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Objective This study aimed to determine whether the intra-articular injection of human adipose-derived mesenchymal stem cells (ADSCs) protects against the progression of murine post-traumatic osteoarthritis. Design ADSCs were isolated from human abdomen or buttock adipose tissues. In in vitro study, ADSCs conditioned medium was added to human chondrocytes pre-treated with interleukin-1β (IL-1β), and resultant gene expression of target inflammatory genes was measured by real-time quantitative polymerase chain reaction. A mouse model of knee osteoarthritis was generated by unilaterally transecting the medial meniscus in the right hind limb of 20 female C57BL/6 mice. Mice were randomly assigned to 2 treatment groups that received 6 µl intra-articular injections of either phosphate-buffered saline (control) or 2 × 104 cells/μl of ADSCs 14, 28, and 42 days post-surgery. Mice were euthanized 84 days post-surgery and histological and micro-computed tomography evaluation of knee joints were analyzed. Hind limb weight-bearing distribution was measured pre-surgery and 28 and 84 days post-surgery. Results Conditioned medium from cultured human adipose-derived mesenchymal stem cells suppressed the expression of target inflammatory genes in chondrocytes pre-treated with IL-1β, suggesting anti-inflammatory properties ( P < 0.01). Histological analyses indicated that the progression of destabilization of medial meniscus-induced knee osteoarthritis was suppressed by the administration of ADSCs compared with control group at medial femorotibial joint in vivo. This protective effect was related to a reduction in articular cartilage loss. Conclusion The intra-articular injection of ADSCs suppressed articular cartilage loss in a mouse model of knee osteoarthritis, possible through anti-inflammatory mechanisms.

Background This study aimed to validate and determine the minimal clinically important difference (MCID) in the Japanese version of the International Knee Documentation Committee Subjective Knee Form (Japanese IKDC-SKF) for patients with anterior cruciate ligament (ACL) injuries. Methods This prospective study was performed using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guideline to assess the measurement properties of reliability, responsiveness, validity, and interpretability of the Japanese IKDC-SKF. Results A total of 152 patients were enrolled in the study. The Japanese IKDC-SKF had excellent internal consistency [Cronbach's alpha (95% confidence interval, CI) was 0.90 (0.88–0.92), and the test–retest reliability [intraclass correlation coefficient, ICC2,1 (95% CI)] was 0.97 (0.94–0.98). The content validity (r), which was interpretable between the Japanese IKDC-SKF and the Japanese Anterior Cruciate Ligament questionnaire 25 was −0.87 (P Conclusions Our results indicate that the Japanese version of the IKDC-SKF is a reliable, valid, and responsive measurement instrument with which to evaluate the physical function of patients with ACL injuries.

ObjectiveDisrupted sleep and training behaviors in athletes have been reported during the COVID-19 pandemic. We aimed at investigating the combined effects of Ramadan observance and COVID-19 related lockdown in Muslim athletes.MethodsFrom an international sample of athletes (n = 3,911), 1,681 Muslim athletes (from 44 countries; 25.1 ± 8.7 years, 38% females, 41% elite, 51% team sport athletes) answered a retrospective, cross-sectional questionnaire relating to their behavioral habits pre- and during- COVID-19 lockdown, including: (i) Pittsburgh sleep quality index (PSQI); (ii) insomnia severity index (ISI); (iii) bespoke questions about training, napping, and eating behaviors, and (iv) questions related to training and sleep behaviors during-lockdown and Ramadan compared to lockdown outside of Ramadan. The survey was disseminated predominately through social media, opening 8 July and closing 30 September 2020.ResultsThe lockdown reduced sleep quality and increased insomnia severity (both p < 0.001). Compared to non-Muslim (n = 2,230), Muslim athletes reported higher PSQI and ISI scores during-lockdown (both p < 0.001), but not pre-lockdown (p > 0.05). Muslim athletes reported longer (p < 0.001; d = 0.29) and later (p < 0.001; d = 0.14) daytime naps, and an increase in late-night meals (p < 0.001; d = 0.49) during- compared to pre-lockdown, associated with lower sleep quality (all p < 0.001). Both sleep quality (χ2 = 222.6; p < 0.001) and training volume (χ2 = 342.4; p < 0.001) were lower during-lockdown and Ramadan compared to lockdown outside of Ramadan in the Muslims athletes.ConclusionMuslim athletes reported lower sleep quality and higher insomnia severity during- compared to pre-lockdown, and this was exacerbated by Ramadan observance. Therefore, further attention to Muslim athletes is warranted when a circadian disrupter (e.g., lockdown) occurs during Ramadan.

Background/aimsThis study aimed to assess the efficacy and sterility of stored platelet-rich plasma (PRP) eye-drops for corneal epithelial wound healing compared with those of autologous serum (AS) eye-drops.MethodsAt our single institution, PRP and AS eye-drops were prepared using peripheral blood obtained from six healthy volunteers and stored at 4°C. Platelet and leucocyte counts and transforming growth factor (TGF)-β1, epidermal growth factor (EGF), and fibronectin levels were assessed during storage for up to 4 weeks. Sterility was assessed by culturing 4-week poststorage samples. PRP, AS, and phosphate-buffered saline (PBS) eye-drop efficacies were compared using corneal epithelial wound healing assays in vitro and in vivo and monitoring wound areas under a microscope every 3 hours.ResultsHigher platelet and lower leucocyte counts were seen in PRP than in whole blood on the day of preparation. After storage, TGF-β1, EGF, and fibronectin levels were significantly higher in PRP than in AS eye-drops. In vitro and in vivo, PRP eye-drops used on the day of preparation significantly promoted corneal epithelial wound healing compared with PBS. Moreover, PRP eye-drops stored for 4 weeks significantly promoted corneal wound healing compared with PBS and AS eye-drops.ConclusionPRP eye-drops stored at 4°C for 4 weeks promoted corneal epithelial wound healing with higher levels of growth factors than those observed in AS eye-drops, while maintaining sterility, suggesting that this preparation satisfies the unmet medical needs in the treatment of refractory keratoconjunctival epithelial disorders.

