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Introduction: Bone remodeling relies on a delicate balance between formation and resorption of bone tissues, processes in which bone-forming osteoblasts and bone-resorbing osteoclasts play central roles. Recently, we reported that anticoagulant activated protein C (APC) promotes osteoblast proliferation, but the role of the blood coagulation system in bone remodeling remains unclear. In this study, to further elucidate the relationship between bone remodeling and blood coagulation, we investigated the effect of APC on osteoclast differentiation., Materials and Methods: Normal human osteoclast precursor cells were cultured in their growth medium including soluble RANKL, M-CSF, and FBS, and on days 4 and 7, the culture medium was replaced with the same medium containing various concentrations of APC, protein C (PC), sphingosine 1-phosphate (S1P) receptor agonist, FTY720, or APC+various substances without FBS. On day 8, TRAP-positive multinucleated cells (≥3 nuclei) were counted manually using a light microscope. The effects of APC on NF-κB and NFATc1 activation were evaluated using specific ELISA., Results: APC suppressed RANKL-induced osteoclast differentiation, and this APC-induced suppression of osteoclast differentiation was inhibited by zymogen protein C and aprotinin, a serine protease inhibitor. Immunohistochemistry and RT-PCR analyses suggested that endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) were expressed in osteoclast precursor cells and osteoclasts. Both anti-PAR-1 antibody and anti-EPCR antibody (RCR-252), which blocks APC binding to EPCR, inhibited the APC-induced suppression of osteoclast differentiation. FTY720 had no effect on osteoclast differentiation. However, FTY 720 and S1P receptor antagonist, VP 23019, inhibited the APC-induced suppression of osteoclast differentiation. On the other hand, recombinant soluble human ApoER2 and anti-human ApoER2 inhibited the APC-induced suppression of osteoclast differentiation. Further, APC had no effect on NF-κB and NFATc1 activation., Conclusions: APC suppresses human osteoclast differentiation mainly by inhibiting the formation of multinucleated cells via EPCR, PAR-1, S1P receptor, and ApoER2 in a manner that depends on APC protease activity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of the study is to assess the orientation and distance of the popliteal artery (PA) from both the anteromedial and anterolateral portals., Methods: The records of 97 patients (100 knees) who underwent knee arthroscopy were reviewed. The shortest distance from the posterior tibial cortex to the PA on the lines from both the medial and lateral borders of the patellar tendon to the PA was evaluated by magnetic resonance imaging at full knee extension. The figure-of-four position was compared between patients with intact and deficient anterior cruciate ligaments (ACLs). The shortest distances from the posterior cruciate ligament (PCL) to the lines running from the medial and lateral borders of the patellar tendon to the PA were also measured., Results: The shortest distances from the posterior tibial cortex to the PA were significantly longer in the figure-of-four position than at full knee extension and during extension in the ACL-deficient than intact group. Distances did not significantly differ in the figure-of-four position. The PA was hidden from the anteromedial portal by the PCL, but remained vulnerable from the anterolateral portal., Conclusions: All-inside meniscus suturing of the posterior horn of the lateral meniscus inserted through the anteromedial portal is safer when the knee is in the figure-of-four position than fully extended. Meniscus repairs should be completed before ACL reconstruction due to vascular positions and the ease of approach., Level of Evidence: Prospective correlation study, Level IV.

Prevention of deep vein thrombosis (DVT) is important in patients undergoing major orthopedic surgery. Although the detection of an elevated D-dimer level is useful for predicting DVT, it is not efficacious in postoperative patients being treated with anti-Xa agents. The soluble platelet glycoprotein VI (sGPVI) level is a marker of activated platelets, but not bleeding. Therefore, sGPVI levels are usually examined as a predictor of DVT in such patients. In the present study, 83 orthopedic patients were treated with 30 mg of edoxaban for prophylaxis of DVT. Fourteen patients developed DVT and 17 patients discontinued the prophylaxis due to decreased hemoglobin levels. Plasma levels of sGPVI in the patients were significantly higher after surgery than before surgery. On day 1, the sGPVI levels increased, while the platelet counts decreased. There were no significant differences in D-dimer, soluble fibrin, or FDP levels in orthopedic patients with and without DVT before surgery and on days 1, 4, and 8. Plasma sGPVI levels were significantly higher in the patients with DVT than in those without DVT on days 1 and 4. Plasma levels of D-dimer were significantly higher in patients with withdrawal than in those without. However, there were no significant differences in sGPVI levels between those with and without withdrawal. As D-dimer levels are known to increase in patients with withdrawal, this parameter is not useful for evaluating the risk of DVT in these patients. In contrast, the sGPVI level is not increased in those with withdrawal and may therefore be useful for evaluating the risk of DVT in postoperative patients treated with an anticoagulant.

Objectives: The present study aims to determine the relationship between osteoporosis (OP), vertebral fracture (VF) and mortality., Methods: We followed up 1024 residents of Miyagawa village every 2 years for a mean of 8.4 years between 1997 and 2009. The residents were assessed every 2 years. We defined OP as T scores for bone mineral density that were < 2.5 standard deviations below peak bone mass. VF was assessed by lateral radiography of the thoracic and lumbar spine. The participants were allocated as follows depending on the presence or absence of OP and VF: with OP and without VF (OP group), with VF and without OP (VF group), with OP and VF (OP + VF group) and without OP and VF (Control group). We determined survival/mortality rates until 2011 by reviewing medical histories and death certificates., Results: By 2011, 304 participants had died. The respective 5-year survival rates for the OP + VF, OP, VF and Control groups were 80.6%, 93.7%, 87.8% and 94.2%. Mortality rates were significantly worse for the OP + VF group than the Control group (OP + VF Hazard Ratio: 1.89; 95% CI, 1.27-2.77)., Conclusion: Prevention of osteoporotic VF in elderly persons is very important from the viewpoint of increasing life expectancy.

Aim: We undertook studies to determine the lethal dose 50 (LD50) of acridine orange (AO) using mice in order to confirm the safety of intravenous administration of AO., Materials and Methods: We used 40 mice and AO was administered once intravenously. General behavior and mortality were continuously observed for 14 days. At the end of the experiment, all animals were sacrificed for subsequent studies., Results: The LD50 for AO in male and female mice was determined to be 32 mg/kg and 36 mg/kg, respectively. Histopathological abnormalities were observed in only one mouse which died three days after the administration of AO. The other nine mice which died immediately after the administration of AO had no pathological findings in major organs., Conclusion: The clinical use of AO can be kept at 1.0 mg/kg or below and, therefore, intravenous administration of AO might be safe for use as cancer therapy., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: The Japanese Musculoskeletal Oncology Group have developed an original prosthesis called the Kyocera Modular Limb Salvage system (KMLS system). This prosthesis has a semi-rotating hinge joint and is particularly designed for people with an Asian body type. The metallic parts of the prosthesis are made entirely of titanium alloy. The purpose of this study is to evaluate the clinical outcomes of treatment using this system following tumour resection of primary bone sarcoma of the distal femur., Methods: Between 2002 and 2010, 82 patients with primary bone sarcomas of the distal femur were treated. Seventeen patients underwent stem cementation, while 65 patients were treated with cementless prostheses. The mean follow-up period after surgery was 61 months., Results: Complications were observed in 28 of the 82 patients. Forty-one complications occurred in these 28 patients. Thirteen prostheses (16%) required revision surgery due to complications, including five cases of stem breakage, three deep infections, three cases of aseptic loosening, one case of displacement of the shaft cap and one case of breakage of the tibial tray. The five-year overall prosthetic survival rate was 80.0%. Four of the 82 patients underwent subsequent amputation due to local recurrence. The five-year limb salvage rate was 94.5%. The mean function score according to the scoring system of the Musculoskeletal Tumour Society was 21.8 points (72.5%)., Conclusions: Although further follow-up is required to determine the performance, this prosthesis is considered to be satisfactory for reconstruction of the distal femur after resection of bone sarcoma.

