Sideline Management of Joint Dislocations.

Athletes can sustain a large variety of injuries from simple soft tissue sprains to complex fractures and joint dislocations. This article reviews and provides the most recent information for sports medicine professionals on the management of simple and complex joint dislocations, i.e., irreducible and/or associated with a fracture, from the sidelines without the benefit of imaging. For each joint, the relevant anatomy, common mechanisms, sideline assessment, reduction techniques, initial treatment, and potential complications will be discussed, which allow for the safe and prompt return of athletes to the field of play.

SU-E-T-640: Development of Liver SBRT Planning and Delivery at the Mean Respiratory Position Using Deformable Image Registration.

PURPOSE: Deformable image registration (DIR) allows modeling of liver tumors on respiratory correlated (4D) imaging. The mid-position CT was reconstructed for liver SBRT plans using DIR, and the potential for dose-escalation was investigated. METHODS: Thirty patients were planned clinically with IMRT for 27-48 Gy in 6 fractions on static exhale 4DCT with PTVs encompassing the breathing amplitude. For research, exhale 4DCT was deformed to the inhale 4DCT using biomechanical DIR. The mid-position CT was created by applying a percentage (the time-averaged normalized position between exhale and inhale calculated from daily 4D cone-beam CT) to this deformation map, assuming a linear trajectory. A probability-based PTV margin, using patient-specific breathing amplitude from DIR of 4DCT, was created around the GTV on the mid-position CT where IMRT was re-optimized. Dose was maximally escalated according to clinical protocol (e.g. liver NTCP <5%). The 4D predicted breathing dose was accumulated by interpolating the elements' positions at exhale, mid-position and inhale onto the respective dose matrices (weighted by time spent nearest each matrix) then summed. RESULTS: Compared the exhale plans, the GTV-to-PTV volume decreased on the mid-position plans by a mean of 31% (p<0.01, range: 24-38%). Static re-planning on the mid-position CT decreased the mean effective liver volume by 7% (p=0.032), enabling escalation of the nominal prescribed dose in 80% of patients of 6-12 Gy. Reconstruction of the 4D predicted breathing dose resulted in a mean increase of 6.7 Gy (p<0.01, maximum increase of 15.0 Gy) in mean GTV dose for the mid-position versus the exhale plan. For the mid-position plan, the minimum 0.5 cm3 GTV dose received 100% of the prescription in the 4D distribution. CONCLUSIONS: Liver SBRT Planning at the mean respiratory position enables PTV reduction and a mean dose escalation of 6.7 Gy, potentially improving local control. Dr. Brock has financial interest in deformable registration technology through the licensing of Morfeus to RaySearch Laboratories. Research is funded by NIH 1R01CA124714.

Long-term durability of autologous chondrocyte implantation: a multicenter, observational study in US patients.

BACKGROUND: Autologous chondrocyte implantation for full-thickness lesions of the distal femur has demonstrated good short- to midterm clinical improvement. However, long-term durability (>5 years) of autologous chondrocyte implantation has not been evaluated in US patients to date. HYPOTHESIS: Patients who improve from baseline to early follow-up will sustain improvement at later follow-up. STUDY DESIGN: Case series, Level of evidence, 4. METHODS: Cartilage Repair Registry patients with full-thickness distal femur lesions who were treated with autologous chondrocyte implantation before December 31, 1996 and had modified overall Cincinnati scores at baseline and 1- to 5-year follow-up scores were re-evaluated at 6- to 10-year follow-up. Autologous chondrocyte implantation durability was determined by comparing early (1-5 years) to long-term (6-10 years) outcomes. Adverse events and treatment failures were recorded. Results Seventy-two patients met eligibility criteria (at baseline: mean age, 37 years; mean lesion size, 5.2 cm(2); and overall condition score, 3.4 points [poor]). Eighty-seven percent of patients (47 of 54) who improved at the earlier follow-up period sustained a mean improvement in overall condition score of 3.8 points from baseline to the later follow-up period (P < .001). From baseline to 10-year follow-up (mean follow-up, 9.2 years), 69% improved, 17% failed, and 12.5% reported no change from baseline. Most failures (75% [9 of 12]) occurred at a mean follow-up of 2.5 years. Thirty patients (42%) had 42 operations after autologous chondrocyte implantation; 24 operations (57%) occurred in patients who met the study definition of failure. CONCLUSION: Treatment with autologous chondrocyte implantation for large, symptomatic, full-thickness lesions of the distal femur can result in early improvement that is sustained at longer follow-up (up to 10 years) in the majority of patients.

