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Background Central sleep apnea (CSA) due to occipitocervical compression myelopathy is an extremely rare condition. Here we report a case of surgical treatment for CSA due to occipitocervical compression myelopathy in a patient with Klippel-Feil syndrome. Case Description A 60-year-old man had become aware of a gradually progressive clumsiness and gait disturbance without any cause of injury 5 years before. He had complicated respiratory discomfort during sleep for the previous month and visited our hospital. Neurologic examination revealed severe myelopathy. Polysomnography showed CSA and Cheyne-Stokes respiration. Imaging findings showed C2-3 vertebral fusion and severe spinal cord compression caused by hypoplasia of the C1 posterior arch complicated by an anomaly of the vertebral artery. We diagnosed the patient with CSA due to occipitocervical compression myelopathy complicated by Klippel-Feil syndrome. After a simulation using a full-scale 3-dimensional model, resection of the C1 posterior arch and C4-5 laminoplasty was performed. After surgery, both clumsiness and gait disturbance gradually improved. Polysomnography 1 month after surgery showed that the CSA and the Cheyne-Stokes respiration disappeared. Conclusions Although a recent report has indicated the cause of sleep apnea in patients with rheumatoid arthritis and occipitocervical disorders as obstructive sleep apnea, a significant improvement of CSA was observed with decompression surgery in this case. Appropriate surgical planning resulted in a favorable outcome.

Atlantoaxial rotatory fixation (AARF) in an adult without any trauma is an extremely rare condition. Here we report a case of surgical treatment for existing atlantoaxial rotatory fixation in an adult with spastic torticollis. A 50-year-old man had become aware of torticollis without any cause of injury 6 weeks before he visited our hospital, where he presented with a one-week history of severe neck pain. Based on the local and imaging findings, we diagnosed him as having existing AARF of Fielding classification type I. The AARF was not reduced by 3 weeks of Glisson traction. Thus, we performed C1–C2 posterior fusion surgery 3 months after his initial visit. Although CT findings just after surgery showed that the C1-2 facet subluxation was reduced, the complaint of torticollis was not improved, with scoliosis at the middle to lower cervical level because of left sternocleidomastoid hypertonia. Administration of diazepam was initiated 2 weeks after surgery and botulinum toxin injections to the left sternocleidomastoid were added 2 months after surgery under the neurological diagnosis of spastic torticollis. As a result, the complaint of his torticollis was significantly improved 3 months after surgery. There were no relapses of the torticollis and complete fusion of the C1–C2 laminae was observed at the 2-year final follow-up. Surgical treatment for AARF in an adult should be considered if the diagnosis of AARF is delayed. In addition, appropriate treatment for spastic torticollis applied after surgery resulted in a favorable outcome of this case.

Introduction Reactive oxygen metabolites (ROMs) are metabolite hydroperoxides in the blood, and their serum levels were associated with the disease activity score 28 (DAS28) in patients with rheumatoid arthritis (RA). In this study, we aimed to investigate whether ROMs would be predictive of the clinical disease activity index (CDAI) remission, simplified disease activity index (SDAI) remission, or Boolean remission. Materials and methods Fifty-one biologic agents (BA)-naïve RA patients were included in this observational study. Associations between ROMs, C-reactive protein, matrix metalloproteinase-3, DAS28-erythrocyte sedimentation rate (ESR), CDAI, SDAI, and health assessment questionnaire (HAQ) at 12 weeks and the DAS28, CDAI, SDAI, and Boolean remission rates at 52 weeks were investigated. Results The DAS28, CDAI, SDAI, and Boolean remission rates at 52 weeks were 66.7, 52.9, 54.9, and 54.9%, respectively. A multivariate logistic regression analysis revealed that ROMs and HAQ at 12 weeks were associated with the CDAI, SDAI, and Boolean remission at 52 weeks. Receiver operating characteristic analyses demonstrated that the cut-off value for CDAI, SDAI, and Boolean remission was 389.5 U.Carr. Conclusion Reactive oxygen metabolites at 12 weeks of initial treatment with BAs was a predictor for CDAI, SDAI, and Boolean remission at 52 weeks. Serum levels of ROMs may be a useful biomarker in the current treatment strategy aiming at early remission of RA.

Objective: Atopic dermatitis (AD) is one of the known risk factors for Staphylococcus aureus infection. The authors report the case of a patient with cervical spondylosis and AD who developed delayed surgical site infection after posterior cervical instrumented surgery. Patient: A 39-year-old male presented to our hospital with paralysis of the left upper extremity without any cause or prior injury. He had a history of severe AD. We performed C3–C7 posterior decompression and instrumented fusion based on the diagnosis of cervical spondylotic amyotrophy. One year after surgery, his deltoid and bicep muscle strength were fully recovered. Nevertheless, his neck pain worsened 2 years after surgery following worsening of AD. One month after that, he developed severe myelopathy and was admitted to our hospital. Radiographic findings showed that all the screws had loosened and the retropharyngeal space had expanded. Magnetic resonance imaging and computed tomography showed severe abscess formation and destruction of the C7/T1 vertebrae. Result: We diagnosed him with delayed surgical site infection. Methicillin-resistant Staphylococcus aureus was identified on abscess culture. The patient responded adequately to treatment with antibiotic therapy and two debridements and the infection subsided. Conclusion: We should consider the possibility of delayed surgical site infection when conducting instrumented spinal surgery in patients with severe AD.

