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Clodronate-liposome is used for depleting mononuclear phagocytes associated with ischemia-reperfusion injury. We hypothesized that administration of clodronate-liposome into the perfusate during ex vivo lung perfusion could reduce mononuclear phagocytes and attenuate ischemia-reperfusion injury.First, the number of mononuclear phagocytes in flushed grafts (minimum cold ischemic time, 6-hour cold ischemic time, 15-hour cold ischemic time, and 18-hour cold ischemic time; n = 6 each) was determined using flow cytometry. Second, grafts (15-hour cold ischemic time) were allocated to control or clodronate (n = 5 each). In the clodronate group, clodronate-liposome is administered into the perfusate. After 4 hours of ex vivo lung perfusion, the number of mononuclear phagocytes in the perfusate and lung tissues was measured. Third, grafts (15-hour cold ischemic time) were allocated to control or clodronate (n = 6 each). After 4 hours of ex vivo lung perfusion, the left lungs were transplanted and reperfused for 2 hours. Lung function was evaluated, and samples were analyzed.First, mononuclear phagocytes remain in flushed grafts after prolonged cold ischemia. Second, the number of mononuclear phagocytes in lung tissues after ex vivo lung perfusion was significantly reduced in the clodronate group (P = .008). Third, lung compliance and vascular resistance during ex vivo lung perfusion were significantly improved in the clodronate group (P .001 for both). Blood oxygenation and pulmonary edema were significantly improved in the clodronate group after 2 hours of reperfusion (P = .015 and P = .026, respectively). Histological findings showed reduced lung injury in the clodronate group (P = .013).Administration of clodronate-liposome into the perfusate during ex vivo lung perfusion resulted in a significant reduction of mononuclear phagocytes in donor lungs, leading to attenuation of ischemia-reperfusion injury.

Objective We have previously reported that stimulation of mouse bone marrow-derived macrophages with tumor necrosis factor (TNF) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells. We undertook this study to clarify the characterization and function of human TNF and IL-6-induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. Methods Peripheral blood monocytes were cultured with a combination of TNF and IL-6, TNF alone, IL-6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL-6-induced osteoclasts or RANKL-induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole-body bone mineral density (BMD) was examined. Results Peripheral blood monocytes stimulated with a TNF and IL-6-induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL-6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL-6-induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL-6-induced osteoclasts, but not in RANKL-induced osteoclasts. The number of TNF and IL-6-induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL-induced osteoclast numbers negatively correlated with the whole-body BMD of the same patients. Conclusion Our results demonstrate that TNF and IL-6-induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.

To validate and establish targets for the physician-based clinical scale for foot surgery in rheumatoid arthritis (RA) patients based on patient-reported outcomes from a multicenter prospective cohort.We collected data on demographics, values from the RA foot and ankle scale by the Japanese Society for Surgery of the Foot (JSSF-RA), and patient-reported outcomes (PROs) including the Health Assessment Questionnaire Disability Index (HAQ-DI) before (baseline) and 6 and 12 months after joint surgery. Target values for JSSF-RA were determined according to the lower limit of the 95% CI of JSSF-RA in patients with HAQ-DI ≤0.5 after adjusting for age and sex. We used multiple linear regression analysis to examine potential predictors of JSSF-RA target achievement at baseline.Cross-sectional analysis was conducted on data from 417 cases. The JSSF-RA target for foot and ankle surgery was set at 74 according to the JSSF-RA value corresponding to HAQ-DI ≤0.5 (mean 77.6, 95% CI: 74.3-80.9). Longitudinal analysis of patients who underwent foot surgery (A JSSF-RA value of 74 represents an important target for patients with RA who have undergone foot surgery. In order to achieve this target, the timing of the surgery should be considered in the treatment of established RA patients.

Lung ischemia-reperfusion injury (IRI) is a form of acute lung injury characterized by nonspecific alveolar damage and lung edema due to robust inflammation. Little is known about the roles of specialized proresolving lipid mediators (SPMs) in lung IRI. Therefore, we aimed to evaluate the dynamic changes in endogenous SPMs during the initiation and resolution of lung IRI and to determine the effects of SPM supplementation on lung IRI.We used a rat left hilar clamp model with 90 min of ischemia, followed by reperfusion. Dynamic changes in endogenous SPMs were evaluated using liquid chromatography-tandem mass spectrometry.Endogenous SPMs in the left lung showed a decreasing trend after 1 h of reperfusion. Oxygenation improved between 3 and 7 d following reperfusion; however, the level of endogenous SPMs remained low compared with that in the naïve lung. Among SPM receptors, only formyl peptide receptor type 2 (ALX/FPR2) gene expression in the left lung was increased 3 h after reperfusion, and the inflammatory cells were immunohistochemically positive for ALX/FPR2. Administration of aspirin-triggered (AT) resolvin D1 (AT-RvD1) and AT lipoxin A4 (AT-LXA4), which are agonistic to ALX/FPR2, immediately after reperfusion improved lung function, reduced inflammatory cytokine levels, attenuated lung edema, and decreased neutrophil infiltration 3 h after reperfusion. The effects of AT-RvD1 and AT-LXA4 were not observed after pretreatment with the ALX/FPR2 antagonist.The level of intrapulmonary endogenous SPMs decreased during lung IRI process and the administration of AT-RvD1 and AT-LXA4 prevented the exacerbation of lung injury via ALX/FPR2.

