Mesenchymal Stem Cells Preconditioned with Hypoxia and Dexamethasone Promote Osteoblast Differentiation Under Stress Conditions.

Bone marrow-derived mesenchymal stem cells (MSCs), which are capable of differentiating into osteoblasts, are used in effective regenerative therapies. MSCs must be prompted to differentiate into osteoblasts for MSC transplantation to be effective. In this study, osteoblast differentiation markers involved in bone formation were evaluated to investigate the stress resistance of bone marrow-derived rat MSCs to dexamethasone and hypoxia and their ability to differentiate into osteoblasts. MSCs were allowed to differentiate into osteoblasts for 21 days in three different environments (dexamethasone treatment, hypoxic conditions [1% oxygen], or both). Osteoblast differentiation potential was evaluated according to alkaline phosphatase levels and a mineralisation assay. Immunofluorescence staining was used to determine the protein expression of the osteoblast differentiation markers type I collagen and osteopontin. MSCs differentiated into osteoblasts under hypoxic conditions but differentiated more slowly upon treatment with dexamethasone and dexamethasone plus hypoxia relative to the control. MSCs preconditioned with dexamethasone or hypoxia and then allowed to differentiate into osteoblasts under similar conditions differentiated comparably to control MSCs. MSCs that developed resistance to dexamethasone or hypoxia differentiated more quickly into osteoblasts than those that did not. The findings suggest that increasing the resistance of MSCs to stress by preconditioning them via dexamethasone or hypoxia exposure could result in more rapid differentiation into osteoblasts following transplantation.

Comparative Study of Highly Cross-Linked Polyethylene Liner Wear by Hip Center Location Using Elevated Hip Center Technique in Crowe I to III Hip Dysplasia: Outcomes for a Minimum of Eighteen Years of Follow-Up.

BACKGROUND: The literature has reported that supero-lateralization of the femoral head increases the rates of aseptic loosening and prosthesis revision. However, there are few reports on the influence of different hip center positions on liner wear with more than a 15-year follow-up period. METHODS: From April 2000 to August 2003, 91 patients underwent 108 total hip arthroplasties using a highly cross-linked polyethylene liner combined with zirconia femoral head and cup components. Pelvic radiographs were used to assess the vertical and horizontal distances to the center of the hip and the amount of liner wear. Mean patient age at the time of surgery was 54 years (range, 33 to 73), and mean follow-up duration was 19 years (range, 18 to 21). RESULTS: Average liner wear was 0.221 mm, with average annual wear of 0.012 mm/year. Mean vertical and horizontal distances for the hip center were 24.9 and 31.8 mm, respectively. There was no difference in linear wear between patients who had different hip center heights (<20, 20 to 30, and >30 mm), and quadrant partitioning showed no differences across the 4 quadrant zones. CONCLUSION: At a minimum of 18 years of follow-up in patients having developmental dysplasia of the hip who had different Crowe subtypes and different hip centers, elevated hip center and uncemented fixation techniques using a highly cross-linked polyethylene on ceramic components were associated with very low wear rates and excellent functional scores.

Clinical outcomes following total en bloc spondylectomy for spinal metastases from lung cancer.

BACKGROUND: The current guidelines for the treatment of non-small cell lung cancer encourage local curative treatment for selected patients with oligometastases. This study evaluated the surgical results of total en bloc spondylectomy (TES) for isolated spinal metastases originating from lung cancer in carefully selected patients. METHODS: We retrospectively reviewed 14 patients (7 men and 7 women) who underwent TES for spinal metastases originating from lung cancer between 2000 and 2017. The primary outcome measure was the postoperative overall survival time. The histological types included adenocarcinoma (n = 12), pleomorphic carcinoma (n = 1), and small cell lung carcinoma (SCLC) (n = 1 patient). We assessed postoperative survival using Kaplan-Meier analysis and the log-rank test. RESULTS: The median postoperative survival time was 83.0 months (6-162 months) in 13 patients with non-small cell lung carcinoma (NSCLC) and 6 months in 1 patient with SCLC. The 3-, 5-, and 10-year overall survival rates in patients with NSCLC were 61.5%, 53.8%, and 15.4%, respectively. Poor postoperative performance status (PS) and Frankel grade, and preoperative irradiation to the vertebrae to be resected were significantly associated with short-term survival after TES in patients with NSCLC (p < 0.05). CONCLUSIONS: The surgical results of TES for spinal metastases of lung cancer were relatively favorable among carefully selected patients. TES may be indicated for spinal metastases of lung cancer in patients with controlled primary lung cancer, NSCLC histology, prospect of good postoperative PS, and preferably no irradiation to the target vertebrae.