Sliding characteristic and material compressibility of human lung: parametric study and verification.

PURPOSE: To find and verify the optimum sliding characteristics and material compressibility that provide the minimum error in deformable image registration of the lungs. METHODS: A deformable image registration study has been conducted on a total of 16 lung cancer patients. Patient specific three dimensional finite element models have been developed to model left and right lungs, chest (body), and tumor based on 4D CT images. Contact surfaces have been applied to lung-chest cavity interfaces. Experimental test data are used to model nonlinear material properties of lungs. A parametric study is carried out on seven patients, 20 conditions for each, to investigate the sliding behavior and the tissue compressibility of lungs. Three values of coefficient of friction of 0, 0.1, and 0.2 are investigated to model lubrication and sliding restriction on the lung-chest cavity interface. The effect of material compressibility of lungs is studied using Poisson's ratios of 0.35, 0.4, 0.45, and 0.499. The model accuracy is examined by calculating the difference between the image-based displacement of bronchial bifurcation points identified in the lung images and the calculated corresponding model-based displacement. Furthermore, additional bifurcation points around the tumor and its center of mass are used to examine the effect of the mentioned parameters on the tumor localization. RESULTS: The frictionless contact model with 0.4 Poisson's ratio provides the smallest residual errors of 1.1 +/- 0.9, 1.5 +/- 1.3, and 2.1 +/- 1.6 mm in the LR, AP, and SI directions, respectively. Similarly, this optimum model provides the most accurate location of the tumor with residual errors of 1.0 +/- 0.6, 0.9 +/- 0.7, and 1.4 +/- 1.0 mm in all three directions. The accuracy of this model is verified on an additional nine patients with average errors of 0.8 +/- 0.7, 1.3 +/- 1.1, and 1.7 +/- 1.6 mm in the LR, AP, and SI directions, respectively. CONCLUSIONS: The optimum biomechanical model with the smallest registration error is when frictionless contact model and 0.4 Poisson's ratio are applied. The overall accuracies of all bifurcation points in all 16 patients including tumor points are 1.0 +/- 0.7, 1.2 +/- 1.0, and 1.7 +/- 1.4 mm in the LR, AP, and SI directions, respectively.

Adapting liver motion models using a navigator channel technique.

Deformable registration can improve the accuracy of tumor targeting; however for online applications, efficiency as well as accuracy is important. A navigator channel technique has been developed to combine a biomechanical model-based deformable registration algorithm with a population motion model and patient specific motion information to perform fast deformable registration for application in image-guided radiation therapy. A respiratory population-based liver motion model was generated from breath-hold CT data sets of ten patients using a finite element model as a framework. The population model provides a biomechanical reference template of the average liver motions, which were found to be (absolute mean +/-SD) 0.12 +/- 0.10, 0.84 +/- 0.13, and 1.24 +/- 0.18 cm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. The population motion model was then adapted to the specific liver motion of 13 patients based on their exhale and inhale CT images. The patient motion was calculated using a navigator channel (a narrow region of interest window) on liver boundaries in the images. The absolute average accuracy of the navigator channel to predict the 1D SI and AP motions of the liver was less than 0.11, which is less than the out-of-plane image voxel size, 0.25 cm. This 1D information was then used to adapt the 4D population motion model in the SI and AP directions to predict the patient specific liver motion. The absolute average residual error of the navigator channel technique to adapt the population motion to the patients' specific motion was verified using three verification methods: (1) vessel bifurcation, (2) tumor center of mass, and (3) MORFEUS deformable algorithm. All three verification methods showed statistically similar results where the technique's accuracy was approximately on the order of the voxel image sizes. This method has potential applications in online assessment of motion at the time of treatment to improve image-guided radiotherapy and monitoring of intrafraction motion.

