Total knee arthroplasty (TKA) is recognised as an effective treatment for end-staged knee osteoarthritis. Up to 20% of these patients is unfortunately unsatisfied due to anterior knee pain from unknown origin (Bourne and al. 2010). The aim of this study is to compare knee 3D kinematics during gait of patients with anterior knee pain after TKA to an asymptomatic TKA group. Our hypothesis is that the painful TKA group would exhibit known kinematics characteristics during gait that increase patellofemoral (PF) stresses (i.e. dynamic flexion contracture, valgus alignment, valgus collapse or a quick internal tibial rotation movement) compared to the TKA asymptomatic group.

Thirty-eight patients (45 knees) were recruited 12–24 months post-surgery done by one of three experienced orthopaedic surgeons (31 unilateral TKA and seven bilateral TKA, all using the same knee implant). Patients were divided according to their KOOS pain score (with a cut-off at 6/20 to be included in the painful group). The KOOS questionnaire was also used to assess activities of daily living, symptoms, sports and quality of life. A complete clinical and radiological work up was done on the painful group to exclude those with known explanation for pain (i.e. loosening, malrotation, infection and clinical instability). 3D knee kinematics during treadmill walking was captured and computed using the KneeKGTM system.

For the painful and asymptomatic groups, demographic results show respectively: age of 64.4 ± 7.6 and 69.8 ± 8.3 years, BMI of 31.9 ± 5.0 and 28.1 ± 3.6 kg.m−2, speed of 1.8 ± 0.6 and 1.67 ± 0.5 miles/h., and 50% of women in each group. Only age and BMI showed to be statistically different between groups. The painful TKA group exhibited a valgus alignment when walking (at initial contact and during stance, p<0.001). No significant difference has been put forward for the flexion/extension and internal/external tibial rotation.

Since a higher valgus alignment increases the Q angle, which lateralise the patella and increases PF stresses, results provide new insight on origin of symptoms. Conservative treatments for PF pain syndrome have shown to address the valgus alignment and improve symptoms, therefore the next step will be to assess the impact on pain level and alignment during gait of a personalised conservative management for the painful TKA group. Additionally, a study assessing the change in the radiological and dynamic alignment from pre to post surgery could bring valuable insight on the impact of surgical procedure on anterior knee pain.

Introduction

From the many human studies that attempt to identify genes for adolescent idiopathic scoliosis (AIS), the view emerging is that AIS is a complex genetic disorder with many predisposing genes exhibiting complex phenotypes through environmental interactions. Although advancements in genomic technology are transforming how we undertake genetic and genomic studies, only some success has been reached in deciphering complex diseases such as AIS. Moreover, the present challenge in AIS research is to understand the causative and correlative effects of discovered genetic perturbations. An important limitation to such investigations has been the absence of a method that can easily stratify patients with AIS.

To overcome these challenges, we have developed a functional test that allows us to stratify patients with AIS into three functional subgroups, representing specific endophenotypes. Interestingly, in families with multiple cases of AIS, a specific endophenotype is shared among the affected family members, indicating that such a transmission is inherited. Moreover, increased vulnerability to AIS could be attributable to sustained exposure to osteopontin (OPN), a multifunctional cytokine that appears to be at the origin of the Gi-coupled receptor signalling dysfunction discovered in AIS. We examined the molecular expression profiles of patients with AIS and their response to OPN.

Introduction: Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis, which appears to be caused by a melatonin signalling dysfunction proved recently in osteoblasts. This pathology occurs and progresses during the time of pre-puberty and puberty growth. This period is known to be under the hormonal control and coincides with many biological changes related to the secretion of estrogens, of which estradiol (E2) is the most active. The female prevalence of AIS disease is clearly evident. Indeed, in Quebec the spine deformities considered clinically significant (at least 11° of deformity) are found in a girl:boy ratio of approximately 2:1 for reduced scoliosis, and this ratio increases to 10:1 for scoliosis of more than 30o of deformation. However, the reason for this female prevalence as well as the role of estrogens and estrogen receptors in AIS is not clear despite the fact that these hormones are known for their impact on bone and bone growth, including the spine.

The purpose of the present study was to investigate the role of E2 on the responsiveness of the AIS cells to the melatonin, to determine the expression of estrogens receptors (ERα and ERβ) in AIS tissues and to clarify the impact of estrogen receptor gene polymorphisms in the pathogenesis of AIS.