Objectives: Current advancements in neuromuscular electrical stimulation (NMES) include belt-shaped electrode skeletal muscle electrical stimulation (B-SES), which was developed to induce whole leg muscle contraction in a single session. Delivering the optimal amount of stimulation is critical in NMES; therefore, we set out to establish a method to determine the B-SES stimulation intensity needed to induce muscle contraction sufficient for clinical purposes. Methods: We used the Auto Tens Pro system (Homer Ion Laboratory), which is a B-SES device. Stimulation at 20 Hz was delivered for 5 s, followed by 2 s rest. Twenty-four patients who were hospitalized for musculoskeletal diseases were enrolled at two hospitals. Patients were randomly assigned to one of three groups of subjectively graded stimulation intensities: moderate, strong, or very strong. To achieve each target intensity, we developed a structured verbal instruction protocol that aimed to help therapists deliver the target level of stimulation. As a physiological assessment of muscle contraction, serum lactate levels were measured before and after a single 20-min B-SES session. Results: The electric current intensity required to achieve a target subjective muscle contraction gradually increase according to the subjective contraction level. The increase in serum lactate level was significantly larger in the very strong group than in the moderate group. Conclusions: B-SES stimulators have the potential to induce efficient muscle strengthening in patients with musculoskeletal diseases. The structured verbal protocol developed here could help therapists achieve the appropriate stimulation intensity for each patient.

Oncologic emergency (OE) was observed in as many as 36% of patients with skeletal metastasis from unknown primary malignancy in this study. Delirium and respiratory failure were only two significant prognostic risk factors, which suggest that many of the OEs in untreated advanced cancer patients have probable chance to resolve. Early detection followed by appropriate treatment of such OEs is recommended., Aim Patients with skeletal metastasis from prediagnosed primary malignancy sometimes have concurrent oncologic emergency (OE) during the first visit. This study aims to investigate the types of OEs and treatment outcome in such patients. Methods We have experienced 359 patients with skeletal metastasis from unknown primary malignancy. Among them, 130 patients required immediate admission for OE treatment (OE group), 229 patients had no OE and did not required immediate admission (non‐OE group). Results The recognized types of OE were spinal cord compression in 60 patients, cancer pain in 30, hypercalcemia in 19, delirium in 16, deep vein thrombosis in 13, acute renal failure in 6, respiratory failure in 3, gastrointestinal hemorrhage in 3, and disseminated intravascular coagulation in 1. The overall 5‐year survival rates were 28% and 37% in the OE and non‐OE groups, respectively (P

X-ray Talbot-Lau interferometry is one of the x-ray phase imaging methods that has high sensitivity in depicting soft tissues. Unlike earlier x-ray phase imaging methods that required particular types of x-ray sources, such as a synchrotron or a micro-focus x-ray tube, x-ray Talbot-Lau interferometry enables to perform clinical x-ray phase imaging using a conventional x-ray source with a relatively compact configuration. We developed an apparatus to depict cartilage in the metacarpophalangeal joints of the hands. In addition, we examined the apparatus performance by applying it to healthy volunteers and patients with rheumatoid arthritis (RA). Cartilage deformation, which is thought to be a precursor of destruction of the joints, was successfully depicted by the apparatus, suggesting a potential early diagnosis of RA.

1 Recently, powerful methods for determining grain boundary structures with the aid of machine learning techniques have been proposed. However, the application of these methods to oxide materials has not been reported. Herein, we describe a Bayesian optimization method (Kriging) for effective and accurate determination of grain boundary structures of complex materials, namely metal oxides, including MgO, TiO2, and CeO2. The efficiency of this method is ~500 times higher than that of conventional all candidate calculations. We reveal that the grain boundary energy surface of metal oxides is very similar to that of metallic materials, enabling the use of the Kriging method to determine grain boundary structures.