Contact surface and material nonlinearity modeling of human lungs.

A finite element model has been developed to investigate the effect of contact surfaces and hyperelastic material properties on the mechanical behavior of human lungs of one lung cancer patient. The three-dimensional model consists of four parts, namely the left lung, right lung, tumor in the left lung and chest wall. The interaction between the lungs and chest wall was modeled using frictionless surface-based contact. Hyperelastic material properties of the lungs are used in the model. The effect of the two parameters is investigated by tracking the tumor movement, and by comparing the analytical results to the patient bifurcation points: 45 points in each lung and 18 points around the tumor. The accuracy of the model is improved by including the contact surface and hyperelastic material properties. The average error and the standard deviation (SD) in modeling the displacement in the SI direction are reduced from 0.68 (SD = 0.34) cm in the elastic model to 0.09 (0.21) cm in the contact-hyperelastic model. Similarly, the average error (SD) of tumor location decreases from 0.71 (0.21) cm in the elastic material without contact to -0.03 (0.24) cm in the hyperelastic material with contact model.

Treatment outcomes of autologous chondrocyte implantation for full-thickness articular cartilage defects of the trochlea.

BACKGROUND: The treatment of trochlear cartilage lesions is challenging given the likely presence of other patellofemoral joint pathologies, the topography of the area, and the limited available treatment options. Only 1 other study has examined the effectiveness of autologous chondrocyte implantation for lesions of the patellofemoral joint. HYPOTHESIS: Patients treated with autologous chondrocyte implantation for moderate to large isolated lesions located on the trochlea will report improvement in the modified overall condition scale score of the Cincinnati Knee Rating System at a minimum 2-year follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Using modified scales of the Cincinnati Knee Rating System, 40 Cartilage Repair Registry patients rated their overall condition and symptoms at baseline and at a mean follow-up of 59 +/- 18 months. Factors likely to affect outcomes also were analyzed. RESULTS: At baseline, patients were between ages 16 to 48 years, had a mean total defect size of 4.5 cm(2), and reported an overall condition score of 3.1 points (poor). Many failed a prior marrow-stimulation procedure (48%). Other procedures performed before baseline included tibiofemoral osteotomy in 23% and lateral release or Fulkerson for patella maltracking in 13%. Forty-three percent were receiving workers' compensation at baseline. Patients reported statistically significant improvement in their mean overall condition (3.1 points preoperatively to 6.4 points postoperatively), pain (2.6 to 6.2 points), and swelling (3.9 to 6.3 points) scores. Eleven patients experienced 17 subsequent procedures, and no patients had a failed implantation. CONCLUSION: Autologous chondrocyte implantation appears to improve function and reduce symptoms in young to middle-aged patients with symptomatic, full-thickness articular cartilage lesions of the trochlea.

Articular cartilage defects of the distal femur in children and adolescents: treatment with autologous chondrocyte implantation.