Background: To investigate the prevalence and severity of radiographically detected hallux valgus (HV) as well as associated risk factors among Japanese residents of Miyagawa, a mountain village located in the center of Mie Prefecture., Methods: The height, weight and body mass index (BMI) of 403 participants (male n = 135, female n = 268) recruited from among the residents of Miyagawa Village, Japan aged ≥65 years were measured, and baseline data, including age, sex and medical history were obtained from interviews and questionnaires. Knee osteoarthritis (KOA) was determined from radiographs of the feet and knees, and osteoporosis was determined by measuring bone mineral density. Hallux valgus, defined as angulation of the big toe at the first metatarsophalangeal joint of >20°, was classified as: mild (20°-30°), moderate (30°-40°) or severe (>40°). Risk factors for HV were calculated using multivariate logistic regression analysis that included age, sex, obesity (BMI ≥25), KOA, osteoporosis, Heberden's nodes and low back pain as variables., Results: The overall prevalence of definite radiographic HV was 22.8 % (184/806), and mild, moderate and severe HV was found in 66.3, 27.2 and 6.5 % of the participants, respectively. Hallux valgus was found in at least one foot in 120 (29.8 %) of the participants and the prevalence significantly differed between females with and without HV and KOA (odds ratios: 2.54 and 1.71, respectively)., Conclusions: The prevalence of definite radiographic HV was 29.8 %. Female sex and KOA were significantly associated with increased risk for radiographic HV.

The aim of the present study was to determine whether serum high-sensitivity CRP (hs-CRP) levels can be used to predict the differentiation of benign soft tissue tumors and soft tissue sarcomas (STS) and whether there are any links between increased hs-CRP levels and patients' characteristics. Serum samples were collected from 14 healthy subjects, 35 patients with benign soft tissue tumors and 60 patients with STS. The Hs-CRP levels in the patients with STS were statistically higher than those observed in patients with benign soft tissue tumors (p<0.0001) and control subjects (p<0.0001). There were no significant differences in the hs-CRP levels between patients with benign soft tissue tumors and control subjects (p=0.16). In the receiver operating characteristic analysis, a value of 0.95 μg/ml was found to be an appropriate threshold for identifying patients at-risk for STS. The area under the curve was 0.747. The serum hs-CRP level exhibited a sensitivity and specificity STS of 50% and 94.3%, respectively, for identifying. The current analyses showed that an elevated hs-CRP level is associated with the presence of STS and may, therefore, be used as an additional marker for the differential diagnosis of soft tissue tumors.

Objective: We aimed to confirm the effect of combined treatment with celecoxib and rebamipide would be more effective than celecoxib alone for prevention of upper gastrointestinal (GI) events., Methods: Patients with rheumatoid arthritis, osteoarthritis, and low back pain were enrolled in this study. Patients were randomized to two groups: a monotherapy group (100 mg celecoxib twice daily) and a combination therapy group (add on 100 mg of rebamipide three times a day). The GI mucosal injury was evaluated by endoscopic examination before treatment and at 3 months. The primary endpoint was to evaluate the preventive effect of the combination therapy group for GI events, endoscopic upper GI ulcers and intolerable GI symptoms, compared with the monotherapy group., Results: Seventy-five patients were enrolled. Sixty-five patients were analyzed (16 males, 49 females; mean age: 67 ± 13 years). The prevalence of upper GI events, five of endoscopic GI ulcers and one of intolerable GI symptoms, were 6/34 (17.6%) in the monotherapy group and 0/31 in the combination therapy group, p = 0.0252., Conclusions: The combination therapy group was more effective than the monotherapy group for prevention of upper GI events in this study. Rebamipide might be a candidate for an option to prevent COX-2 selective inhibitor-induced upper GI events.

Background: The relationships among the hemostatic markers, the development of deep vein thrombosis (DVT) and the withdrawal of fondaparinux due to a reduction in the hemoglobin levels were examined., Methods: Two-hundred twenty-one Japanese patients who underwent major orthopedic surgery and were treated with 1.5mg of fondaparinux instead of 2.5mg of fondaparinux were studied. Forty-seven of 221 patients discontinued fondaparinux treatment (withdrawal group) and 37 patients developed DVT., Results: The age, frequency of total knee arthroplasty (TKA), withdrawal of fondaparinux, reduction of hemoglobin and the plasma levels of soluble fibrin (SF), D-dimer and fibrinogen and fibrin degradation product (FDP) on day 1 after the operation were significantly higher in the patients with DVT. Elevated SF, D-dimer or FDP levels were associated with the risk for DVT. The age, frequency of TKA or DVT, anti-Xa activity and the creatinine, FDP and D-dimer levels were significantly higher in the withdrawal group. An anti-Xa level >0.33 mg/l and an elevated D-dimer or FDP level were associated with the risk of withdrawal., Conclusion: The age and SF levels, TKA and withdrawal of fondaparinux were related to the risk of DVT, and the anti-Xa activity, creatinine level and DVT were related to the risk of withdrawal of fondaparinux due to a reduction in hemoglobin., (© 2013.)

Background: Breast cancer has the potential to metastasize to bone, causing debilitating symptoms. Although many tumor cells have thrombin-generating systems originating from tissue factor (TF), therapy in terms of the coagulation system is not well established. To elucidate the efficacy of the thrombin inhibitor, argatroban, on bone metastasis, we investigated TF activation and vascular endothelial growth factor (VEGF) secretion on treatment with thrombin and argatroban., Methods: MDA-231 breast cancer cells were treated with thrombin in presence or absence of argatroban, and TF activity was measured in the form of activated factor X. Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF concentrations in the medium. MDA-231 cells were injected into the left heart ventricle of mice, and then argatroban or saline was administered intraperitoneally for 28 days. After 28 days, incidence of bone metastasis was evaluated in the limbs by radiography., Results: TF activity and VEGF secretion were upregulated by thrombin. Argatroban inhibited the enhancement of TF activity and VEGF secretion induced by thrombin. In vivo analysis revealed that the number of metastasized limbs in the argatroban group was significantly lower compared with the saline group (P < 0.05)., Conclusions: Thrombin not only enhances VEGF secretion but also has a positive feedback mechanism to reexpress TF. These results indicate that inhibition of thrombin is of great value in suppression of tumor metastasis. Argatroban is a noteworthy and useful thrombin inhibitor because it has already been used in the clinical setting and has antimetastatic effects in vivo.