Background Loss of physical function is a clinical feature of RA. Total management including reconstructive joint surgery and rehabilitation should be needed for further improvements of physical function for established RA patients. In these days, it is very important to evaluate the effectiveness of joint surgery as well as drug therapy based on patient-reported outcome (PRO). Objectives The purpose of this study is to explore the relationship among depression, clinical variables and other PROs including physical function and improving of depressive status with joint surgery. Methods Multicenter prospective observational cohort study was conducted among patients who underwent elective joint surgery for RA from April 2012 to March 2016 (Study registration: UMIN000012649) (ref.1). In this study, we collected data at baseline and at 6 or 12 months after the surgery. These data were as follow; age, sex, disease duration, drug therapies, and disease activity (DAS28-CRP), and PRO measures [HAQ-DI, EQ-5D (QOL), pain VAS and BDI-II (depression)]. Correlation between BDI-II and other variables were determined using multiple liner regression analysis with forward stepwise. Results Totally, 346 patients before elective joint surgery were analyzed cross-sectionally. Mean age, disease duration, pain(VAS), DAS28, HAQ-DI, EQ-5D and BDI-II were 64.2 years, 17.0 years, 36.2 mm, 3.02, 1.111, 0.641 and 13.0, respectively. 52.6% of elective joint surgeries were in upper limbs and 47.4% were in lower limbs. Multiple liner regression analysis showed that HAQ-DI [β:-0.48, p Conclusion Loss of physical function is an important factor for impairment of depressive status as well as QOL in established RA patients. Improving of physical function with joint surgery in lower limbs caused improving of depressive status. Rheumatologists should take the joint surgery into consideration as effective intervention for treatment of established RA patients. References [1] Kojima T, et al. Int J Rheum Dis. 2018. doi: 10.1111/1756-185X.13394. Acknowledgement The registry used in this study was supported by a grant from the Ministry of Health, Labour and Welfare (H2424YN002-00) to Naoki Ishiguro Disclosure of Interests Toshihisa Kojima Grant/research support from: Chugai Pharmaceutical (Investigator Initiated Study), Novartis, Nippon Kayaku, Eli Lilly, Eisai, Speakers bureau: Chugai Pharmaceutical, Takeda Pharmaceutical, Pfizer, Eli Lilly Japan, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Astelas, UCB, Janssen Pharmaceutical, Tanabe Mitsubishi, Masayo Kojima: None declared, Hajime Ishikawa: None declared, Sakae Tanaka Grant/research support from: KYOCERA Corporation and Asahi Kasei Corporation, Consultant for: Amgen Astellas BioPharma K.K., KYOCERA Corporation, Pfizer and Daiichi Sankyo Co., Ltd., Speakers bureau: Asahi Kasei Corporation, Astellas Pharma Inc, Ayumi Pharmaceutical Corporation, Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe pharma Corporation, Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eli Lilly, Hisamitsu Pharmaceutical Co, Inc., Pfizer, Bristol-Myers., Keiichiro Nishida: None declared, Nobuhiko Haga: None declared, Yukio Masaoka: None declared, Jun Hashimoto: None declared, Hisaaki Miyahara: None declared, Yasuo Niki: None declared, Tomoatsu Kimura: None declared, Hiromi Oda: None declared, Shuji Asai Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Janssen, Takeda, and UCB Japan, Koji Funahashi: None declared, Naoki Ishiguro Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi-Sankyo, Eisai, Kaken, Mitsubishi Tanabe, Otsuka, Pfizer, Takeda, and Zimmer Biomet, Consultant for: Ono, Speakers bureau: Astellas, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, and Taisho Toyama

Background It is unclear whether antecedent primary malignancies (APMs) have any negative impact on the prognosis of soft tissue sarcoma (STS). We retrospectively reviewed STS patients with APMs (STS-APM) and compared their survival to those of STS only (STS-O). Methods Twenty-one cases of STS-APM from 2008 to 2017 in our institution were analyzed. One hundred and seventy cases of STS-O at the same period were compared as a control group. Overall survival was estimated using Kaplan-Meier survival curves and prognostic factors were analyzed using logistic regression analyses and contingency table analyses. Results As the final status of STS-APM patients, 12 patients were in disease-free survival, 5 were alive with disease, 3 have died of disease, and 1 has died of another disease. There was no case that died of APM. The 5-year overall survival rates were 88% in STS-APM and 78% in STS-O, showing no statistical significant ( p = 0.65). The 5-year overall survival rates in each stage of STS-APM and STS-O were 100/100% in stage I, 100/85% in stage II, 86/72% in stage III, and the 3-year overall survival rates were 67/51% in stage IV, with no statistical significance. With regard to prognostic factor, histological grade of STS was the only significant factor. Although antecedent radiotherapy tended to show a high odds ratio, the association was not statistically significant. Antecedent chemotherapy did not show any estimated prognostic risk. Conclusions Our study suggested that APM in STS patient would not be a negative prognostic factor.

To reduce the production of wear particles and subsequent aseptic loosening, we created a human articular cartilage-mimicked surface for a highly cross-linked polyethylene liner, whose surface grafted layer consisted of a biocompatible phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine). Although our previous in vitro findings showed that poly(2-methacryloyloxyethyl phosphorylcholine)-grafted particles were biologically inert and caused no subsequent bone resorptive responses, and poly(2-methacryloyloxyethyl phosphorylcholine) grafting markedly decreased wear in hip joint simulator tests, the clinical safety, and in vivo wear resistance of poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners remained open to question. Therefore, in the present study, we evaluated clinical and radiographic outcomes of poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners 5 years subsequent to total hip replacement in 68 consecutive patients. No reoperation was required for any reason, and no adverse events were associated with the implanted liners. The average Harris Hip Score increased from 38.6 preoperatively to 96.5 5 years postoperatively, and health-related quality of life, as indicated by the Short Form 36 Health Survey, improved. Radiographic analyses showed no periprosthetic osteolysis or implant migration. Between 1 and 5 years postoperatively, the mean steady-state wear rate was 0.002 mm/year, which represented a marked reduction relative to other highly cross-linked polyethylene liners, and appeared to be unaffected by patient-related or surgical factors. Although longer follow up is required, poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners improved mid-term clinical outcomes. The clinical safety and wear-resistance results are encouraging with respect to the improvement of long-term clinical outcomes with poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2007–2016, 2017.