PURPOSE: Procedures aimed at biologically repairing cartilage injuries may have the greatest potential benefit in young patients because of their long-life expectancy and high-functional demands. Most cartilage-repair studies focus on older patient populations. This study assesses the outcomes of patients who were treated with autologous chondrocyte implantation before the age of 18. STUDY DESIGN: This is a Registry-based, multicenter, observational, cohort study of 37 patients from whom follow-up data was prospectively collected. Patient-rated assessments of overall condition, pain, and swelling were measured using modified, 10-point scales of the Cincinnati Knee Rating System. RESULTS: Mean age was 16 years (11-17); 22 boys and 15 girls. Twenty-three patients underwent at least 1 cartilage repair procedure before the cartilage harvest, including 11 who had a marrow stimulation procedure. Fourteen patients were diagnosed with osteochondritis dessicans lesions. Thirty-five patients had single defects (mean size, 5.4 cm). Thirty-two patients completed self-evaluations at a minimum of 2 years after implantation (mean follow-up = 4.3 years). The mean change in scale scores measuring overall condition, pain, and swelling were 3.8, 4.1, and 3.4 points, respectively. One patient had an implantation that failed. CONCLUSIONS: Results highlight significant clinical improvements from baseline to follow-up for 32 patients who submitted follow-up data, including 28 patients who reported a minimum 1-point improvement in the overall condition score. CLINICAL RELEVANCE: These results suggest that autologous chondrocyte implantation may be an effective option for children and adolescents with large symptomatic chondral lesions of the distal femur.

Injury risk in professional basketball players: a comparison of Women's National Basketball Association and National Basketball Association athletes.

BACKGROUND: Gender-based differences in injury rates have been reported in scholastic and collegiate basketball. The purpose of this study was to retrospectively compare injury rates in women's and men's professional basketball. HYPOTHESIS: Female professional basketball players are injured at a higher rate than are men. STUDY DESIGN: Cohort study (prevalence); Level of evidence, 2. METHODS: Women's National Basketball Association and National Basketball Association injury data were retrospectively reviewed for 6 full seasons. The frequency of all injuries and the rate of game-related injuries were calculated. RESULTS: Complete player profiles were obtained on 702 National Basketball Association athletes and 443 Women's National Basketball Association athletes who competed in their respective leagues during the data collection period. Total game exposures totaled 70,420 (National Basketball Association) and 22,980 (Women's National Basketball Association). Women's National Basketball Association athletes had a higher overall game-related injury rate (24.9 per 1000 athlete exposures; 95% confidence interval, 22.9-26.9; P < .05) when compared with National Basketball Association athletes (19.3 per 1000 athlete exposures; 95% confidence interval, 18.3-20.4) and sustained a higher rate of lower extremity injuries (14.6 per 1000 athlete exposures; 95% confidence interval, 13.1-16.2; P < .05) than seen in the National Basketball Association (11.6 per 1000 athlete exposures; 95% confidence interval, 10.8-12.4). The lower extremity was the most commonly injured body area (65%), and lateral ankle sprain (13.7%) was the most common diagnosis in both leagues. The incidence of game-related knee injury was higher in Women's National Basketball Association players. The incidence of anterior cruciate ligament injury in the National Basketball Association (n = 22, 0.8%) and Women's National Basketball Association (n = 14, 0.9%) accounted for 0.8% of the 4446 injuries reported. CONCLUSION: The lower extremity is the most frequently injured body area in both leagues, and Women's National Basketball Association athletes are more susceptible than are National Basketball Association athletes. There were, however, few statistical differences in the actual injuries occurring between the 2 leagues.

Autologous chondrocyte implantation versus debridement for treatment of full-thickness chondral defects of the knee: an observational cohort study with 3-year follow-up.

BACKGROUND: Studies that compare the effectiveness of different cartilage repair treatments are needed to update treatment algorithms. HYPOTHESIS: Autologous chondrocyte implantation provides greater improvement in overall condition score than does debridement at a minimum of 3 years' follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Cohorts for debridement and autologous chondrocyte implantation each included 58 Cartilage Repair Registry patients who met study criteria. A retrospective analysis was performed on prospectively collected baseline and follow-up data. RESULTS: Patients in the autologous chondrocyte implantation and debridement groups had similar demographics and chondral lesions at baseline. However, more autologous chondrocyte implantation patients failed a previous debridement or marrow stimulation procedure than did debridement patients. Follow-up outcome assessments were completed by 54 autologous chondrocyte implantation patients and 42 debridement patients. Eighty-one percent of the autologous chondrocyte implantation patients and 60% of the debridement patients reported median improvements of 5 points and 2 points, respectively, in the overall condition score. Autologous chondrocyte implantation patients also reported greater improvements in the median pain and swelling scores than did debridement patients. The treatment failure rate was the same for both autologous chondrocyte implantation and debridement patients. Eighteen autologous chondrocyte implantation patients and 1 debridement patient had at least 1 subsequent operation. CONCLUSION: Although patients treated with debridement for symptomatic, large, focal, chondral defects of the distal femur had some functional improvement at follow-up, patients who received autologous chondrocyte implantations obtained higher levels of knee function and had greater relief from pain and swelling at 3 years.