Background: Platelet-rich plasma (PRP) has emerged as a treatment for osteoarthritis (OA). However, the effect that leukocyte concentrations in PRP have on OA remains unclear. Purpose: To clarify the optimal PRP formulation for OA treatment by comparing pure PRP, leukocyte-poor PRP (LP-PRP), and leukocyte-rich PRP (LR-PRP) in a rat arthritis model. Study Design: Controlled laboratory study. Methods: Knee arthritis was induced bilaterally in male Wistar rats with intra-articular injections of monosodium iodoacetate (MIA) on day 0. Rats were randomly assigned to 1 of 3 treatment groups (pure PRP, LP-PRP, and LR-PRP). On day 1, allogenic PRP was injected into the right knee of rats and phosphate-buffered saline was injected into the left knee as a control. Weight distribution on the hindlimbs was measured for 14 days to assess pain behavior. Rats were euthanized at day 5 or 14 for histological assessment of synovial tissue and cartilage. Immunohistochemical staining of calcitonin gene-related peptide (CGRP) and α-smooth muscle actin was performed to determine the mechanism of pain relief induced by the PRP preparations. Results: In all groups, PRP increased the load-sharing ratio on PRP-injected knees, with pure PRP eliciting the largest effect among the 3 kinds of PRP ( P < .05). Structural changes in the synovial tissue were significantly inhibited in the pure-PRP group compared with the control group after both 5 and 14 days ( P < .001 and P = .025, respectively), whereas no significant difference was found between the control, LP-PRP, and LR-PRP groups. An inhibitory effect on cartilage degeneration was observed only in the pure-PRP group on day 14. Pure PRP also significantly inhibited expression of CGRP-positive nerve fibers in the infrapatellar fat pad compared with the other groups ( P < .05). Conclusion: In an MIA-induced arthritis model, pure PRP injection was the most effective treatment for reduction of pain-related behavior and inhibition of synovial inflammation and pain sensitization. Clinical Relevance: PRP formulations should be optimized for each specific disease. This study shows the superiority of pure PRP for treatment of arthritis and joint pain.

IntroductionThe elevated cytokine levels in patients suffering from anterior cruciate ligament (ACL) rupture may lead to acute post-traumatic arthritis (APTA) and post-traumatic osteoarthritis (PTOA). Due to its chondrogenerative and anti-inflammatory effect, platelet-rich plasma (PRP) therapy is expected to show a positive outcome in APTA and PTOA. The proposed trial aims to quantitatively measure the efficacy of PRP injection in arresting post-traumatic cartilage degeneration among patients after ACL reconstruction.Methods and analysisThis will be a single-blind, randomised, prospective, controlled clinical trial designed following the Consolidated Standards of Reporting Trials guidelines. After ACL reconstruction, 80 patients will be randomised to receive either leucocyte-poor PRP injection after joint aspiration or a placebo control group receiving only joint aspiration. Participants (age 20–49 years) will be those who have undergone ACL reconstruction within the past 2 weeks with a body mass indexEthics and disseminationThe study was approved by The Independent Ethics Committee for Clinical Trials of the Japanese Association for the Promotion of State-of-the-Art Medicine. Results of the trial and each of the outcomes will be shared via conferences and publication in a peer-reviewed journal.Trial registration numberjRCTb030200391.

It is difficult to investigate clinical features in a single-center study because atypical periprosthetic femoral fracture (APFF) is rare. This study aims to perform a nationwide survey of APFF to investigate the characteristics of this fracture and compare the clinical outcome with that of typical periprosthetic femoral fracture (typical PFF). A nationwide survey was performed asking for cooperation from 183 councilors of the Japanese Society for Fracture Repair. The subjects were patients with APFF injured between 2008 and 2017. The control group was comprised of patients with typical PFF of our facility injured in the same period. A total of 43 patients met the APFF definition. The control group was comprised of 75 patients with typical PFF. The rate of bisphosphonate use was significantly higher in the APFFs group than in the typical PFF group (62.8% and 32%, p p p = 0.045). However, no significant association between PFF and APFF was observed in the patients with arthroplasty for other hip diseases. The risk of complications was higher in the APFF group than in the typical PFF group in the patients with arthroplasty for fracture. When AFPP after arthroplasty for the fracture is suspected, it may be necessary to add not only internal fixation with a normal plate but also some additional treatment.

Introduction Platelet-rich plasma (PRP) therapy is used to treat pathological conditions such as degenerative inflammatory diseases including osteoarthritis (OA) by enhancing tissue repair and promoting anti-inflammatory effects. Although PRP therapy for patients with knee OA improved pain and functional scores, the association of clinical outcomes and quality of PRP including cell composition and concentration is unclear. Methods Therefore, this study analyzed blood cell counts, including the immature platelet fraction (IPF), in peripheral blood and PRP of 144 patients with knee OA who underwent PRP therapy. The mean leukocyte and platelet concentrations in whole blood and PRP were analyzed using an XN-1000 automated hematology analyzer. Visual analogue scale (VAS) scores and knee injury and osteoarthritis outcome scores (KOOS) before and 1 month after a single PRP injection were also determined. Results Higher platelet and lower leukocyte concentration rates were observed in PRP compared with whole blood. The platelet concentration in whole blood was negatively correlated with VAS improvement. The percentage of IPF (IPF%) in whole blood was positively correlated with VAS improvement and KOOS (pain) improvement, whereas the IPF% in PRP tended to correlate with VAS improvement. Furthermore, multivariate logistic regression demonstrated the high IPF% in whole blood was significantly associated with VAS improvement. The low percentage of neutrophil (neutrophil%) in PRP was significantly associated with the VAS improvement and KOOS (ADL) improvement. Conclusions Therefore, PRP efficacy for OA might depend on the patient's biological status., Highlights • High percentage of IPF (IPF%) in whole blood was significantly associated with VAS improvement. • Low neutrophil% in PRP was significantly associated with VAS improvement and KOOS (ADL) improvement. • The PRP efficacy for knee OA might depend on the patient's biological status.