We previously showed that reactive oxygen metabolites (ROM) serum levels were associated with the DAS28 in patients with rheumatoid arthritis (RA). In this study, we aimed to investigate whether ROM would be predictive of the CDAI-, SDAI- or Boolean-remission. Fifty-one biologic agents (BA)-naïve RA patients were included in this observational study. Associations between ROM, C-reactive protein (CRP), MMP (matrix metalloproteinase)-3, DAS28-ESR, CDAI, SDAI, and health assessment questionnaire (HAQ) at 12 weeks and the DAS28-, CDAI-, SDAI-, and Boolean-remission at 52 weeks were investigated. The DAS28-, CDAI-, SDAI- and Boolean-remission rates at 52 weeks were 66.7, 52.9, 54.9 and 54.9%, respectively. A multivariate logistic regression analysis revealed that ROM and HAQ at 12 weeks were associated with the CDAI-, SDAI- and Boolean-remission at 52 weeks. Receiver operating characteristic (ROC) analyses demonstrated that the cut-off value for CDAI remission was 389.5 U.Carr, and that for SDAI and Boolean remission was 389.5 U.Carr. ROM at 12 weeks of initial treatment with BAs was a predictor for the CDAI-, SDAI-, and Boolean-remission at 52 weeks. Serum levels of ROM may be a useful biomarker in the current treatment strategy aiming at the early remission of RA.

Objective To elucidate the time course of magnetic resonance imaging (MRI)–based morphological and qualitative outcomes after an atelocollagen-assisted autologous chondrocyte implantation (ACI) and to analyze the correlation between arthroscopic and MRI-based assessment. Design We included ACI recipients from a multicenter registration study (CaTCh [Cartilage Treatment in Chiba] study). Morphological (3-dimensional magnetic resonance observation of cartilage repair tissue: 3D-MOCART, MOCART2.0) and qualitative assessment (T2- and T1rho-mapping) by MRI were conducted at 6, 12, and 24 months post-implantation. Global T2 and T1rho indices (T2 and T1rho in repair tissue divided by T2 and T1rho in normal cartilage) were calculated. Arthroscopic second-look assessment was performed in 4 and 15 knees at 12 and 24 months post-implantation, respectively. Results The 3D-MOCART over 12 months witnessed significant patient improvement, but some presented subchondral bone degeneration as early as 6 months. The MOCART2.0 improved from 57.5 to 71.3 between 6 and 24 months ( P = 0.02). The global T2 index decreased from 1.7 to 1.2 between 6 and 24 months ( P < 0.001). The global T1rho index decreased from 1.5 to 1.3 between 6 and 24 months ( P = 0.004). Normal or nearly normal ICRS-CRA (cartilage repair assessment scale developed by the International Cartilage Repair Society) grades were achieved in 86% and 93% of the lesions at 12 and 24 months, respectively. Better ICRS-CRA grade corresponded to better MOCART2.0, with no trend in the T2 and T1rho values. Conclusions Atelocollagen-assisted ACI improved the MRI-based morphological and qualitative outcomes until 24 months post-surgery, and normal or nearly normal grades were achieved in most lesions by arthroscopic assessment. MRI assessment may be an alternative to arthroscopic assessment.

Background: Several authors have reported favorable results in low back pain (LBP) for patients with lumbar disc herniation (LDH) treated with discectomy. However, detailed changes over time in the characteristics and location of LBP before and after discectomy for LDH remain unclear. To clarify these points, we conducted an observational study to determine the detailed characteristics and location of LBP before and after discectomy for LDH, using a detailed visual analog scale (VAS) bilaterally.Methods: We included 65 patients with LDH treated by discectomy in this study. A detailed VAS for LBP was administered with the patient under 3 different conditions: in motion, standing, and sitting. Bilateral VAS was also administered (affected versus opposite side) for LBP, lower extremity pain (LEP), and lower extremity numbness (LEN). The Oswestry Disability Index (ODI) was used to quantify clinical status. Changes over time in these VAS and ODI were investigated. Pfirrmann grading and Modic change as seen by magnetic resonance imaging (MRI) were reviewed before and 1 year after discectomy to determine disc and endplate condition.Results: Before surgery, LBP on the affected side while the patients were in motion was significantly higher than LBP while they were sitting. This increased LBP on the affected side in motion was improved significantly after discectomy. By contrast, the residual LBP while sitting at 1 year after surgery was significantly higher than the LBP while they were in motion or standing. At 1 year following discectomy, residual LBP while sitting was significantly greater in cases showing changes in Pfirrmann grade or Modic type.Conclusions: Improvement of LBP on the affected side while the patient is in motion suggests that radicular LBP is improved following discectomy by nerve root decompression. Furthermore, that residual LBP is found while the patient is sitting is reflective of the load and pressure put on the disc and endplate.

Objectives: Little information is available regarding long-term follow-up of radiographic progression of damage (RPD) to large joints during treatment of rheumatoid arthritis (RA) with biological disease-modifying antirheumatic drugs (bDMARDs). We evaluated 3- to 4-year follow-up results and the associations between RPD and patient background and Larsen grade (LG) of joints.Methods: Seventy-one RA patients receiving bDMARDs for 3 to 4 years or who achieved bDMARD-free status were included. The mean age and disease duration at the start of bDMARDs were 62.4 years and 10.8 years, respectively. A total of 314 joints, including shoulders, elbows, hips, knees, and ankles, were evaluated to determine whether RPD was present by comparing radiographs before and after treatment.Results: RPD was observed in 24 patients (33.8%) and 34 joints (10.8%). Joints with an LG of III or higher had significantly higher rates of RPD than those with LGs I and II. Multivariate logistic regression analysis revealed that stage and health assessment questionnaire (HAQ) score at 18-months were independent risk factors for RPD (cut-off value: 2.5, odds ratio: 7.222 for stage; cut-off value: 0.9375, odds ratio: 6.278 for HAQ at 18-months).Conclusion: Stage, HAQ at 18-months, and LG at the start of bDMARDs were predictive of RPD after 3 to 4 years. bDMARDs should be started before both stage and LG exceed III and the therapeutic strategy should be determined so that HAQ does not exceed 1.0 during treatment.

