Clinical and quality-of-life outcomes of a combined synthetic scaffold and autogenous tissue graft procedure for articular cartilage repair in the knee.

BACKGROUND: Injuries to the articular cartilage of the knee often fail to heal properly due to the hypocellular and avascular nature of this tissue. Subsequent disability can limit participation in sports and decrease quality of life. Subchondral bone perforations are used for the treatment of small defects. Filling out the central portion in larger lesions becomes difficult, and scaffolds can be used as adjuvants, providing a matrix onto which the defect can be filled in completely. Also, autogenous cartilage grafts can be combined, acting as an inducer and improving healing quality, all in a single procedure. METHODS: This observational study evaluated the clinical and quality-of-life outcomes of patients with articular cartilage lesions of the knee undergoing repair via a microfracture technique combined with a synthetic scaffold and autogenous cartilage graft, with transosseous sutures and fibrin glue fixation, at 12 months of follow-up. Secondarily, it assessed whether combined procedures, previous surgical intervention, traumatic aetiology, lesion location, and age affect outcomes. The sample consisted of adult patients (age 18-66 years) with symptoms consistent with chondral or osteochondral lesions, isolated or multiple, ICRS grade III/IV, 2-12 cm2 in size. Patients with corrected angular deviations or instabilities were included. Those with BMI > 40 kg/m2, prior total or subtotal (> 30%) meniscectomy, second-look procedures, and follow-up < 6 months were excluded. Pain (VAS), physical activity (IKDC), osteoarthritis (WOMAC), and general quality of life (SF-36) were assessed. RESULTS: 64 procedures were included, comprising 60 patients. There was significant improvement (P < 0.05) in VAS score (5.92-2.37), IKDC score (33.44-56.33), and modified WOMAC score (53.26-75.93) after surgery. The SF-36 showed significant improvements in the physical and mental domains (30.49-40.23 and 46.43-49.84 respectively; both P < 0.05). CONCLUSIONS: Combination of microfractures, autogenous crushed cartilage graft, synthetic scaffold, and transosseous sutures with fibrin glue provides secure fixation for treatment of articular cartilage lesions of the knee. At 12-month follow-up, function had improved by 20 points on the IKDC and WOMAC, and quality of life, by 10 points on the SF-36. Age > 45 years had a negative impact on outcomes.

Rationale, study design, and descriptive data of the Lucky Bone™ Fracture Liaison Service.

The study design of a multidisciplinary Fracture Liaison Service (2-year follow-up) aiming to optimize fragility fracture management in an outpatient setting is presented. Patient characteristics, investigation, and treatment initiation data at baseline were recorded. Results corroborate the care gap in osteoporosis management, reinforcing the need for secondary fracture prevention programs. PURPOSE: This paper describes the study design, implementation, and baseline characteristics of a multidisciplinary Fracture Liaison Service (FLS) in Quebec (Canada). METHODS: A FLS was implemented as a prospective cohort study. After identification, fracture risk was assessed and patients were started on treatment or referred, according to guidelines and risk assessment. Thereafter, patients were systematically followed over 2 years. Clinical data (fractures, bone density, blood testing (bone turnover markers), quality of life, physical disability) as well as administrative data (pharmacological, health services, hospitalization) was collected. Baseline descriptive data was analyzed and presented. RESULTS: Of 542 recruited participants, 532 underwent baseline assessment (85.7% female, mean age 63.4 years). Overall, 29.7% of participants either withdrew from the study or were lost to follow-up. Almost 27% were referred to a specialist, while > 70% received anti-osteoporosis medication prescriptions through the FLS at baseline. Mean femoral T-score was - 1.6 ± 1.0 and vertebral T-score was - 1.7 ± 1.4. Nearly 19% of subjects reported being under anti-osteoporosis medication at the time of incident fracture. Thirty-three percent of participants reported a prior fracture history, of which 29.7% reported being given anti-osteoporosis therapy. Most fracture sites were to the wrist and ankle, while < 19% were hip/femur or vertebral fractures. CONCLUSIONS: These results highlight the important care gap in fragility fracture management and reinforce the need for secondary fracture prevention programs. This prospective study will allow the evaluation of key performance indicators for outpatient clinic-based FLS, such as medication usage, by combining prospective clinical and administrative data.

Incidence of symptomatic venous thromboembolism in 2372 knee and hip replacement patients after discharge: data from a thromboprophylaxis registry in Montreal, Canada.