Introduction: Muscle strain of the gastrocnemius medial head mainly occurs at the musculotendinous junction (MTJ), and stiffness is a risk factor. Shear wave elastography (SWE) measures elasticity by determining the propagation velocity. The aim of this study was to measure the elasticity of the normal muscle and aponeurosis in the MTJ of the gastrocnemius medial head using SWE, thus obtaining information relevant to muscle strain at this point. Materials and Methods: Forty-one volunteers (82 legs) were recruited and the gastrocnemius medial heads were examined at four points: three on the aponeurosis, namely at the center of the MTJ (Central), 10 mm proximal to it (Proximal) and 10 mm distal to it (Distal); and at one on the muscle belly (Muscle). The measurements were compared among the points, between males and females, and between younger and middle-aged subjects. Correlations between the elastic modulus and age were also examined. Results: The elastic moduli at Proximal, Central, Distal, and Muscle were 2.82 ± 0.53 m/s, 3.43 ± 0.83 m/s, 4.83 ± 1.56 m/s, and 2.25 ± 0.43 m/s, respectively. These values differed significantly among the points of the aponeurosis, Distal having the highest modulus followed by Central. The elastic moduli were significantly greater in males than females at Distal and Muscle and in younger subjects than middle-aged subjects at Muscle. No significant correlations between elastic modulus and age were observed for any point. Conclusions: SWE could be a feasible method for quantifying the elasticity of muscle and aponeurosis in the MTJ of the gastrocnemius medial head. This article is protected by copyright. All rights reserved.

“Locomotive syndrome” is defined as a condition associated with restriction in one’s ability to walk or lead a normal life due to a dysfunction in one or more of the parts of the locomotion system, including the muscles, bones, joints, cartilage or intervertebral discs. This syndrome especially refers to individuals who have come to need nursing care services because of problems with the locomotive organs, or those who have conditions which may require them to need such services in the near future. Recent epidemiological studies revealed that the one-fourth of elderly individuals who require special assistance or nursing care have locomotive disorders in Japan. Osteoarthritis of the knee (knee OA) and hip (hip OA), and osteoporosis and spinal canal stenosis due to spondylosis are three major locomotive disorders that cause elderly individuals require special assistance or nursing care. In this review, we focus on the effects of knee and hip OA on the lives of elderly individuals and the recent advantages in clinical research on the pathophysiology and management of these diseases.

Introduction: Knee osteoarthritis (KOA), the most common form of osteoarthritis (OA) is a considerable health concern worldwide. Platelet-rich plasma (PRP) is a common therapeutic option for KOA. Different types of PRPs have varying efficacies. However, a comparative analysis of the qualities of these PRPs is lacking. Methods: Two types of PRPs, including autologous protein solution (APS), and leukocyte-poor PRP (LP-PRP) along with whole blood (WB) and platelet-poor plasma (PPP) were characterized for platelet content, leukocyte content, and composition in 10 healthy volunteers (HV) (the controlled laboratory study) and 16 KOA patients (a retrospective observational study). Additionally, the levels of the platelet-derived growth factor (PDGF)-BB, and different cytokines were estimated in HV. Results: In HV, the concentrations of platelets and leukocytes, levels of different cytokines, including interleukin 1 receptor antagonist (IL-1Ra), soluble TNF receptor type II (sTNF-RII), and IL-1β, and the ratio of IL-1Ra/IL-1β were significantly higher in APS, whereas the PDGF-BB was higher in LP-PRP than APS. In KOA patients, a higher concentration of platelets was observed in LP-PRP, and a higher concentration of leukocytes was observed in APS than LP-PRP. Following the PAW classification system, LP-PRP was classified as P2-B type in HV (51.3 × 104/μl) and KOA (53.4 × 104/μl), whereas APS was classified as P3-A type in HV (110.1 × 104/μl) and P2-A type in KOA (29.0 × 104/μl). In a retrospective observational study, the KOA patients who underwent APS injection had a higher incidence of arthralgia, and this arthralgia lasted for a longer time than LP-PRP injection in the same individual. Discussion: The quality of the two PRPs differed distinctively depending on their preparation methods, which might affect their clinical efficacies and adverse events. Therefore, the characterization of these parameters should be prioritized while choosing PRP.

To identify factors associated with quantified rotatory stability (pivot-shift phenomenon) in the anterior cruciate ligament (ACL)-injured knee joint. A consecutive sample of 54 patients who were diagnosed with an ACL injury and admitted to our hospital to undergo ACL reconstruction were enrolled in this study. Antero-lateral rotatory laxity of the knee joint was quantified using a Kinematic Rapid Assessment device (KiRA; Orthokey LTD) under spinal block before initiating reconstruction of the ACL. Univariate and multivariate regressions were performed assuming relationships between patient characteristics (independent variables) and quantified antero-lateral rotatory stability (a dependent variable). It was observed that a low BMI (t = − 1.659, n.s.), greater passive knee extension angle (t = 2.374, P = 0.023), and a narrower lateral femoral condyle width index (t = − 1.712, n.s.) could be candidates associated with the antero-lateral rotatory instability, using univariate analysis. Employing multivariate analysis controlling for these three variables, that the range of passive knee extension was found to be significantly associated with antero-lateral rotatory instability in the ACL-injured knee joint (t = 2.21, P = 0.035). Patients were then divided into two groups (pivot-shift negative versus positive groups) based on the KiRA-documented quantified pivot-shift test. Interestingly, 23.3% of patients were pivot-shift negative, even though their ACL was confirmed as a complete rupture by arthroscopic observations. The degree of passive knee extension was 2.3 ± 4.5 (mean ± SD) in the pivot-shift negative group, while it was 6.8 ± 6.6 in the pivot-shift positive group (n.s.). The lateral femoral condyle width index was 36.6 ± 2.0% in the pivot-shift negative group, and it was significantly wider than in the pivot-shift positive group (33.8 ± 2.6%, P = 0.0046). Finally, we estimated that the risk of positive pivot-shift depends on the degree of knee extension. The logistic regression analysis revealed that genu recurvatum significantly increased the odds ratio for positive pivot-shift (OR = 3.08, P = 0.047, 95% CI = 1.017–9.350). This study revealed that greater antero-lateral rotatory instability in patients with a complete ACL rupture was associated with genu recurvatum and small lateral femoral condyle. These factors should be considered as predictors of a poor outcome from an ACL reconstruction due to a higher load on the ACL graft, and therefore, the attending physicians should modify the treatment strategies accordingly. This study indicates that joint hyperlaxity and bone morphology contribute to the rotational stability of the knee joint, in addition to the ACL and antero-lateral complex (ALC). IV.