Background Previously, we reported that novel osteoclast-like cells (OLCs) were induced, both in vitro and in vivo, from mouse bone marrow-derived macrophages (BMMs) by addition of a combination of TNFα and IL-61. Recently, O’Brien et al showed that TNF/IL-6 can drive osteoclastogenesis in BMMs from RANK-deficient mice2. Objectives We aimed to examine the differentiation of OLCs, which were induced by a combination of TNFα and IL-6 from human peripheral blood mononuclear cells (PBMCs) and CD14 +monocytes and to identify differences in molecular expression patterns between OLCs and conventional osteoclasts. Furthermore, we identified OLCs and osteoclasts on the bone tissue of the joint in patients with rheumatoid arthritis (RA). Methods PBMCs and CD14 +monocytes from healthy volunteers and/or RA patients were stimulated with TNFα and IL-6 or RANKL. Quantitative RT-PCR was used to measure mRNA expression levels of RANK, cathepsin K, calcitonin receptor, and dendritic cell-specific transmembrane protein. Prepared undecalcified tibial bone from 6 RA or osteoarthritis (OA) patients undergoing joint surgery were stained by tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry with anti-RANK antibody, expression of which were analysed. Osteoclasts and OLCs were identified as multinucleated TRAP+/RANK +cells and TRAP+/RANK- cells, respectively, adherent to the bone surface. Results The number of OLCs treated with a combination of TNFα and IL-6 from PBMCs or CD14 +monocytes in RA patients was significantly increased compared to that in healthy volunteers. Expression levels of RANK mRNA was clearly up-regulated in osteoclasts, and was obviously down-regulated in OLCs compared to that in osteoclast precursors. In cancellous bone, the number of TRAP+/RANK +osteoclasts was significantly increased in RA patients compared to that in OA patients. Interestingly, numerous TRAP+/RANK- OLCs were present in the cancellous bone of RA patients, while almost none were observed in the cancellous bone of OA patients. Conclusions The combination of TNFα and IL-6 strongly induced the differentiation of OLCs from PBMCs or CD14 +monocytes in RA patients. OLCs was characterised with TRAP+/RANK- multinucleated cells, which can distinguish conventional TRAP+/RANK +multinucleated osteoclasts. TRAP+/RANK- OLCs also were present in the bone tissue of RA patients. These results suggest that conventional osteoclasts and novel OLCs could be involved in the pathogenic mechanisms of inflammatory bone destruction such as RA. References [1] Yokota K, Sato K, Miyazaki T, Kitaura H, Kayama H, Miyoshi F, Araki Y, Akiyama Y, Takeda K, Mimura T. Combination of tumor necrosis factor α and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo. Arthritis Rheumatol 2014Jan;66(1):121–9. [2] O’Brien W, Fissel BM, Maeda Y, Yan J, Ge X, Gravallese EM, Aliprantis AO, Charles JF. RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis. Arthritis Rheumatol.2016Dec;68(12):2889–2900. Disclosure of Interest None declared

Background Total management including reconstructive joint surgery and rehabilitation should be needed for further improvements of physical function for long-standing RA patients. It is very important to set treatment goal for those management. Objectives The purpose of this study is to set treatment target using Timed Up and Go test (TUG) in relation to achievement of HAQ-DI remission (HAQ-DI Methods Multicenter prospective observational cohort study was conducted among patients who underwent elective joint surgery for RA from April 2012 to March 2016 (Study registration: UMIN000012649). In this study, we collected data including age, sex, disease duration, drug therapies, and disease activity (DAS), TUG, and patient-reported outcome [HAQ-DI, EQ-5D (QOL), patient’s global assessment (PtGA) and BDI-II (depression)] at baseline and at 6 or 12 months after the surgery. Association between TUG and achievement of HAQ remission and cut-off values for HAQ remission were also determined using logistic regression analysis with adjustment of age and sex and ROC curve, respectively. Results Totally, 139 patients with elective joint surgery in lower limbs were analysed. Mean age, disease duration, HAQ-DI and TUG were 65.4 years, 17.5 years, 1.022, and 12.7 s, respectively. Performed joint surgeries were total hip arthroplasty; 10.1%, total knee arthroplasty; 33.8%, total ankle arthroplasty or ankle fixation; 10.1%, and forefoot arthroplasty; 46.0%. The surgeries can significantly improve the outcome measures, including TUG, DAS, PtGA, pain, EQ-5D and BDI-II other than HAQ-DI. In this study, 45 of 139 patients (32.4%) had HAQ remission status at baseline. 18 of 94 patients (19.1%) who had HAQ-DI >0.5 can achieve HAQ remission with the surgery. Notably, TUG at last observation was significantly associated with achievement of HAQ remission even after adjustment for age, sex, and DAS (1 s increasing of TUG. OR:0.72, 95% CI: 0.53–0.97). The adjusted-TUG at last observation of patients with achievement of HAQ remission was 9.2 s (95% CI: 5.6–12.8) (figure 1). Cut-off of TUG at observation for achievement of HAQ remission was 9.2 s based on ROC analysis (figure 2). Importantly, We confirmed significant more improving of EQ-5D, HAQ-DI and TUG in patients who achieved TUG 9.2 s at last observation than in patients who did not (figure 3). Conclusions TUG was significantly associated with PRO; HAQ-DI and EQ-5D. The cut-off values of TUG (9.2 s) should be important to achieve good QOL and physical function for patients with joint surgery in lower limbs and could be suitable target for surgical procedure. Acknowledgements This study is supported by grant from the Japanese Ministry of Health, Labour and Welfare Disclosure of Interest None declared

