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Purpose The purpose of this study was to investigate the clinical results of single-stage revision anterior cruciate ligament reconstruction (ACLR) after synthetic ligament failure. Methods The subjects comprised 20 patients who underwent revision ACLR after synthetic ligament failure. All revisions were performed with bone–patellar tendon–bone graft, and bone tunnel expansion after removal of synthetic materials was treated with bone plugs sized and trimmed as necessary to fill the bone tunnels. Clinical results were assessed at a mean of 2.8 years postoperatively, followed by comparison with the results of 20 primary ACLRs selected as case-matched controls. Assessment included the Lysholm score, International Knee Documentation Committee (IKDC) evaluation, instrumented laxity testing, and radiologic examination. Results Bone tunnel enlargement to 11 mm in diameter or greater was found in 10 of 20 revision ACLRs. However, favorable anteroposterior stability was obtained at final follow-up (1.4 ± 2.0 mm in revision ACLR group and 1.5 ± 1.5 mm in primary ACLR group). The overall Lysholm score improved significantly from preoperatively to final follow-up, but the revision ACLR group showed significantly worse results for the pain parameter than the primary ACLR group. The final IKDC results also showed significant postoperative improvement, but the number of cases with grade C was significantly higher in the revision ACLR group than in the primary ACLR group, which was attributed to radiologically confirmed osteoarthritis in the revision ACLR group. Conclusions Single-stage revision ACLR with bone–patellar tendon–bone graft after synthetic ligament failure yielded favorable results in terms of IKDC grade, Lysholm score, and anteroposterior stability, despite enlarged bone tunnels after removal of synthetic material. Inferior results for the radiologic and pain parameters of the IKDC and Lysholm scores were attributed to osteoarthritic changes inherent to the revision ACLR group. Level of Evidence Level III, therapeutic case-control study.

Background: A variety of osteotomies has been proposed to correct posttraumatic cubitus varus deformity as well as any associated hyperextension and/or rotational deformities. However, lateral closing-wedge osteotomy and step-cut osteotomy, both of which have been used extensively with satisfactory outcomes, correct only in the coronal plane. To date, no direct comparison has been made between three-dimensional and simple coronal plane osteotomies. Methods: Between 1983 and 2007, we treated eighty-six elbows with a posttraumatic varus deformity. We classified patients who underwent three-dimensional osteotomies as Group I and those who underwent simple coronal plane osteotomies as Group II, and we compared the outcomes between the groups. Clinical evaluation included an assessment of the carrying angle and measurement of the passive range of motion before surgery and at the time of the final follow-up. To evaluate the remodeling capacity of the bone to recover elbow flexion in Group II, we assessed the range of motion before surgery and at the time of the final follow-up in patients who were less than ten years old and those who were more than ten years old. Results: There was no significant difference between the groups with regard to the carrying angle or the elbow range of motion, either before surgery or at the time of the final follow-up. However, Group I had more significant loss of correction (p = 0.018). In Group II, elbow motion reached the physiological range by the time of the final follow-up in patients who were less than ten years old. Conclusions: For osteotomies to correct cubitus varus deformity, correction of internal rotation is not needed. With a three-dimensional osteotomy, it is difficult to maintain correction and to acquire the planned carrying angle because of the small area of bone contact. It is necessary to correct hyperextension in patients older than ten years of age, as after that age bone remodeling is not expected to increase elbow flexion. Level of Evidence: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.

Various types of induced pluripotent stem (iPS) cells have been established by different methods, and each type exhibits different biological properties. Before iPS cell-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Here we show the directed neural differentiation of murine iPS cells and examine their therapeutic potential in a mouse spinal cord injury (SCI) model. “Safe” iPS-derived neurospheres, which had been pre-evaluated as nontumorigenic by their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse brain, produced electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro. Furthermore, when the safe iPS-derived neurospheres were transplanted into the spinal cord 9 d after contusive injury, they differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in remyelination and induced the axonal regrowth of host 5HT + serotonergic fibers, promoting locomotor function recovery. However, the transplantation of iPS-derived neurospheres pre-evaluated as “unsafe” showed robust teratoma formation and sudden locomotor functional loss after functional recovery in the SCI model. These findings suggest that pre-evaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.