To evaluate and compare the femoral tunnel aperture position, graft bending angle and the magnetic resonance imaging (MRI) graft signal intensity after anatomical double-bundle anterior cruciate ligament (ACL) reconstruction between transtibial and transportal drilling techniques of the femoral tunnel. Eighty-seven patients who underwent anatomic double-bundle ACL reconstruction with hamstring tendon autograft between January 2012 and December 2014 were included in this retrospective study. Forty-one patients underwent reconstruction using a transportal technique (TP group) and 46 patients underwent reconstruction using a transtibial technique (TT group). The anteromedial (AM) femoral aperture position and the graft bending angle were assessed using transparent three-dimensional CT 2 weeks postoperatively. MRI assessment was performed with proton density-weighted images in an oblique coronal plane 6 and 12 months postoperatively. Signal/noise quotient was calculated for two specific graft sites (femoral tunnel site and mid-substance site). Femoral aperture position, the graft bending angle and signal/noise quotient were compared between the TP and TT groups. There was no significant difference in the aperture position between the two groups. The graft bending angle of the AM tunnel in the axial plane was significantly greater in the TP group (p

Objectives To compare the effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament (ACL) reconstruction animal model. Methods Anterior cruciate ligament reconstruction using the plantaris tendon as graft material was performed on both knees of 24 rabbits (48 knees) to mimic ACL reconstruction by two different suspensory fixation devices for graft fixation. For the adjustable fixation device model (Socket group; group S), a 5 mm deep socket was created in the lateral femoral condyle (LFC) of the right knee. For the fixed-loop model (Tunnel group; group T), a femoral tunnel penetrating the LFC was created in the left knee. Animals were sacrificed at four and eight weeks after surgery for histological evaluation and biomechanical testing. Results Histologically, both groups showed a mixture of direct and indirect healing patterns at four weeks, whereas only indirect healing patterns were observed in both groups at eight weeks. No significant histological differences were seen between the two groups at four and eight weeks in the roof zone (four weeks, S: mean 4.8 sd 1.7, T: mean 4.5 sd 0.5, p = 0.14; eight weeks, S: mean 5.8 sd 0.8, T: mean 4.8 sd 1.8, p = 0.88, Mann-Whitney U test) or side zone (four weeks, S: mean 5.0 sd 1.2, T: mean 4.8 sd 0.4, p = 0.43; eight weeks, S: mean 5.3 sd 0.8,T: mean 5.5 sd 0.8, p = 0.61, Mann-Whitney U test) . Similarly, no significant difference was seen in the maximum failure load between group S and group T at four (15.6 sd 9.0N and 13.1 sd 5.6N) or eight weeks (12.6 sd 3.6N and 17.1 sd 6.4N, respectively). Conclusion Regardless of bone tunnel configuration, tendon-bone healing after ACL reconstruction primarily occurred through indirect healing. No significant histological or mechanical differences were observed between adjustable and fixed-loop femoral cortical suspension methods. Cite this article: Y. Sato, R. Akagi, Y. Akatsu, Y. Matsuura, S. Takahashi, S. Yamaguchi, T. Enomoto, R. Nakagawa, H. Hoshi, T. Sasaki, S. Kimura, Y. Ogawa, A. Sadamasu, S. Ohtori, T. Sasho. The effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament reconstruction: An animal study. Bone Joint Res 2018;7:327–335. DOI: 10.1302/2046-3758.75.BJR-2017-0238.R2.

Purpose To determine the time-dependent change in strain ratios (SRs) at the healing site of an Achilles tendon rupture in a rabbit model of tendon transection and to assess the correlation between SRs and the mechanical and histologic properties of the healing tissue. Materials and Methods Experimental methods were approved by the institutional animal care and use committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected. The SRs of Achilles tendons were calculated by using compression-based quantitative ultrasonographic elastography measurements obtained 2, 4, 8, and 12 weeks after transection. After in vivo elastography, the left Achilles tendon was harvested for mechanical testing of ultimate load, ultimate stress, elastic modulus, and linear stiffness, and the right tendons were harvested for tissue histologic analysis with the Bonar scale. Time-dependent changes in SRs, mechanical parameters, and Bonar scale scores were evaluated by using repeated-measures analysis of variance. The correlation between SRs and each measured variable was evaluated by using the Spearman rank correlation coefficient. Results Mean SRs and Bonar scale values decreased as a function of time after transection, whereas mechanical parameters increased (P < .001). SR correlated with ultimate stress (ρ = 0.68, P

Background: An intra-articular injection of platelet-rich plasma (PRP) may be an effective treatment for osteoarthritis (OA). However, its efficacy in ankle OA has not been investigated yet. The purpose of this study was to assess the safety and efficacy of an intra-articular injection of PRP in patients with ankle OA during a 24-week period. Methods: Twenty ankles of 20 patients with varus-type ankle OA who received intra-articular injections of PRP were evaluated. PRP was extracted from whole blood by using the double-spin technique. Three injections of 2-mL PRP were administered to the ankle at an interval of 2 weeks under ultrasonographic guidance. Adverse events and efficacy were assessed at 4, 12, and 24 weeks after the last injection. Clinical outcomes were assessed by using the visual analog scale (VAS) for pain, the Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot scale, and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). Results: No serious adverse effects were observed during the follow-up period. The VAS and JSSF scale scores significantly decreased from baseline to 4, 12, and 24 weeks after treatment ( P < .001). The mean score in the pain-related subscale of the SAFE-Q significantly improved from baseline to 12 weeks after treatment ( P = .04). Overall, the amount of pain reduction was maximal at 12 weeks after the last injection, and the effect was reduced at 24 weeks. The patients with late-stage OA had worse scores in all outcomes than those with early-stage OA. Conclusion: Intra-articular injections of PRP resulted in no serious adverse effects and significantly reduced pain in the patients with ankle OA. PRP treatment can be safe and effective and may be an option in the treatment of ankle OA. Level of Evidence: Level IV, case series.