Objective This prospective observational cohort study aimed to set targets for lower limb joint surgery based on the Timed Up and Go test (TUG), an objective functional outcome measure, in patients with established rheumatoid arthritis (RA). Methods We validated TUG as an outcome measure of lower limb joint surgery and compared it with changes in patient-reported outcomes, including the Health Assessment Questionnaire Disability Index (HAQ-DI) and European Quality of life scale with five dimensions (EQ-5D). Changes in these outcomes were compared by performed surgery and by achievement of the minimal clinically important difference (MCID) for EQ-5D using univariate analysis of variance. Associations between TUG and HAQ remission (HAQ-DI ≤0.5) were determined using logistic regression analysis. Cut-off values of TUG at baseline and 6 months after surgery for HAQ remission were determined using receiver operating characteristic curves. Results A total of 126 patients were analyzed. Mean age, HAQ-DI, and TUG were 65.4 years, 1.036, and 12.8 seconds, respectively. After surgery, patients showed improvements in TUG as well as HAQ-DI. TUG at 6 months after surgery was significantly associated with HAQ remission (adjusted OR: 0.78; 95% CI: 0.65-0.93). TUG cut-off values at baseline and 6 months after surgery for achieving HAQ remission were 12.1 and 8.8 seconds, respectively. Significant improvements in TUG (∆TUG, 3.7 seconds) were associated with achievement of the MCID for EQ-5D (≥0.05) at 6 months after surgery. Conclusion Timed Up and Go test is a useful tool for assessing the outcome of lower limb joint surgery in RA patients. We propose that TUG ≤9 seconds could be an objective target for achieving good physical function after lower limb joint surgery.

Daily and weekly administration of teriparatide (PTH1–34) reduces the risk of osteoporotic bone fractures. However, their effects on markers of bone formation and bone resorption differ. These results indicate that the dosing frequency of teriparatide may affect bone metabolism and bone structure, with different effects on bone strength. In the present study, to evaluate the dose-related effects of a low administration frequency of teriparatide on bone status, we investigated the effects of three-times-weekly administration of teriparatide (1.1, 5.6, or 28.2 µg/kg) for 12 months on bone parameters, including bone metabolism markers, bone mineral density (BMD), micro-computed tomography, and bone strength, using 6-month-old ovariectomized (OVX) rats. Three-times-weekly administration of teriparatide dose-dependently increased the BMD of the lumbar vertebra and femur in OVX rats, and increased serum osteocalcin (a marker of bone formation), but not type I collagen C-telopeptide (a marker of bone resorption). The trabecular number and thickness increased in the vertebrae and femur, as in prior reports of daily teriparatide administration in OVX rats. Cortical thickness increased only toward the endocortical side of the femur, unlike with daily administration. Bone strength of the vertebrae and proximal and shaft of the femur was correlated with the changes in BMD and bone structure. These results demonstrate the effects of low frequency, intermittent administration of teriparatide on the biomechanical, and microstructural properties of bone in OVX rats. Electronic supplementary material The online version of this article (doi:10.1007/s00223-015-9998-0) contains supplementary material, which is available to authorized users.

Aim This study aimed to validate the Timed Up and Go test (TUG) for measuring objective functional impairment in patients with established rheumatoid arthritis (RA) based on a prospective observational cohort of RA patients undergoing joint surgery. Methods We collected data on demographics, Health Assessment Questionnaire Disability Index (HAQ-DI), and associations between TUG and HAQ-DI and other patient-reported outcomes, including European Quality of life scale (EQ-5D) were determined. Cut-off values of TUG for HAQ remission (HAQ-DI ≤0.5), normal HAQ (HAQ-DI ≤0.25), and the absence of disability in each HAQ-DI category were also determined by age. Results A total of 435 patients were enrolled and analyzed. Mean age was 64.2 years, mean disease duration was 17.1 years, mean HAQ-DI was 1.14, and mean TUG was 11.1 sec. TUG was significantly correlated with aging, EQ-5D, and HAQ-DI categories related to lower limb function (arising, walking, reach and activity). After adjusting for age and sex, mean TUG values were 9.0 sec (95% CI, 7.7-10.3) in patients with HAQ remission and 8.7 sec (7.4-10.4) in those with normal HAQ. By age, mean TUG values for HAQ remission were 7.2 sec (5.9-8.5) in young patients (≤61 years), 9.1 sec (7.6-10.5) in middle-aged patients (62-70 years) and 10.0 sec (5.7-14.2) in old patients (≥71 years). Conclusion TUG was significantly associated with functional impairment and aging in patients with long-standing RA. Thus, TUG could be useful in setting treatment goals for joint surgery and rehabilitation in established RA patients.