Here, a case of Ewing's sarcoma family of tumors (ESFT) of the femur with an unusual clinical course is reported. At 20 years of age, the patient had undergone curettage of a bone tumor of the right femur which was diagnosed as ESFT. One cycle of chemotherapy with vincristine and cyclophosphamide and radiotherapy for a total dose of 40 Gy was administered. The patient did not develop any recurrence or metastases for the following 18 years, in spite of the inadequacy of the initial treatment. At 38 years of age, he was referred to our institution with right thigh pain that had persisted for several months. Radiographs and magnetic resonance imaging findings showed a mass lesion in his proximal femur extending to the soft tissue. An open biopsy was performed and the lesion was diagnosed as recurrence of ESFT, although a molecular biological investigation did not reveal any expression of the characteristic fusion genes that have previously been reported. The patient received standard multimodal therapy employing standard combination chemo-therapy for ESFT and wide surgical excision. The patient has been disease-free for 9 years since the treatment. This patient may have a rare subtype of ESFT with an unknown chromosomal translocation and relatively non-aggressive biological behavior.

Background: Neural-cadherin (N-cadherin) is one of the most important molecules involved in tissue morphogenesis, wound healing, and the maintenance of tissue integrity. Recently, the cleavage of N-cadherin has become a focus of attention in the field of cancer biology. Cadherin and their ectodomain proteolytic shedding play important roles during cancer progression. The aims of this study are to investigate the serum soluble N-cadherin (sN-CAD) levels in patients with malignant bone and soft tissue tumors, and to evaluate the prognostic significance of the sN-CAD levels., Methods: We examined the level of serum sN-CAD using an ELISA in 80 malignant bone and soft tissue tumors (bone sarcoma, n = 23; soft tissue sarcoma, n = 50; metastatic cancer, n = 7) and 87 normal controls. The mean age of the patients was 51 years (range, 10-85 years) and the mean follow-up period was 43 months (range, 1-115 months)., Results: The median serum sN-CAD level was 1,267 ng/ml (range, 135-2,860 ng/ml) in all patients. The mean serum sN-CAD level was 1,269 ng/ml (range, 360-2,860 ng/ml) in sarcoma patients, otherwise 1,246 ng/ml (range, 135-2,140 ng/ml) in cancer patients. The sN-CAD levels in patient were higher than those found in the controls, who had a median serum level of 108 ng/ml (range, 0-540 ng/ml). The patients with tumors larger than 5 cm had higher serum sN-CAD levels than the patients with tumors smaller than 5 cm. The histological grade in the patients with higher serum sN-CAD levels was higher than that in the patients with lower serum sN-CAD levels. A univariate analysis demonstrated that the patients with higher serum sN-CAD levels showed a worse disease-free survival rate, local recurrence-free survival rate, metastasis-free survival rate, and overall survival rate compared to those with lower serum sN-CAD levels. In the multivariate analysis, sN-CAD was an independent factor predicting disease-free survival., Conclusions: sN-CAD is a biomarker for malignant bone and soft tissue tumors, and a potentially valuable pre-therapeutic prognostic factor in patients with bone and soft tissue sarcoma.

Background: The incidence of sarcoma diagnosed in the elderly population may be rising due to the increasing life expectancy. The purpose of our study was to evaluate the efficacy of lung metastasectomy and radiofrequency (RF) ablation in elderly sarcoma patients (65 years or older) with lung metastases, compared with adult sarcoma patients younger than 65 years (20-64 years)., Materials and Methods: We retrospectively evaluated the clinical efficacy of metastasectomy and lung RF ablation in sarcoma patients with lung metastases., Results: Between 2001 and 2010, lung metastases were detected in 66 adult patients with musculoskeletal sarcomas. Twenty-five patients with lung metastasis were elderly. Twelve of the 25 patients were treated with lung metastasectomy and/or RF ablation. In contrast, 41 patients were adult patients younger than 65 years. Twenty of these 41 patients were treated with lung metastasectomy and/or RF ablation. The 1 and 3-year survival rates after initial treatment for lung metastases were 81.8% and 38.4% in 12 elderly patients, respectively. Compared with the control group, the survival rate in the elderly patients was not significantly different., Conclusion: We conclude that elderly sarcoma patients with lung metastases should always be considered for either metastasectomy or RF ablation.

Background: Studies have shown that ischemia-reperfusion (I/R) produces free radicals leading to lipid peroxidation and damage to skeletal muscle. The purposes of this study were 1) to assess the histological findings of gastrocnemius muscle (GC) and tibialis anterior muscle (TA) in I/R injury model mice, 2) to histologically analyze whether a single pretreatment of edaravone inhibits I/R injury to skeletal muscle in murine models and 3) to evaluate the effect of oxidative stress on these muscles., Methods: C57BL6 mice were divided in two groups, with one group receiving 3 mg/kg intraperitoneal injections of edaravone (I/R + Ed group) and the other group receiving an identical amount of saline (I/R group) 30 minutes before ischemia. Edaravone (3-methy-1-pheny1-2-pyrazolin-5-one) is a potent and novel synthetic scavenger of free radicals. This drug inhibits both nonenzymatic lipid peroxidation and the lipoxygenase pathway, in addition to having potent antioxidant effects against ischemia reperfusion. The duration of the ischemia was 1.5 hours, with reperfusion at either 24 or 72 hours (3 days). Specimens of gastrocnemius (GC) and anterior tibialis (TA) were removed for histological evaluation and biochemical analysis., Results: This model of I/R injury was highly reproducible in histologic muscle damage. In the histologic damage score, the mean muscle fibers and inflammatory cell infiltration in the I/R + Ed group were significantly less than the corresponding values of observed in the I/R group. Thus, pretreatment with edaravone was observed to have a protective effect on muscle damage after a period of I/R in mice. In addition, the mean muscle injury score in the I/R + Ed group was also significantly less than the I/R group. In the I/R + Ed group, the mean malondialdehyde (MDA) level was lower than in the I/R group and western-blotting revealed that edaravone pretreatment decreased the level of inducible nitric oxide synthase (iNOS) expression., Conclusions: Edaravone was found to have a protective effect against I/R injury by directly inhibiting lipid peroxidation of the myocyte by free radicals in skeletal muscles and may also reduce the secondary edema and inflammatory infiltration incidence of oxidative stress on tissue.

Study Design: Immunohistochemical and biochemical analyses of the rat intervertebral disc (IVD) tissue renin-angiotensin system (tRAS)., Objective: To examine the expression and function of tRAS in the rat IVD., Summary of Background Data: Angiotensin II (Ang II), the major effector of tRAS, is a hormone that contributes to inflammation and fibrosis in many organs. The expression of tRAS in the rat IVD has not been determined., Methods: tRAS expression in rat and bovine IVDs was examined using real-time polymerase chain reaction (rat) and immunohistochemistry (rat and bovine). Rat annulus fibrosus cells in monolayer culture were used to examine the biological role of tRAS in vitro. The effect of Ang II peptide on extracellular matrix metabolism was assessed by real-time polymerase chain reaction., Results: mRNA of tRAS components, including angiotensin converting enzyme, Ang II, Ang II receptor type 1, Ang II receptor type 2, and Cathepsin D (a renin-like enzyme), was clearly confirmed by real-time polymerase chain reaction analysis. In rat and bovine annulus fibrosus and nucleus pulposus cells in monolayer culture, immunohistochemical analysis showed that each tRAS component was clearly expressed. In rat IVD tissues, immunoreactivity to each antibody for tRAS components was also observed. Proliferation of rat annulus fibrosus cells was mildly stimulated by Ang II peptide. Ang II peptide also had minor stimulatory effect on the expression of the extracellular matrix components, growth factors, and catabolic proteins., Conclusion: Our results demonstrate for the first time that the tRAS components necessary to activate tRAS have been found in the normal rat IVD at both mRNA and protein levels. To elucidate the association between tRAS and the process of IVD degeneration, the expression and function of tRAS in the human degenerated IVD should be examined in a future study.