Clinical outcome of autologous chondrocyte implantation at 5 years in US subjects.

UNLABELLED: Peterson's pioneering experience with the first clinical application of autologous chondrocyte implantation showed improvement in clinical outcomes, durable as much as 11 years, for a difficult patient population. An assessment of the general applicability of this technology in the United States requires long-term, multicenter followup. The purpose of this multicenter cohort study was to assess the clinical outcomes of patients treated with autologous chondrocyte implantation for lesions of the distal femur. Modified 10-point scales of the Cincinnati knee rating system were used to measure outcomes assessments at baseline and at 5 years. Eighty-seven percent (87 of 100) of patients completed 5-year followup assessments. Patients were an average 37 years of age, had a mean total defect size of 4.9 cm2, and had low baseline overall condition scores. At least one prior cartilage repair procedure had failed in 70% of the patients. At followup, 87 patients reported a mean improvement of 2.6 points in the overall condition score, including 62 with improved conditions, six with no change in condition, and 19 with worsened conditions. Of the 62 patients who improved, the mean overall condition score improved 4.1 points at followup. Patients treated with autologous chondrocyte implantation for large cartilage defects in the distal femur reported improvement in outcome scores at 5 years followup. LEVEL OF EVIDENCE: Therapeutic study, Level II-1 (prospective cohort study). See the Guidelines for Authors for a complete description of levels of evidence.

Effect of nuclear factor-kappa B inhibitors and peroxisome proliferator-activated receptor-gamma ligands on PTHrP release from human fetal membranes.

Parathyroid hormone-related protein (PTHrP) has been implicated in many processes during normal and pathological pregnancies. In the human fetal membranes, PTHrP exhibits cytokine-like actions. We have recently shown that inhibitors of the nuclear factor-kappa B (NF-kappaB) and activators of the peroxisome proliferator-activated receptor (PPAR)-gamma signalling pathways down-regulate cytokine release from human gestational tissues. Therefore, the aim of this study was to determine whether NF-kappaB and PPAR-gamma also regulate PTHrP release from human fetal membranes. Human amnion and choriodecidua explants were incubated in the absence (control) or presence of two known NF-kappaB inhibitors (1, 5 and 10 mM sulphasalazine (SASP) or 5, 10 and 15 mM N-acetyl-cysteine (NAC)), and two PPAR-gamma ligands (15 and 30 microM 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) or 15 and 30 microM troglitazone), under basal conditions. After 18 h incubation, the tissues were collected and NF-kappaB p65 DNA binding activity in nuclear extracts was assessed by ELISA, and the incubation medium was collected and the release of PTHrP was quantified by RIA. Treatment of amnion and choriodecidual tissues with SASP concentrations greater than 5 mM, 15 mM NAC, 30 microM 15d-PGJ(2) and 30 microM troglitazone significantly reduced the release of PTHrP (p < 0.05). This study demonstrates that PTHrP release from human fetal membranes is regulated by inhibitors of NF-kappaB, and ligands of PPAR-gamma.

PTH/PTHrP receptor and mid-molecule PTHrP regulation of intrauterine PTHrP: PTH/PTHrP receptor antagonism increases SHR fetal weight.

