricians, and for whom the radiographic findings met the criteria for flatfoot, were randomly assigned to one of four groups: Group I, controls; Group II, treatment with corrective orthopaedic shoes; Group III, treatment with a Helfet heel-cup; or Group IV, treatment with a custom-molded plastic insert. All of the patients in Groups II, III, and IV had a minimum of three years of treatment, and ninety-eight patients whose compliance with the protocol was documented completed the study. Analysis of radiographs before treatment and at the most recent follow-up demonstrated a significant improvement in all groups (p less than 0.01), including the controls, and no significant difference between the controls and the treated patients (p greater than 0.4). We concluded that wearing corrective shoes or inserts for three years does not influence the course of flexible flatfoot in children.

OBJECTIVE: To determine whether aggressive treatment initiated early in the course of rheumatoid factor (RF)-positive or RF-negative polyarticular juvenile idiopathic arthritis (JIA) can induce clinical inactive disease within 6 months. METHODS: Between May 2007 and October 2010, a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 2 aggressive treatments was conducted in 85 children ages 2-16 years with polyarticular JIA of <12 months' duration. Patients received either methotrexate (MTX) 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks (arm 1), or MTX (same dosage as arm 1), etanercept placebo, and prednisolone placebo (arm 2). The primary outcome measure was clinical inactive disease at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous clinical inactive disease) at 12 months. RESULTS: By 6 months, clinical inactive disease had been achieved in 17 (40%) of 42 patients in arm 1 and 10 (23%) of 43 patients in arm 2 (χ(2) = 2.91, P = 0.088). After 12 months, clinical remission on medication was achieved in 9 patients in arm 1 and 3 patients in arm 2 (P = 0.053). There were no significant interarm differences in adverse events. CONCLUSION: Although this study did not meet its primary end point, early aggressive therapy in this cohort of children with recent-onset polyarticular JIA resulted in clinical inactive disease by 6 months and clinical remission on medication within 12 months of treatment in substantial proportions of patients in both arms.

Tuberous sclerosis complex is a dominantly inherited disorder affecting multiple organs; because of its phenotypic variability, the diagnosis of tuberous sclerosis complex can be difficult in the young or in individuals with subtle findings. Recently revised consensus diagnostic criteria for tuberous sclerosis complex reflect an improved understanding of its clinical manifestations and its genetic and molecular mechanisms. The diagnostic criteria are based on the premise that there are probably no truly pathognomonic clinical signs for tuberous sclerosis complex; signs that were once regarded as specific occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Consequently, the revised criteria require tuberous sclerosis complex-associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis. The addition of DNA testing complements clinical diagnosis and allows more precise genetic counseling and, in some individuals, prenatal diagnosis. Nevertheless, the 15% false-negative rate for DNA testing and the occurrence of germline mosaicism in about 2% of individuals with tuberous sclerosis complex make it difficult to exclude the diagnosis of tuberous sclerosis complex in family members.

STUDY DESIGN: Retrospective multicenter review. OBJECTIVE: Determine the definition, indications, results, and outcomes, focusing on complications of vertebral column resection (VCR) for severe pediatric spinal deformity. SUMMARY OF BACKGROUND DATA: The strict definition of the VCR procedure, indications, results, outcomes, and the numerous, potentially serious complications are unknown or controversial, and a large multicenter review has never been performed. METHODS: A total of 147 patients treated by 7 pediatric spinal deformity surgeons were reviewed-seventy-four females and 73 males, with an average age of 13.7 years, an average of 1.6 (range, 1-5) vertebrae resected, and an average follow-up of 17 months (range, 0.5-64 mo). The strict definition of VCR used was a "3-column circumferential vertebral osteotomy creating a segmental defect with sufficient instability to require provisional instrumentation." RESULTS: Indications for a VCR were divided into 5 diagnostic categories: kyphoscoliosis (n = 52), severe scoliosis (n = 37), congenital deformity (n = 28), global kyphosis (n = 17), and angular kyphosis (n = 13). Eighty-four primary and 63 revision patients with 174 operative procedures, 127 posterior-only (17 staged), and 20 patients combined anterior-posterior (10 staged) were reviewed. Average preoperative upright, flexibility, and postoperative Cobb measures (% correction or average kyphosis decrease) were kyphoscoliosis: 91°, 65°, 44° (51% coronal), 104°, 81°, and 47° (decrease, 57° sagittal); severe scoliosis: 104°, 78°, and 33° (67%); congenital deformity: 47°, 38°, 22° (46% coronal), 56°, 48°, and 32° (decrease, 24° sagittal); global kyphosis: 101°, 79°, and 47° (decrease, 54°); and angular kyphosis: 88°, 90°, and 38° (decrease, 50°), respectively. Operative time averaged 545 minutes (range, 204-1355 min) and estimated blood loss averaged 1610 mL (range, 50-8244 mL) for an average 65% blood volume loss (range, 6%-316%). Eighty-six patients (59%) developed a complication, 39 patients (27%) having an intraoperative neurological event (spinal cord monitoring change or failed wake-up test); however, no patient had complete permanent paraplegia. CONCLUSION: A total of 147 consecutive pediatric VCRs performed by 7 surgeons demonstrated excellent radiographical correction. However, these complex reconstructions were associated with a 59% complication rate, thus emphasizing the challenging nature of these patients and procedures.