Angular changes in pelvic tilt and cup orientation at a minimum of eighteen years after primary total hip arthroplasty with an uncemented cup.

BACKGROUND: Changes in pelvic tilt angle (PTA) and cup orientation have been reported in patients after total hip arthroplasty, but the current literature generally has a brief follow-up period. This study will be the first to report PTA and cup orientation changes in the supine position for a minimum 18 years after total hip arthroplasty (THA) and investigate the factors associated with pelvic tilt and cup orientation changes. METHODS: In this study, 101 patients (120 hips) who underwent THA were retrospectively analyzed. The aims of our study were to evaluate the PTA and cup orientation change over 18 years after THA to assess differential PTA, cup inclination, and anteversion. We also investigated whether factors such as gender, body mass index, and age have any influence on PTA and cup orientation after THA. RESULTS: Patients showed a significant incremental change in PTA pre-operatively, immediately post-operatively, and at final follow-up. Cup orientation increased significantly at the final follow-up compared to the immediate post-operative period. Gender subgroup analysis showed that PTA was significantly greater in females than in males at the final follow-up (p = 0.025). Age subgroup analysis showed that PTA was significantly greater in the over 60 years group than in the other groups. CONCLUSION: Our patients showed significant changes in PTA and cup orientation at a minimum 18 years after surgery, especially in females over 60 years. Female patients over 60 are a risk factor after THA.

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

A morphological study of adipose-derived stem cell sheets created with temperature-responsive culture dishes using scanning electron microscopy.

Adipose-derived stem cell (ADSC) sheets have potential to be effective in various therapies. In this study, we first demonstrated that a cell sheet composed of human ADSCs could be created using a new temperature-responsive culture dish from the DIC Corporation. The dish can cause detachment of adherent cells due to temperature changes, but a few morphological analyses have evaluated the presence or absence of damage on the detached surface of cell sheet. To characterize our ADSC sheet, we tried to observe the surface of ADSC sheets with scanning electron microscope (SEM) using the ionic liquid, which enables the rapid preparation of samples. No damage was found on the surface of the ADSC sheets on the side that had been in contact with the surface of the culture dishes. In addition, when the transcriptomes of the harvested cell sheets were compared with those of monolayer cultures, no up-regulation of cell death related genes were detected. These results propose that the detachment from temperature-responsive culture dish causes no serious damage on the prepared ADSC sheet. It is also suggested that the SEM with ionic liquids is a useful and rapid method for the analysis of ADSC sheets for therapy.

Clinical outcomes and prognostic factors following the surgical resection of renal cell carcinoma spinal metastases.