Summary Objective The role of postmenopause on the pathogenesis of cartilage degeneration has been an open question. We assessed cartilage degeneration in estrogen receptor (ER)α null mice and examined the role of glucocorticoid receptor-interacting protein 1 (GRIP1) in the ERα-dependent transcription of a type II collagen gene ( col2a1 ) with special reference to a crosstalk with the transforming growth factor (TGF)-β signaling pathway. Methods The vertebral cartilaginous endplate from female ERα null mice was subjected to histological analyses. Col2a1 expression of primary chondrocytes (PCs) obtained from ERα null mice after 17β-estradiol (E 2 ) and TGF-β1 stimulation was examined by reverse transcription polymerase chain reaction (RT-PCR). Estrogen response element (ERE) or col2a1 promoter–enhancer luciferase reporter system was used to investigate the crosstalk among ERα, GRIP1, and MKK6. Col2a1 expression and glycosaminoglycan (GAG) content were measured in ATDC5 cells treated with GRIP1 small interfering RNA (siRNA). Results ERα deficiency clearly accelerated impairment of the vertebral cartilaginous endplate. E 2 and TGF-β1 stimulation increased col2a1 expression in PC from wild-type mice, but not that from ERα null mice. The same stimulation increased the col2a1 promoter–enhancer reporter activity, and the elevated activity was decreased by dominant-negative ERα and p38 mitogen-activated protein kinase (MAPK) inhibitor. GRIP1 increased the E 2 -dependent ERE activation in the presence of ERα and constitutive-active MKK6. GRIP1 siRNA repressed col2a1 expression and GAG production in ATDC5 cells. Conclusions Crosstalks between ERα/GRIP1 and TGF-β/MKK6/p38 MAPK pathway have protective roles on cartilage metabolism via regulating the extracellular matrices expression. The finding may lead to the development of a novel therapeutic approach for cartilage degeneration.

OBJECTIVES: The purpose of this study was to longitudinally evaluate relationships between the incidence of stiff shoulder and sagittal alignments of the cervical spine, age-related changes on magnetic resonance imaging (MRI) and life styles of the subjects. METHODS: The subjects were 69 men and 93 women. The mean follow-up period was 11.3 +/- 0.7 years. Sagittal alignments of the cervical spine were classified into the following 4 types: lordosis, straight, kyphosis and sigmoid. MRI findings were evaluated for the progression of 1) decrease in signal intensity of disc, 2) posterior disc protrusion, and 3) disc space narrowing. RESULTS: Stiff shoulder was found in 29.6% of the subjects over the 10 years. In the group of subjects 30-49 years old, the incidence of stiff shoulder was 40.4%, and it was higher than those in other age groups. Stiff shoulder was significantly more frequent in women (45.2%) than in men. Its incidence was significantly lower in those who regularly participated in sports or exercise. There were no significant relationship between the incidence of stiff shoulder and the progressions in any of MRI findings during the follow-up period. CONCLUSIONS: Stiff shoulder was more frequent in middle-aged, female and non-exercising subjects. There was no correlation between the incidence of stiff shoulder and sagittal alignments of the cervical spine, or progression of age-related changes of the cervical disc on MRI.