Using intra-operative findings and clinical results, including return to play (RTP) at the pre-injury level, this study investigated the causes of primary graft failure after revision anterior cruciate ligament (ACL) reconstruction with bone-patellar-tendon-bone (BPTB) autografts.A total of 54 patients were followed for a mean of 38.2 ± 10.2 months post-surgery. Subjective and objective results were evaluated using single assessment numeric evaluation (SANE) scores, Lachman tests, KT-2000 arthrometer results, and pivot-shift tests. The change in each patient's Tegner activity scale and RTP at the pre-injury level were also evaluated.Inappropriate positioning of the tunnels was the most important reason (54%) for primary graft failure. After revision surgery, anterior knee stability was significantly improved (1.2 (mean) ± 1.2 (SD)mm vs 4.5(mean) ± 1.9 (SD)mm; P0.01). Two (4%) patients sustained revision graft ruptures while two (4%) sustained contralateral knee ACL tears. The rate of RTP at the pre-injury level was 67% (36 patients), and mean SANE scores at the time of RTP were higher than before surgery (74.8 ± 13.8 points vs 24.1 ± 16.4; P0.001). The average time from primary graft failure to revision surgery was shorter (12.2 (mean) ± 4.0 (SD) vs 37.6 (mean) ± 8.8 (SD)months; P0.01) and the ratio of major cartilage injury was lower (39% vs 83%; P0.05) in the RTP group than that in the non-RTP group.The time from primary graft failure to revision surgery and the extent of the cartilage injury are major factors in RTP after revision ACL reconstructions.

Over a 11-year period, we investigated the incidence of anterior cruciate ligament (ACL) injuries and the clinical outcomes after ACL reconstruction with hamstring autografts in two homogenous cohorts of rugby players.Two teams, including those in elite (94 players) and high school (290 players) clubs, were followed.Isolated ACL injuries occurred in 28 players (12 elite, 16 high school). The incidence during match play was 1.26 per 1000 player-hours (95% confidence interval [95% CI]: 0.48-2.05) among elite players and 0.97 per 1000 player-hours (95% CI: 0.30-1.64) among high school players. After ACL reconstruction, 26 players (12 elite, 14 high school) were successfully contacted for follow-up at a mean of 71.9 months. None (0%) of the elite and 4 (29%) of the high school players experienced graft ruptures. Seven (58%) elite and 10 (91%) high school players were fearful of reinjury; the mean time to overcome this fear was 6.1 ± 4.9 months among elite players and 17.5 ± 26.0 months among high school players.In conclusion, young rugby players experienced inferior outcomes after ACL reconstruction with hamstring autografts compared with their older counterparts.

Summary Objective The aim of this study was to examine the osteoarthritis (OA)-related structural changes associated with histological synovitis in end-stage knee OA patients. Methods Forty end-stage knee OA patients (female: 88%, mean age: 71.8 y) were enrolled. All participants underwent 3.0-T MRI. The structural changes, such as cartilage morphology, subchondral bone marrow lesion (BML), subchondral bone cyst (SBC), subchondral bone attrition (SBA), osteophytes, meniscal lesion and synovitis, were scored using the whole-organ MRI scoring (WORMS) method. Synovial samples were obtained from five regions of interest (ROIs) of the knee joint during total joint replacement surgery. The associations between the histological synovitis score (HSS) and WORMS or the synovial expression levels of cyclooxygenase (COX)-2, interleukin (IL)-1β, IL-6 and transforming growth factor (TGF)–β were examined using Spearman's correlation coefficient. Results Among the seven OA-related structural changes, the BML, SBC, SBA and synovitis were significantly associated with the HSS ( r = 0.33, 0.35, 0.48 and 0.36, respectively), while other morphological changes were not. Although synovial COX-2, IL-1β or IL-6 expression levels were not associated with the HSS, the synovial TGF-β expression levels were associated with the HSS. Conclusion The presence of BML, SBC and SBA was associated with histological synovitis in end-stage knee OA patients.

Osteoporosis is a disease characterized by a low bone volume and deterioration of the bone quality, which increases the risk of low-energy fractures. Bisphosphonate (BP) treatment increases the bone mass and reduces the risk of fractures in patients with osteoporosis by suppressing bone resorption. In spite of its clinical benefits, the long-term use of BPs has been linked to the occurrence of atypical femoral fractures (AFFs). Although the evidence had been controversial regarding the association between the occurrence of AFFs and BP use, more recent studies with radiographic adjudication have indicated the significant associations between them. However, the pathogenesis of AFFs is not completely understood. The most popular hypothesis has suggested that the suppression of bone turnover by BPs is responsible; however, some recent reports have implied the involvement of pathophysiological alterations of the bone quality and fracture repair process. In this review, we summarize and discuss the epidemiology, risk factors and pathology of AFFs.

Despite objectively good results, up to 70 % of individuals may not return to their pre-injury level of sports activity after anterior cruciate ligament (ACL) reconstruction surgery. Although psychological responses have been shown to affect outcomes after ACL injury, an appropriate means of measuring their effects, in addition to functional status, has not been determined. The purpose of this study was to develop a patient-reported questionnaire for measuring psychological factors associated with outcomes after ACL injury and to evaluate its reliability, validity, and responsiveness. After item analysis based on the results of two pilot studies and a short relevance assessment, 25 questionnaire items were selected for the Japanese Anterior Cruciate Ligament Injury Questionnaire 25 (JACL-25) and assessed for validity, reliability, and responsiveness in subjects with ACL injury. The JACL-25 had no floor or ceiling effects and no confounding factors. A Cronbach’s alpha coefficient of 0.981 and a Guttman split-half coefficient of 0.983 indicated excellent reliability. Large standardized response means (1.30–1.62) and effect sizes (0.96–1.51) from the preoperative to postoperative period indicated good responsiveness. Construct structures were created, and these items were separated into three domains. Strong correlations between the JACL-25 and the International Knee Documentation Committee Subjective Knee Form (r s = −0.86), Lysholm Score (r s = −0.73), and Tegner Activity Scale (r s = −0.65) indicated good concurrent validity of the JACL-25. The present study demonstrated that the JACL-25 was valid, reliable, and responsive enough to evaluate psychological factors associated with outcomes in individuals with ACL injuries. Diagnostic study, Level III.