BACKGROUND: Symptomatic femoroacetabular impingement (FAI) is associated with hip pain, functional limitations, and secondary osteoarthritis. There is limited information from large patient cohorts defining the specific population affected by FAI. Establishing a large cohort will facilitate the identification of "at-risk" patients and will provide a population for ongoing clinical research initiatives. The authors have therefore established a multicenter, prospective, longitudinal cohort of patients undergoing surgery for symptomatic FAI. PURPOSE: To report the clinical epidemiology, disease characteristics, and contemporary surgical treatment trends in North America for patients with symptomatic FAI. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Upon approval of the institutional review boards at 8 institutions, 12 surgeons enrolled consecutive patients undergoing surgical intervention for symptomatic FAI. Patient demographics, physical examination data, radiographic data, diagnoses, operative data, and standardized patient-reported outcome measures were collected. The first 1130 cases are summarized in this study. RESULTS: A total of 1076 consecutive patients (1130 hips) were enrolled; 55% (n = 622) were female, and 45% (n = 508) were male, with an average age of 28.4 years and average body mass index (BMI) of 25.1. Demographics revealed that 88% of patients who were predominantly treated for FAI were white, 19% reported a family history of hip surgery, 47.6% of hips had a diagnosis of cam FAI, 44.5% had combined cam/pincer FAI, and 7.9% had pincer FAI. Preoperative clinical scores (pain, function, activity level, and overall health) indicated a major dysfunction related to the hip. Surgical interventions were arthroscopic surgery (50.4%), surgical dislocation (34.4%), reverse periacetabular osteotomy (9.4%), limited open osteochondroplasty with arthroscopic surgery (5.8%), and limited open by itself (1.5%). More than 90% of the hips were noted to have labral and articular cartilage abnormalities at surgery; femoral head-neck osteochondroplasty was performed in 91.6% of the surgical procedures, acetabular rim osteoplasty in 36.7%, labral repair in 47.8%, labral debridement in 16.3%, and acetabular chondroplasty in 40.1%. CONCLUSION: This multicenter, prospective, longitudinal cohort is one of the largest FAI cohorts to date. In this cohort, FAI occurred predominantly in young, white patients with a normal BMI, and there were more female than male patients. The disease pattern of cam FAI was most common. Contemporary treatment was predominantly arthroscopic followed by surgical hip dislocation.

BACKGROUND: Current literature describing the periacetabular osteotomy (PAO) is mostly limited to retrospective case series. Larger, prospective cohort studies are needed to provide better clinical evidence regarding this procedure. The goals of the current study were to (1) report minimum 2-year patient-reported outcomes (pain, hip function, activity, overall health, and quality of life), (2) investigate preoperative clinical and disease characteristics as predictors of clinical outcomes, and (3) report the rate of early failures and reoperations in patients undergoing contemporary PAO surgery. METHODS: A large, prospective, multicenter cohort of PAO procedures was established, and outcomes at a minimum of 2 years were analyzed. A total of 391 hips were included for analysis (79% of the patients were female, and the average patient age was 25.4 years). Patient-reported outcomes, conversion to total hip replacement, reoperations, and major complications were documented. Variables with a p value of ≤0.10 in the univariate linear regressions were included in the multivariate linear regression. The backward stepwise selection method was used to determine the final risk factors of clinical outcomes. RESULTS: Clinical outcome analysis demonstrated major clinically important improvements in pain, function, quality of life, overall health, and activity level. Increasing age and a body mass index status of overweight or obese were predictive of improved results for certain outcome metrics. Male sex and mild acetabular dysplasia were predictive of lesser improvements in certain outcome measures. Three (0.8%) of the hips underwent early conversion to total hip arthroplasty, 12 (3%) required reoperation, and 26 (7%) experienced a major complication. CONCLUSIONS: This large, prospective cohort study demonstrated the clinical success of contemporary PAO surgery for the treatment of symptomatic acetabular dysplasia. Patient and disease characteristics demonstrated predictive value that should be considered in surgical decision-making. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

