The T-lymphocyte secreted pro-inflammatory cytokine, interleukin-17F (IL-17F), was found to be a key mediator in the cellular response of the immune system in the early phase of fracture repair but its intracellular signaling processes are currently not known in osteoblasts. The objective of this study was to identify the signaling proteins and crucial gene targets involved in osteoblast activation via IL-17F. It was hypothesised that IL-17F stimulated osteoblast maturation through a novel GSK3beta / beta-catenin independent pathway. Mouse pre-osteoblast cell line (MC3T3-E1) was used for IL-17F or Wnt3a treatment. Desired proteins were detected using western blot analysis (antibodies: Phospho-GSK-3beta (Tyr 216), Phospho-GSK-3beta (Ser9), Runx2/cbfa1, TRAF6, Act1, p-ERK2, p-JNK and p-MAPK, C/EBP-beta and & delta). Gene-specific siRNAs of mouse IL-17Ra, IL-17Rc and a non-targeting siRNA (control) were utilised. MC3T3-E1 were transfected with IL-17Ra, IL-17Rc or Negative Control and treated with IL-17F. Chromatin Immunoprecipitation (ChIP-qPCR) was used to evaluate the mouse Runx2 P1 promoter region. IL-17F increased expression of Col1, BSP, Runx2/cbfa1 and osteocalcin in MC3T3-E1 cells. Western blot analysis confirmed expression of known Wnt signaling proteins TRAF6, Act1, p-ERK2, p-JNK and p-MAPK in both IL-17F and Wnt3a treated cultures, including up-regulation of Runx2/cbfa1, a key transcription factor associated with osteoblast differentiation. IL-17F up-regulation of Runx2/cbfa1 appears independent of the Wnt/beta-catenin pathway as phosphorylated GSK-3beta at the Ser9 site was not detected with IL-17F treatment. Despite this, IL-17F treatment still increased expression of Runx2/cbfa1 downstream, lending evidence for a GSK3beta/beta-catenin independent manner of IL-17F stimulated osteogenesis. While IL-17F and Wnt3a both induced expression of C/EBP-delta, only IL-17F treatment induced expression of C/EBP-beta, an upstream transcription factor of Runx2/cbfa1. Further, siRNA knock down of the IL-17 receptors directly decreased Act1, C/EBP-beta and Runx2/cfba1 expression. By ChIP analysis, IL-17F was shown to upregulate C/EBP-beta expression and stimulated its binding to the P1 Promoter of the Runx2/cbfa1 gene. The C/EBP-beta transcription factor was shown to be a key regulator of early osteogenesis. C/EBP-beta up-regulates Runx2/cbfa1 expression by directly binding to the Runx2/cbfa1 P1 promoter in osteoblasts. C/EBP-beta was activated in the osteoblast by IL-17F but not by Wnt3a adding further support to a novel GSK3beta/beta-catenin independent pathway. Our data shows that IL-17F, a cytokine secreted by T-lymphocytes, stimulates osteoblast maturation through a novel GSK3beta/beta-catenin independent pathway and reveals a crucial interaction between C/EBP-beta and the Runx2/cbfa1 P1 promoter not previously been shown in osteogenesis signaling further.
Purpose We report the long term outcome of a minimally invasive technique avoiding the risks associated with open reduction and bone grafting in paediatric lateral condyle fracture non-unions. Methods The Toronto Hospital for Sick Children's radiology database was searched to isolate all those who sustained a lateral condyle elbow fracture and had developed a non-union between the years 1998 and 2008. This identified 16 patients who had undergone percutaneous fixation for the treatment of their non union. Each individuals clinical notes and radiographs were reviewed from presentation to final follow-up. Results Median age at injury was 5.1 (3.2, 7.2) in the successful and 2.8 (2.1, 4.7) in the unsuccessful groups (p=0.18). 11 patients (68.7%) had been initially managed non-operatively. Median time from injury to non-union diagnosis was 15.7 weeks in the successful, and 225.5 weeks in the unsuccessful group (p=0.039). Mean time to union post fixation was 16.2 weeks (+/- 6.74) and mean time to surgery was 5.2 weeks (+/- 4.11). Surgery was successful, defined as radiological and clinical union, in 12 of 16 patients (75%). 43.8% had metalwork removal and no cases of avascular necrosis were reported. Conclusion We have demonstrated this technique to be successful in those non-unions addressed within 16 weeks from initial injury to diagnosis. We had 4 failures, these occurred in patients whose non-unions were diagnosed more than 31 weeks from the time of injury (31; 68; 383; 427 weeks). Each of these failures had been managed non-operatively as part of their primary treatment plan. Percutaneous fixation is feasible and safe. Patients not achieving union were diagnosed significantly later. There was a trend towards successfully treated patients being younger.