In this study, we analyzed long-term survival, limb function and associated complications after prosthetic limb salvage treatment in patients with bone and soft tissue tumors around the knee joint. A total of 63 patients treated with prosthetic limb salvage surgery around the knee were reviewed. The bone tumors involved the distal femur in 45 patients, the proximal tibia in 14 patients and the soft tissue tumors of the proximal lower leg in 4 patients. The median follow-up period after the first operation was 8.0 years. The medical records of the patients, surgical reports, radiographs and histological specimens were retrospectively reviewed. The 5-year overall survival rate was 63.2% in the patients with distal femur tumors and 86.2% in those with tumors of the proximal lower leg. The 5‑year prosthetic survival rate was 72.8% in the distal femur and 74.6% in the proximal lower leg. The mean functional score according to the scoring system of the Musculoskeletal Tumor Society (MSTS) was 81% in the patients with distal femur tumors and 82% in the patients with proximal lower leg tumors. Post-operative complications occurred in 27 patients. Limb salvage surgery is considered to be an effective treatment option. However, the high complication rate is a major concern for prosthetic replacement. Future improvements of prostheses are very important.

Introduction: Platelet-rich plasma (PRP) is a fraction of plasma in which several growth factors are concentrated at high levels. The active soluble releasate isolated following platelet activation of PRP (PRP-releasate) has been demonstrated to stimulate the metabolism of IVD cells in vitro. The in vivo effect of PRP-releasate on degenerated IVD remains unknown. The purpose of this study was to determine the reparative effects of autologous PRP-releasate on degenerated intervertebral discs (IVDs)., Methods: To induce disc degeneration, New Zealand white rabbits (n = 12) received anular puncture in two noncontiguous discs. Autologous PRP and PPP (platelet-poor plasma) were isolated from fresh blood using two centrifugation techniques. Four weeks after the initial puncture, releasate isolated from clotted PPP or PRP (PPP- or PRP-releasate), or phosphate-buffered saline (PBS; control) was injected into the punctured discs. Disc height, magnetic resonance imaging (MRI) T2-mapping and histology were assessed., Results: Anular puncture produced a consistent disc narrowing within four weeks. PRP-releasate induced a statistically significant restoration of disc height (PRP vs. PPP and PBS, P<0.05). In T2-quantification, the mean T2-values of the nucleus pulposus (NP) and anulus fibrosus (AF) of the discs were not significantly different among the three treatment groups. Histologically, the number of chondrocyte-like cells was significantly higher in the discs injected with PRP-releasate compared to that with PBS., Conclusions: The administration of active PRP-releasate induced a reparative effect on rabbit degenerated IVDs. The results of this study suggest that the use of autologous PRP-releasate is safe and can lead to a clinical application for IVD degeneration.

We measured the thickness of the transverse structures associated with the bovine coccygeal transverse processes (bone specimen) by using ultrasonic waves and examined the reliability of this measurement for use in spinal surgery. We first measured the velocity of ultrasonic waves propagating in the spinous process. We then made a hole in the transverse process with an air drill and placed an ultrasonic transducer with a center frequency of 10 MHz in the hole. The time of reflection of the ultrasonic wave from the underside of the transverse process was detected to estimate the remaining bone thickness. The thickness estimated by using ultrasound was compared with the thickness measured by microscopic examination. We could detect reflection waves from the underside of the transverse process in 91.7% of cases (i.e., 22 of 24 measurements using 6 bones from 3 cows). The thickness of the transverse processes in which we detected the waves varied from 0.24 to 6.8 mm. The 95% limit of agreement between ultrasonic and histological measurement was 0.71 mm. Pearson's correlation coefficient showed a strong and positive relationship between the two measurements (r = 0.97, n = 22, P <0.0001).

Background: The purpose of this study was to investigate the prevalence and characteristics of unilateral knee osteoarthritis (KOA), to investigate what percent of contralateral healthy knees in patients with unilateral KOA progress to KOA, and to investigate whether knee fractures influence unilateral KOA., Methods: Studies were performed every two years from 1997 to 2009 in Miyagawa village, for a total of seven studies. A total of 1239 village inhabitants aged ≥65 years participated in these studies at least once. KOA was defined as a Kellgren-Lawrence (K/L) grade ≥2. Based on the knee X-ray at the first examination, participants were divided into three groups: no KOA (N group), unilateral KOA (U group), and bilateral KOA (B group). The U group was divided into two subgroups: K/L grade II-I combination (II-I group), and the U group without the II-I combination (G>2 group). To investigate whether knee fractures influence unilateral KOA, the fracture history was considered., Results: The percentages of participants classified into the N, B, and U groups (II-I and G>2 group) were 68.4, 21.6, and 10.0% (7.8 and 2.1%), respectively. Most of the U group had the II-I combination (78.7%). The percentages of knee fractures in the N, B, II-I, and G>2 groups were 3.3, 5.3, 6.3, and 38.5%, respectively. Overall, 49.2% of the U group proceeded to bilateral KOA over an average of 5.3 years., Conclusions: The prevalences of definite radiographic bilateral and unilateral KOA were 21.6 and 10.0%, respectively. Overall, 49.2% of the participants with unilateral KOA developed KOA in the contralateral knee over an average of 5.3 years. If bilateral KOA advanced simultaneously, the II-I group was considered to represent the midpoint of progression to bilateral KOA. Bilateral KOA advanced simultaneously except in cases with a history of knee trauma, such as fractures.

The poliovirus receptor CD155, is essential for poliovirus to infect and induce death in neural cells. Recently, CD155 has been shown to be selectively expressed on certain types of tumor cells originating from the neural crest, including malignant glioma and neuroblastoma. However, the expression pattern of CD155 in soft tissue sarcoma has not been examined. Therefore, we first examined CD155 expression in sarcoma cell lines, and found the expression of both CD155 mRNA and protein in 12 soft and bone tissue sarcoma cell lines. Furthermore, we examined the effect of live attenuated poliovirus (LAPV) on 6 bone and soft tissue sarcoma cell lines in vitro, and found that LAPV induced apoptosis by activating caspases 7 and 3 in all of these cell lines. Furthermore, in BALB/c nu/nu mice xenotransplanted with HT1080 fibrosarcoma cells, administration of live attenuated poliovirus caused growth suppression of the tumors. These results suggest that oncolytic therapy using a LAPV may represent a new option for the treatment of bone and soft tissue sarcomas.

We report a case of recurrent knee valgus deformity in a patient with Ellis-van Creveld syndrome. Varus osteotomy, distraction osteogenesis, or epiphyseal stapling is one treatment option for valgus malalignment to improve appearance, gait, and function. However, surgical correction of valgus knee deformity by varus osteotomies of the proximal tibia was not maintained postoperatively, necessitating additional varus osteotomies of the distal femur in this case. The main cause of recurrence was attributed to large bony defect of the anterior segment of the proximal tibia, in addition to depression of the lateral tibial plateau.