BACKGROUND: Low-molecular-weight heparin (LMWH) is a recommended anticoagulant for thromboprophylaxis after major orthopedic surgery. Dabigatran etexilate is an oral anticoagulant recognized as noninferior to LMWH. We aimed to assess the incidence of symptomatic venous thromboembolic events (VTEs) after discharge in patients who underwent joint replacement, using a hospital registry. PATIENTS AND METHODS: Patients who underwent total knee and hip arthroplasty between September 2011 and March 2015 were selected. Subcutaneous enoxaparin (30 mg twice daily) was given during hospitalization. At discharge, patients received either enoxaparin 30 mg twice daily/40 mg once daily or dabigatran 220 mg/150 mg once daily. Patients were seen or called at 2, 6, and 12 weeks after surgery. Outcomes were the number of VTEs, including deep venous thrombosis, pulmonary embolism, and the number of major/minor bleeding events after discharge. RESULTS: After discharge, 1468 patients were prescribed enoxaparin and 904 dabigatran (1396 total knee arthroplasty and 976 total hip arthroplasty patients). Mean age was 66±10 years, and 60% were female. The cumulative incidence of VTEs during the 12-week follow-up was 0.7%. One patient sustained a VTE during the switch window. Seven patients sustained a pulmonary embolism (0.3%). There was no statistical difference between the total knee arthroplasty and total hip arthroplasty groups. The incidence of major and minor bleeding events during follow-up was 0.3% and 30.3%, respectively. These events had a higher incidence in the dabigatran group compared to the enoxaparin group after discharge (p<0.05), but not between knee and hip replacement groups for major bleeding events. CONCLUSION: A pharmaceutical prophylaxis protocol using LMWH and dabigatran during the post-discharge period resulted in low incidences of VTE and equivalence between treatments. However, the increased number of major and minor bleeding events in patients taking dabigatran is of concern regarding the safety and needs to be evaluated using analyses adjusted for risk factors.

LARS synthetic ligaments for the acute management of 111 acute knee dislocations: effective surgical treatment for most ligaments.

PURPOSE: The purpose of this study was to describe the longitudinal outcomes of acute repair and augmentation for the reconstruction of dislocated knees, using LARS synthetic ligaments. METHODS: Patients with a knee dislocation surgically treated using LARS synthetic ligament augmentation, with a minimum follow-up of 24 months, were enrolled between 1996 and 2014. Range of motion, Lachman, pivot shift, posterior drawer, step off sign, valgus, varus, KT-1000 arthrometer, Telos technique, IKDC, Lysholm, Tegner, and Meyers scores were obtained every 2 years up to 10 years. RESULTS: Median age was 32.1 years (IQR 23.2-43.3) at time of surgery. Median time from trauma to surgery was 9 days and mean follow-up time was 6.6 years. Median questionnaire scores were: Lysholm 79.5 (IQR 65.0-89.0), Tegner 4.0 (IQR 3.7-6.0), Meyers 3.0 (IQR 3.0-4.0), and mean IKDC was 63.8 (SD 18.9). Median flexion and extension of the injured knee was 124° (IQR 115-129.5) and 0° (IQR - 5 to 0), respectively. Median KT-1000 differential was 0.7 mm (IQR 0.1-3.1) for ACL and 0.9 mm (IQR 0.2-1.4) for PCL. Mean differential for Telos was 2.5 mm (SD 5.8) for ACL, 4 mm (IQR 2-6.3) for PCL 30°, and 8.2 mm (SD 4.4) for PCL 90° (consistent with PCL laxity). More than 90% of patients had good anterior articular stability and > 60% of patients had good posterior articular stability. CONCLUSIONS: Acute repair and augmentation of knee dislocations with LARS synthetic ligaments resulted in satisfactory outcomes for the ACL and collateral structures. Telos stress radiography showed PCL laxity in more than half of cases despite low laxity results with KT-1000. The perception of patients about knee function was sustained in time. LEVEL OF EVIDENCE: IV.

Total knee arthroplasty with unexplained pain: new insights from kinematics.