Objective To assess the longitudinal outcomes of osteochondritis dissecans (OCD) fixation and to detect the influencing factor for the results of OCD. Methods 22 OCD fixation using bioabsorbable pins were assessed Lysholm score, Tegner activity scale and KOOS4 at preoperative, postoperative short (3.0 years) and mid-long (11.9 years) term. Results Postoperative Lysholm score was significantly better than the preoperative time. There was no factor influencing KOOS4 at mid-long term. Conclusion OCD fixation contributes good results for a long time regardless of skeletal maturity, the size and the severity of OCD.

SummaryObjectiveThe aim of the present study was to examine whether the degenerative and morphological changes of articular cartilage in early stage knee osteoarthritis (OA) occurred equally for both femoral- and tibial- or patellar- articular cartilage using magnetic resonance imaging (MRI)-based analyses.DesignThis cross-sectional study was approved by the ethics committee of our university. Fifty patients with early stage painful knee OA were enrolled. The patients underwent 3.0 T MRI on the affected knee joint. Healthy volunteers who did not show MRI-based OA changes were also recruited as controls (n = 19). The degenerative changes of the articular cartilage were quantified by a T2 mapping analysis, and any structural changes were conducted using Whole Organ Magnetic Resonance Imaging Score (WORMS) technique.ResultsAll patients showed MRI-detected OA morphological changes. The T2 values of femoral condyle (FC) (P

Purpose Atypical femoral fractures (AFFs) are stress-related fractures that are speculated to associate with long-term treatment with bisphosphonates for osteoporosis. A history of AFF is a high risk factor for the development of a subsequent AFF in the same location of the contralateral femur, suggesting that a patient's individual anatomical factor(s) are related to the fracture site of AFFs. In this study, we investigated the radiographs of fourteen AFFs (four bilateral fractures among ten patients) treated at six hospitals associated with our university between 2005 and 2010. The fracture site and standing femorotibial angle (FTA), which reflects the mechanical axis of the lower limb, were measured on weight-bearing lower limb radiographs. The fracture site and FTA of patients with typical femoral fractures (TFF) were compared to those of patients with AFFs. The correlations were examined using Spearman's rank correlation coefficients. The fracture locations in the femora were almost the same in the patients with bilateral AFFs. There was a positive correlation between the fracture site and the standing FTA in the patients with AFFs (r = 0.82, 95% confidence interval; 0.49 to 0.94), indicating that the larger the standing FTA (varus alignment), the more distal the site of the fracture in the femur. The FTA of the patients with atypical diaphyseal femoral fracture were significantly larger compared to that of those with not only atypical subtrochanteric fractures but also TFFs. In conclusion, the fracture sites of AFFs are associated with the standing lower limb alignment, while those of TFFs are not.

The long-term treatment with anti-resorptive drugs for osteoporotic patients is suggested to be associated with an increase in atypical femoral fractures (AFFs). However, their incidence, patient characteristics, and risk factors have not been fully elucidated especially in Asian countries. This retrospective observational cohort study found fourteen AFFs in ten patients (four bilateral fractures) among 2,238 hip and femoral shaft fractures treated in our associated hospitals between 2005 and 2010; this incidence (0.63%) was similar to Caucasians. Of the ten patients with AFFs, nine (90%) and six (60%) were using bisphosphonates (BPs) and glucocorticoids (GCs), respectively, compared to 14.3 and 8.6% for patients with typical femoral fractures who were using these agents. As comorbid conditions, five patients had collagen disease (CD) and two had diabetes. A fracture location-, age- and gender-matched (1:3) case-control study revealed that administration of BPs, GCs, and suffering from collagen disease (CD) were significant risk factors for developing AFFs [odds ratios 36.0 (95% confidence intervals 3.8-342.2), 13.0 (2.3-74.1) and 9.0 (1.6-50.3), respectively]. Interestingly, all of the patients with atypical subtrochanteric femoral fractures, defined as those within 5 cm of the lesser trochanter, were taking GCs due to CD, and the age of these patients (average of 54.8 years) was significantly younger than those with atypical diaphyseal femoral fractures (average of 77.2 years, p < 0.05). In conclusion, the incidence of AFFs in the Japanese population was similar to that of Caucasians, and taking BPs and GCs and suffering from CD were risk factors for developing AFFs.

ObjectiveThe fifth metatarsal stress fracture is a common injury among football players. Although several risk factors have been proposed, the association between the playing surface and development of fifth metatarsal stress fractures (MT-5) has not been evaluated. We conducted an epidemiological study using a computer-based survey to investigate the association between the playing surface and development of MT-5.MethodsThis study included 1854 football players, of which 41 experienced MT-5 within the past 24 months. Baseline demographic data and the percentage of time spent playing on artificial turf and clay fields were compared between the non-MT-5 and MT-5 player groups, and the risks for development of MT-5 associated with the playing surfaces were estimated by univariate and multivariate analyses.ResultsThere were significant differences in body mass index, years of play, playing categories and playing time on artificial turf between non-MT-5 and MT-5 groups (p80% of the time increased (3.44: 1.65 to 7.18), and for playing on a clay field 61%–80% of the time, the OR decreased (0.25: 0.11 to 0.59).ConclusionsA higher percentage of playing time on an artificial turf was a risk factor for developing MT-5 in football players. This finding could be beneficial for creating strategies to prevent MT-5.