Objective: To explore the characteristics of functional impairment in patients with established rheumatoid arthritis (RA) based on the range of motion (ROM) of joints in a prospective observational study of RA patients undergoing joint surgery. Methods: We collected data on demographics, Health Assessment Questionnaire Disability Index (HAQ-DI), and the ROM of large joints including the shoulder, elbow, wrist, hip, knee, and ankle. Associations between the ROM of each joint and disability in the eight HAQ-DI categories were determined using receiver operating characteristic (ROC) and logistic regression analyses. ROM cut-off values of each joint for the absence of disability in each HAQ-DI category were determined using ROC curves. Results: A total of 460 patients were enrolled and analyzed in this study. Based on ROC analysis, the ROM of each joint was significantly associated with disability in each category. After adjusting for disease activity, age, and sex, shoulder abduction had the highest independent impact on disability in activity [cut-off: 139 degrees (OR: 5.26)], elbow flexion-extension in dressing [121 degrees (OR: 2.22)], wrist flexion-extension in reach [86 degrees (OR: 2.71)], hip flexion-extension in walking [126 degrees (OR: 3.42)], and knee flexion-extension in walking [134 degrees (OR: 2.97)]. Conclusions: Limited ROM of multiple joints was significantly associated with functional impairment in patients with long-standing RA. Motion in daily activity involves multiple joints, and at least two joints were independently involved in disability., Published online: 25 Jul 2017

Complete circumferential osseous extension in the acetabular rim has been reported to occur in the deep hip with pincer impingement. However, this phenomenon occasionally is observed in dysplastic hips without pincer impingement, and the degree to which this finding might or might not be associated with hip pain, and how often it occurs bilaterally among patients, are not well characterized. (1) To determine the proportion of patients with complete circumferential osseous extension in the acetabular rim using three-dimensional (3-D) CT in patients with and without hip pain who had CT scans obtained for various reasons. (2) To elucidate how often this complete circumferential osseous extension occurred bilaterally among those patients. (3) To investigate the relationship between the proportions of patients with complete circumferential osseous extension observed on CT scans among three different acetabular coverage groups: dysplasia, normal, and overcoverage. (4) To determine how often the finding of hip pain was associated with complete circumferential osseous extension. Between September 2011 to July 2016, we evaluated 3788 patients with pelvic complaints such as hip, groin, thigh, buttock, or sacroiliac joint pain. We obtained consent from 26% (992 of 3788) of them, and obtained 3-D CT scans as part of that evaluation. For the current retrospective study, we excluded patients younger than 20 years or 80 years or older (181 patients), patients who had previous hip surgery (185 patients), patients with severe osteoarthritis with Tonnis Grades 2 or 3 (301 patients), and patients who could not have an accurate lateral center-edge (LCE) angle measured owing to poor-quality radiographs (24 patients), leaving 301 patients (602 hips) for this analysis. In this study population, patients reported pain in 131 hips (22%), defined as all types of hip pain except for trauma, including activity pain, pain with sports, pain on motion, and impingement pain; the others did not report hip pain. The mean age of the patients was 56 ± 16 years, and the mean LCE angle was 26° ± 8° (range, −9° to 47°). We first determined the proportion of patients with complete circumferential osseous extension in the acetabular rim using 3-D CT for those with and without hip pain who had CT obtained for various reasons. We next elucidated how often this complete circumferential osseous extension occurred bilaterally among the patients, and finally we investigated the relationship between the proportion of patients with complete circumferential osseous extension observed on CT scans among the three groups: dysplasia (defined as LCE angles of 22° or smaller), normal, and overcoverage (defined as LCE angles of 34° or larger) groups. We finally determined how often the finding was associated with hip pain attributable to complete circumferential osseous extension. The proportion of patients with complete circumferential osseous extension was 6% (18 of 301 patients). Eighty-nine percent (16 of 18) of the patients had bilateral complete circumferential osseous extension. There were no differences in the proportions of patients with complete circumferential osseous extension among the three groups: 5.3% (odds ratio [OR], 1.02; 95% CI, 0.45-2.31; p = 0.97), 5.3%, and 7.4% (OR, 0.70; 95% CI, 0.28-1.73; p = 0.44) in the dysplasia, normal, and overcoverage groups, respectively, with the numbers available. Eighteen percent (six of 34) of the hips with complete circumferential osseous extension had pain. Complete circumferential osseous extension in the acetabular rim is relatively uncommon. When it occurs, it usually is bilateral, it occurs regardless of acetabular coverage, and it is associated with pain in a minority of patients. Level III, prognostic study.

Objective. To clarify the obstacles preventing the implementation of the treat-to-target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice. Methods. A total of 301 rheumatologists in Japan completed a questionnaire. In the first section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application. Results. Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations. Conclusion. Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain.