INTRODUCTION: Up to 20% of total knee arthroplasty patients remain unsatisfied post-surgery, and a large proportion of them report anterior knee pain. This study aims to verify whether patients who experience anterior knee pain after total knee arthroplasty (TKA) will exhibit kinematic characteristics similar to those associated with patellofemoral syndrome, including in the frontal and transverse planes. MATERIALS AND METHODS: Using four different assessment methods [radiological, patient-reported outcome, musculoskeletal assessment with functional performance testing, and a 3D kinematic assessment during gait], the clinical and 3D knee kinematic profiles of three groups were compared: a painful and an asymptomatic TKA group and a healthy control group. All three groups underwent a three-dimensional kinematic knee assessment while walking on a treadmill. Prosthetic component rotation was assessed through a CT scan measurement performed by one experienced radiologist. Flexion/extension, ab/adduction, and tibial internal rotation curves were compared, and significant differences were highlighted through ANCOVA analysis performed on SPSS. RESULTS: A total of 62 knees were evaluated, 24 asymptomatic, 21 painful, and 17 control. A dynamic flexion contracture during gait was observed in the painful group, which was associated with a lack of flexibility of the thigh muscles. Moreover, painful TKA cases exhibited a valgus alignment (- 1.5°) during stance, which increases the Q angle and lateralizes the patella. Finally, CT scan evaluation of painful total knee arthroplasty patients revealed that their combined components rotation was in slight internal rotation (- 1.4°, SD 7.0°). CONCLUSIONS: Painful TKA patients presented three well-known characteristics that tend to increase patellofemoral forces and that could be the cause of the unexplained pain: a stiff knee gait, a valgus alignment when walking, and combined TKA components slightly internally rotated.

Patient Satisfaction with In-Home Telerehabilitation After Total Knee Arthroplasty: Results from a Randomized Controlled Trial.

Background and Introduction: Telerehabilitation after total knee arthroplasty (TKA) is supported by strong evidence on the effectiveness of such intervention and from a cost-benefit point of view. Satisfaction of patients toward in-home telerehabilitation after TKA has not yet been examined thoroughly in large-scale clinical trials. This study aims to compare satisfaction level of patients following in-home telerehabilitation (TELE) after TKA to one of the patients following a usual face-to-face home visit (STD) rehabilitation. Secondarily, to determine if any clinical or personal variables were associated to the level of satisfaction. MATERIALS AND METHODS: This study was embedded in a multicenter randomized controlled trial with 205 patients randomized into two groups. Rehabilitation intervention was the same for both groups; only approach for service delivery differed (telerehabilitation or home visits). Participants were assessed at baseline (before TKA), at hospital discharge, and at 2 and 4 months postdischarge (E4) using functional outcomes. Patient satisfaction was measured using the validated Health Care Satisfaction Questionnaire (HCSQ) at E4. RESULTS: Characteristics of all participants were similar at baseline. Satisfaction level of both groups did not differ and was very high (over 85%). It was neither correlated to personal characteristics nor to improvements of functional level from preoperative to E4. Satisfaction was rather found associated to walking and stair-climbing performances. CONCLUSIONS: These results, in conjunction with evidences of clinical effectiveness and cost benefits demonstrated in the same sample of patients, strongly support the use of telerehabilitation to improve access to rehabilitation services and efficiency of service delivery after TKA.

The role of resolvin D1 in the regulation of inflammatory and catabolic mediators in osteoarthritis.

OBJECTIVE AND DESIGN: Resolvin D1 (RvD1), an omega-3 fatty acid derivative, has shown remarkable properties in resolving inflammation, promoting tissue repair and preserving tissue integrity. In this study, we investigated RvD1 effects on major processes involved in osteoarthritis (OA) pathophysiology. MATERIALS AND METHODS: Human OA chondrocytes were treated with either 1 ng/ml interleukin-1ß (IL-1ß) or 20 µM 4-hydroxynonenal (HNE), then treated or not with increased concentrations of RvD1 (0-10 µM). RvD1 levels were measured by enzyme immunoassay in synovial fluids from experimental dog model of OA and sham operated dogs obtained from our previous study. Cell viability was evaluated by 3-(4,5-dimethyl-thiazoyl)-2,5-diphenyl-SH-tetrazolium bromide assay. Parameters related to inflammation, catabolism and apoptosis were determined by enzyme-linked immunosorbent assay, Western blotting, and quantitative polymerase chain reaction. Glutathione (GSH) was assessed by commercial kit. The activation of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) pathways was evaluated by Western blot. RESULTS: We showed that RvD1 levels were higher in synovial fluids from OA joint compared to controls. In OA human chondrocytes, we demonstrated that RvD1 was not toxic up to 10 µM and stifled IL-1ß-induced cyclooxygenase 2, prostaglandin E2, inducible nitric oxide synthase, nitric oxide, and matrix metalloproteinase-13. Our study of signalling pathways revealed that RvD1 suppressed IL-1ß-induced activation of NF-κB/p65, p38/MAPK and JNK(1/2). Moreover, RvD1 prevented HNE-induced cell apoptosis and oxidative stress, as indicated by inactivation of caspases, inhibition of lactate dehydrogenase release, and increased levels of Bcl2 and AKT, as well as GSH. CONCLUSION: This is the first in vitro study demonstrating the beneficial effect of RvD1 in OA. That RvD1 abolishing a number of factors known to be involved in OA pathogenesis renders it a clinically valuable agent in prevention of the disease.