Objectives The aim of this study was to investigate the effect of granulocyte-colony stimulating factor (G-CSF) on mesenchymal stem cell (MSC) proliferation in vitro and to determine whether pre-microfracture systemic administration of G-CSF (a bone marrow stimulant) could improve the quality of repaired tissue of a full-thickness cartilage defect in a rabbit model. Methods MSCs from rabbits were cultured in a control medium and medium with G-CSF (low-dose: 4 μg, high-dose: 40 μg). At one, three, and five days after culturing, cells were counted. Differential potential of cultured cells were examined by stimulating them with a osteogenic, adipogenic and chondrogenic medium. A total of 30 rabbits were divided into three groups. The low-dose group (n = 10) received 10 μg/kg of G-CSF daily, the high-dose group (n = 10) received 50 μg/kg daily by subcutaneous injection for three days prior to creating cartilage defects. The control group (n = 10) was administered saline for three days. At 48 hours after the first injection, a 5.2 mm diameter cylindrical osteochondral defect was created in the femoral trochlea. At four and 12 weeks post-operatively, repaired tissue was evaluated macroscopically and microscopically. Results The cell count in the low-dose G-CSF medium was significantly higher than that in the control medium. The differentiation potential of MSCs was preserved after culturing them with G-CSF. Macroscopically, defects were filled and surfaces were smoother in the G-CSF groups than in the control group at four weeks. At 12 weeks, the quality of repaired cartilage improved further, and defects were almost completely filled in all groups. Microscopically, at four weeks, defects were partially filled with hyaline-like cartilage in the G-CSF groups. At 12 weeks, defects were repaired with hyaline-like cartilage in all groups. Conclusions G-CSF promoted proliferation of MSCs in vitro. The systemic administration of G-CSF promoted the repair of damaged cartilage possibly through increasing the number of MSCs in a rabbit model. Cite this article: T. Sasaki, R. Akagi, Y. Akatsu, T. Fukawa, H. Hoshi, Y. Yamamoto, T. Enomoto, Y. Sato, R. Nakagawa, K. Takahashi, S. Yamaguchi, T. Sasho. The effect of systemic administration of G-CSF on a full-thickness cartilage defect in a rabbit model MSC proliferation as presumed mechanism: G-CSF for cartilage repair. Bone Joint Res 2017;6:123–131. DOI: 10.1302/2046-3758.63.BJR-2016-0083.

Recent reports indicate that oxidative stress is involved in the pathobiology of acute spinal cord injury or compression myelopathy. We conducted an observational study to determine levels of oxidative stress markers in serum from 80 patients who underwent spinal surgery to treat neurological symptoms related to lumbar degenerative disorders. Serum samples were collected before surgery and at 3 months, 6 months, and 1 year after surgery. Derivatives of reactive oxygen metabolites (ROM) in the serum samples were measured to gauge the level of oxidative stress. For preoperative neurological evaluation, patients were assessed for motor weakness in the lower extremities. We divided the patient samples into two groups: ROM decreasing at 1 year after surgery (G group) and ROM increasing at 1 year after surgery (W group). Then, we evaluated clinical outcomes using the visual analog scale and Oswestry disability index (ODI). Among the samples from the 80 enrolled patients, mean ROM levels before surgery increased to 388.5 ± 92.0 , indicating the presence of moderate oxidative stress. The level of ROM gradually decreased after surgery and 1 year after surgery: the levels had significantly decreased to 367.6 ± 83.3 ( p < 0.05 ). In patients who exhibited motor weakness, ROM values were significantly increased compared to those patients who had no motor weakness ( p < 0.05 ). In analyses of clinical outcomes, ODI values for the W group 1 year after surgery were significantly higher than those for the G group ( p < 0.05 ). Moderate oxidative stress was present in patients who had lumbar degenerative disorders and the degree of oxidative stress gradually improved within 1 year after surgery. The clinical results suggest that neurogenic oxidative stress can be mitigated by surgery for patients with lumbar degenerative disorders, and residual oxidative stress reflects poor surgical outcomes.

Background Recent reports indicate that oxidative stress induced by reactive oxygen species is associated with the pathobiology of neurodegenerative disorders that involve neuronal cell apoptosis. Here we conducted a cross-sectional study to evaluate serum levels of oxidative stress in cervical compression myelopathy. Methods Thirty-six serum samples were collected preoperatively from patients treated for acutely worsening compression myelopathy (AM) and chronic compression myelopathy (CM). Serum levels of oxidative stress markers were evaluated by measuring derivatives of reactive oxygen metabolites (ROM), which reflect concentrations of hydroperoxides. ROM in healthy individuals range from 250 to 300 (U. CARR), whereas ROM >340–400 and > 400 define moderate and severe levels of oxidative stress, respectively. Difference of ROM by the cause of disorders whether cervical spondylotic myelopathy (CSM) or cervical ossification of longitudinal ligament (OPLL), correlations between ROM and patient age, body mass index (BMI), history of smoking, existence of diabetes were examined. Neurological evaluations according to Japanese Orthopaedic Association (JOA) scores were performed and correlated with ROM. Results ROM increased to 349.5 ± 54.8, representing a moderate oxidative stress, in CM samples. ROM increased to 409.2 ± 77.9 in AM samples, reflecting severe oxidative stress which were significantly higher than for CM samples (p p 2 = 0.454, p = 0.047) was observed in the AM group. Conclusions Although moderate oxidative stress was present in patients with CM, levels of oxidative stress increased in severity in patients with AM. These results suggest that postsurgical neurological recovery is influenced by severe oxidative stress in AM.