Oxidative stress contributes to the pathogenesis of age-related diseases as well as bone fragility. Our previous study demonstrated that copper/zinc superoxide dismutase (Sod1)-deficient mice exhibit the induction of intracellular reactive oxygen species (ROS) and bone fragility resulting from low-turnover bone loss and impaired collagen cross-linking (Nojiri et al. J Bone Miner Res. 2011;26:2682–94). Mechanical stress also plays an important role in the maintenance of homeostasis in bone tissue. However, the molecular links between oxidative and mechanical stresses in bone tissue have not been fully elucidated. We herein report that mechanical unloading significantly increased intracellular ROS production and the specific upregulation of Sod1 in bone tissue in a tail-suspension experiment. We also reveal that Sod1 loss exacerbated bone loss via reduced osteoblastic abilities during mechanical unloading. Interestingly, we found that the administration of an antioxidant, vitamin C, significantly attenuated bone loss during unloading. These results indicate that mechanical unloading, in part, regulates bone mass via intracellular ROS generation and the Sod1 expression, suggesting that activating Sod1 may be a preventive strategy for ameliorating mechanical unloading–induced bone loss. © 2013 American Society for Bone and Mineral Research.

To identify unknown risk factors associated with fifth metatarsal stress fracture (Jones fracture). A case–controlled study was conducted among male Japanese professional football (soccer) players with (N = 20) and without (N = 40) a history of Jones fracture. Injury history and physical examination data were reviewed, and the two groups were compared. Univariate and multivariate logistic regression controlling for age, leg dominance and body mass index were used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to describe the association between physical examination data and the presence or absence of Jones fractures. From 2000 to 2014, among 162 professional football club players, 22 (13.6%; 21 Asians and one Caucasian) had a history of Jones fracture. Thirteen out of 22 (60%) had a Jones fracture in their non-dominant leg. The mean range of hip internal rotation (HIR) was restricted in players with a history of Jones fracture [25.9° ± 7.5°, mean ± standard deviation (SD)] compared to those without (40.4° ± 11.1°, P

Muscle strain of the gastrocnemius medial head mainly occurs at the musculotendinous junction (MTJ), and stiffness is a risk factor. Shear wave elastography (SWE) measures elasticity by determining the propagation velocity. The aim of this study was to measure the elasticity of the normal muscle and aponeurosis in the MTJ of the gastrocnemius medial head using SWE, thus obtaining information relevant to muscle strain at this point. Forty-one volunteers (82 legs) were recruited and the gastrocnemius medial heads were examined at four points: three on the aponeurosis, namely at the center of the MTJ (Central), 10 mm proximal to it (Proximal) and 10 mm distal to it (Distal); and at one on the muscle belly (Muscle). The measurements were compared among the points, between males and females, and between younger and middle-aged subjects. Correlations between the elastic modulus and age were also examined. The elastic moduli at Proximal, Central, Distal, and Muscle were 2.82 ± 0.53 m/s, 3.43 ± 0.83 m/s, 4.83 ± 1.56 m/s, and 2.25 ± 0.43 m/s, respectively. These values differed significantly among the points of the aponeurosis, Distal having the highest modulus followed by Central. The elastic moduli were significantly greater in males than females at Distal and Muscle and in younger subjects than middle-aged subjects at Muscle. No significant correlations between elastic modulus and age were observed for any point. SWE could be a feasible method for quantifying the elasticity of muscle and aponeurosis in the MTJ of the gastrocnemius medial head. Clin. Anat. 30:114-119, 2017. © 2016 Wiley Periodicals, Inc.

Osteoporosis is a systemic skeletal disease that is characterized by low bone mass and the structural deterioration of bone tissue leading to bone fragility and an increased risk of fracture. Fractures, most notably of the hip, are associated with significant morbidity and mortality. From a patient’s perspective, a hip fracture and the subsequent loss of mobility and autonomy often represent a major drop in the quality of life.

The aging process correlates with the accumulation of cellular and tissue damage caused by oxidative stress. Although previous studies have suggested that oxidative stress plays a pathologic role in the development of bone fragility, little direct evidence has been found. In order to investigate the pathologic significance of oxidative stress in bones, we analyzed the bone tissue of mice deficient in cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD, encoded by the Sod1 gene; Sod1(-/-)). In this study, we showed for the first time that in vivo cytoplasmic superoxide caused a distinct weakness in bone stiffness and decreased BMD, aging-like changes in collagen cross-linking, and transcriptional alterations in the genes associated with osteogenesis. We also showed that the surface areas of osteoblasts and osteoclasts were decreased significantly in the lumbar vertebrae of Sod1(-/-) mice, indicating the occurrence of low-turnover osteopenia. In vitro experiments demonstrated that intracellular oxidative stress induced cell death and reduced the proliferation in primary osteoblasts but not in osteoclasts, indicating that impaired osteoblast viability caused the decrease in osteoblast number and suppressed RANKL/M-CSF osteoclastogenic signaling in bone. Furthermore, treatment with an antioxidant, vitamin C, effectively improved bone fragility and osteoblastic survival. These results imply that intracellular redox imbalance caused by SOD1 deficiency plays a pivotal role in the development and progression of bone fragility both in vivo and in vitro. We herein present a valuable model for investigating the effects of oxidative stress on bone fragility in order to develop suitable therapeutic interventions.

The sympathetic nervous system suppresses bone mass by mechanisms that remain incompletely elucidated. Using cell-based and murine genetics approaches, we show that this activity of the sympathetic nervous system requires osteopontin (OPN), a cytokine and one of the major members of the noncollagenous extracellular matrix proteins of bone. In this work, we found that the stimulation of the sympathetic tone by isoproterenol increased the level of OPN expression in the plasma and bone and that mice lacking OPN (OPN-KO) suppressed the isoproterenol-induced bone loss by preventing reduced osteoblastic and enhanced osteoclastic activities. In addition, we found that OPN is necessary for changes in the expression of genes related to bone resorption and bone formation that are induced by activation of the sympathetic tone. At the cellular level, we showed that intracellular OPN modulated the capacity of the β2-adrenergic receptor to generate cAMP with a corresponding modulation of cAMP-response element binding (CREB) phosphorylation and associated transcriptional events inside the cell. Our results indicate that OPN plays a critical role in sympathetic tone regulation of bone mass and that this OPN regulation is taking place through modulation of the β2-adrenergic receptor/cAMP signaling system.