The efficacy of surgical resection in metastatic renal cell carcinoma is an active and important research field in the postcytokine era. Bone metastases, especially in the spine, compromise patient performance status. Metastasectomy is indicated, if feasible, because it helps to achieve the best clinical outcomes possible compared with other treatments. This study examined the postoperative survival and prognostic factors in patients who underwent metastasectomy of spinal lesions. The retrospective study included 65 consecutive patients with metastatic renal cell carcinomas who were operated on by spinal metastasectomy between 1995 and 2017 at our institution. The cancer-specific survival times from the first spinal metastasectomy to death or the last follow-up (≥3 years) were determined using Kaplan-Meier analysis. Potential factors influencing survival were analyzed using Cox proportional hazard models. Planned surgical resection of all the spine tumors was achieved in all patients. Of these, 38 had complete metastasectomy of all visible metastases, including extraspinal lesions. In all patients, the estimated median cancer-specific survival time was 100 months. The 3-, 5-, and 10-year cancer-specific survival rates were 77%, 62%, and 48%, respectively. The survival times after spinal metastasectomy were similar in both cytokine and postcytokine groups. In multivariate analyses, postoperative disability, the coexistence of liver metastases, multiple spinal metastases, and incomplete metastasectomy were significant risk factors associated with short-term survival. Complete metastasectomy, including extraspinal metastases, was associated with improved cancer-specific survival. Proper patient selection and complete metastasectomy provide a better prognosis in metastatic renal cell carcinoma patients.

Surgical Metastasectomy in the Spine: A Review Article.

BACKGROUND: The use of surgical metastasectomy (SM) has increased across cancer types in recent decades despite the increasing efficacy of modern systemic treatment modalities. Symptomatic spinal metastases severely compromise patients' performance status. However, as spinal SM is a complex surgery with potentially significant complications, it is not considered the treatment of choice. METHODS: We reviewed the articles on SM in several primary cancers with different types of metastatic lesions and extracted the data from relevant articles to provide a comprehensive review including the surgical techniques, indications, reported outcomes, and future prospects of SM in spinal metastases. RESULTS: Total en bloc spondylectomy (TES) is a method of spinal SM associated with a lower risk of tumor recurrence and complications. Intralesional transpedicular osteotomy using a fine threadwire saw allows prevention of spinal cord and nerve root injuries. Spinal SM is considered suitable for patients with controlled primary disease having no evidence of disseminated extraspinal metastases, a completely resectable solitary lesion in the spine, and adequate cardiopulmonary reserve to tolerate the surgery. Metastatic lesions from kidney and thyroid cancers have been reported as the best candidates for spinal SM. Although data about spinal SM are limited, the reported outcomes are favorable with acceptable local recurrence rates in long-term follow-up. CONCLUSION: In patients with isolated resectable spinal metastases, complete SM including TES is a useful option as it can improve function and survival. However, appropriate patient selection and surgical feasibility remain the most important aspects of management. IMPLICATIONS FOR PRACTICE: Surgical metastasectomy for spinal metastases may be a potentially curative treatment option with a low risk of local recurrence and lead to prolonged long-term survival if appropriate patients are selected and if the surgery is carried out by experienced surgeons in high-volume centers.

Resistance of bone marrow mesenchymal stem cells in a stressed environment - Comparison with osteocyte cells.

Introduction: Recently, the efficacy of mesenchymal stem cells (MSCs) mediated by their tissue repair and anti-inflammatory actions in the prevention and therapy of various disorders has been reported. In this research, our attention was focused specifically on the prevention and therapy of glucocorticoid-induced osteonecrosis. We investigated the stress resistance of MSC against glucocorticoid administration and hypoxic stress, which are factors known to induce osteocytic cell death. Materials and Methods: Mouse bone cells (MLO-Y4) and bone-marrow derived mouse MSCs were exposed to dexamethasone (Dex), hypoxia of 1% oxygen or both in vitro. Mitochondrial membrane potentials were estimated by mitochondria labeling with a cell-permeant probe (Mito tracker red); expression of these apoptosis-inducing molecules, oxidative stress marker (8-hydroxy-2'-deoxyguanosine), caspase-3, -9, and two apoptosis-inhibiting molecules, energy-producing ATP synthase (ATP5A) and X-linked inhibitor of apoptosis protein (XIAP), were analyzed by both immunofluorescence and western blot. Results: With exposure to either dexamethasone or hypoxia, MLO-Y4 showed reduced mitochondrial membrane potential, ATP5A and upregulation of 8-OHdG, cleaved caspases and XIAP. Those changes were significantly enhanced by treatment with dexamethasone plus hypoxia. In MSCs, however, mitochondrial membrane potentials were preserved, while no significant changes in the pro-apoptosis or anti-apoptosis molecules analyzed were found even with exposure to both dexamethasone and hypoxia. No such effects induced by treatment with dexamethasone, hypoxia, or both were demonstrated in MSCs at all. Discussion: In osteocyte cells subjected to the double stresses of glucocorticoid administration and a hypoxic environment osteocytic cell death was mediated via mitochondria. In contrast, MSC subjected to the same stressors showed preservation of mitochondrial function and reduced oxidative stress. Accordingly, even under conditions sufficiently stressful to cause the osteocytic cell death in vivo, it was thought that the function of MSC could be preserved, suggesting that in the case of osteonecrosis preventative and therapeutic strategies incorporating their intraosseous implantation may be promising.