Instability after primary and revision total hip arthroplasty continues to be a problem. The use of a constrained system helps manage this problem. A new constrained total hip arthroplasty, Trilogy constrained liner (Zimmer, Warsaw, IN), is currently in use. We report a case showing dislocation following a Trilogy constrained total hip arthroplasty. In this case, when an impingement between the femoral neck and the anterior part of the polyethylene liner occurred, the hip dislocated easily although both polyethylene and reinforcing ring were properly positioned. The lever-out test showed that the Trilogy constrained liner is safe and compares favourably with other implants. Surgeons should be aware that constrained acetabular systems are not infallible and they should pay attention to place implants in good position even when constrained THA is performed.

We evaluated hemostatic markers in patients who underwent major orthopedic surgery, including total hip and total knee arthroplasty, and were treated for the prophylaxis of deep vein thrombosis (DVT) with or without fondaparinux (anti-Xa group, n = 98 and without anti-Xa group, n = 20). The frequency of DVT was significantly higher in the without anti-Xa group than in the anti-Xa group, but the reduction of hemoglobin and fibrinolytic marker levels was significantly lower in the without anti-Xa group than in the anti-Xa group. Eighteen patients in the anti-Xa group showed a reduction in hemoglobin of more than 2 g/dl, and those individuals were considered to be the increased bleeding (IB) group. The concentration of fibrinolytic markers in the anti-Xa group was significantly higher in the IB group than in the non-IB group. There were also no significant differences in the levels of anti-Xa activity, plasminogen activator inhibitor-I, soluble fibrin and antithrombin between the IB and non-IB groups. In conclusion, elevated fibrinolysis induced by increased bleeding may lead to further increases in bleeding in patients receiving thromboprophylaxis with fondaparinux following major orthopedic surgery.

During the past 20 years, we have found that acridine orange (AO) selectively accumulates in musculoskeletal sarcomas in vivo or exerts selective cytocidal effects against sarcoma cells in vitro after illumination of the tumor cells with visible light or irradiation of the cells with low-dose X-rays. Based on the data obtained from basic research, we have employed reduction surgery followed by photo- or radiodynamic therapy using AO (AO-PDT & RDT) in 71 patients with musculoskeletal sarcomas, in an attempt to maintain excellent limb function in the patients. We have obtained good local control rates and remarkably better limb functions with this approach as compared to the results obtained with the conventional wide resection surgery. Our basic research demonstrated that AO accumulates densely in intracellular acidic vesicles, especially lysosomes, in an acidity-dependent manner. In cancer cells that proliferate under hypoxic conditions or with Warburg's effect, active glycolysis produces an enormous number of protons, which are released by the cells via proton pumps into the extracellular fluid or lysosomes to maintain a neutral pH of the cytosolic fluid. Cancer cells contain many strongly acidic lysosomes of large sizes; therefore, AO shows marked and prolonged accumulation in the acidic lysosomes of cancer cells. Photon energy excites the AO resulting in the production of activated oxygen species, which oxidize the fatty acids of the lysosomal membrane, resulting in the leakage of lysosomal enzymes and protons, followed by apoptosis of the cancer cells. Based on these observations, we conclude that AO-PDT & RDT target acidic vesicles, especially the lysosomes, in cancer cells, to exhibit selective anti-cancer cell activity. Therefore, it is suggested that AO excited by photon energy has excellent potential as an anticancer "Magic Bullet".

Deep venous thrombosis (DVT) is a life-threatening postoperative complication and occurs frequently after total-knee-replacement arthroplasty (TKA) and total-hip-replacement arthroplasty (THA). Fondaparinux (FPX) has been used to treat and prevent DVT, however interindividual difference of the drug efficacy exists. Therefore, this chart review was retrospectively conducted to research risk factors for a residual DVT after FPX treatment. Total of 112 patients undergone TKA or THA were treated with 2.5 mg FPX once a day between postoperative day (POD) 1 and 14 from July 2007 through December 2008. Among these patients, 30 patients who were detected DVT on POD 4 were enrolled in this study. Thirty patients were divided into two groups according to the presence (n=11) or absence (n=19) of DVT on POD14. The DVT (-) group had a significantly longer activated partial thromboplastin time (APTT, median 31.4 s) on POD 1 than the DVT (+) group (28.5 s) (p<0.02). Multivariate logistic regression analysis revealed that APTT lower than 28.5 seconds on POD1 was considered to be independent risk factor significantly contributing to residual DVT (odds ratio 17.5, 95% confidential interval 2.0-295.4, p=0.02). These findings should provide useful information for understanding the interindividual difference of the efficacy of FPX after TKA or THA.

Background: Malignant soft tissue tumors of the foot are extremely rare and thus can be prematurely excised without appropriate preoperative evaluation. The present study compares adverse effects between unplanned and planned surgical excisions., Methods: We retrospectively reviewed the clinical records, radiographs, pathology reports and pathological specimens of 14 consecutive patients with soft tissue sarcoma of the foot among 592 with sarcomas between 1973 and 2009. We then compared the incidence and clinical outcomes after unplanned (UT; n = 5) and planned (PT; n = 9) surgical excisions of foot sarcomas., Results: The most frequent diagnosis was synovial sarcoma (n = 4; 28.6%). The overall 5-year survival rates of the PT and UT groups were 65.6% and 60.0%, respectively, and the event-free 5-year survival rates were 63.5% and 40.0%, respectively. Event-free and overall survival rates did not significantly differ between the two groups. However, tumors were significantly larger in the PT group than in the UT group (p < 0.05)., Conclusions: Unplanned resection lead to a relatively worse prognosis and a likelihood of recurrence despite additional resections. We recommend that soft tumors of the foot should only be excised after appropriate preoperative evaluation regardless of the size of the tumor.

The efficacy of measuring anti-Xa activity was evaluated in major orthopedic surgery patients receiving thrombo-prophylaxis with Fondaparinux. Although 98 orthopedic patients including those receiving total hip replacement (THR) and total knee replacement (TKR) were treated with 1.5 mg of Fondaparinux for prophylaxis of deep vein thrombosis (DVT). Sixteen patients developed DVT, but none was associated with a fatal pulmonary embolism. There was a wide range of anti-Xa activity, but there were no patients with less than 0.15 mg/l or more than 0.90 mg/l. Anti-Xa activity gradually increased from days 1 to 8 and showed no significant difference between patients with and without DVT. Anti-Xa activity was correlated with weight, height, body mass index, and antithrombin activity. Postoperative plasma levels of D: -dimer and soluble fibrin (SF) were markedly high, and those were significantly reduced at days 1 and 4 of treatment with Fondaparinux. Plasma levels of SF were significantly reduced at days 8 and 15, but D: -dimer was not. These findings suggested that there was continued thrombin generation after the injection of Fondaparinux until day 8 and secondary fibrinolysis occurred on day 8. In conclusion, 1.5 mg of Fondaparinux may not be sufficient for the prophylaxis of silent DVT, but it was found to be useful for that of fatal pulmonary embolism. Consequently, monitoring anti-Xa activity may be unnecessary for the administration of Fondaparinux at such doses.