Conditions of Use, Reliability, and Quality of Audio/Video-Mediated Communications During In-Home Rehabilitation Teletreatment for Postknee Arthroplasty.

BACKGROUND: Audio/video-mediated communication between patients and clinicians using videoconferencing over telecommunication networks is a key component of providing teletreatments in rehabilitation. OBJECTIVE: The objectives of this study were to (1) document the conditions of use, performance, and reliability of videoconferencing-based communication in the context of in-home teletreatment (TELE) following total knee arthroplasty (TKA) and (2) assess from the perspective of the providers, the quality attributes of the technology used and its impact on clinical objectives. MATERIALS AND METHODS: Descriptive embedded study in a randomized controlled trial using a sample of 97 post-TKA patients, who received a total of 1,431 TELE sessions. Technical support use, service delivery reliability, performance, and use of network connection were assessed using self-report data from a costing grid and automated logs captured from videoconferencing systems. Physical therapists assessed the quality and impact of video-mediated communications after each TELE session on seven attributes. RESULTS: Installation of a new Internet connection was required in 75% of the participants and average technician's time to install test and uninstall technology (including travel time) was 308.4 min. The reliability of service delivery was 96.5% of planned sessions with 21% of TELE session requiring a reconnection during the session. Remote technical support was solicited in 43% of the sessions (interventions were less than 3-min duration). Perceived technological impacts on video-mediated communications were minimal with quality of the overall technical environment evaluated as good or acceptable in 96% of the sessions and clinical objectives reached almost completely or completely in 99% of the sessions. CONCLUSIONS: In-home rehabilitation teletreatments can be delivered reliably but requires access to technical support for the initial setup and maintenance. Optimization of the processes of reliably connecting patients to the Internet, getting the telerehabilitation platform in the patient's home, installing, configuring, and testing will be needed to generalize this approach of service delivery.

In-Home Telerehabilitation Compared with Face-to-Face Rehabilitation After Total Knee Arthroplasty: A Noninferiority Randomized Controlled Trial.

BACKGROUND: The availability of less resource-intensive alternatives to home visits for rehabilitation following orthopaedic surgeries is important, given the increasing need for home care services and the shortage of health resources. The goal of this trial was to determine whether an in-home telerehabilitation program is not clinically inferior to a face-to-face home visit approach (standard care) after hospital discharge of patients following a total knee arthroplasty. METHODS: Two hundred and five patients who had a total knee arthroplasty were randomized before hospital discharge to the telerehabilitation group or the face-to-face home visit group. Both groups received the same rehabilitation intervention for two months after hospital discharge. Patients were evaluated at baseline (before total knee arthroplasty), immediately after the rehabilitation intervention (two months after discharge), and two months later (four months after discharge). The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire at the last follow-up evaluation. Secondary outcome measures included the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, functional and strength tests, and knee range of motion. The noninferiority margin was set at 9% for the WOMAC. RESULTS: The demographic and clinical characteristics of the two groups of patients were similar at baseline. At the last follow-up evaluation, the mean differences between the groups with regard to the WOMAC gains, adjusted for baseline values, were near zero (for 182 patients in the per-protocol analysis): -1.6% (95% confidence interval [CI]: -5.6%, 2.3%) for the total score, -1.6% (95% CI: -5.9%, 2.8%) for pain, -0.7% (95% CI: -6.8%, 5.4%) for stiffness, and -1.8% (95% CI: -5.9%, 2.3%) for function. The confidence intervals were all within the predetermined zone of noninferiority. The secondary outcomes had similar results, as did the intention-to-treat analysis, which was conducted afterward for 198 patients. CONCLUSIONS: Our results demonstrated the noninferiority of in-home telerehabilitation and support its use as an effective alternative to face-to-face service delivery after hospital discharge of patients following a total knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Cost analysis of in-home telerehabilitation for post-knee arthroplasty.