Feasibility of achieving planned surgical margins in primary spine tumor: a PTRON study.

OBJECTIVE: Oncological resection of primary spine tumors is associated with lower recurrence rates. However, even in the most experienced hands, the execution of a meticulously drafted plan sometimes fails. The objectives of this study were to determine how successful surgical teams are at achieving planned surgical margins and how successful surgeons are in intraoperatively assessing tumor margins. The secondary objective was to identify factors associated with successful execution of planned resection. METHODS: The Primary Tumor Research and Outcomes Network (PTRON) is a multicenter international prospective registry for the management of primary tumors of the spine. Using this registry, the authors compared 1) the planned surgical margin and 2) the intraoperative assessment of the margin by the surgeon with the postoperative assessment of the margin by the pathologist. Univariate analysis was used to assess whether factors such as histology, size, location, previous radiotherapy, and revision surgery were associated with successful execution of the planned margins. RESULTS: Three hundred patients were included. The surgical plan was successfully achieved in 224 (74.7%) patients. The surgeon correctly assessed the intraoperative margins, as reported in the final assessment by the pathologist, in 239 (79.7%) patients. On univariate analysis, no factor had a statistically significant influence on successful achievement of planned margins. CONCLUSIONS: In high-volume cancer centers around the world, planned surgical margins can be achieved in approximately 75% of cases. The morbidity of the proposed intervention must be balanced with the expected success rate in order to optimize patient management and surgical decision-making.

Long-Term Outcomes for Cementless Anatomic Femoral Components, Compared by Area of Porous Coating, in Patients Younger Than 50 Years Treated for Hip Dysplasia.

BACKGROUND: We investigated whether the proximal circumferential porous coating of cementless stems would make implant survival of >20 years possible in young patients. METHODS: Data for patients younger than 50 years with hip dysplasia who had an anatomic stem implanted with a proximal porous coating with hydroxyapatite/tricalcium phosphate were reviewed. Noncircumferential porous (non-C-type) stems were used in 17 hips (13 cases), and circumferential porous (C-type) stems were used in 87 hips (68 cases). Acetabular components with conventional polyethylene were used for all hips. The mean ages at surgery for patients with non-C-type stems and those with C-type stems were 43.3 and 44.7 years, respectively. Stems that had not loosened were retained at the time of acetabular revision. The average duration of follow-up for patients with non-C-type stems was 26.9 years and was 22.3 years for those with C-type stems. RESULTS: Mean survival rates as determined by the Kaplan-Meier method were 74.9% at 20 years and 59.9% at 25 years for non-C-type stems and were 100% at 20 years and 94.0% at 25 years for C-type stems. The survivorship for C-type stems was significantly higher than that for non-C-type stems (P < .01). Focal osteolysis in the shoulder of 37 hips with C-type stems suppressed the spread of osteolysis to the distal femur. CONCLUSION: Anatomic femoral stems with a circumferential porous coating provide excellent durability in patients with hip dysplasia who are 50 years of age or younger. LEVEL OF EVIDENCE: Therapeutic Level IV.

Mitochondrial Transcription Factor A added to Osteocytes in a Stressed Environment has a Cytoprotective Effect.