Objectives. This study aimed to evaluate the clinical safety and wear-resistance of the novel highly cross-linked polyethylene (HXLPE) acetabular liner with surface grafting of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) at 3 years after total hip replacement (THR).Methods. Eighty consecutive patients underwent cementless THR using a 26-mm diameter cobalt–chromium–molybdenum alloy femoral head and a PMPC-grafted HXLPE liner for the bearing couplings. We evaluated the clinical and radiographic outcomes of 76 patients at 3 years after the index surgery.Results. The clinical results at 3 years were equivalent to a Harris hip score of 95.6 points. No adverse events were associated with the implanted PMPC-grafted HXLPE liner, and no periprosthetic osteolysis was detected. The mean femoral head penetration rate was 0.002 mm/year, representing marked reduction compared with other HXLPE liners.Conclusions. A PMPC-grafted HXLPE liner is a safe option in THR and probably reduces the generation of ...

To describe an exceedingly rare case of tumor-induced osteomalacia (TIO) caused by a benign phosphaturic mesenchymal tumor that recurred after two surgical resections at two different medical institutions.A 69-year-old man complained of a 3-year history of persistent whole body pain and presented with hypophosphatemia, elevated serum levels of bone-specific alkaline phosphatase and fibroblast growth factor-23 (FGF-23), and multiple fractures. The patient was suspected of having TIO. We conducted the following diagnostic modalities considered useful to detect the tumor: serum FGF-23 level measurement in the extremities, positron emission tomography (PET)-computed tomography (CT),and magnetic resonance imaging (MRI).The causative tumor could be detected in the right humerus not by venous catheterization for serum FGF-23 level measurement but by the combination of PET-CT and MRI. The authors, who had successfully treated two patients with TIO, visually confirmed the absence of any tumor residue during tumorectomy. Nevertheless, the tumor recurred after surgery. The residual tumor could be localized in the right humerus not by PET-CT but by the combination of superficial venous sampling at 10 sites and MRI. The residual tumor recurred after the second tumorectomy at another hospital. This patient indicates that the possibility--a benign causative tumor may not be completely resected by surgery--cannot be ruled out thoroughly.Superficial venous sampling at multiple sites may be a surrogate for venous catheterization. Patients with TIO should be meticulously followed-up after surgery to detect any residual tumor by periodic biochemical monitoring and by imaging modalities accordingly.

A virtual screening method achieved a maximum boost in speed of several tens of thousands–fold while determining the interface structure., Interfaces markedly affect the properties of materials because of differences in their atomic configurations. Determining the atomic structure of the interface is therefore one of the most significant tasks in materials research. However, determining the interface structure usually requires extensive computation. If the interface structure could be efficiently predicted, our understanding of the mechanisms that give rise to the interface properties would be significantly facilitated, and this would pave the way for the design of material interfaces. Using a virtual screening method based on machine learning, we demonstrate a powerful technique to determine interface energies and structures. On the basis of the results obtained by a nonlinear regression using training data from 4 interfaces, structures and energies for 13 other interfaces were predicted. Our method achieved an efficiency that is more than several hundred to several tens of thousand times higher than that of the previously reported methods. Because the present method uses geometrical factors, such as bond length and atomic density, as descriptors for the regression analysis, the method presented here is robust and general and is expected to be beneficial to understanding the nature of any interface.

Aberrant histone lysine methylation (HKM) has been reported in rheumatoid arthritis (RA) synovial fibroblasts (SFs). As histone lysine methyltransferases (HKMTs) and demethylases (HKDMs) regulate HKM, these enzymes are believed to be dysregulated in RASFs. The aim of this study is to clarify whether gene expressions of HKMTs and HKDMs are altered in RASFs.SFs were isolated from synovial tissues obtained from RA or osteoarthritis (OA) patients during total knee joint replacement. The mRNA levels of 34 HKMTs and 22 HKDMs were examined after stimulation with tumour necrosis factor α (TNF-α) in RASFs and OASFs.The gene expression of the 12 HKMTs, including MLL1, MLL3, SUV39H1, SUV39H2, PRDM2, EZH2, SETD2, NSD2, NSD3, SMYD4, DOT1, and PR-set7, that catalyse the methylation of H3K4, H3K9, H3K27, H3K36, H3K79, or H4K20 was higher after TNFα stimulation in RASFs vs. OASFs. The gene expression of the 4 HKDMs, including FBXL10, NO66, JMJD2D, and FBXL11, that catalyse the methylation of H3K4, H3K9, or H3K36 was higher after TNFα stimulation in RASFs vs. OASFs.The study findings suggest that the HKM-modifying enzymes are involved in the alteration of HKM, which results in changes in the gene expression of RASFs.

Wolff’s law indicates that mechanical loading plays a central role in controlling skeletal strength, as evidenced by marked bone gain in the dominant arms of professional tennis players or rapid bone loss in the weight-bearing sites of astronauts during space flight. Among various experimental methods of mechanical stimulation, the noninvasive axial loading model of the mouse tibia/fibula is useful to assess both cortical and trabecular compartments in vivo. The bone normally responds to local mechanical environment at each skeletal site to maintain resultant “elastic” deformation (strain), and this mechanical strain-related feedback control, known as the mechanostat, acts continuously throughout the physiologic range as recently shown in humans as well as animals. The response of the bone to mechanical loads would be impaired with aging but can be enhanced by intermittent treatment with parathyroid hormone. Increased bone strength by an osteoporosis drug results in decreased bone strain, suggesting that the effect of osteoporosis therapy is limited by skeletal adaptation to mechanical strain, which confirms the attractive efficacy of alternative drugs of mechanical strain-related stimulus such as anti-sclerostin antibodies. In contrast, although lower bone quality is linked to weaker bone strength, the mechanostat could compensate mineral-related, but not collagen-related, impairment of bone quality. Bone mechanobiology is important toward a cure for osteoporosis.