BACKGROUND: Rehabilitation provided through home visits is part of the continuum of care after discharge from hospital following total knee arthroplasty (TKA). As demands for rehabilitation at home are growing and becoming more difficult to meet, in-home telerehabilitation has been proposed as an alternate service delivery method. However, there is a need for robust data concerning both the effectiveness and the cost of dispensing in-home telerehabilitation. OBJECTIVE: The objective of this study was to document, analyze, and compare real costs of two service delivery methods: in-home telerehabilitation and conventional home visits. METHODS: The economic analysis was conducted as part of a multicenter randomized controlled trial (RCT) on telerehabilitation for TKA, and involved data from 197 patients, post-TKA. Twice a week for 8 weeks, participants received supervised physiotherapy via two delivery methods, depending on their study group allocation: in-home telerehabilitation (TELE) and home-visit rehabilitation (VISIT). Patients were recruited from eight hospitals in the province of Quebec, Canada. The TELE group intervention was delivered by videoconferencing over high-speed Internet. The VISIT group received the same intervention at home. Costs related to the delivery of the two services (TELE and VISIT) were calculated. Student's t tests were used to compare costs per treatment between the two groups. To take distance into account, the two treatment groups were compared within distance strata using two-way analyses of variance (ANOVAs). RESULTS: The mean cost of a single session was Can $93.08 for the VISIT group (SD $35.70) and $80.99 for the TELE group (SD $26.60). When comparing both groups, real total cost analysis showed a cost differential in favor of the TELE group (TELE minus VISIT: -$263, 95% CI -$382 to -$143). However, when the patient's home was located less than 30 km round-trip from the health care center, the difference in costs between TELE and VISIT treatments was not significant (P=.25, .26, and .11 for the <10, 10-19, and 20-29 km strata, respectively). The cost of TELE treatments was lower than VISIT treatments when the distance was 30 km or more (30-49 km: $81<$103, P=.002; ≥50 km: $90<$152, P<.001). CONCLUSIONS: To our knowledge, this is the first study of the actual costs of in-home telerehabilitation covering all subcosts of telerehabilitation and distance between the health care center and the patient's home. The cost for a single session of in-home telerehabilitation compared to conventional home-visit rehabilitation was lower or about the same, depending on the distance between the patient's home and health care center. Under the controlled conditions of an RCT, a favorable cost differential was observed when the patient was more than 30 km from the provider. Stakeholders and program planners can use these data to guide decisions regarding introducing telerehabilitation as a new service in their clinic. TRIAL REGISTRATION: International Standard Registered Clinical Study Number (ISRCTN): 66285945; http://www.isrctn.com/ISRCTN66285945 (Archived by WebCite at http://www.webcitation.org/6WlT2nuX4).

Evaluation of reconstructive surgery using artificial ligaments in 71 acute knee dislocations.

This retrospective study assessed the results of 71 patients with knee dislocations who underwent acute combined repair and reconstruction using Ligament Advancement Reinforcement System (LARS) artificial ligaments between June 1996 and May 2008 with a follow-up between two and eight years. The outcome measures used were the Lysholm score, the International Knee Documentation Committee form (IKDC 2000), the Tegner activity level score, the Meyers ratings, Telos stress radiography, range of motion and clinical knee stability testing. When comparing high- versus low-energy dislocations and knee dislocation (KD) II/III versus KD IV injuries, a better Lysholm score for the knee dislocation (KD) II/III group was found compared with the KD IV group. The subjective and objective findings from our study are satisfactory and comparable with the results of other studies of knee dislocations. Our findings suggest that with a mean follow-up of 54 months, acute combined repair and reconstruction with LARS ligaments is a valid alternative for treating knee dislocations.

Objective grading of the pivot shift phenomenon using a support vector machine approach.

The pivot shift test is the only clinical test that has been shown to correlate with subjective criteria of knee joint function following rupture of the anterior cruciate ligament. The grade of the pivot shift is important in predicting short- and long-term outcome. However, because this grade is established by a clinician in a subjective manner, the pivot shift's value as a clinical tool is reduced. The purpose of this study was to develop a system that will objectively grade the pivot shift test based on recorded knee joint kinematics. Fifty-six subjects with different degrees of knee joint stability had the pivot shift test performed by one of eight different orthopaedic surgeons while their knee joint kinematics were recorded. A support vector machine based algorithm was used to objectively classify these recordings according to a clinical grade. The grades established by the surgeons were used as the gold standard for the development of the classifier. There was substantial agreement between our classifier and the surgeons in establishing the grade (weighted kappa=0.68). Seventy-one of 107 recordings (66%) were given the same grade and 96% of the time our classifier was within one grade of that given by the surgeons. Moreover, grades 0 and 1 were distinguished from grade 2 to 3 with 86% sensitivity and 90% specificity. Our results show the feasibility of automatically grading the pivot shift in a manner similar to that of an experienced clinician, based on knee joint kinematics.

Accounting for velocity of the pivot shift test manoeuvre decreases kinematic variability.