The study aimed to develop and assess a new classification system for Segmentation Defects of the Vertebrae (SDV), a frequent cause of congenital scoliosis. Existing nomenclature for the wide range of SDV phenotypes is inadequate and confusing eg ‘Jarcho-Levin syndrome’. A multidisciplinary group of the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) met to formulate a new classification system, based primarily on radiology. SDV are identified by number affected, contiguity, and spinal region(s). The size, shape and symmetry of the thoracic cage, and rib number, symmetry and fusion are included, and familiar vertebral morphology terms retained, together with accepted syndrome names. The terms spondylocostal and spondylothoracic dysostosis apply only to phenotypes typified by the monogenic disorders due to mutated DLL3, MESP2, LNFG and HES7 genes. Five ICVAS members (Group 1) then independently assessed 10 new cases, inter-observer reliability assessed using kappa. Seven independent radiologists (Group 2) then assessed the same cases before and after introduction to the new system. Inter-observer reliability for Group 1 yielded a kappa value of 0.21 (95% confidence intervals (CI) 0.052, 0.366, p=0.0046). For Group 2, before introduction to the new system, 1/70 responses (1.4%) agreed with the Group 1 consensus,12 different diagnoses were offered, and 38/70 (54.3%) responses were ‘Unknown’. After introduction to the new system 47/70 responses (67.1%; 95% CI 55.5, 77.0) agreed with Group 1 consensus, a 65.7% improvement (95% CI 52.5, 75.6, p<
0.00005). The system was well received by 6/7 radiologists. The new system was found to be reliable and acceptable.
The purpose of this study was to investigate if there is a relationship between the timing of reduction of displaced supracondylar humerus fractures in children and post-operative complications and open reduction rate and to evaluate the usefulness of the definition of early (eight hours or less following injury) and delayed (more than eight hours following injury) treatment used in the literature. The case notes of children who were treated at our institution for a Gartland grade 2b and 3 supracondylar humerus fracture between July 1995 and June 2002 were reviewed. We identified 431 patients with a Gartland grade 3 and 141 patients with a Gartland grade 2b fracture. The time from injury to surgery ranged from 2 hours to 13 days. The average time to reduction was 12 hours for grade 3 injuries and 21 hours for grade 2b injuries. None of the patients had an initial closed reduction in the emergency department. 229 patients were treated early with two compartment syndromes, five ulnar nerve, one lateral cutaneous nerve of the forearm, one median nerve - and one radial nerve palsy, one septic arthritis, one pin site infection, six open reductions; one re-manipulation was required for loss of reduction. The delayed group consisted of 343 patients with six ulnar nerve, three median nerve, one radial nerve and one lateral cutaneous nerve of the forearm palsy, three pin site infections, five open reductions; re-manipulation was required in one patient. All nerve palsies recovered post-operatively. The open reduction rate was two percent. The majority of displaced supracondylar humerus fractures in children do not need to be operated on as an emergency. Operation of fractures not associated with a neurovascular compromise within eight hours of the injury does not seem to reduce the rate of significant complications and open reduction rate. In contrary the most severe complication, the development of a compartment syndrome was only seen in the early group. We did not identify an association between complication rateS and a time threshold. Therefore the differentiation between early and delayed treatment used in the literature seems to be arbitrary and not useful.