OBJECTIVE: We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS: This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS: Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION: Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

Systemic onset juvenile idiopathic arthritis (SoJIA) represents up to 20% of juvenile idiopathic arthritis. We recently reported that interleukin (IL) 1 is an important mediator of this disease and that IL-1 blockade induces clinical remission. However, lack of specificity of the initial systemic manifestations leads to delays in diagnosis and initiation of therapy. To develop a specific diagnostic test, we analyzed leukocyte gene expression profiles of 44 pediatric SoJIA patients, 94 pediatric patients with acute viral and bacterial infections, 38 pediatric patients with systemic lupus erythematosus (SLE), 6 patients with PAPA syndrome, and 39 healthy children. Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared with healthy children. These genes, however, were also changed in patients with acute infections and SLE. An analysis of significance across all diagnostic groups identified 88 SoJIA-specific genes, 12 of which accurately classified an independent set of SoJIA patients with systemic disease. Transcripts that changed significantly in patients undergoing IL-1 blockade were also identified. Thus, leukocyte transcriptional signatures can be used to distinguish SoJIA from other febrile illnesses and to assess response to therapy. Availability of early diagnostic markers may allow prompt initiation of therapy and prevention of disabilities.

A previous study of 4 patients defined Andersen's syndrome (AS) as a triad of potassium-sensitive periodic paralysis, ventricular dysrhythmias, and dysmorphic features. AS appears to be distinct in terms of its genetic defect from the alpha-subunit of skeletal muscle sodium channel and the cardiac potassium channel responsible for most long QT syndromes (LQT1). We studied 11 additional patients with AS from 5 kindreds. Spontaneous attacks of paralysis were associated with hypokalemia, normokalemia, or hyperkalemia. All 11 patients had similar dysmorphic features. The QT interval was prolonged in all patients although only 4 were symptomatic. Genetic linkage studies excluded linkage to the alpha-subunit of the skeletal muscle sodium channel and to four distinct LQT loci. In addition, none of the common dihydropyridine receptor mutations responsible for hypokalemic periodic paralysis were present. We conclude that (1) AS is a genetically unique channelopathy affecting both cardiac and skeletal membrane excitability, (2) attacks of paralysis may be either hypokalemic or hyperkalemic, (3) a prolonged QT interval is an integral feature of this syndrome, and (4) a prolonged QT interval may be the only sign in an individual from an otherwise typical AS kindred. This may be confused with more common, potentially lethal LQT syndromes.

STUDY DESIGN: Repeated measures (3 separate day sessions) to determine test reliability; single-session repeated measures to compare stability between limbs. OBJECTIVES: To develop a functional test measuring dynamic stability that is capable of differentiating between the injured and uninjured lower limb in 2 populations: (1) people with anterior cruciate ligament deficiency (ACLd) and (2) people with anterior cruciate ligament reconstruction (ACLr), and to establish the reliability of this test. BACKGROUND: Many functional tests of the lower limb used by clinicians, such as the 1-legged hop for distance, the 1-legged hop for time, the vertical jump, the triple hop for distance, shuttle run, and single-limb standing, do not allow the clinician to discern differences between function in the injured and uninjured limbs. METHODS AND MEASURES: Twenty-five nonimpaired subjects (14 men, 11 women, aged 31.2 +/- 9.1 years), 11 subjects with ACLr (9 men, 2 women, aged 26.3 +/- 10.4 years), and 13 subjects with ACLd (5 men, 8 women, aged 40.4 +/- 12.6 years) were tested. Twelve nonimpaired subjects participated in 3 testing sessions to determine the reliability of the force plate measures. Ground reaction forces (vertical, medial-lateral, and anterior-posterior) were measured while the subjects performed 1-legged hop and step-down tests onto a force plate. Stability was defined as the ability to transfer the vertical projection of the center of gravity to the supporting base and keep the knee still. A repeated-measures analysis of variance (2-factor; limbs by trials) was used to compare the stability between limbs. RESULTS: The majority of the measures used to calculate dynamic stability were reliable. Moreover, the data provide normal standards of functional knee stability for step-down and hop tests. In the step-down test, changes in vertical force did identify dysfunction in the injured limb (stabilization time = 1527 +/- 216 ms) compared to the uninjured limb (stabilization time = 892 +/- 498 ms) for subjects with ACLr. CONCLUSIONS: The normal standards may serve as a reference for comparing functional differences in ACLr or ACLd populations. The vertical force parameter during a step-down may be useful as an outcome measure to monitor progress during rehabilitation.