The pivot shift test is the only clinical test which correlates with knee function following rupture of the ACL. A grade is given to the pivot shift in a subjective manner, leading to efforts to quantify the bone movements and correlate them to the grade. However, the dynamic and unconstrained nature of the manoeuvre introduces important kinematic variability. Our main objective was to develop a method to lessen the variability attributable to clinician technique, therefore increasing inter-grade differences. Three different orthopaedic surgeons each performed the pivot shift test on 12 subjects. Knee joint kinematics were recorded using electromagnetic motion capture devices. Inter-clinician variability was quantified and a method was developed to diminish it, using the angular velocity of flexion. This method was then applied to a larger population composed of 127 knees with various degrees of instability, evaluated by one of eight different orthopaedic surgeons. The clinical grades given by the clinicians were in almost perfect agreement (kappa=0.83). Normalization of kinematic parameters using the angular velocity of knee joint flexion produced by the clinicians reduced the intra-clinician variability by 20%, resulting in an intra-class correlation coefficient (ICC) of 0.52, up from 0.41 before normalization. This allowed for more significant differences between the grades of pivot shift. Simple normalisation of pivot shift kinematics using the angular velocity of flexion reduces clinician-related variability and allows for significant differences between the different grades. These results are an important step towards developing an objective measurement tool for the pivot shift phenomenon.

Gait adaptation in chronic anterior cruciate ligament-deficient patients: Pivot-shift avoidance gait.

BACKGROUND: A variety of biomechanical adaptations of the knee during gait have been reported in ACL-deficient patients to cope with anteroposterior knee instability. However, strategies to prevent rotatory knee instability are less recognized. We hypothesized that ACL-deficient patients would make distinctive gait changes to prevent anterolateral rotatory knee instability. Specifically, we hypothesized that during the terminal stance phase of the gait cycle, ACL-deficient patients would reduce the internal rotation knee joint moment and exhibit a higher knee flexion angle. We call this altered gait a pivot-shift avoidance gait. We also hypothesized that patients would not be able to adapt their knee biomechanics as efficiently at a fast gait speed. METHODS: Twenty-nine patients with chronic ACL deficiency and 15 healthy volunteers took part in a treadmill gait analysis. The terminal stance phase was analyzed under both comfortable and fast gait speed conditions. FINDINGS: At both gait speeds, ACL-deficient patients significantly reduced the internal rotation knee joint moment and showed larger knee flexion angles during the terminal stance phase of the gait cycle than did the control group. However, the difference in the minimum knee flexion angle between groups under the fast gait speed condition was not statistically significant. INTERPRETATION: ACL-deficient patients adopted the proposed pivot-shift avoidance gait, possibly to prevent anterolateral rotatory knee instability. The patients were not able to adapt their knee biomechanics as effectively during fast-paced walking. This study reinforces the pertinence of gait analysis in ACL-deficient knees to acquire more information about the function of the knee joint.

Feature selection using a principal component analysis of the kinematics of the pivot shift phenomenon.

The pivot shift test reproduces a complex instability of the knee joint following rupture of the anterior cruciate ligament. The grade of the pivot shift test has been shown to correlate to subjective criteria of knee joint function, return to physical activity and long-term outcome. This severity is represented by a grade that is attributed by a clinician in a subjective manner, rendering the pivot shift test poorly reliable. The purpose of this study was to unveil the kinematic parameters that are evaluated by clinicians when they establish a pivot shift grade. To do so, eight orthopaedic surgeons performed a total of 127 pivot shift examinations on 70 subjects presenting various degrees of knee joint instability. The knee joint kinematics were recorded using electromagnetic sensors and principal component analysis was used to determine which features explain most of the variability between recordings. Four principal components were found to account for most of this variability (69%), with only the first showing a correlation to the pivot shift grade (r = 0.55). Acceleration and velocity of tibial translation were found to be the features that best correlate to the first principal component, meaning they are the most useful for distinguishing different recordings. The magnitudes of the tibial translation and rotation were amongst those that accounted for the least variability. These results indicate that future efforts to quantify the pivot shift should focus more on the velocity and acceleration of tibial translation and less on the traditionally accepted parameters that are the magnitudes of posterior translation and external tibial rotation.

4-Hydroxynonenal induces apoptosis in human osteoarthritic chondrocytes: the protective role of glutathione-S-transferase.