Little is known about the priorities of patients undergoing surgery for idiopathic scoliosis. This study explores the priorities of adolescents and contrasts them from their parents and their surgeons. Fifty-five pairs of children and parents underwent structured interviews separately, to explore their concerns, desires and expectations both about scoliosis and surgery. Surgeons of these patients and from across Canada completed a similar questionnaire. We found a significant mismatch between child, parent and surgeon priorities. This mismatch has implications on matters relating to decision making, informed consent, understanding of patient satisfaction, and measuring outcomes that are meaningful to patients. To define the concerns, desires (goals) and expectations of adolescents undergoing surgery for idiopathic scoliosis and to contrast them from their parents and surgeons. We conducted structured interviews of fifty-five pairs of adolescents and parents separately. The questionnaire had sections on concerns, desires and expectations regarding both scoliosis and surgery, with items pertaining to present and future effects on appearance, pain, physical and psychosocial function and health. Parents also reported what their child’s responses might be. Their surgeons (four) and paediatric spine surgeons (twenty-four) across Canada completed the same questionnaire. Analysis involved repeated measures ANOVA, intra-class correlation coefficients and kappa statistics. Parents were more concerned than their children about present and future consequences of scoliosis. Surgeons were least concerned. Children, parents and surgeons agreed that improving physical appearance was the primary goal of surgery. Surgeons agreed very little about the natural history of scoliosis, other goals of surgery and the likelihood of specific outcomes. Parents wanted more from surgery than their children. Parents and patients had greater expectations of surgery than surgeons. Adolescents had different priorities from their parents, but parents were aware of this difference and knew what their child’s priorities were. Adolescents with idiopathic scoliosis, their parents and surgeons have different priorities. This mismatch might stem from uncertainty about the natural history of idiopathic scoliosis for Knowledge of patient priorities is vital for shared decision making, informed consent, understanding patient satisfaction, and for measuring outcomes that matter most to patients.
Orthopaedic Research &
Education Foundation: (Unni. G. Narayanan: AAOS/OREF Health Services research Fellowship award) Canadian Institutes of Health Research: (James G. Wright, Douglas M. Hedden, Benjamin Alman, Andrew Howard, Sandra Donaldson) DePuyAcroMed-Johnson &
Johnson Medical Products (James G. Wright, Douglas M. Hedden, Benjamin Alman, Andrew Howard, Sandra Donaldson) Synthes, Canada (James G. Wright, Douglas M. Hedden, Benjamin Alman, Andrew Howard, Sandra Donaldson)
Five surgeons independently rated clinical photographs of forty patients with AIS. Ratings of shoulder blades, shoulder symmetry, and waist symmetry were related to “overall appearance”, and were also correlated with rib prominence and Cobb angle. Because the components of surgeons’ ratings of appearance differed, this may lead to inconsistent recommendations regarding surgery. To identify patient characteristics associated with surgeons’ ratings of patient physical deformity in Adolescent Idiopathic Scoliosis (AIS). Five surgeons independently rated clinical photographs of forty patients with AIS. Surgeons separately rated the appearance of patients’ shoulder blades, shoulder symmetry, waist symmetry and also rated their “overall appearance Surgeons’ mean rating for “overall appearance” was moderately correlated with rib prominence (r = 0.48), vertebral rotation (r = 0.44) and Cobb angle (r = 0.53). Surgeons’ rating of patients’ “overall appearance” was affected by each of: shoulder blades (p = 0.001), shoulder symmetry (p = 0.01) and waist symmetry (p = 0.001). However, each surgeon weighted components of patients’ appearance differently to arrive at their overall rating of appearance (p<
0.006). Because patients’ physical appearance is an important element of surgical decision making, differences among surgeons could be contributing to inconsistent recommendations. Surgeons’ ratings of physical appearance are based on surgeons’ ratings of patients’ shoulder blades, waist symmetry and shoulder symmetry but surgeons weight those elements differently. Surgeon decision making is complicated. It is based on radiographs and subjective assessment. Patients’ appearance undoubtedly influences surgeon recommendation for surgery. We need to clarify surgeons’ ratings and improve the criteria for surgeon decision making.