Per-1 is one of the clock genes and is known to regulate various biological events including bone mass determination. Parathyroid hormone is anabolic to bone while the mechanism of its action is not fully understood. Here, we examined the role of PTH on Per-1 gene expression under osteoblast specific PTH signaling. Constitutively active PTH receptor (caPPR) expressed specifically in osteoblasts in transgenic mice activates Per-1 gene expression in bone. This is specific as expression of other clock gene Bmal-1 is not affected by caPPR over-expression. Per-1 is also expressed in osteoblastic cell line. Interestingly, Per-1 expression is required for PTH signaling-induced CRE dependent transcription. This is forming a positive feed back loop in the anabolic action of PTH signaling and Per-1 in bone. These data indicate that PTH singling in osteoblasts activates Per-1 gene expression in vivo in association with its anabolic action in bone at least in part through the regulation of transcriptional events.

Acupuncture as a vital component of traditional medical systems of the Far East has been used to restore and maintain health for over three millennia. However, the neurobiological correlates of this therapy remain largely unknown. The purpose of this study was therefore to determine the effect of enpishin acupuncture (press tack needles (PTN)) on autonomic function, WBC count, and oxidative stress between subjects that received either verum or placebo PTN treatment. Twenty men (mean(SD) age: 36.7(5.1) years) who provided oral consent were randomized to receive either verum PTN (n = 9) or placebo PTN (n = 11). Bi-Digital O-Ring Test (BDORT) was used to select the acupoints for each participant. Autonomic function and oxidative stress level were analyzed before and after the treatment via heart rate variability (HRV) and free radical analysis system (FRAS4), respectively. Pre- and post-treatment WBC count was also evaluated. Verum PTN group had a statistically significant increase (p = 0.008) in Ln TP, an index of overall autonomic activity. Subjects in this group also had a significantly greater (p = 0.006) variation in Ln TP than the placebo PTN group in response to the treatment. Similarly, Ln HF of subjects receiving verum PTN showed a marked increase (p = 0.0026) after the treatment. Moreover, a significantly greater (p < 0.001) variation in mean Ln HF before and after the treatment was noted in the verum group than the placebo group, reflecting a greater parasympathetic activation in the former. In contrast, sympathetic activity was not significantly influenced by verum PTN based on the lack of observed changes in LF/HF ratio. In addition, both groups failed to demonstrate significant variations in pre- and post-treatment mean Ln LF/HF ratio. Further, no significant intergroup difference was found with regard to mean variation in Ln LF/HF ratio. Verum PTN did not induce significant changes in WBC count and markers of oxidative stress, namely reactive oxygen species (ROM) and biological antioxidant potential (BAP). However, a comparison of variations in pre- and post-treatment mean WBC count showed a significant difference (p = 0.020) between the two treatment modes: verum group showed a slight increase (225 ± 384.5), while placebo group showed a minimal decrease (–190 ± 272.6). Our findings suggest that PTN increases overall autonomic activity, particularly the parasympathetic function.

Schnurri (Shn)-2 is a transcriptional modulator of bone formation and bone resorption and its deficiency causes low turnover state with higher cancellous bone mass due to the defects in osteoclasts that exceeds the defects in osteoblasts in mice. We addressed whether such low turnover of bone remodeling in Shn2 deficiency may be modulated in the absence of estrogen that induces high turnover state in vivo. Ovariectomy reduced bone mass in wild type compared to sham operated control mice and such reduction in bone mass was also observed in Shn2 deficient mice. However, due to the high levels of basal bone mass in Shn2 deficient mice, the bone mass levels after ovariectomy were still comparable to sham operated wild-type mice. Analysis indicated that estrogen depletion increased bone resorption at similar levels in wild type and Shn2 deficient mice though the basal levels of osteoclast number was slightly lower in Shn2-deficient mice. In contrast, basal levels of bone marrow cell mineralization in cultures were low in Shn2-deficeint mice while estrogen depletion increased the mineralization levels to those that were comparable to sham wild type. This indicates that Shn2-deficient mice maintain bone mass at the levels comparable to wild-type sham mice even after ovariectomy-induced bone loss and this correlates with the high levels of mineralization activity in bone marrow cells after ovariectomy. J. Cell. Physiol. 226: 573–578, 2011. © 2010 Wiley-Liss, Inc.

Bone marrow abnormalities (BMAs) detected on magnetic resonance imaging (MRI) are suggested to be involved in the pathogenesis of osteoarthritis (OA), and the size of the BMAs is associated with the progression of OA. However, it still remains unclear as to whether the associations of BMA size and OA severity are observed equally or whether they differ from early to advanced stages of OA. In the present study we examined whether BMA enlargement and OA progression differed according to the severity of OA.One hundred and eighty patients with knee OA were enrolled in the present study, and 122 of these patients completed this study. Radiography and knee MRI were done two times in all patients, at the baseline and 6 months or later at the time of patient follow-up. The severity of OA was evaluated by radiography using the Kellgren-Lawrence (K-L) grade. The patients who showed a deterioration in the K-L grade during the follow-up examination (59/122) were defined as the deterioration group. T2-weighted fat-suppressed MR images were used to score the size of the BMAs according to the whole-organ magnetic resonance imaging score (WORMS). A new scoring system, the spacial BMA score (s-score) was defined to assess the size of the BMAs three-dimensionally.In patients with K-L grade 2, the s-score changes during the follow-up period in the deterioration group were significantly increased in comparison to those in the no-change group (P = 0.04), and no significant s-score changes were observed in patients with either K-L grade 1 or 3 (P = 0.07 and 0.57) between the deterioration group and the no-change group during the follow-up examination. In patients with K-L grade 3, the s-score at the baseline in the deterioration group was higher than that in the no-change group (P = 0.05).The relationship between the size and enlargement of BMAs and the progression of OA changed depending upon the severity of OA.