The main precipitant of glucocorticoid-associated femoral head osteonecrosis is widely accepted to be an ischemic-hypoxic event, with oxidative stress also as an underlying factor. Mitochondrial DNA is more vulnerable to oxidative injury than the nucleus, and mitochondrial transcription factor A (TFAM), which plays roles in its function, preservation, and regulation is being increasingly investigated. In the present study we focused on the impact of TFAM on the relation between the oxidative injury induced by the addition of glucocorticoid to a hypoxic environment and osteocytic cell necrosis. Using cultured osteocytes MLO-Y4 in a 1% hypoxic environment (hypoxia) to which 1µM dexamethasone (Dex) was added (Dex(+)/hypoxia(+)), an immunocytochemical study was conducted using 8-hydroxy-2'-deoxyguanosine (8-OHdG), an index of oxidative stress, and hypoxia inducible factor-1α (HIF-1α), a marker of hypoxia. Next, after adding TFAM siRNA, TFAM knockdown, cultured for 24h, and mitochondrial membrane potential were measured, they were stained with ATP5A which labels adenosine triphosphate (ATP) production. Dex was added to MLO-Y4 to which TFAM had been added, and cultured for 24h in hypoxia. The ratio of dead cells to viable cells was determined and compared. Enhanced expression of 8-OHdG, HIF-1α was found in osteocytes following the addition of glucocorticoid in a hypoxic environment. With TFAM knockdown, as compared to normoxia, mitochondrial function significantly decreased. On the other hand, by adding TFAM, the incidence of osteocytic cell necrosis was significantly decreased as compared with Dex(+)/hypoxia(+). TFAM was confirmed to be important in mitochondrial function and preservation, inhibition of oxidative injury and maintenance of ATP production. Moreover, prevention of mitochondrial injury can best be achieved by decreasing the development of osteocytic cell necrosis.

Clinical outcomes and survivals after total en bloc spondylectomy for metastatic leiomyosarcoma in the spine.

PURPOSE: Leiomyosarcoma (LMS) is generally resistant to radiation and chemotherapy. Our study aimed to examine the outcomes of total en bloc spondylectomy (TES) for spinal metastatic LMS and to analyze potential factors associated with survival. METHODS: This study included 10 consecutive patients who underwent TES for spinal metastatic LMS at our institute between 2005 and 2016 and were followed up at a minimum of 3 years after surgery. At the time of TES, all the 10 patients had solitary bone metastases in the spine. Seven patients had a lowered performance status (PS) with an eastern cooperative oncology group (ECOG) grade of 2 or 3 due to back pain or neurological symptoms. The cancer-specific survival (CSS) time from TES to death or last follow-up was the main endpoint. Potential factors associated with survival were evaluated using the Kaplan-Meier analysis and the log-rank test. RESULTS: Five patients underwent a single vertebral resection, and the other five patients underwent two or three consecutive vertebral resections. Three patients developed perioperative complications including pulmonary thromboembolism and pneumothorax. Nine patients improved or fairly maintained their PS with an ECOG grade of 1. The 1-, 3-, and 5-year CSS rates after TES were 90%, 70%, and 47%, respectively. Only postoperative disability (ECOG PS grade 3) was significantly associated with short-term survival after TES. CONCLUSIONS: The clinical outcomes of 10 patients who underwent TES for spinal metastatic LMS were favorable without severe complications. Postoperative disability was significantly associated with short-term survival after TES.

How good are the outcomes of instrumented debulking operations for symptomatic spinal metastases and how long do they stand? A subgroup analysis in the global spine tumor study group database.