Methodology: The effects of oestrogen on the AIS osteoblasts (n=10) response to the melatonin was determined by measuring the reduction of forskolin-induced cAMP accumulation. The forskolin treated osteoblasts were incubated in the presence of increasing amounts of melatonin (10–11 to 10-5 M) with or without physiological concentrations (10-10 M) of 17-β-estradiol for 16 hours, and the intracellular cAMP measured by radio-immunoassay using Biotrak Kit. Using RT-PCR, we determined ERα and ERβ mRNA expression in osteoblasts from AIS patients (n=14). Polymorphisms of the first intron of the ERα gene, which contains the XbaI and PvuII polymorphisms, were investigated by PCR following digestion with restriction enzyme and using the genomic DNA from lymphocytes isolated from scoliotic patients (n=33). Using the restriction enzymes XbaI and PvuII, the allelic variants XX, Xx, xx, PP, Pp, and pp were identified in 33 AIS patients (uppercase letters represent absence, and lowercase letters represent presence of restriction sites).

Results: The intracellular level of cAMP was significantly increased (p< 0.01) in the presence of a physiological concentration of 17-β-estradiol (10-10 M) when compared to the level observed in the presence of melatonin alone (10-9 M) (melatonin + estradiol: 109.46 ± 20.07; melatonin 76.09 ± 12.32 (mean ± SD)). As previously described by Dr Moreau’s team, the same pattern (three type of response to melatonin) takes place in the presence of 17-β-estradiol. We observed the loss of ERβ gene expression in 8/ 14 AIS patients contrasting with ERα gene expression that was found in all AIS patients. The XbaI and PvuII polymorphisms were found in 70% (23/33) and 80% (26/33) of the cases respectively. Of the 33 cases, 21 presented both digestion sites, 24 presented PvuII digestion site (6 homozygote, 18 heterozygote) and 23 (8 homozygote, 15 heterozygote) presented XbaI digestion site. The allelic variants were found as follows: XX: n=8, Xx: n=15, xx: n=8, PP: n=6, Pp: n=18 and pp: n=6. Classified by their location in the spine, seven right thoracic, one left thoracic, one right thoracolumbar, three left thoracolumbar and nine right thoracic-left lumbar were found among the patients presenting PvuII positive polymorphism. Among the patients with XbaI positive polymorphism, six right thoracic, one left thoracic, one right thoracolumbar, three left thoracolumbar and eight right thoracic left lumbar were found.

Conclusion: These results show the antagonistic effects of the 17-β-estradiol on AIS osteoblasts response to the melatonin. Thus estrogens interference with melatonin signalling activity would act as a triggering or aggravating factor in the pathogenesis of AIS. At the molecular level, it is possible that estrogens attenuate the response of AIS cells to melatonin through the desensitization of melatonin receptors. The loss of ERβ expression in a significant number of AIS patients appears to be important for the change of the ERα/ERβ receptors ratio that consequently may perhaps alter estrogens signalling pathways. The XbaI and PvuII polymorphisms are present in a significant number of AIS patients but this was not dependant of the curve pattern. These results clearly support the interplays and crosstalk between estrogens and melatonin signalling pathways in AIS aetiopathogenesis.

Supported by the Fondation Yves Cotrel, Institut de France

Introduction: Spinal deformities and scoliosis in particular, represent the most prevalent type of orthopaedic deformities in children and adolescents. At present, the most significant problem for clinicians is that there is no proven method or test available to identify children or adolescents at risk of developing AIS or to identify which of the affected individuals are at risk of progression. As a consequence, the application of current treatments, such as bracing or surgical correction, has to be delayed until a significant deformity is detected or until a significant progression is clearly demonstrated, resulting in a delayed and less optimal treatment. Among patients with AIS needing treatment, 80% to 90% will be treated by brace and 10% will need surgery to correct the deformity by spinal instrumentation and fusion of the thoracic and/or lumbar spine. About 15000 such surgeries are done every year in North America, resulting in significant psychological and physical morbidity. Moreover, there is no pharmacotherapy available to either prevent or reduce spinal deformities due mainly to our limited knowledge of AIS aetiopathogenesis. We have recently reconciled the role of melatonin in AIS aetiopathogenesis by demonstrating a melatonin signalling dysfunction occurring in a cell autonomous manner in cells derived from AIS patients exhibiting severe scoliotic deformities. This defect could potentially explain the majority of abnormalities reported in AIS since melatonin receptors and signalling activities are normally found in all tissues and systems affected in AIS, thus offering a very innovative and unifying concept to explain the aetiology of AIS. Moreover, several lines of evidence suggested that inactivation of Gi proteins by an increased phosphorylation of serine residues could be at the source of this signalling defect in AIS. The goals of that study were to assess the possibility to establish a molecular classification of AIS patients and to demonstrate the feasibility to correct this melatonin signalling defect in cells of AIS patients using therapeutic compounds.