Osteoarthritis (OA) is a disease that primarily results in the degeneration and destruction of the articular cartilage. However, synovitis that occurs secondarily by this primary phenomenon is crucial for both the structural and symptomatic progression of the disease. The Japanese Knee Osteoarthritis Measure (JKOM) was created as an outcome measure for Japanese patients with knee OA. This study was conducted to determine whether synovitis in knee OA correlates with the current disability of patients with knee OA who required total knee arthroplasty (TKA). Thirty-four Japanese patients with end-stage knee OA who required TKA were included in this study. The visual analog scale (VAS, 0-100) for pain and the JKOM score, as well as the Western Ontario and McMaster Universities Arthritis Index (WOMAC), were examined before the operation. Synovial samples were taken at the time of the operation. A histological analysis and gadolinium-enhanced magnetic resonance imaging (Gd-MRI) were conducted to evaluate synovitis. Correlations between the synovitis score evaluated by histological analysis and Gd-MRI with either the pain VAS score or the JKOM score were examined using Spearman's rank correlation coefficient. Neither the synovitis scores evaluated by the histological analysis nor those by a Gd-MRI correlated with the pain VAS score (n = 34, r = 0.25, p = 0.18 and r = 0.08, p = 0.75, respectively) and WOMAC (n = 14, r = 0.35, p = 0.22 and r = 0.45, p = 0.16, respectively) of the patients. However, they significantly correlated with the JKOM score of the patients (n = 34, r = 0.55, p = 0.001 and r = 0.71, p = 0.001, respectively). The severity of synovitis in OA was closely correlated with the current functional impairment and disability of the patients receiving TKA with end-stage knee OA.

Background:The fifth metatarsal bone is a common site of stress fractures in soccer athletes. Although several endocrine risk factors for stress fractures have been proposed, the endocrine risks for fifth metatarsal (5-MT) stress fractures have not been evaluated.Methods:To evaluate the endocrine risks of fifth metatarsal stress fractures, we conducted a cumulative case-control study. The present study included 37 athletes, of which 18 had a history of a zone 2 or zone 3 fifth metatarsal stress fracture and 19 controls. We analyzed serum 25-hydroxyvitamin D (25-OHD), serum parathyroid hormone (PTH), as well as biochemical markers of bone turnover by univariate or multivariate analyses.Results:Logistic regression analyses adjusted for multiple confounders revealed that insufficient serum 25-OHD levels less than 30 ng/mL (odds ratio [OR], 23.3), higher serum PTH levels (OR, 1.01), or higher serum bone-specific isoform of alkaline phosphatase levels (OR, 1.10) rather than serum tartrate-resistant acid phosphatase 5b were associated with statistically significantly increased odds of 5-MT stress fractures. A postestimation calculation demonstrated that 25-OHD levels of 10 and 20 ng/mL were associated with 5.1 and 2.9 times greater odds for 5-MT stress fractures, respectively.Conclusion:25-OHD insufficiency was associated with an increased incidence of 5-MT stress fractures. This insight may be useful for intervening to prevent 5-MT stress fractures.Level of Evidence:Level III, case-control study.

Background Platelet-rich plasma (PRP) therapy has become an increasingly popular treatment for orthopaedics and sports-related injuries, and various clinically available PRP preparation methods exist. However, the differences in PRP quality among numerous preparation methods remain unclear. Specifically, the benefit of including leukocytes in the PRP product remains controversial, and few studies have been conducted to evaluate the effects of the interaction between platelets and leukocytes on the growth factor concentrations. The aim of the present study was to compare the biological characteristics of PRPs focusing on the leukocyte concentration and composition. Methods Leucocyte rich (LR)-PRP, leucocyte poor (LP)-PRP, and pure-PRP were prepared from the peripheral blood of 6 healthy male volunteers (mean age: 31.3 years). The concentrations of platelets, leukocytes, erythrocytes, growth factors (transforming growth factor-beta 1: TGF-β1; fibroblast growth factor-basic: FGF-b; platelet-derived growth factor-BB: PDGF-BB; vascular endothelial growth factor: VEGF) and matrix metalloproteinase-9 (MMP-9) from each of the PRP samples were measured. Considering the interaction between platelets and leukocytes, correlations between platelets/leukocytes and growth factors/MMP-9 were analyzed using partial correlation coefficients. Results The platelet concentration did not differ among the three PRP preparation methods. Conversely, the leukocyte concentration was dramatically different: 14.9 ± 4.5 (10 3 /μl) in LR-PRP, 2.4 ± 1.3 (10 3 /μl) in LP-PRP, 0.2 ± 0.2 (10 3 /μl) in pure-PRP. The platelet concentration positively correlated with all growth factors. On the other hand, the leukocyte concentration positively correlated with PDGF-BB and the VEGF concentration, while it negatively correlated with FGF-b. Regarding catabolic factors, the MMP-9 concentration strongly correlated with the leukocyte concentration, while there was no correlation between the platelet and MMP-9 concentrations. Conclusions These findings demonstrate that leukocytes strongly influence the quality of PRPs. Therefore, modifying the PRP preparation method according to the pathology is essential to achieve better clinical results with PRP therapy.

To assess return to play and the frequencies of graft failure in rugby players after anterior cruciate ligament (ACL) reconstruction using a hamstring autograft augmented with an artificial ligament and to compare outcomes between rugby players aged20 and ≥20 years over the long term.A consecutive series of 146 rugby players who underwent ACL reconstruction with a hamstring autograft augmented with an artificial ligament were retrospectively reviewed. The study population was further divided into 2 groups aged20 years and20 years and compared.Twenty-five patients could not be followed up, and 121 (83%) were evaluated. Most patients (90%,20 years; 92%, ≥20 years) returned to play after ACL reconstruction. At an average follow-up period of 56.5 months, 16% of the patients sustained an ACL graft rupture. Regarding age,20 years (n = 58, 48%) and ≥20 years (n = 63, 52%), younger players had a significantly higher failure rate (23% vs 5%, respectively; P = .006) and a shorter time to failure (22.8 ± 13.2 vs 35.4 ± 15.4 months, respectively; P = .006) than older players.Rugby players were likely to return to play after ACL reconstruction with a hamstring autograft. However, there was a higher risk of graft failure in younger players than in older players. On the basis of this study, we conclude that the hamstring autograft may not be an appropriate graft source to use in a younger active population, including rugby players.Level III, retrospective comparative study.