BACKGROUND: The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as cancer treatments improve and overall survival lengths increase, the incidence of recurrent spinal cord compression after debulking may increase. The aim of the current paper is to document the postoperative evolution of neurological function, pain, and quality of life following debulking and instrumentation in the Global Spine Tumor Study Group (GSTSG) database. METHODS: The GSTSG database is a prospective multicenter data repository of consecutive patients that underwent surgery for a symptomatic spinal metastasis. For the present analysis, patients were selected from the database that underwent decompressive debulking surgery with instrumentation. Preoperative tumor type, Tomita and Tokuhashi scores, EQ-5D, Frankel, Karnofsky, and postoperative complications, survival, EQ-5D, Frankel, Karnofsky, and pain numeric rating scores (NRS) at 3, 6, 12, and 24 months were analyzed. RESULTS: A total of 914 patients underwent decompressive debulking surgery with instrumentation and had documented follow-up until death or until 2 years post surgery. Median preoperative Karnofsky performance index was 70. A total of 656 patients (71.8%) had visceral metastases and 490 (53.6%) had extraspinal bone metastases. Tomita scores were evenly distributed above (49.1%) and below or equal to 5 (50.9%), and Tokuhashi scores almost evenly distributed below or equal to 8 (46.3%) and above 8 (53.7%). Overall, 12-month survival after surgery was 56.3%. The surgery resulted in EQ-5D health status improvement and NRS pain reduction that was maintained throughout follow-up. Frankel scores improved at first follow-up in 25.0% of patients, but by 12 months neurological deterioration was observed in 18.8%. CONCLUSION: We found that palliative debulking and instrumentation surgeries were performed throughout all Tomita and Tokuhashi categories. These surgeries reduced pain scores and improved quality of life up to 2 years after surgery. After initial improvement, a proportion of patients experienced neurological deterioration by 1 year, but the majority of patients remained stable.

Computed Tomographic Osteolytic Analysis of a First-Generation Remelted Highly Cross-Linked Polyethylene in Total Hip Arthroplasty-At a Minimum of 15-Year Follow-Up.

BACKGROUND: Low polyethylene wear rate and low incidence of osteolysis have been reported after total hip arthroplasty (THA) using first-generation remelted highly cross-linked polyethylene (HXLPE). However, osteolysis has not been evaluated in long-term studies of these patients (15 years or more). The present study assessed computed tomography (CT) images to determine the incidence of osteolysis associated with HXLPE in THA during at least 15 years of follow-up. METHODS: We evaluated 105 primary THAs in 84 patients (77 women and 7 men). Mean follow-up was 15.9 years (range, 15-18 years). All THAs used a Longevity HXLPE liner and a 26-mm zirconia femoral head. Areas of osteolysis were identified from CT images using 3D and multiplanar reconstruction views. RESULTS: CT 3D multiplanar reconstruction images at 15-year follow-up showed no obvious osteolysis in the acetabulum or femur of any patient. No patients developed cup loosening or liner breakage. CONCLUSION: Our study indicates that first-generation remelted HXLPE liners do not increase the risk of osteolysis during 15-year follow-up and suggests that the wear particles from first-generation remelted HXLPE are less biologically active than those generated by conventional polyethylene devices.

Taurine Inhibits Glucocorticoid-Induced Bone Mitochondrial Injury, Preventing Osteonecrosis in Rabbits and Cultured Osteocytes.