Methods: Primary cell cultures were prepared from musculoskeletal tissues of AIS patients (n=150) and age- and gender-matched controls (n=35) obtained intra-operatively. An informed consent was obtained for each subject as approved by our Institutional Ethical Committee. The osteoblasts, the bone-forming cells, were selected to assess whether or not an alteration of melatonin signalling pathway occurs in AIS and accordingly to identify which component of the melatonin transduction machinery could be involved. Co-immunoprecipitation experiments with membrane extracts were performed to identify interacting molecules with key components of melatonin signal transduction machinery. The functionality of melatonin signalling was assessed by investigating the ability of Gi proteins to inhibit stimulated adenyl cyclase activity in osteoblast cultures. Inhibition curves of cAMP production were generated by adding melatonin to the forskolin-containing samples in concentrations ranging from 10-11M to 10-5M in a final volume of 1 ml of _-MEM media containing 0.2% bovine serum albumin (BSA) alone or in presence of 2.5 _M of therapeutic compound A or therapeutic compound B (the nature of both compounds tested cannot be disclosed at this stage). The cAMP content was determined using an enzyme immunoassay kit (Amersham-Pharmacia Biosciences). All assays were performed in duplicate. A non-parametric test, the Wilcoxon matched pairs test was performed to verify the significance between 2 means. Significance was defined as P< 0.05.

Results: Osteoblasts from patients with AIS showed a lack or a markedly reduced inhibition of forskolin-stimulated adenyl cyclase activity by melatonin generating three distinct response-curves corresponding to three functional groups. In order to identify candidate genes involved in AIS aetiopathogenesis, we focused our attention on known kinases and phosphatases modulating Gi protein functions and characterised their interacting partners. Interestingly, PKC_ was initially targeted owing to its property to phosphorylate Gi proteins in vitro. Indeed, in normal osteoblast interactions occurring between MT2 melatonin receptor and RACK1 (a cytosolic protein that bind to and stabilises the actives form of PKC and permits its translocation to different sites within the cells) and PKC_ were detected although those interactions among different AIS patients were altered. Interestingly, treatment with compound A or B rescued melatonin signal defect in cells derived from 36% and 47% of AIS patients respectively. Overall, melatonin signal transduction was restored in cells of 64% of AIS patients (23/36) when treated by one of these therapeutic compounds.

Conclusions: The functional classification of AIS patients is correlated at the molecular level by distinct interactions between key molecules normally involved in melatonin signal transduction in spite that these patients exhibited the same curve type (right thoracic, Lenke type 1). Collectively, these data strongly argue that traditional curve pattern classification is not a relevant stratification of AIS patients to identify its genetic causes. Moreover, using that molecular system we have demonstrated also the possibility to identify therapeutic compounds to rescue the melatonin signalling defect observed in AIS without any prior knowledge of mutations in any defective genes causing AIS because we are measuring a function.

Research project supported by La Fondation Yves Cotrel de l’Institut de France

The most commonly used surgical techniques used to treat recurrent or habitual patellar dislocation in the child do not specifically address the patella alta, one of the major causes of patellar dislocation. Twelve knees in eight patients had a lowering of the patella by total tendon transfer, lateral release and vastus medialis obliquus advancement. At two years of follow-up, only one knee had redislocated. Radiographically, the patellar height was anatomically restored in all other knees. All patients were pain free. This surgical technique is a good treatment option in the immature patient with recurrent or habitual patellar dislocation.

Patella alta is one of the major causes known to predispose children to recurrent or habitual patellar dislocation. However, the surgical treatment of such a condition, before squeletal maturity, is rarely if ever mentioned in the literature.

Twelve knees in eight patients were treated with a surgical procedure designated to correct patella alta, the major predisposing factor causing recurrent patellar dislocation. The technique involves lowering of the patella by total tendon transfer, lateral release and vastus medialis obliquus advancement. All patients were complaining of recurrent or habitual dislocations leading to functional disability. Patellar height was assessed radiographically by the Koshimoto index (PT/FT) and Caton-Deschamps index (AT/AP). The average at surgery was 10.9 years and mean follow-up was 45.1 months.