Studies on the role of the RNA receptor TLR8 in inflammation have been limited by its different function in human versus rodents. We have generated multiple lines of transgenic mice expressing different levels of human TLR8. The high copy number chimeras were unable to pass germline; developed severe inflammation targeting the pancreas, salivary glands, and joints; and the severity of the specific phenotypes closely correlated with the huTLR8 expression levels. Mice with relatively low expression levels survived and bred successfully but had increased susceptibility to collagen-induced arthritis, and the levels of huTLR8 correlated with proinflammatory cytokines in the joints of the animals. At the cellular level, huTLR8 signaling exerted a DC-intrinsic effect leading to up-regulation of co-stimulatory molecules and subsequent T cell activation. A pathogenic role for TLR8 in human diseases was suggested by its increased expression in patients with systemic arthritis and the correlation of TLR8 expression with the elevation of IL-1β levels and disease status. We found that the consequence of self-recognition via TLR8 results in a constellation of diseases, strikingly distinct from those related to TLR7 signaling, and points to specific inflammatory diseases that may benefit from inhibition of TLR8 in humans.

Biomechanical testing was done on 15 matched pairs of central-third bone-patellar tendon-bone and double-looped semitendinosus-gracilis grafts harvested from 15 cadaveric knees. Load to failure, composite graft stiffness, and the modulus of elasticity were calculated for each graft. Specimens were from 2 female and 13 male donors (average age, 40 years; range, 17 to 53). Average load to failure for the patellar tendon grafts was 1784 N (+/- 580), compared with 2422 N (+/- 538) for the hamstring tendon grafts (significantly different). There was no statistically significant difference in stiffness between grafts (patellar tendon, 210 N/mm; hamstring tendon, 238 N/mm). The elastic modulus was 225 MPa (+/- 129) for the patellar tendon grafts and 145 MPa (+/- 58) for the hamstring tendon grafts (significantly different). The average cross-sectional area for the hamstring tendon grafts was 57 mm2, compared with the 45 mm2 for the patellar tendon grafts. The hamstring tendon grafts were significantly stronger than the matched central-third patellar tendon grafts, but the two grafts were similar in stiffness. The patellar tendon grafts had a higher modulus than the hamstring tendon grafts.

OBJECTIVE: To formulate consensus treatment plans (CTPs) for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (SLE). METHODS: A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance after considering the existing medical evidence and current treatment approaches. RESULTS: After an initial Delphi survey (response rate = 70%), a 2-day consensus conference, and 2 followup Delphi surveys (response rates = 63-79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypical patients defined by eligibility characteristics, and included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized dosages for 6 months. Additionally, the CTPs describe 3 options for standardized use of glucocorticoids, including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be candidates for the treatment with the CTPs. CONCLUSION: CTPs for induction therapy of proliferative LN in juvenile SLE based on the available scientific evidence and pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies for proliferative LN in juvenile SLE.

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

In Brief Study Design. Retrospective comparison study of patients who had a delayed infection following a posterior spinal fusion and instrumentation (PSFI) for adolescent idiopathic scoliosis (AIS). Objective. To define risk factors for the development of delayed infections following PSFI for AIS by comparing those patients who developed this complication to a randomly selected group of patients who did not. Summary of Background Data. Despite studies reporting the incidence and treatment of delayed infection following PSFI for AIS, there are no studies analyzing risk factors for its occurrence. Methods. All patients who required treatment for delayed infections following PSFI for AIS were identified (infection group, n = 36). A random selection of patients who did not develop a delayed infection (no infection, n = 90) was made in a ratio of 3:1 (no infection/infection). The 2 groups were compared using statistical methods. Results. Parameters associated with the infection group included: presence of a significant medical history, surgeon, less surgical time, a more distal fusion level (16% infection rate with a thoracic LIV vs. 33% infection rate with a lumbar LIV), not using postoperative drains, and increased drainage when drains were used. Other factors associated with infection were use of a blood transfusion and when increasing units of transfusion were used. Multivariate logistic regression analysis identified 3 factors that remained statistically significant: 1) significant medical history, 2) receiving a blood transfusion, and 3) not using a postoperative drain. Factors that were not associated with delayed infection included body mass index, the number of anchor points used, use of allograft bone, and the total number of levels instrumented and antibiotic regimen. Conclusion. The occurrence of a delayed infection is most likely multifactorial and is related to a positive past medical history and the use of blood transfusions. Postoperative use of a drain may be important to avoid delayed infection. A retrospective review to define risk factors for the development of delayed infections following PSFI for AIS was performed between patients who developed this complication and those who did not. Risk factors that were identified include a significant past medical history in the patient, a more distal fusion level, not using a postoperative drain, and the use of blood transfusions. Careful consideration should be given to these parameters in an effort to avoid this complication.