Mitochondrial injury has recently been implicated in the pathogenesis of glucocorticoid-induced osteonecrosis. Using cultured osteocytes and a rabbit model, we investigated the possibility that taurine (TAU), which is known to play a role in the preservation of mitochondrial function, might also prevent the development of osteonecrosis. To reduplicate the intraosseous environment seen in glucocorticoid-induced osteonecrosis, dexamethasone (Dex) was added to MLO-Y4 cultured in 1% hypoxia (H-D stress environment). An in vitro study was conducted in which changes in mitochondrial transcription factor A (TFAM), a marker of mitochondrial function, and ATP5A produced by mitochondria, induced by the presence/absence of taurine addition were measured. To confirm the effect of taurine in vivo, 15 Japanese White rabbits were administered methylprednisolone (MP) 20 mg/kg as a single injection into the gluteus muscle (MP+/TAU- group), while for 5 consecutive days from the day of MP administration, taurine 100 mg/kg was administered to 15 animals (MP+/TAU+ group). As a control 15 untreated rabbits were also studied. The rabbits in each of the groups were sacrificed on the 14th day after glucocorticoid administration, and the bilateral femora were harvested. Histopathologically, the incidence of osteonecrosis was quantified immunohistochemically by quantifying TFAM and ATP5A expression. In the rabbits exposed to an H-D stress environment and in MP+/TAU- group, TFAM and ATP5A expression markedly decreased. With addition of taurine in the in vitro and in vivo studies, the expression of TFAM and ATP5A was somewhat decreased as compared with Dex-/hypoxia- or MP-/TAU- group, while improvement was noted as compared with Dex+/hypoxia+ or MP+/TAU- group. In rabbits, the incidence of osteonecrosis was 80% in MP+/TAU- group, in contrast to 20% in the taurine administered group (MP+/TAU+), representing a significant decrease. Since taurine was documented to exert a protective effect on mitochondrial function by inhibiting the mitochondrial dysfunction associated with glucocorticoid administration, we speculated that it might also indirectly help to prevent the development of osteonecrosis in this context. Since taurine is already being used clinically, we considered that its clinical application would also likely be smooth.

Patient satisfaction with treatment outcomes after surgery and/or radiotherapy for spinal metastases.

BACKGROUND: Patient satisfaction is infrequently investigated despite its importance in assessing efficacy and patient comprehension. The purpose of this study was to investigate patient satisfaction with treatment outcomes after surgery and/or radiotherapy for spinal metastases and to evaluate how health-related quality of life (HRQOL) is related to patient satisfaction. METHODS: Patients with spinal metastases treated with surgery and/or radiotherapy were enrolled in a prospective, international, observational study. Demographic, histologic, treatment, and HRQOL data were collected. HRQOL was evaluated with the Numeric Rating Scale pain score, the 3-level version of the EuroQol 5-Dimension (EQ-5D-3L) instrument, and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0). Patient satisfaction was derived from the SOSGOQ2.0 at 6, 12, and 26 weeks after treatment. Patients were classified as satisfied, neutral, or dissatisfied. RESULTS: Twelve weeks after treatment, 183 of the surgically treated patients (84%) were satisfied, and only 11 (5%) were dissatisfied; in contrast, 101 of the patients treated with radiotherapy alone (77%) were satisfied, and only 7 (5%) were dissatisfied. Significant improvements in pain, physical function, mental health, social function, leg function, and EQ-5D were associated with satisfaction after surgery. Satisfaction after radiotherapy was associated with significant improvements in pain, mental health, and overall SOSGOQ2.0 scores. Dissatisfaction after treatment was associated with lower baseline values for leg strength and lower social functioning scores for surgically treated patients and with lower social functioning scores and being single for patients treated with radiotherapy. CONCLUSIONS: High levels of satisfaction with treatment outcomes are observed after surgery and/or radiotherapy for spinal metastases. Posttreatment satisfaction is associated with significant improvements in pain and different dimensions of HRQOL.

Inversion of the acetabular labrum causes increased localized contact pressure on the femoral head: a biomechanical study.

PURPOSE: Although studies suggest that subchondral insufficiency fracture of the femoral head may cause rapidly progressive osteoarthritis of the hip, the mechanism of that relationship remains unclear. Our biomechanical study aimed to provide more data in this area by quantifying pressure distribution on the femoral head for normal and inverted hips and by determining the effects of labral inversion on pressure distribution across the joint, focusing on types of fracture under load. METHODS: We tested mid-sized fourth-generation composite femurs at 15° of adduction, and applied 1 mm/min of axial compressive force to the femoral heads until failure. Additionally, single loads (3000 N) were applied using Prescale film to investigate pressure distribution on the femoral head, with or without silicone rubber representing entrapment of an inverted acetabular labrum. RESULTS: In tests with an external load of 3000 N, the mean pressure for 10 × 5 mm of silicone rubber was 11.09 MPa, significantly greater (about 5.7-fold) than 1.94 MPa without silicone rubber. Different fracture patterns were observed with and without the 10 × 5 mm silicone rubber; when the 10 × 5 mm silicone rubber specimens were used, all eight cases showed fractures in the anterior femoral head. CONCLUSIONS: When silicone rubber representing an inverted acetabular labrum was placed between a hemispherical metallic platen and a composite bone model, the silicone rubber areas were subjected to extreme concentration of stress. The fractures that developed at the silicone rubber areas clearly represented subchondral fractures of the femoral head, rather than fractures of the femoral neck.