Parathyroid hormone-related protein (PTHrP) has important roles in fetal growth and development through stimulation of placental calcium transport, vasodilatation of the uteroplacental vasculature and regulation of cellular growth and differentiation. The growth restricted spontaneously hypertensive rat (SHR) has reduced fetal plasma, placental and amniotic fluid PTHrP concentrations compared to its progenitor, the Wistar Kyoto (WKY) rat. The aim of this study was to determine whether intrauterine PTHrP infusions can restore PTHrP levels and promote SHR fetal growth. PTHrP(1-34), midmolecule PTHrP(67-94), the PTH/PTHrP receptor antagonist [Asn(10), Leu(11)]-PTHrP(7-34) or vehicle were infused via a mini-osmotic pump between 10 and 20 days of gestation into the uterine lumen of SHR and WKY rats. Uterine, placental, amniotic fluid and plasma (fetal and maternal) PTHrP were measured via N-terminal radioimmunoassay. PTH/PTHrP receptor antagonism and mid-molecule PTHrP(67-94) induced endogenous intrauterine PTHrP production with receptor antagonism eliciting a greater and more wide spread effect. The PTH/PTHrP receptor antagonist [Asn(10), Leu(11)]-PTHrP(7-34) acting through a receptor other than the PTH/PTHrP receptor increased SHR fetal and placental weights above vehicle (P<0.05) to that of the WKY and restored SHR amniotic fluid volume (P<0.05). This was associated with a highly significant up regulation of placental, uterine and plasma (fetal and maternal) PTHrP (P<0.05). Modest increases in placental and uterine PTHrP (P<0.05) following intrauterine infusions of PTHrP(1-34) and PTHrP(67-94) had no effect on WKY and SHR fetal weight. Effective growth promoting actions of increased endogenous PTHrP were observed following PTH/PTHrP receptor antagonism rather than exogenous PTHrP administration. A novel finding was that mid-molecule PTHrP also up regulates endogenous intrauterine N-terminal PTHrP production supporting the existence of a mid-molecule receptor. This study highlights that an increase in endogenous uterine, placental and fetal plasma PTHrP following PTH/PTHrP receptor antagonism was associated with increased SHR fetal growth presumably by improving placental growth and function.

Impaired mammary function and parathyroid hormone-related protein during lactation in growth-restricted spontaneously hypertensive rats.

Evidence implicates pivotal roles for parathyroid hormone-related protein (PTHrP) during lactation, including stimulation of mammary and pup growth. As spontaneously hypertensive rat (SHR) pups are growth restricted compared with the control Wistar Kyoto (WKY), we examined the relative roles of pup suckling and maternal lactational environment on pup growth, mammary PTHrP, and milk PTHrP and calcium concentrations. SHR pups were lighter compared with the control from 6 days. SHR mammary PTHrP content and milk PTHrP were lower but maternal plasma PTHrP was raised compared with WKY. SHR mammary morphological development was also impaired compared with control. Cross fostering growth-restricted pups onto WKY mothers increased pup weight in association with normal mammary function and higher milk PTHrP and calcium. Control pups suckling on an SHR mother had reduced body weight. Both cross fostering groups were associated with increased maternal and milk PTHrP concentrations, indicating the importance of suckling, together with a functional mammary gland. The results suggested that impaired SHR mammary function and milk PTHrP are associated with a reduced SHR postnatal growth. Our data also indicated that milk and mammary PTHrP are regulated by different mechanisms but that they are influenced by the maternal lactational environment and the suckling pup.

Joint-specific multidimensional assessment of pain (J-MAP): factor structure, reliability, validity, and responsiveness in patients with knee osteoarthritis.