All supracondylar humeral fractures managed with closed or open reduction and pin fixation at the Hospital for Sick Children between 1995 and 2002 were retrospectively reviewed. Time from injury to treatment, post reduction complications and need for open reduction were recorded. Fractures treated ≥ 8 hours from injury were considered in the early treatment group while >
8 hours were considered in the late treatment group. Fractures presenting with a cold hand (four patients) were taken to the operating room as quickly as possible and were excluded from the study. There were 431 patients with a Gartland grade 3 and 141 patients with a Gartland grade 2b. The time from injury to surgery ranged from 2 hours to 13 days. The average time to reduction was 12 hours for grade 3 injuries and 21 hours for grade 2b injuries. None of the patients had an initial closed reduction in the emergency department. The early treatment group consisted of 230 patients with two compartment syndromes, six ulnar-, one superficial radial-, one median- and one radial nerve palsy, one septic arthritis, one pin site infection, six open reductions and one re-manipulation was required for loss of reduction. The late treatment group consisted of 342 patients with six ulnar-, three median-, one radial nerve palsy and one lateral cutaneous nerve of the forearm palsy, three pin site infections, five open reductions and re-manipulation was required in one patient. All nerve palsies recovered post-operatively. Conclusion: There was no significant difference in the proportion of complications between the early and late treatment group, but the most severe complication, the development of a compartment syndrome was only seen in the early group. Delayed treatment of supracondylar humeral fractures seems to be safe in a large number of patients, and in fact, most of our patients were treated more than eight hours from the injury. Early operation of fractures not associated with a neurovascular compromise also does not seem to reduce the complication rate. Nevertheless the decision when to operate needs to be decided for each patient individually.
The purpose of this retrospective study was to determine if open reduction, with pelvic and femoral osteotomy, for a dislocated hip in children with severe spastic quadriplegia alters the function or symptoms of the patient, and to determine radiographic factors that correlate with symptoms. Between 1989 and 1997 56 patients/hips were operated on. The validated Pediatric Evaluation of Disability Inventory (PEDI) and a self-constructed questionnaire asking about pain, hygiene, sitting status, sitting tolerance, weight bearing for transfers, and ambulatory status were sent to all families. Radiographs were reviewed for changes in the centre edge angle (CE), acetabular index (AI), migration index (MI) and femoral head defect (FHD). 27 caregivers completed the questionnaires. Radiographs (pre-operative – latest follow-up) were available for 42 patients. 21 patients had both questionnaire and radiograph information. Logistic regressions were used to test whether the radiographic measures could predict each of the questionnaire outcomes which were grouped as ‘improved’ and ‘not improved’. The average age at surgery was 8.9 years (n=56: 1.8 – 16.5) for all patients, for patients with a completed questionnaire 9.4 years (n=27: 4.2–15.4). Time from surgery to follow-up was in average 5.5 years (1.8–9.5). All but 2 of the patients with completed questionnaire were nonambulatory (2 were functional ambulatory). As a group, the results of the PEDI did not significantly change following surgery. From the results of the second questionnaire: hygiene care improved for 11 patients, weight bearing for transfers improved for 7, sitting status improved for 10, and sitting tolerance improved for 18 patients. At follow-up, pain worsened in 2 patients, did not improve in 2 patients, and the remainder were pain free. The ability to provide hygiene care worsened for the 2 patients with worsening pain. Weight bearing for transfers and sitting status worsened in 3 patients, 2 of who were the patients with worsening pain, and the other had an unreduced dislocation of the opposite hip. Sitting tolerance worsened in 3 patients, 2 of who were the patients with worsening pain. Four patients who did not have femoral head defects prior to surgery developed them after surgery. Two of these four patients were the ones who developed worsening pain but had normal CE, AI and MI measures. Other radiographic measures of the hips did not correspond with function or symptoms. Eight patients had a femoral head defect prior to surgery and none were symptomatic at follow-up. Our assessment method shows that open reduction for the dislocated hip in children with severe cerebral palsy can result in a decrease in pain and a modest improvement in function. However, the postoperative development of a femoral head defect is associated with worse pain and poorer function. A pre-existing femoral head defect is not a contraindication to surgery.
Seventy-eight children, with 79 femoral fractures, treated with titanium elastic intramedullary nails were reviewed for complications. Insertion site symptoms (41), malunion (8), refracture (2), transient neurological deficit (2), superficial wound infection (2), and reoperation prior to union (10). Malunion/loss of reduction was increased with mismatched nails (p=0.02) and comminution (p=0.02). Insertion site symptoms were increased with nail ends that were bent (p=0.02), or >
10mm prominent (p=0.002). Nails remain implanted in 25 children without problems. Nail ends should lie against the femur to avoid insertion site symptoms. Nails of different diameters should not be implanted. Comminuted fractures require close monitoring.