Mitochondrial stress and redox failure in steroid-associated osteonecrosis.

The purpose of the role of antioxidant enzymes and mitochondria in the developmental mechanism of steroid-associated osteonecrosis in the femur. In the present study Japanese white rabbits (mean weight 3.5kg) were injected into the gluteus with methylprednisolone (MP) 20mg/kg, and killed after 3 days (MP3 group), 5 days (MP5 group), and 14 days (MP14 group) (n=3 each). As a Control group (C group) Japanese white rabbits not administered MP were used. In experiment 1, the expression of the antioxidant enzymes Superoxide dismutade (SOD) and catalase was compared in liver, kidney, heart, humerus, and femur in C group, and the presence/absence of mitochondria transcription factor A (TFAM) expression was determined by Western blotting (WB) and used to evaluate the number of mitochondria and their function. In experiment 2, the presence/absence of necrosis was determined by immunohistochemistry, while changes in the expression of SOD, catalase, and TFAM in the femur after steroid administration were determined by Western blotting (WB). In experiment 1, intense expression of all of SOD, catalase, and TFAM was found in the liver, kidney, and heart as compared to the humerus and femur. In experiment 2, the expression of all of SOD, catalase, and TFAM in MP3 and MP5 groups was decreased on WB as compared with C group, while in MP14 group a tendency to improvement was seen. Accordingly, steroid-associated mitochondrial injury and redox failure are concluded to be important elements implicated in the pathogenesis of osteonecrosis.

Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model.

Persistent inflammation is well known to promote the progression of arthropathy. mesenchymal stem cells (MSCs) have been shown to possess anti-inflammatory properties and tissue differentiation potency. Although the experience so far with the intraarticular administration of mesenchymal stem cell (MSC) to induce cartilage regeneration has been disappointing, MSC implantation is now being attempted using various surgical techniques. Meanwhile, prevention of osteoarthritis (OA) progression and pain control remain important components of the treatment of early-stage OA. We prepared a shoulder arthritis model by injecting monoiodoacetate (MIA) into a rat shoulder, and then investigated the intraarticular administration of MSC from the aspects of the cartilage protective effect associated with their anti-inflammatory property and inhibitory effect on central sensitization of pain. When MIA was administered in this rat shoulder arthritis model, anti-Calcitonin Gene Related Peptide (CGRP) was expressed in the joint and C5 spinal dorsal horn. Moreover, expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a marker of joint cartilage injury, was similarly elevated following MIA administration. When MSC were injected intraarticularly after MIA, the expression of CGRP in the spinal dorsal horn was significantly deceased, indicating suppression of the central sensitization of pain. The expression of ADAMTS 5 in joint cartilage was also significantly inhibited by MSC administration. In contrast, a significant increase in the expression of TNF-α stimulated gene/protein 6 (TSG-6), an anti-inflammatory and cartilage protective factor shown to be produced and secreted by MSC intraarticularly, was found to extend to the cartilage tissue following MSC administration. In this way, the intraarticular injection of MSC inhibited the central sensitization of pain and increased the expression of the anti-inflammatory and cartilage protective factor TSG-6. As the least invasive conservative strategies possible are desirable in the actual clinical setting, the intraarticular administration of MSC, which appears to be effective for the treatment of pain and cartilage protection in early-stage arthritis, may achieve these aims.