OBJECTIVE: To develop a reliable and valid instrument for measuring and monitoring joint-specific pain. METHODS: Developed using patient interviews, reviews of pain literature, and expert input from orthopedic surgeons, the final Joint-Specific Multidimensional Assessment of Pain (J-MAP) includes the 6-item Pain Sensory and the 4-item Pain Affect subscales. Scores on the J-MAP Pain Sensory and Affect subscales range from 0 to 100, with higher scores indicating more pain intensity and worse pain distastefulness, respectively. Following the assessment of the factor structure, patients' scores (n = 180) on the J-MAP subscales were converted to equal interval scores using Rasch analyses. A psychometric evaluation of the items and Rasch-calibrated scores was conducted and included an assessment of reliability, validity, and responsiveness for use with patients with radiographic knee osteoarthritis. RESULTS: Evidence from the factor analyses showed that the J-MAP Pain Sensory and Affect items made up 2 distinct factors. Internal consistency estimates for the J-MAP subscales exceeded 0.85. The J-MAP subscales showed evidence for validity and were shown to be internally and externally responsive, demonstrating greater responsiveness than the Arthritis Impact Measurement Scale or the Medical Outcome Study Short Form-36 pain subscales. Finally, evidence was found supporting the J-MAP subscales' ability to distinguish target joint pain from pain emanating from other musculoskeletal conditions. CONCLUSION: The J-MAP is a reliable, valid, and responsive measure for assessing joint-specific pain at a single time point, or changes over time for one or a group of patients with knee osteoarthritis. With this initial evidence of its psychometric rigor, further testing of the measurement properties of the J-MAP in other joints and in other populations should be undertaken.

Interleukin-18 is a novel mitogen of osteogenic and chondrogenic cells.

IL-18 was identified due to its ability to induce interferon-gamma (IFNgamma) production by T cells. It is a pleiotropic factor that shares structural features with IL-1 and functional activities with IL-12. IL-18 has a role in T cell development, where it has been demonstrated to act cooperatively with IL-12 to regulate IFNgamma. In bone, IL-18 is mainly produced by macrophages, but is also expressed by osteoblasts and inhibits osteoclast formation through granulocyte-macrophage colony-stimulating factor (GM-CSF) and not IFNgamma production by T cells. We have investigated the effects of IL-18 on mature osteoclast activity and for potential actions on osteoblasts or chondrocytes. The effects of IL-18 on mature osteoclast activity were determined using two assays: isolated mature osteoclast cell culture and neonatal murine calvarial organ culture. IL-18 did not affect bone resorption in either assay system. The actions of IL-18 on osteogenic cells (primary cell cultures of fetal rat and neonatal mouse osteoblasts, as well as neonatal mouse calvarial organ culture) and primary chondrocytes (canine) were assessed by proliferation assays (quantification of cell numbers and thymidine incorporation). In each assay system, IL-18 acted as a mitogen to the osteogenic and chondrogenic cells. Since IL-18 signal transduction may involve IFNgamma or GM-CSF, we assessed their involvement in the IL-18 response. IL-18 did not induce IFNgamma production by primary osteoblasts, but, of greater significance, IFNgamma had the opposing action to IL-18 in that it inhibited the primary osteoblast cell proliferation. Although IL-18 rapidly induced GM-CSF production by primary osteoblasts, IL-18 was still mitogenic in osteoblast preparations established from GM-CSF-deficient mice. Combined, these studies indicate that IL-18 may have an autocrine/paracrine mitogen role for both osteogenic and chondrogenic cells, independent of the production of IFNgamma or GM-CSF.

A controlled trial of arthroscopic surgery for osteoarthritis of the knee.