Background Total knee arthroplasty (TKA) is the major surgical treatment for end-stage osteoarthritis (OA). Despite its effectiveness, there are about 20% of patients who are dissatisfied with the outcome. Predicting the surgical outcome preoperatively could be beneficial in order to guide clinical decisions. Methods One-hundred and ten knees of 110 consecutive patients who underwent TKAs for varus knees resulting from OA were included in this study. Preoperative varus deformities were evaluated by femorotibial angle (FTA), medial proximal tibial angle (MPTA) and lateral distal femoral angle (LDFA), and classified as a severe varus (SV) or a mild varus (MV) group. The osteophyte score (OS), which we developed originally, was also calculated based on the size of the osteophytes and classified as groups with more or less osteophytes. We compared preoperative and 1-year postoperative range of motion, the Knee Society Score, and Japanese Knee injury Osteoarthritis Outcome Score (KOOS) between SV and MV groups (varus defined by FTA, MPTA, or LDFA), in each group with more or less osteophytes. Results When varus deformities were defined by FTA, regardless of OS, postoperative KOOS subscales and/or the improvement rates were significantly higher in the SV group than in the MV group. When varus defined by MPTA, regardless of OS, there were no significant differences in postoperative KOOS subscales between groups. However, when varus defined by LDFA, scores for pain, activities of daily living (ADL), and quality of life (QOL) on postoperative KOOS and/or the improvement rates were significantly higher in the SV group than in the MV group only in patients with less osteophytes. No significant differences were found between groups in patients with more osteophytes. Conclusions We classified OA types by radiographic measurements of femur and tibia in combination with OS. Postoperative patient-reported outcomes were better in patients with SV knees but were poor in patients with knees with MV deformity and less osteophytes.

Matrix metalloproteinase 13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) are thought to play critical roles in cartilage degradation at the early phase of osteoarthritis (OA). The aim of this study is to examine the effect of chemically modified Mmp13 or Adamts5 small interfering RNA (siRNA), alone or in combination, in a mouse OA model. OA pathology was surgically induced in 9-week-old male C57/BL6 mice (n = 64) via destabilization of the medial meniscus (DMM). We used chemically modified siRNA (Accell siRNAs®) for Mmp13 and Adamts5, as well as a non-targeting control and evaluated their combined and individual effects after injection in the DMM model. The control group (n = 16) was injected with non-targeting siRNA and the normal group (n = 16) did not undergo any surgical induction or intra-articular injection. Histological assessment of the articular cartilage was conducted at 4 and 8 weeks post-DMM surgery to evaluate OA progression. Significant improvement in the histological score was observed at 8 weeks after DMM in all three siRNA-treated groups compared to the control siRNA-injected group. The score of the combined group was significantly lower than that of the Adamts5 siRNA-only group. No significant differences were noted between the Mmp13 siRNA-only group and the combined group. Combined intra-articular injection of Mmp13 and Adamts5 siRNA resulted in almost the same inhibitory effects as Mmp13 siRNA alone on cartilage degradation at the early phase of OA.

Background Although damage to large joints such as the shoulder, elbow, hip, knee, and ankle has a substantially larger impact on functional ability than damage to the small joints of the hand and foot,1 2 large joints are not routinely monitored for progressive damage in patients with rheumatoid arthritis (RA). Furthermore, a little information is available regarding long-term follow-up results of radiographic progression of damage (RPD) to the large joints during treatment with biological disease-modifying antirheumatic drugs (bDMARDs). Objectives We investigated ratios of RPD to the large joints in RA patients treated with bDMARDs for 3 to 4 years and analysed association between RPD and patient backgrounds or Larsen grades of individual large joint. Methods Sixty-eight patients (naive: 42, switch: 26) receiving bDMARDs (IFX: 5, ETN: 9, ADA: 7, GLM: 3, CZP: 5, TCZ: 28, ABT: 11) for 3 to 4 years or achieving bDMARDs-free status were included in this study. The mean age and disease duration at the start of bDMARDs was 62.7 year-old and 10.7 years, respectively, and baseline DAS28-ESR and HAQ was 4.61 and 1.014, respectively. A total of 311 joints including shoulder, elbow, hip, knee, and ankle were evaluated whether there was RPD during the observation period by comparing radiographs before and after the treatment. Results RPD was found in 22 patients (31.4%) and 32 joints (10.0%), and it occurred during the former half period in 17 joints and during the latter half period in 15 joints. Joints with Larsen grade (LG) III or more had significantly higher ratios of RPD than those with LG II or less (p Conclusions The stage and baseline HAQ were associated with RPD to the large joints, and progressive damage is expected to increase when the stage exceeds III and/or functional disability exceeds an HAQ score of 1.5. Progressive damage also increases when LG exceeds III. Treatment with bDMARDs should be started before stage, HAQ, and LG exceed III, 1.5, and III, respectively. References [1] Drossaers-Bakker KW, Kroon HM, Zwinderman AH, Breedveld FC, Hazes JM. Radiographic damage of large joints in long-term rheumatoid arthritis and its relation to function. Rheumatology (Oxford)2000;39:998–1003. [2] Kuper HH, van Leeuwen MA, van Riel PL, Prevoo ML, Houtman PM, Lolkema WF, van Rijswijk MH. Radiographic damage in large joints in early rheumatoid arthritis: relationship with radiographic damage in hands and feet, disease activity, and physical disability. Br J Rheumatol1997;36:855–60. Disclosure of Interest None declared