Background: The well-known suture technique configurations used for hamstring tendon autograft preparation in anterior cruciate ligament (ACL) reconstruction are the Krackow locking stitch and nonlocking stitch, such as a baseball stitch and a whipstitch. However, there are few data in the literature regarding biomechanical comparisons of suture techniques. Purpose: The purpose of this study was to determine the properties of several current techniques of tendon graft suture employed in ACL reconstruction. Study Design: Controlled laboratory study. Methods: Forty-two fresh-frozen porcine flexor digitorum tendons were used. Three stitch configurations (Krackow stitch [group K], baseball stitch [group B], and whipstitch [group W]) were assessed with varying suture throws (6 throws, group×6; 10 throws, group×10) using No. 5 Ethibond sutures. Each group was tested at 1500 loading cycles between 50 and 200 N. After loading cycles, the surviving tendons underwent a load-to-failure test. Results: During the loading cycles, 3 of 7 specimens in group B×6 and all specimens in group W×6 failed by suture pullout. Four of 7 specimens in group B×10 and all specimens in group W×10 showed partial tearing of the tendon. Elongation of group B×10 and group W×10 showed significantly greater elongation than other groups ( P < .05). Maximum loads at failure showed significant differences between group K and the other groups (K×6, 436 ± 52 N; K×10, 419 ± 34 N; P < .05). Most specimens failed by rupture of the suture thread in group K. Pullout of the suture from the tendon was observed most in groups B and W. Conclusion: The Krackow stitch was superior to other stitch methods. There was, however, no significant effect of the number of throws on the holding strength. Clinical Relevance: The Krackow stitch could prevent suture slippage by a locking mechanism. The whipstitch is not suitable for clinical application even with an increased number of throws.

To analyze cervical spondylotic myelopathy (CSM) predictive factors in patients with lumbar spinal stenosis (LSS). Two hundred thirty-seven patients who visited for low back pain, lower limb pain and/or lower limb numbness and who were diagnosed with LSS were enrolled in this study. The ratio of males to females was 117–120, and the mean age was 68.8 years (range 45–87 years). LSS and CSM were diagnosed by characteristic symptoms, physical findings and MRI. We examined gender, age, Torg-Pavlov ratio (TPR), spondylolisthesis or spondylosis, LSS symptom types and number of stenosis segments with LSS to clarify predictive factors for CSM. There were 21 (8.86%) patients with coexistent CSM among 237 LSS patients. CSM morbidity was significantly more common among males compared with females. TPR was 0.71 ± 0.09 in the CSM patients and 0.81 ± 0.10 in the non-CSM patients. TPR of the CSM patients was significantly smaller than that of the non-CSM patients. We analyzed to determine the predictive factors of CSM and TPR was identified. The predictive value of TPR for CSM was 0.78. Torg-Pavlov ratio was the most important predictive factor of CSM in patients with LSS.

Steffel et al. [(1)][1] found that elderly atrial fibrillation patients receiving anticoagulation therapy and at increased fall risk had increased rate of bone fractures due to falling, which was similar between the use of 2 anticoagulants, edoxaban and warfarin (adjusted hazard ratio: 0.94; 95%

Since biologic agents were introduced to treat rheumatoid arthritis (RA) in 2003, the number of orthopedic surgical procedures under treatment with biologic agents has been increasing in Japan. However, whether biologic agents cause an increase in the prevalence of postoperative complications is as yet unknown. The Committee on Arthritis of the Japanese Orthopedic Association investigated the prevalence of postoperative complications in patients with RA in teaching hospitals in Japan.Between January 2004 and November 2008, surveillance forms about medications and surgical procedures in patients with RA were sent to 2,019 teaching hospitals. Data were analyzed by the Rheumatoid Arthritis Committee.Biologic agents were administered to RA patients in 632 of 1,245 hospitals (50.8%); 430 of the 1,245 hospitals (34.5%) used surgical intervention under treatment with biologic agents. The number of surgical procedures under treatment with biologic agents was 3,468, and the prevalence of infection was 1.3% (46 cases). The prevalence of infection was 1.0% (567 procedures) in 56,339 procedures under treatment with nonbiologic disease-modifying anti-rheumatic drugs. There were no significant differences between biological and nonbiological treatment groups with respect to the prevalence of infection. In the joint arthroplasty group, the number of procedures under biological and nonbiological treatment was 1,626 and 29,903, and the prevalence of infection was 2.1% (34 procedures) and 1.0% (298 procedures), respectively. There was a significant difference between groups. The odds ratio was 2.12 (95% confidence interval 1.48-3.03, P0.0001).The chance of having biological treatment with joint arthroplasty was more than twofold greater in patients with surgical-site infections compared with those treated with nonbiologic agents. Caution is required for surgical procedure, perioperative course, and obtaining consent for joint arthroplasty for patients with RA undergoing surgery under biological agents.