Follow-up revealed redislocation in one knee. This patient required a second operation to achieve patellar stability. At the latest follow-up, all operated knees were functionally stable and pain free. The average preoperative ratios were 1.28 (PT/FT) and 1.53 (AT/AP) which improved to 0.97 (PT/FT) and 0.96 (AT/AP) at the time of follow-up. Few complications were noted.

This technique is a valid surgical alternative to treat the immature patient presenting with functional disability related to recurrent or habitual patellar dislocation associated with patella alta.

Purpose: Recently, we highlighted a dysfunction in the melatonin signalling pathway in the osteoblasts from adolescent idiopathic scoliosis patients (AIS). The objective of this project is to verify if in the cells coming from the SIA patients, estrogens interfere with melatonin signalling pathways and to identify mechanisms through which these effects are carried out.

Methods: The effects of estrogens on the melatonin signalling pathway, in osteoblasts from AIS patients (n=7), were determined by measuring the capacity of the Gi proteins to inhibit the accumulation of cAMP. The osteoblasts were incubated in the presence of increasing amounts of melatonin (10–11 to 10–5 M) with or without 17-& #946;-estradiol in physiological concentrations (10–10 M) (n=7). Moreover, coimmunoprecipitations using anti-phosphoserine antibodies were carried out and then followed with a Western blot in order to detect melatonin receptors (MT1 and MT2).

Results: The intracellular level of cAMP is higher in the presence of a physiological concentration of 17-& #946;-estradiol among scoliotic patients compared to the level observed in the presence of melatonin alone. Moreover, the preliminary results of the coimmunoprecipitations seem to show an increase in the phosphorylation of proteins interacting with MT1 and MT2 receptors. The precise nature of these proteins remains to be identified.

Conclusions: These results seem to show the antagonistic effects of the 17-& #946;-estradiol on the melatonin signalling pathway in the osteoblasts from AIS patients. However, more cAMP dosages in the presence and absence of 17-& #946;-estradiol are underway so as to increase the number of patients. The results of this study could contribute to the development of the first molecular screening tests as well as the development of new therapeutic approaches.

The aim of this study is to compare the adulthood quality of life of subjects with adolescent idiopathic scoliosis who have had surgery to subjects without. Inclusion criteria were being operated or having not operated but having a scoliosis with a Cobb angle ≥ 35° at the last visit. Self-administered questionnaires (five) were sent to all eligible patients. A total of two hundred and four had surgery. The mean Rolland score for subjects was significantly higher for the group who had surgery. The only variable affecting physical component of the SF-36 was the alcohol consumption. The EuroQol score was predicted by the marital status, people being married having a better score. In conclusion, there is not significant difference in the quality of life in adulthood between the subjects with AIS whether they had surgery or not. Subjects who had surgery tend to be less in pain than people not operated on.

The aim of this study is to compare adulthood quality of life of patients with AIS who have had surgery to subjects without.

Overall, there is not significant difference in the quality of life in adulthood between the subjects with AIS whether they had surgery or not. Subjects who had surgery tend to be less in pain than people not operated on.

This preliminary study will help the health professionals involved with the management of patients with AIS make clinical decisions and better understand the long-term quality of life in idiopathic scoliosis.

Among the two hundred and ninety-nine AIS responding, two hundred and four had surgery and ninety-five none and their mean Cobb angle was respectively fifty-eight and forty-four degrees. All patients had a follow up more than twenty years. There was no significant difference as for sex, life status, education, working areas, alcoholism, smoking habits, chronic illness and reproductive health between the two groups. Same proportion of subjects in both groups had no back pain (≅30%); but more non-operated subjects had physiotherapy and/or chiropractic treatments (p< 0.001). The mean Rolland score for subjects was significantly higher for the group who had surgery (p = 0.02). Using multiple regression analysis, the only variable affecting physical component of the quality of life measured with the SF-36 was the alcohol consumption whereas the psychological of the SF-36 was predicted by alcohol consumption as well and the gender. The quality of life measured by the EuroQol was predicted mainly by the marital status, people being married having a better score.

The study was designed as a comparative retrospective cohort study. Subjects referred for Adolescent Idiopathic Scoliosis between 1960 and 1979 to Sainte-Justine Hospital were entered into the cohort. Inclusion criteria were being operated or having not operated but having a scoliosis with a Cobb angle ≥ 35° at the last visit.

A self-administered questionnaire was sent to all eligible patients. The questionnaires that were used were all reliable and valid. More specifically the instruments used were the Oswestry, Roland, SF-36, Quebec Back Pain Disability Scale, Scoliosis Research Society and the EuroQol-5D.