This longitudinal study aimed to identify risk factors for the incidence and progression of radiographic knee osteoarthritis (OA). We examined the inhabitants of Miyagawa village aged ≥ 65 years every two years between 1997 and 2007. Anteroposterior radiographs of both knees were graded for OA using the Kellgren-Lawrence (K/L) grading system. Knee OA was defined as grade ≥ 2. We recorded the incidence of knee OA among participants in whom both knees changed from K/L grades 0 or 1 to ≥ 2 over a four-year follow-up period. We also recorded the progression of knee OA using this threshold among patients in whom one or both knees changed from K/L grades 2 or 3 to any higher grade over the follow-up period. Baseline data obtained from standard questionnaires, physical findings and X-rays included age, gender, body mass index (BMI), osteoporosis, Heberden's nodes, knee range of motion (ROM), knee pain and cigarette smoking. The rates of incidence and progression of knee OA among 360 participants (241 women, 119 men) who fulfilled the study criteria were 4.0 and 6.0% per year, respectively. Female gender (odds ratio [OR] 2.849, 95% confidence interval [CI] 1.170-6.944) and high BMI (OR 1.243, 95% CI 1.095-1.411) were significantly associated with the incidence of knee OA, and restricted knee ROM (OR 0.941, 95% CI 0.892-0.992) was significantly associated with knee OA progression. Patients with a low knee ROM relative to grade of radiographic knee OA require more careful follow-up than those with a higher ROM.

In the evolution of cancer, tumor necrosis factor-alpha (TNF-α) plays a paradoxical role. High doses induce significant anticancer effects, but conversely, physiologic and pathologic levels of TNF-α may be involved in cancer promotion, tumor growth, and metastasis. Infliximab is a chimeric murine monoclonal antibody that binds with high affinity to soluble and membrane TNF-α and inhibits binding of TNF-α to its receptors. In the present study, we investigated the effect of infliximab, a TNF-α antagonist, on breast cancer aggressiveness and bone metastases. Infliximab greatly reduced cell motility and bone metastases in a metastatic breast cancer cell line, MDA-MB-231. The mechanism of bone metastasis inhibition involved decreased expression of CXC chemokine receptor 4 (CXCR4) and increased expression of decorin, which is the prototype of an expanding family of small leucine-rich proteoglycans. These results suggest a novel role for TNF-α inhibition in the reduction or prevention of bone metastases in this breast cancer model. Our study suggests that inhibition of TNF-α using infliximab may become a preventive therapeutic option for breast cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Patients with bone metastases in the extremities sometimes require surgical intervention to prevent deterioration of quality of life due to a pathological fracture. The use of localized radiotherapy combined with surgical reinforcement has been a gold standard for the treatment of bone metastases. However, radiotherapy sometimes induces soft tissue damage, including muscle induration and joint contracture. Moreover, cancer cells are not always radiosensitive. Hyperthermia has been studied since the 1940s using an experimental animal model to treat various types of advanced cancer, and studies have now reached the stage of clinical application, especially in conjunction with radiotherapy or chemotherapy. Nevertheless, bone metastases have several special properties which discourage oncologists from developing hyperthermic therapeutic strategies. First, the bone is located deep in the body, and has low thermal conductivity due to the thickness of cortical bone and the highly vascularized medulla. To address these issues, we developed new hyperthermic strategies which generate heat using magnetic materials under an alternating electromagnetic field, and started clinical application of this treatment modality. The purpose of this review is to summarize the latest studies on hyperthermic treatment in the field of musculoskeletal tumors, and to introduce the treatment strategy employing our novel hyperthermia approach.

Background and Objectives: The KYOCERA Physio Hinge Total Knee System Type III (PHKIII) was developed to reconstruct bony defects of the distal femur. The PHKIII is originative in that the metallic parts are fully made of titanium alloy, and this prosthesis has a unique semi-rotating hinge joint and was designed especially for people with the Asian physical body-type. The clinical outcomes of the PHKIII after the resection of musculoskeletal tumors of the distal femur were evaluated., Methods: There were 41 males and 28 females with a median age of 48-years. The median duration of follow-up was 57 months., Results: Eleven early complications and 37 late complications were observed, including 10 recurrences, 7 deep infections, 7 aseptic loosenings, 4 stem breakages, 4 displacements of shaft cap, and one wear of rotation sleeve. Twenty four prosthesis (35%) required a secondary operation because of complications. The five-year overall prosthetic survival rates, -prosthetic survival rate without aseptic loosening, and -limbs preservation rate were 85%, 90%, and 86%, respectively. The mean functional score according to the classification system of the Musculoskeletal Tumor Society was 20.5 points (68%)., Conclusions: Although continuous follow-up is required, reconstructions using PHKIII are considered to achieve more acceptable functional results., (Copyright © 2010 Wiley-Liss, Inc.)

Numerous studies have reported the survival of metastatic sarcoma patients who have undergone either a lung metastasectomy or chemotherapy. However, little is known with regards to the clinical course of patients with bone or soft tissue sarcomas who have succumbed to disease. This study aimed to analyze the metastatic patterns of sarcoma patients and to describe the clinical course after the detection of distant metastasis. We reviewed the clinical records of 255 patients with a diagnosis of sarcoma who were referred to our institution, and found 63 patients who succumbed due to metastasis. We examined the clinical features of the initially detected distant metastases, the subsequent clinical course up to the time of patient death and the survival time of patients who died of lung metastasis. Of the 63 patients who died of distant metastasis, 52 (83%) developed lung metastasis as the first metastatic site, while 22 (35%) developed extra-pulmonary metastasis. The majority (77%; 49 of 63 patients) died of primary metastasis. While all 18 bone sarcoma patients died of lung metastasis, 11 of the 45 soft tissue sarcoma patients died of extra-pulmonary metastasis. Six patients died of brain metastasis. The survival of the patients with lung metastasis was only approximately 6 months following the cessation of treatment, regardless of the type of treatment used. These results indicate that planned follow-up and treatment of sarcomas require a precise knowledge of tumor clinical behavior, particularly of the preponderant activity.

Extraskeletal osteosarcoma (ESOS) occurs in approximately 1% of soft tissue sarcomas and 2-4% of all osteosarcomas. In particular, subcutaneous osteosarcoma is extremely rare, occurring in less than 10% of ESOS cases. This report presents a case of a subcutaneous tumor in the upper arm of a 79-year-old male. Imaging and pathological findings led to the conclusion that the soft tissue tumor should be diagnosed as subcutaneous osteosarcoma. Additionally, this case report documented the clinicopathological findings of the extraskeletal subcutaneous osteosarcoma in this case and discussed its clinical features by reviewing cases previously described in the literature.

Purpose: To compare percutaneous transpedicular vertebroplasty using calcium phosphate cement (CPC) versus conservative treatment for osteoporotic vertebral fractures., Methods: Eight men and 28 women aged 61 to 99 (mean, 80) years with osteoporotic vertebral fractures underwent percutaneous transpedicular vertebroplasty using CPC. During the same period, 6 men and 32 women aged 53 to 93 (mean, 77) years underwent conservative treatment. The indication for vertebroplasty was a painful unstable fracture, with mobility of the vertebral body shown on flexion and extension lateral radiographs. Fractures without mobility despite deformity were treated conservatively., Results: In the vertebroplasty group, all patients benefited from reduced back pain immediately after surgery, and pain relief was maintained at the latest follow-up. However, correction loss continued until one month after the operation. The mean visual analogue score for pain decreased significantly from preoperation to one day after surgery (9.3 vs. 6.2, p=0.02), and further decreased to 2.8 (p = 0.04) on day 3 or 4 when ambulation began, and to 1.5 at the one month follow-up and 1.4 at the final follow-up (mean, 14 months). The mean duration of analgesic treatment was significantly shorter in the vertebroplasty than conservatively treated group (10.2 vs. 63.5 days). All patients in the vertebroplasty group achieved bone union, with no adjacent vertebral fractures. However, in patients having conservative treatment, there were 2 adjacent vertebral fractures and 4 pseudarthroses, and the collapse continued for several months., Conclusion: Percutaneous transpedicular vertebroplasty using CPC achieves immediate pain relief and reduces the risk of vertebral body collapse and pseudarthrosis among elderly patients with osteoporotic vertebral compression fractures.