OBJECTIVES The purposes of this study were to measure intraobserver and interobserver repeatability of quantitative elastography using an acoustic coupler for the Achilles tendon, to compare elastographic values among different age groups, and to assess the correlation between quantitative and conventional qualitative measurements. METHODS One hundred asymptomatic Achilles tendons of 50 volunteers were examined. For quantitative elastography, the strain value of the tendon was divided by that of the acoustic coupler with a known Young modulus, and the strain ratio was calculated. B-mode image assessment and qualitative elastography were also performed. Intraobserver repeatability and interobserver repeatability of strain ratio measurements were calculated. The strain ratios were compared among age groups by the Kruskal-Wallis test. Additionally, strain ratios for each B-mode grade and qualitative elastographic grade were compared by the Wilcoxon signed rank test. RESULTS Intraobserver repeatability intraclass correlation coefficient (1, 3) values were 0.87 and 0.93, respectively. The correlation coefficient between the observers' measurements was 0.61. The strain ratio for the 30s age group was 0.27, which was significantly lower than the values for the other age groups (P < .001). Although 97 of 100 tendons were normal on B-mode evaluations, 36 of the 97 tendons were degenerated on qualitative elastography and also had higher strain ratio values than normal tendons. CONCLUSIONS Quantitative elastography using an acoustic coupler is a reproducible technique for measuring the elasticity of the Achilles tendon. It may detect early tendon degeneration that is not depicted on B-mode imaging.

Imaging is of great importance in diagnosing meniscal tears. The aim of this study was to assess the accuracy of high-resolution ultrasound in the diagnosis of meniscal tears, with arthroscopic examination as the standard reference, after resolution was confirmed with a target-mounted reference phantom. An additional goal was to elucidate the area of the meniscus that could be visualized with the same ultrasound machine after placement of markers into the menisci of cadaveric knees.Seventy patients were included for the assessment of the accuracy of a high-resolution ultrasound machine with a 14.0 to 6.0-MHz linear transducer. The preoperative ultrasound diagnosis, in terms of the presence and type of tear, was compared with that in the surgical reports. In the cadaveric studies, nine needles were placed in the peripheral zone of the menisci at regular intervals and the number of needles that could be observed with the system was recorded.The overall sensitivity, specificity, positive predictive value, and negative predictive value of ultrasound examination for meniscal tears were 88%, 85%, 85%, and 88%, respectively. These statistical parameters did not differ significantly between the medial and lateral menisci. The sensitivity for diagnosing horizontal, vertical, radial, flap, bucket-handle, and complex tears and for detecting discoid lateral menisci was 83%, 64%, 0%, 64%, 54%, 90%, and 80%, respectively. Ten percent of the lateral menisci could not be evaluated because of poor images. The cadaveric studies revealed that the ultrasound visualized the entire meniscus except for the anterior horn.The findings of this study suggest that ultrasound examination may be suitable for screening for meniscal tears. The fact that almost 10% of the lateral menisci could not be evaluated because of poor images appears to be a weakness of ultrasound.

The objectives of this study are (1) to examine age-dependent longitudinal differences in histological responses after creation of partial-thickness articular cartilage defects (PTCDs) in rats and to use this model (2) to objectively evaluate the effectiveness of interventions for cartilage repair. Linear PTCDs were created at a depth of 100 μm in the weight-bearing region of the medial femoral condyle in rats of different ages (3 weeks, 6 weeks, 10 weeks and 14 weeks). One day, one week, two weeks, four weeks and twelve weeks after PTCD generation, spontaneous healing was evaluated histologically and immunohistochemically. Effects of interventions comprising mesenchymal stem cells (MSCs) or platelet-rich plasma (PRP) or both on 14-week-old PTCD rats were evaluated and compared with natural courses in rats of other ages. Younger rats exhibited better cartilage repair. Cartilage in 3-week-old and 6-week-old rats exhibited nearly normal restoration after 4–12 weeks. Cartilage in 14-week-old rats deteriorated over time and early signs of cartilage degeneration were observed. With injection of MCSs alone or MSCs + PRP, 14-week-old PTCD rats showed almost the same reparative cartilage as 6-week-old rats. With injection of PRP, 14-week-old PTCD rats showed almost the same reparative cartilage as 10-week-old rats. This model will be of great use to objectively compare the effects of interventions for small cartilage lesions and may help to advance the development of disease-modifying osteoarthritis drugs.

Cartilage degeneration is believed to be the primary event in the development of osteoarthritis (OA). On the other hand, meniscal degeneration is observed with high prevalence, and some researchers have pointed out that pathological changes in menisci precede that of cartilage. The purpose of the present study is to investigate comprehensive gene expression pattern of cartilage and menisci in the initial phase of surgically induced OA and to compare them. Secondary OA was surgically induced in 10-week-old male Wistar rats by anterior cruciate ligament transection (ACLT). Articular cartilage and menisci were separately dissected from six ACLT- and six sham-operated rats. Each specimen was analyzed by microarray, histological, and immunohistochemical analysis 3 weeks after surgery. Of the 36,685 transcripts detectable by microarray, the number of upregulated transcripts in ACLT menisci was >2.5-fold compared with that in ACLT menisci in any given threshold. Cluster analysis using the Database for Annotation Visualization and Integrated Discovery (DAVID) showed genes related to OA, such as response to stimulus, angiogenesis, and apoptosis, which were predominantly found in menisci in ACLT rats. Representative proteases including Adamts2, 4, Mmp2, 12, 13, 14, 16, extracellular matrix genes including versican (Vcan), lumican (Lum), syndecan1 (Sdc1), and Prostaglandin endoperoxide synthase2 (Ptgs2) were up-regulated in menisci, but were not up-regulated in cartilage. Our results indicated that the molecular changes that occurred in menisci preceded those occurred in cartilage in the very early phase of surgically induced OA models.