BACKGROUND: Many patients report symptomatic relief after undergoing arthroscopy of the knee for osteoarthritis, but it is unclear how the procedure achieves this result. We conducted a randomized, placebo-controlled trial to evaluate the efficacy of arthroscopy for osteoarthritis of the knee. METHODS: A total of 180 patients with osteoarthritis of the knee were randomly assigned to receive arthroscopic débridement, arthroscopic lavage, or placebo surgery. Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope. Patients and assessors of outcome were blinded to the treatment-group assignment. Outcomes were assessed at multiple points over a 24-month period with the use of five self-reported scores--three on scales for pain and two on scales for function--and one objective test of walking and stair climbing. A total of 165 patients completed the trial. RESULTS: At no point did either of the intervention groups report less pain or better function than the placebo group. For example, mean (+/-SD) scores on the Knee-Specific Pain Scale (range, 0 to 100, with higher scores indicating more severe pain) were similar in the placebo, lavage, and débridement groups: 48.9+/-21.9, 54.8+/-19.8, and 51.7+/-22.4, respectively, at one year (P=0.14 for the comparison between placebo and lavage; P=0.51 for the comparison between placebo and débridement) and 51.6+/-23.7, 53.7+/-23.7, and 51.4+/-23.2, respectively, at two years (P=0.64 and P=0.96, respectively). Furthermore, the 95 percent confidence intervals for the differences between the placebo group and the intervention groups exclude any clinically meaningful difference. CONCLUSIONS: In this controlled trial involving patients with osteoarthritis of the knee, the outcomes after arthroscopic lavage or arthroscopic débridement were no better than those after a placebo procedure.

Autologous chondrocyte implantation of the knee: multicenter experience and minimum 3-year follow-up.

OBJECTIVE: To determine clinical outcome and graft survivorship in patients undergoing autologous chondrocyte implantation (ACI) for the repair of chondral defects of the knee. DESIGN: Prospective cohort study. SETTING: 19 centers in the United States. PATIENTS: 50 patients (37 males, 13 females). Mean age was 36 years (range: 19-53). Defects were grade III or IV with a mean size of 4.2 cm 2. All patients had a minimum of 36 months postoperative follow-up. MAIN OUTCOME MEASUREMENTS: Clinician and patient evaluation based on the modified Cincinnati Knee Rating System. Graft failure was defined as replacement or removal of the graft due to mechanical symptoms or pain. RESULTS: Clinician and patient evaluation indicated median improvements of 4 and 5 points, respectively, at 36 months following ACI (p < 0.001). Previous treatment with marrow stimulation techniques and size of defect did not impact the results with ACI. The most common adverse events reported were adhesions and arthrofibrosis and hypertrophic changes. Three patients had graft failure and required reimplantation or treatment with alternative cartilage repair techniques. Kaplan-Meier estimated freedom from graft failure was 94% at 36 months postoperatively (95% CI = 88-100%). CONCLUSIONS: These results of this study indicate excellent graft survivorship using ACI as well as substantial improvement in functional outcome.

Familial intrahepatic cholestasis 1: studies of localization and function.

Mutations in the FIC1 gene constitute the molecular defect in familial intrahepatic cholestasis I (Fic1 [Byler's disease]) and benign recurrent intrahepatic cholestasis. This report describes the localization of Fic1 in rat liver and intestine, as well as biochemical and transfection studies that support its function as an energy-dependent aminophospholipid translocase. Immunocytochemistry of rat liver and immunoblotting of membrane fractions localized Fic1 to the canalicular, but not basolateral, plasma membrane domain. In the small intestine, Fic1 was localized to the apical membrane of epithelial cells. The distribution of Fic1 in liver plasma membrane fractions from control and taurocholate-treated rats correlated positively with adenosine triphosphate (ATP)-dependent aminophospholipid (phosphatidyl-serine) translocase activity. In canalicular membrane vesicles, translocase activity had an initial velocity of 3.3 nmol phosphatidylserine (PS) translocated per milligram of protein per minute and a K(m) (ATP) = 1.2 mmol/L; was inhibited by vanadate, N-ethylmaleimide, sodium azide, and calcium; and was unidirectional (i.e., from the outer to the inner canalicular plasma membrane leaflet). Transient transfection of CHOK1 cells with FIC1 cDNA resulted in appearance of FIC1 in membrane preparations and energy-dependent PS translocation in cells. These studies indicate that FIC1 is a canalicular P-type ATPase that participates in maintaining the distribution of aminophospholipids between the inner and outer leaflets of the plasma membrane. How this process produces cholestasis is under study.