Purpose: Recent studies have shown that low-intensity resistance training with vascular occlusion (kaatsu training) induces muscle hypertrophy. A local hypoxic environment facilitates muscle hypertrophy during kaatsu training. We postulated that muscle hypertrophy can be more efficiently induced by placing the entire body in a hypoxic environment to induce muscle hypoxia followed by resistance training., Methods: Fourteen male university students were randomly assigned to hypoxia (Hyp) and normoxia (Norm) groups (n = 7 per group). Each training session proceeded at an exercise intensity of 70% of 1 repetition maximum (RM), and comprised four sets of 10 repetitions of elbow extension and flexion. Students exercised twice weekly for 6 wk and then muscle hypertrophy was assessed by magnetic resonance imaging and muscle strength was evaluated based on 1RM., Results: Muscle hypertrophy was significantly greater for the Hyp-Ex (exercised flexor of the hypoxia group) than for the Hyp-N (nonexercised flexor of the hypoxia group) or Norm-Ex flexor (P < .05, Bonferroni correction). Muscle hypertrophy was significantly greater for the Hyp-Ex than the Hyp-N extensor. Muscle strength was significantly increased early (by week 3) in the Hyp-Ex, but not in the Norm-Ex group., Conclusion: This study suggests that resistance training under hypoxic conditions improves muscle strength and induces muscle hypertrophy faster than under normoxic conditions, thus representing a promising new training technique.

The aggregation of chondroprogenitor mesenchymal cells into precartilage condensation represents one of the earliest events in chondrogenesis. N-cadherin is a key cell adhesion molecule implicated in chondrogenic differentiation. Recently, ADAM10-mediated cleavage of N-cadherin has been reported to play an important role in cell adhesion, migration, development and signaling. However, the significance of N-cadherin cleavage in chondrocyte differentiation has not been determined. In the present study, we found that the protein turnover of N-cadherin is accelerated during the early phase of chondrogenic differentiation in ATDC5 cells. Therefore, we generated the subclones of ATDC5 cells overexpressing wild-type N-cadherin, and two types of subclones overexpressing a cleavage-defective N-cadherin mutant, and examined the response of these cells to insulin stimulation. The ATDC5 cells overexpressing cleavage-defective mutants severely prevented the formation of cartilage aggregates, proteoglycan production and the induction of chondrocyte marker gene expression, such as type II collagen, aggrecan and type X collagen. These results suggested that the cleavage of N-cadherin is essential for chondrocyte differentiation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background and Objectives: We recently developed and established a new surgical therapy combining photodynamic surgery and radiodynamic therapy using acridine orange (AO) therapy after marginal or intralesional tumor resection, providing excellent limb function to sarcoma patients. The present study evaluated local recurrence rate and limb function using Disability of Arm, Shoulder, and Hand (DASH) score of patients with primary musculoskeletal sarcoma around the forearm treated with AO therapy, compared to that of patients treated with conventional wide resection., Methods: Subjects were 18 patients with primary musculoskeletal sarcoma around the forearm and treated with AO therapy (AO: n = 8) after marginal or intralesional resection, or conventional wide resection followed by limb reconstruction surgery (WR: n = 10)., Results: Mean age of the 18 patients was 45 years, and mean durations of follow-up for Groups AO and WR were 67 and 74.1 months. Local recurrence rates for AO and WR were 12.5% and 20% (P = 0.63), DASH disability scores were 3.9 and 21 (P = 0.04), and 5-year survival rates were 100% and 90% (P = 0.40), respectively., Conclusions: AO therapy offers maintenance of excellent upper limb function and inhibition of local tumor recurrence, representing a useful modality for limb salvage surgery in patients with sarcoma around the forearm., (2010 Wiley-Liss, Inc.)

Disseminated squamous cell carcinoma (SCC) of the skin is exceedingly rare in children. SCC occurs after immunodeficiency from immunosuppression in organ transplant recipients or patients with HIV infection or leukaemia, but has not been reported in primary immunodeficiencies other than epidermodysplasia verruciformis. Interferon gamma receptor 2 (IFN gamma R2) deficiency is an exceedingly rare primary immunodeficiency, conferring almost selective predisposition to mycobacterial diseases. A disseminated, cutaneous SCC is described that occurred in a patient homozygous for a novel frameshift deletion at positions 949 and 950 (949delTG) in the IFNGR2 gene. The patient first presented at 1 year of age with disseminated Mycobacterium avium infection, with later infections of atypical mycobacteria (Mycobacterium fortuitum and Mycobacterium porcium). At 17 years of age, the patient developed multifocal SCC lesions on the face and both hands. Histopathological examination revealed well differentiated SCC. Despite local tumour excision, multiple lesions occurred and a large SCC on the right arm required amputation. The patient died at 20 years of age of disseminated SCC. Inherited disorders of IFN gamma mediated immunity may predispose patients to SCC.

Background: Tenascin-C (TN-C) is expressed in the cartilage of osteoarthritis (OA). We examined whether TN-C was involved in cartilage repair of the diseased joints. Human articular cartilage samples were obtained from patients with OA and those with normal joints., Methods: Immunohistochemistry testing of TN-C, chondroitin sulfate (CS), and proliferating cell nuclear antigen (PCNA) was performed. Chondrocytes were isolated from human cartilage and cultured. After treatment with TN-C, chondrocyte proliferation s was analyzed by bromodeoxyuridine (BrdU) incorporation assay using an enzyme-linked immunosorbent assay kit. Glycosaminoglycan content was determined by dimethylmethylene blue (DMMB) assay. The mRNA expression of aggrecan was also analyzed, by quantitative real-time polymerase chain reaction (PCR)., Results: In osteoarthritic cartilage, increased TN-C staining was observed with the degeneration of articular cartilage in comparison with normal cartilage. TN-C staining was shown in the cartilage surface overlying CS-positive areas. In addition, the expression of PCNA in the positive areas for TN-C was significantly higher than that in the negative areas. Treatment of human articular chondrocytes with 10 μg/ml TN-C accelerated chondrocyte proliferation, increased the proteoglycan amount in culture, and increased the expression of aggrecan mRNA., Conclusions: Our findings indicate that the distribution of TN-C is related to CS production and chondrocyte proliferation in osteoarthritic cartilage and that TN-C has effects on DNA synthesis, proteoglycan content, and aggrecan mRNA expression in vitro. TN-C may be responsible for repair in human osteoarthritic cartilage.