This study investigated the effect of MMP-13 gene knock down on cartilage degradation by injecting small interfering RNA (siRNA) into knee joints in a mouse model of osteoarthritis (OA). OA was induced in male C57BL/6 mice by destabilization of medial meniscus (DMM) surgery. Change of Mmp13 expression over time was determined by qPCR analysis from 3 days to 6 weeks after surgery. Mmp13 and control chemically modified siRNA were injected into the knee joint 1 week after surgery and expression levels were assessed in synovium by qPCR 48 h later. Cartilage degradation was histologically assessed 8 weeks after DMM surgery according to OARSI recommendations. Mmp13 expression levels were elevated 1 week after surgery and peaked at 77 fold at 2 weeks compared to expression at 3 days. A 55% decrease of Mmp13 levels in cartilage was observed 48 h after injection of Mmp13 siRNA (p = 0.05). Significant reduction in the histological score at 8 weeks after surgery was observed in the Mmp13 siRNA-treated group compared to the control siRNA group (p

Magnetic resonance imaging (MRI) can be used to identify most types of meniscal tears; however, meniscocapsular separation of the medial meniscus can be difficult to identify with MRI. Here we present a technical note on the intrasurgical use of ultrasonography for the detection of meniscocapsular separation and confirmation of the beneficial effect of suturing on the stability of this lesion in a representative case of meniscocapsular separation that could be diagnosed with ultrasonography but not MRI preoperatively. Ultrasonography can detect meniscocapsular separation as a vertical low echoic area and be performed together with arthroscopy using the picture-in-picture function of the ultrasonography machine. Ultrasonography is an effective tool for diagnosing meniscocapsular separation and is helpful during arthroscopic surgery.

Summary Objectives Circadian rhythm (CR) was identified by RNA sequencing as the most dysregulated pathway in human osteoarthritis (OA) in articular cartilage. This study examined circadian rhythmicity in cultured chondrocytes and the role of the CR genes NR1D1 and BMAL1 in regulating chondrocyte functions. Methods RNA was extracted from normal and OA-affected human knee cartilage ( n = 14 each). Expression levels of NR1D1 and BMAL1 mRNA and protein were assessed by quantitative PCR and immunohistochemistry. Human chondrocytes were synchronized and harvested at regular intervals to examine circadian rhythmicity in RNA and protein expression. Chondrocytes were treated with small interfering RNA (siRNA) for NR1D1 or BMAL1, followed by RNA sequencing and analysis of the effects on the transforming growth factor beta (TGF-β) pathway. Results NR1D1 and BMAL1 mRNA and protein levels were significantly reduced in OA compared to normal cartilage. In cultured human chondrocytes, a clear circadian rhythmicity was observed for NR1D1 and BMAL1. Increased BMAL1 expression was observed after knocking down NR1D1, and decreased NR1D1 levels were observed after knocking down BMAL1. Sequencing of RNA from chondrocytes treated with NR1D1 or BMAL1 siRNA identified 330 and 68 significantly different genes, respectively, and this predominantly affected the TGF-β signaling pathway. Conclusions The CR pathway is dysregulated in OA cartilage. Interference with circadian rhythmicity in cultured chondrocytes affects TGF-β signaling, which is a central pathway in cartilage homeostasis.

Our previous study showed that partial-thickness articular cartilage defects (PTCDs) created in immature rats spontaneously healed to resemble normal hyaline cartilage, but that of mature rats did not. To identify molecules involved in the spontaneous cartilage repair observed in this model, gene expression was compared between PTCD and sham-operated cartilage of immature and mature rats.Six sets of gene comparisons were made at 12, 24, and 48 hours after the creation of PTCDs in immature and mature rats using microarrays. All the genes upregulated in immature cartilage at 12 hours were selected for further analysis if their expression pattern was not irregular such that diminished at 24 hours and re-upregulated at 48 hours. Relationships among genes selected through the above steps were analyzed using Ingenuity Pathway Analysis (IPA) software. After deriving networks, important molecules were further narrowed down by location within a network. Genes were regarded as central if they had relationships with more than 10 molecules in a network. Protein localization in tissues was confirmed by immunohistochemistry.Five networks were identified. Their functional annotations were gene expression, cell cycle, growth and proliferation, and cell signaling. Transforming growth factor-beta (TGF-β) was centrally located in the network with the highest IPA score and mothers against decapentaplegic homolog-3 (Smad3) were centrally located in the second highest ranking network. Phosphorylated Smad3 was detected in the nuclei of chondrocytes in immature cartilage.Our data suggest the possible importance of Smad3 in the TGF-β signaling in the spontaneous healing of PTCDs in immature rats.