INTRODUCTION: 4-Hydroxynonenal (HNE) is one of the most abundant and reactive aldehydes of lipid peroxidation products and exerts various effects on intracellular and extracellular signalling cascades. We have previously shown that HNE at low concentrations could be considered as an important mediator of catabolic and inflammatory processes in osteoarthritis (OA). In the present study, we focused on characterizing the signalling cascade induced by high HNE concentration involved in cell death in human OA chondrocytes. METHODS: Markers of apoptosis were quantified with commercial kits. Protein levels were evaluated by Western blotting. Glutathione (GSH) and ATP levels were measured with commercial kits. Glucose uptake was assessed by 2-deoxy-D-[3H]-glucose. The role of GSH-S-transferase A4-4 (GSTA4-4) in controlling HNE-induced chondrocyte apoptosis was investigated by chondrocyte transfection with small interfering RNA (siRNA) or with the expression vector of GSTA4-4. RESULTS: Our data showed that HNE at concentrations of up to 10 microM did not alter cell viability but was cytotoxic at concentrations of greater than or equal to 20 microM. HNE-induced chondrocyte death exhibited several classical hallmarks of apoptosis, including caspase activation, cytochrome c and apoptosis-induced factor release from mitochondria, poly (ADP-ribose) polymerase cleavage, Bcl-2 downregulation, Bax upregulation, and DNA fragmentation. Our study of signalling pathways revealed that HNE suppressed pro-survival Akt kinase activity but, in contrast, induced Fas/CD95 and p53 expression in chondrocytes. All of these effects were inhibited by an antioxidant, N-acetyl-cysteine. Analysis of cellular energy and redox status showed that HNE induced ATP, NADPH, and GSH depletion and inhibited glucose uptake and citric acid cycle activity. GSTA4-4 ablation by the siRNA method augmented HNE cytotoxicity, but, conversely, its overexpression efficiently protected chondrocytes from HNE-induced cell death. CONCLUSION: Our study provides novel insights into the potential mechanisms of cell death in OA cartilage and suggests the potential role of HNE in OA pathophysiology. GSTA4-4 expression is critically important for cellular defence against oxidative stress-induced cell death in OA cartilage, possibly by HNE elimination.

Production of lipid peroxidation products in osteoarthritic tissues: new evidence linking 4-hydroxynonenal to cartilage degradation.

OBJECTIVE: The lipid peroxidation product 4-hydroxynonenal (HNE) is prominently produced in osteoarthritic (OA) synovial cells, but its specific contribution to cartilage destruction is not understood. This study was designed to test whether HNE signaling and binding are involved in OA cartilage degradation through type II collagen (CII) and matrix metalloproteinase 13 (MMP-13) modulation. METHODS: HNE levels in synovial fluid and in isolated OA chondrocytes treated with free radical donors were determined by enzyme-linked immunosorbent assay. The formation of the HNE/CII adducts was measured in cartilage explants by immunoprecipitation. Levels of CII and MMP-13 messenger RNA and protein were determined by reverse transcription-polymerase chain reaction, Western blotting, and by the use of commercial kits. RESULTS: Levels of HNE/protein adducts were higher in OA synovial fluid compared with normal synovial fluid and were higher in OA chondrocytes treated with free radical donors compared with untreated cells. In cartilage explants, HNE induced CII cleavage, as established by the generation of neoepitopes. The level of HNE/CII adducts was increased in OA cartilage explants incubated with free radical donors. Modification of CII by HNE accelerated its degradation by active MMP-13. In isolated OA chondrocytes, HNE inhibited the expression of CII and tissue inhibitor of metalloproteinases 1 and induced MMP-13 mainly through activation of p38 MAPK. In vitro, HNE binding to MMP-13 activated this enzyme at a molar ratio of 1:100 (MMP-13 to HNE). CONCLUSION: The increased level of HNE in OA cartilage and the ability of HNE to induce transcriptional and posttranslational modifications of CII and MMP-13 suggest that this aldehyde could play a role in OA.

Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes.

OBJECTIVE: Elevated production of prostaglandin E2 (PGE2) plays an important role in the pathogenesis of arthritis. Recently, an inducible microsomal prostaglandin E synthase-1 (mPGES-1) was identified. This enzyme is functionally coupled with cyclooxygenase-2 (COX-2) and converts the COX product PGH2 to PGE2. We analyzed expression of mPGES-1 in human normal and osteoarthritic (OA) cartilage and determined the effect of different inflammatory agonists on the expression of mPGES-1 in OA chondrocytes. METHODS: Expression of mPGES-1 mRNA and protein in cartilage was determined by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. OA chondrocytes were treated with different inflammatory agents, and mPGES-1 protein expression was evaluated by Western blot. Activation of the mPGES-1 promoter was assessed in transient transfection experiments. RESULTS: Levels of mPGES-1 mRNA and protein were markedly elevated in OA versus normal cartilage. Treatment of chondrocytes with interleukin 1beta (IL-1beta) induced expression of mPGES-1 protein in a dose- and time-dependent manner. This appears to occur at the transcriptional level, as IL-1beta induced expression of mPGES-1 mRNA and the activity of this gene promoter. Tumor necrosis factor-alpha (TNF-alpha) and IL-17 also upregulated expression of mPGES-1 protein and displayed a synergistic effect with IL-1beta. Peroxisome proliferator-activated receptor-gamma ligands, 15-deoxy-delta(12,14)-prostaglandin J2 and troglitazone, inhibited IL-1beta-induced mPGES-1 protein expression, an effect that was reversed by exogenous PGE2. CONCLUSION: Our study shows that mPGES-1 expression is upregulated in OA versus normal cartilage and that proinflammatory cytokines increased mPGES-1 expression in chondrocytes. These data suggest that mPGES-1 may prove to be an interesting therapeutic target for controlling PGE2 synthesis.

Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis.

OBJECTIVE: To study the mechanisms responsible for the cross-talk between lipoxygenase (LOX) and cyclooxygenase (COX) pathways in human osteoarthritic (OA) synovial explants, and to confirm the arachidonic acid (AA) shunting phenomenon and its influence on interleukin 1beta (IL-1beta) synthesis. METHODS: Synovial membrane explants were cultured in the absence or presence of different drugs that inhibit COX and/or LOX activities. Concentrations of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), lipoxin A4 (LXA4), and IL-1beta were measured. RESULTS: When membrane explants were incubated with naproxen (COX inhibitor) under unstimulated conditions, the production of LTB4 was dose-dependently enhanced, reaching a 5-fold increase over the control. This shunt could be partially reversed by the addition of exogenous PGE2. Under lipopolysaccharide (LPS) stimulation, both licofelone (COX/LOX inhibitor) at therapeutic concentrations and NDGA (LOX inhibitor) inhibited LTB4 production, whereas naproxen did not amplify the LPS-induced LTB4 production. Conversely, using NDGA, it was found that a shunt of AA from the LOX to the COX pathway did not occur. Under LPS conditions, both naproxen and licofelone inhibited LXA4, inducing an increase in the LTB4/LXA4 ratio with naproxen treatment but not with licofelone. Under these conditions, naproxen treatment induced a higher level of IL-1beta production. CONCLUSION: We demonstrated in OA synovium that a shunt from AA to the LOX pathway occurred and that treatment with a nonselective COX inhibitor could increase the production of LTB4 and secondarily the synthesis of IL-1beta. Therefore treatment with licofelone, which can act on both COX and LOX pathways, may have some interesting properties in the treatment of OA.

Inhibition of interleukin-1beta-induced cyclooxygenase 2 expression in human synovial fibroblasts by 15-deoxy-Delta12,14-prostaglandin J2 through a histone deacetylase-independent mechanism.

OBJECTIVE: The cyclooxygenase (COX) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), has been reported to inhibit the expression of a number of genes involved in the pathogenesis of arthritis. However, its effects on COX-2 remain controversial. We undertook this study to investigate the effects of 15d-PGJ(2) on interleukin-1beta (IL-1beta)-induced COX-2 expression in human synovial fibroblasts (HSFs). METHODS: HSFs were cultured with IL-1beta in the absence or presence of 15d-PGJ(2), and the levels of COX-2 protein and messenger RNA (mRNA) expression were evaluated using Western blotting and real-time reverse transcriptase-polymerase chain reaction, respectively. COX-2 promoter activity was analyzed in transient transfection experiments. Chromatin immunoprecipitation assays were performed to evaluate the level of histone acetylation and the recruitment of histone deacetylases (HDACs) 1, 2, and 3 and histone acetylase (HAT) p300 to the COX-2 promoter. RESULTS: IL-1beta-induced COX-2 protein and mRNA expression, as well as COX-2 promoter activation, were inhibited by 15d-PGJ(2). Troglitazone, a selective peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, enhanced COX-2 expression, while GW9662, a specific PPARgamma antagonist, relieved the suppressive effect of 15d-PGJ(2). IL-1beta-induced histone H3 acetylation was selectively blocked by 15d-PGJ(2). The reduction of histone H3 acetylation did not correlate with the recruitment of HDACs to the COX-2 promoter. Also, treatment with the specific HDAC inhibitor, trichostatin A, did not relieve the suppressive effect of 15d-PGJ(2), indicating that HDACs are not involved in the inhibitory effect of 15d-PGJ(2). Furthermore, 15d-PGJ(2) blocked IL-1beta-induced recruitment of p300 to the COX-2 promoter, which may be the mechanism for decreased histone H3 acetylation and COX-2 expression. In accordance with this, overexpression of p300, but not of a mutant p300 lacking HAT activity, relieved the inhibitory effect of 15d-PGJ(2) on COX-2 promoter activation. CONCLUSION: These data suggest that 15d-PGJ(2) can inhibit IL-1beta-induced COX-2 expression by an HDAC-independent mechanism, probably by interfering with HAT p300.