Purpose: To assess the association between vertebral fractures and mortality., Methods: 419 women and 210 men aged 60 to 98 (mean, 73) years participated in an osteoporosis screening exercise. Patient age, gender, comorbidity, lumbar pain, smoking, and alcohol consumption were recorded, as were the number of vertebral fractures and bone mineral density. Vertebral fractures were evaluated using lateral radiographs and quantitative morphometry. Anterior, central, and posterior vertebral heights were measured; vertebral fractures were defined as a decrease of more than or equal to 20% in any of these heights., Results: 131 (21%) of the participants had vertebral fractures. At the 10-year follow-up, 121 (19%) of the participants (55 men and 66 women) had died; 43 of them had vertebral fractures and 78 did not. The respective 10-year survival rates for participants with and without vertebral fractures were 69% and 86% (p<0.0001). The survival rate was lower in those with greater number of vertebral fractures (76% for those with one or 2 fractures and 50% for those with 3 fractures or more). Multiple regression analysis showed that advanced age (p<0.0001), male gender (p=0.003), and presence of vertebral fractures (p=0.013) correlated significantly with survival., Conclusion: The presence and number of vertebral fractures were associated with mortality. Prevention of vertebral fractures may be important for improving the prognosis of patients with osteoporosis.

The objective of this study is to compare the long-term outcomes of infliximab therapy with lower-dose methotrexate (MTX; < or = 4 mg per week) and with standard-dose MTX (> or = 6 mg per week) in Japanese rheumatoid arthritis (RA) patients. One hundred thirty-eight patients with refractory RA were treated with intravenous infliximab; 106 patients underwent lower-dose MTX therapy, and 32 patients underwent standard-dose MTX therapy. Treatment responses at 54 weeks or last observation carried forward (LOCF) assessed using the European League Against Rheumatism (EULAR) response criteria were compared between the two groups. Eighty-eight patients (81.1%) in the lower-dose MTX group and 27 patients (84.3%) in the standard-dose MTX therapy completed 54 weeks of infliximab treatment. A EULAR response criteria good and moderate response was seen in 70.9% in the lower-dose group and 74.1% in the standard-dose group. Good and moderate treatment responses at 54 weeks or LOCF were seen in 66.0% in the lower-dose group and 68.7% in the standard-dose group. The outcome in the lower-dose MTX group was not significantly different from that in the standard-dose group. Therapy with MTX and infliximab was effective in Japanese RA patients, regardless of MTX dosage.

Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of approximately 4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43x10(-8) for rs7775228 and 6.73x10(-8) for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA.

The human homologue of Drosophila disc large tumor suppressor protein (hDlg) is one of the proteins known to act cooperatively in regulating cell polarity and proliferation, suggesting an important connection between epithelial organization and cellular growth control. An abnormal expression of hDlg has been reported in several cancer types. However, the expression of hDlg in soft-tissue sarcomas has not yet been reported. We examined the expression of hDlg immunohistochemically in 46 specimens of malignant fibrous histiocytoma (MFH). The expression of hDlg was negative in 19 specimens, weak in 4, moderate in 16, and strong in 7. The patients with a weak or negative expression of hDlg had a significantly shorter metastasis-free survival rate and disease-free survival rate in comparison with those with a strong or moderate expression in both univariate analysis (p=0.0287 and 0.0237, respectively; log-rank test) and multivariate analysis (p=0.0087 and 0.0126, respectively; Cox proportional hazards regression model). Moreover, the patients with a weak or negative expression of hDlg had a significantly shorter overall survival rate in comparison with those with a strong or moderate expression in a univariate analysis (p=0.0214; log-rank test). This is the first report to demonstrate that a reduced expression of hDlg protein is an independent negative prognostic factor for MFH.

Soluble fibrin (SF) and D-dimer are useful for making the diagnosis of deep vein thrombosis (DVT). However, the evidence for using such markers and optimal timing to diagnose postoperative DVT are unclear. We evaluate the usefulness of SF and D-dimer testing for the diagnosis of postoperative DVT. A total of 207 patients who had total hip arthroplasty or knee arthroplasty were evaluated. SF and D-dimer were tested on postoperative days 1 and 7. DVT was confirmed with ultrasonography. SF level on postoperative day 1 was the most useful, although D-dimer evaluation on postoperative days 1 and 7 was also useful. Using a SF cut-off of more than 4.00 microg ml(-1), the sensitivity was 90%, the specificity was 33%. Although the SF and D-dimer tests cannot be used as stand-alone tests, SF and D-dimer are valuable screening tools. We recommend two-stage screening including first with the SF or D-dimer test, followed by ultrasonography or venography.

Lumbar fusion combined with unilateral pedicle screw fixation has received favourable clinical reports. However, there are very few reports about the biomechanical properties of this system. The purpose of this study was to compare the biomechanics of a unilateral pedicle screw system with a bilateral system. Two fresh lumbar vertebral columns from human cadavers were used. Seven models were prepared by the sequential damage and spinal instrumentation of each specimen. Bending and rotation tests were performed to clarify the range of motion for each model using a 6-axis material tester that we have developed. We showed that the unilateral pedicle screw system offers only uneven fixation. This results in dispersion of rigidity depending on the direction of bending and rotation. The bilateral pedicle screw system, however, allows excellent fixation in all directions., (Copyright 2009 Elsevier Ltd. All rights reserved.)

A rare case of post-radiation epithelioid hemangioendothelioma arising in a congenital hemangioma of the lower leg 18 years after radiotherapy is reported. At 7 years of age, the patient underwent partial resection of a subcutaneous congenital hemangioma with intramuscular extension of the left lower leg, and at 10 years of age, the patient was given radiotherapy with a total dose of 30 Gy for recurrence. At 28 years of age, the patient noticed a large tumor mass with intractable pain at the antero-lateral aspect of the proximal lower leg, and she presented to our hospital. Since microscopic examination of a biopsy specimen showed epithelioid hemangioendothelioma, disarticulation at the knee joint was performed. Although malignant change in a benign vascular tumor is extremely rare, irradiation can induce malignant transformation of a hemangioma.

Introduction: Bone is continually remodeled by the action of osteoblasts, osteocytes, and osteoclasts. Resting osteoblasts are able to proliferate and differentiate into mature osteoblasts when physiologically required, as after tissue injury. Activated protein C (APC) is a serine protease that functions in anticoagulation, anti-inflammation, anti-apoptosis, cell proliferation, and wound repair. In this study, we examined the effect of APC on osteoblast proliferation and differentiation., Materials and Methods: We examined the presence of protein C in human fracture hematoma by immunohistochemical staining. We then evaluated the effect of APC, diisopropyl fluorophosphate-inactivated APC (DIP-APC) or protein C zymogen on normal human osteoblast (NHOst) proliferation using tetrazolium salt assay in the presence or absence of aprotinin, hirudin, protein C, antibody against protein C, endothelial protein C receptor (EPCR) or protease-activated receptor (PAR)-1. Finally, activation of p44/42 MAP kinase was evaluated by Western blot analysis., Results: Both APC and DIP-APC increased osteoblast proliferation in a dose-dependent manner, while protein C did not. The APC-induced increased proliferation of osteoblast was not affected by aprotinin, hirudin, and anti-protein C antibody which inhibits the protease activity of APC. Treatment with protein C or anti-EPCR antibody which inhibits APC binding to EPCR inhibited APC-mediated osteoblast proliferation, while treatment with anti-PAR-1 antibody did not. APC promoted the phosphorylation of p44/42 MAP kinase within osteoblasts; this effect was inhibited by the anti-EPCR antibody., Conclusions: APC stimulates osteoblast proliferation by activating p44/42 MAP kinase through a mechanism that requires EPCR but not PAR-1 or the proteolytic activity of APC. APC generated at fracture sites may contribute to fracture healing by promoting osteoblast proliferation., (Copyright 2009 Elsevier Ltd. All rights reserved.)