To determine if magnetic resonance (MR) imaging T2 mapping can be used to quantify histologic tendon healing by using a rabbit Achilles tendon transection model treated with platelet-rich plasma (PRP).Experiments were approved by the Institutional Animal Care and Use Committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected, and PRP (in the test group) or saline (in the control group) was injected into the transection site. The rabbits were sacrificed 2, 4, 8, and 12 weeks after surgery. Thereafter, T2 mapping and histologic evaluations were performed by using the Bonar scale. A mixed-model multivariate analysis of variance was used to test the effects of time and PRP treatment on the T2 value and Bonar grade, respectively. The correlation between the T2 value and Bonar grade was also assessed by using the Spearman correlation coefficient.The Bonar scale values decreased in both groups during tendon healing. The T2 value also shortened over time (P.001 for both groups). The T2 values were positively correlated with the Bonar grade (ρ = 0.78, P.001). Both the T2 value and Bonar scale value were lower in the PRP group than in the control group at 4, 8, and 12 weeks; however, there was no significant effect of PRP treatment on the T2 value or Bonar grade.The T2 value changes reflected histologic tendon healing. While T2 and Bonar grade were lower at all time points in tendons treated with PRP, there was no significant difference between the treatment and control tendons.

Introduction: Angioleiomyoma is a benign smooth muscle tumor. It originates in the tunica media of veins. In general, it arises from the dermis, subcutaneous fat and fascia of lower extremities in middle-aged women. The case of intra-articular occurrence is very rare. Case presentation: This case report describes a 30-year-old Asian man with a 6-month history of recurrent pain localized in the lateral side of his left knee. Magnetic resonance imaging revealed an isolated intra-articular lesion. We performed a surgical excision of this lesion. On histological examination, the diagnosis of angioleiomyoma was confirmed. After the surgery, he recovered completely. Furthermore, no sign of recurrence was observed 1 year after surgery. Conclusions: In this study, we report a rare case of intra-articular angioleiomyoma of the knee. The mass showed atypical findings on magnetic resonance imaging including gadolinium-enhanced imaging in comparison to previously reported intra-articular lesions. This intra-articular tumor is difficult to diagnose prior to surgery due to paucity of information.

This study investigated the effect of MMP-13 gene knock down on cartilage degradation by injecting small interfering RNA (siRNA) into knee joints in a mouse model of osteoarthritis (OA). OA was induced in male C57BL/6 mice by destabilization of medial meniscus (DMM) surgery. Change of Mmp13 expression over time was determined by qPCR analysis from 3 days to 6 weeks after surgery. Mmp13 and control chemically modified siRNA were injected into the knee joint 1 week after surgery and expression levels were assessed in synovium by qPCR 48 h later. Cartilage degradation was histologically assessed 8 weeks after DMM surgery according to OARSI recommendations. Mmp13 expression levels were elevated 1 week after surgery and peaked at 77 fold at 2 weeks compared to expression at 3 days. A 55% decrease of Mmp13 levels in cartilage was observed 48 h after injection of Mmp13 siRNA (p = 0.05). Significant reduction in the histological score at 8 weeks after surgery was observed in the Mmp13 siRNA-treated group compared to the control siRNA group (p0.001). Intra-articular injection of Mmp13 siRNA at the early phase of OA development resulted in effective knock down of Mmp13 expression and delay in cartilage degradation in vivo.

Partial thickness articular cartilage injuries (PTCIs) were not previously thought to heal spontaneously. Immature rats have the capacity for spontaneous repair of PTCIs, although it is a long-term process. Our aim has been to examine the spontaneous repair response mechanism in immature rats. Single linear PTCIs were created in 3-week-old and 12-week-old rats in the direction of joint motion. On day 1 and at 1, 2, and 4 weeks after PTCI, evaluations of histological changes and immunohistology at the injury site and in the surrounding cartilage were performed. Anti-CD105 and anti-CD166 antibodies (as stem cell markers to identify mesenchymal stem cells in reparative cartilage tissue) were used for immunohistological evaluations. To determine whether endogenous repair ability existed in articular cartilage, an ex vivo experiment was also carried out. Femoral condyles with PTCIs were incubated in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum for 1 day and for 1 and 2 weeks. Histological changes were subsequently examined. Immature cartilage showed a higher repair response than did mature cartilage, and the response occurred immediately after PTCI. In immature rats, CD105- and CD166-positive cells were found in the superficial and transitional zones of the articular cartilage. Few CD166-positive cells were identified in mature articular cartilage. No significant in vivo differences in the spontaneous repair responses to PTCIs were observed between mature and immature groups. Thus, the repair response to PTCIs seems to be associated not only with CD105- and CD166-positive cells, but also with other perichondral factors.

Summary Objective Osteoarthritis (OA) leads to pain and loss of function in affected joints. Gait disturbance results from these symptoms of OA, and gait analysis can be important to evaluate the progression of OA. The purpose of this study was to analyze gait pattern in a rodent model of OA and to assess the effects of intra-articular injection of hyaluronan (IAI-HA) by gait analysis, along with histological evaluation. Design OA was induced by destabilization of the medial meniscus (DMM) of C57BL/6 mice. IAI-HA started 3 weeks after DMM surgery. Mice were allocated to three groups and were given either 800-kDa HA (800-HA), 6000-kDa HA (6000-HA) or saline. We compared these three groups with a sham group by gait analysis using CatWalk™. Histological evaluation was performed to assess articular cartilage changes in the knee joints. Results Mice injected with 800-HA or 6000-HA showed gait patterns similar to that of the sham mice, while the saline-injected group showed gait disturbances 12 and 16 weeks after DMM surgery. Histological changes in articular cartilage were similar among the 800-HA, 6000-HA and saline-treated groups, demonstrating OA progression throughout the experimental time points. Positive gait-related effects of IAI-HA might occur by its pain relieving effect and/or by preventing contracture. Conclusion IAI-HA prevented gait disturbances in the DMM model, but did not prevent histological changes associated with OA progression.