Study Design. Case report. Objective. To report 3 cases of malignant tumors in the upper cervical spine that were treated surgically by a combination of posterior tumor resection and stabilization and anterior tumor resection through a mandible-splitting approach after failed ion-beam radiation therapy. Summary of Background Data. Few clinical reports have described in detail the postoperative complications associated with transoral surgical resection of tumors in the upper cervical spine after unsuccessful ion-beam radiation therapy. Methods. Three patients with malignant tumors in the upper cervical spine who had undergone ion-beam radiotherapy and experienced tumor recurrence were treated by a combination of posterior and anterior surgery through a mandible-splitting approach. One patient (patient 1, a 32-year-old man) had a hemangioendothelioma at the C2 and C3 level, whereas the other 2 patients (patient 2, a 66-year-old woman and patient 3, a 65-year-old man) had a chordoma at the C2 and C3 level. Results. The intralesional but macroscopic total resection of the tumors was achieved in all 3 patients. However, serious complications developed after surgery, including deep wound infection, cerebrospinal fluid leakage, and meningitis in patient 1, prolonged swallowing difficulty, subsidence of the strut graft, and recurrence in patient 2, and deep wound infection and discitis causing progressive paralysis in patient 3. All patients underwent salvage surgery, including debridement of the wound in patient 1, posterior reinforcement using instrumentation and posterior tumor resection for the recurrent tumor in patient 2, and anterior debridement of the wound with a pedicle flap using the pectoral major muscle in patient 3 to address these problems. Patients 1 and 3 had no signs of recurrence at the time of a follow-up examination. Conclusion. Severe complications, mainly associated with the disturbance in healing of the retropharyngeal wall, were observed in all 3 patients. A preventive method, such as primary repair of the retropharyngeal wall using muscular/musculocutaneous flaps, should be considered for patients undergoing resection through a transoral approach after ion-beam irradiation.

Mucoid degeneration of the anterior cruciate ligament (ACL) is an unusual entity that has been described only since 1999. With increasing use of magnetic resonance imaging (MRI) to evaluate the knee, a number of cases with this entity have been accumulated to date, and characteristic features of MRI have been accepted as important diagnostic information. Past experience can be summarized as showing that the patients are middleaged and they present with knee pain and limited motion but without clinical ligament instability. We report herein two cases of mucoid degeneration of the ACL in which the patients were in their twenties. These cases differed substantially from previously reported cases, not only in the much younger age but also in that the patients exhibited substantial subclinical ACL insuffi ciency manifesting only in an anesthetized condition. Despite their young age, both patients also presented with intercondylar osteophyte, which was removed at the time of operation to avoid impingement of the ACL. The causal relation between minor ACL insuffi ciency and such osteophyte formation warrants further consideration. Although partial debridement of degenerative ACL has been reported to alleviate knee pain and is the common therapeutic strategy for this entity, patients should be carefully followed particularly for knee instability postoperatively owing to the inherent loss of ACL integrity associated with mucoid degeneration. Case reports

We herein present a case of osteosarcoma metastasizing to the stomach. An 18-year-old man who underwent amputation of the right arm for osteosarcoma developed persistent pain in the lower abdomen the following year. Endoscopy revealed a tumor that was highly suspicious of Bormann type III gastric cancer; however, based on histopathological studies, the fi nal diagnosis of metastatic osteosarcoma was made. Osteosarcoma rarely metastasizes to the digestive organs, and the stomach is one of the most unlikely destinations. In general, metastatic gastric cancer is regarded as a sign of an extremely poor prognosis with a low 1-year survival rate. The patient also demonstrated multiple metastatic lesions in the lung and died 6 months after the diagnosis of gastric metastasis.

Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 × 10−5). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P < 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G0-G1 arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. Mol Cancer Ther; 9(3); 535–44

Osteoclastogenesis is a highly sophisticated process that involves a variety of membrane-bound proteins expressed in osteoblasts and osteoclast precursors. Over the past several years, proteolytic cleavage and release of the ectodomain of membrane-bound proteins, also referred to as ectodomain shedding, has emerged as an important posttranslational regulatory mechanism for modifying the function of cell surface proteins. In line with this notion, several membrane-bound molecules involved in osteoclastogenesis, including CSF-1R and receptor activator of NF-κB ligand (RANKL), are proteolytically cleaved and released from the cell surface. In this study, we investigated whether receptor activator of NF-κB (RANK), one of the most essential molecules in osteoclastogenesis, undergoes ectodomain shedding. The results showed that RANK is released in the form of a soluble monomeric protein and that TNF-α–converting enzyme is involved in this activity. We also identified potential cleavage sites in the juxtamembrane domain of RANK and found that rRANKL induces RANK shedding in a macrophage-like cell line RAW264.7 via TNFR-associated factor 6 and MAPK pathways. Furthermore, we found that RANKL-induced osteoclastogenesis is accelerated in TNF-α–converting enzyme-deficient osteoclast precursors. These observations suggest the potential involvement of ectodomain shedding in the regulation of RANK functions and may provide novel insights into the mechanisms of osteoclastogenesis.

Purpose: We aimed to identify novel chemotherapy responsiveness biomarkers for osteosarcoma (OS) by investigating the global protein expression profile of 12 biopsy samples from OS patients. Experimental design: Six patients were classified as good responders and six as poor responders, according to the Huvos grading system. The protein expression profiles obtained by 2-D DIGE consisted of 2250 protein spots. Results: Among them, we identified 55 protein spots whose intensity was significantly different (Bonferroni adjusted p-value

The aim of this study was to evaluate weight-bearing condition after unilateral total knee arthroplasty (TKA) during standing and to examine whether the condition affects knee kinetics during gait in both limbs. Twenty-five patients, who underwent unilateral TKA for symptomatic bilateral osteoarthritis and who were on average 74 years old, participated. As a result, operated limbs became dominant in 80% of the patients. The other 20%, who had lack of knee extension during standing, showed more weight bearing in nonoperated knees. Furthermore, extension limitation in the operated knee in standing led to mechanical overload in the contralateral limb during gait. Therefore, to avoid progression of the osteoarthritis in the contralateral knee, it is important to acquire full extension in the operated knees during standing after unilateral TKA.

Introduction: The purpose of this study is to elucidate the feasibility of microendoscopic discectomy (MED) for the treatment of recurrent lumbar disc herniation. Methods: Thirty-six patients with recurrent lumbar disc herniation were treated using MED (30 men and six women; mean age: 45.7 years, range: 26–80 years; mean follow-up: 24.4 months, range: 12–52 months; mean duration between the primary and revision surgery: 65.9 months, range: 1–320 months) (recurrent group). Sex- and age-matched patients with primary lumbar disc herniation treated by MED served as the control group (primary group). The clinical outcomes were evaluated using the Japanese Orthopaedic Association score for low back pain and questionnaires regarding MED. Results: The average Japanese Orthopaedic Association scores before surgery and at the final follow-up were significantly lower in the recurrent group than in the primary group (10.8 ± 3.4 versus 15.0 ± 4.0 before surgery, P=0.001 and 25.4 ± 2.6 versus 26.8 ± 1.9 at follow-up, P=0.013), while the average recovery rates were not significantly different between the two groups (80.3 ± 14.1% versus 84.5 ± 14.6, P=0.22). The surgical time was significantly longer for the recurrent group than for the primary group (83.0 ± 41.8 min versus 67.1 ± 18.1 min,P=0.042). Of the 18 questionnaire respondents, 17 answered that postoperative pain was milder after MED than after a standard discectomy. Conclusion: MED is a feasible surgical option for recurrent lumbar disc herniation, yielding surgical outcomes comparable to those obtained in primary lumbar disc herniation.

Skeletal fracture healing involves a variety of cellular and molecular events; however, the mechanisms behind these processes are not fully understood. In the current study, we investigated the potential involvement of the signal transducer and activator of transcription 1 (STAT1), a critical regulator for both osteoclastogenesis and osteoblast differentiation, in skeletal fracture healing. We used a fracture model and a cortical defect model in mice, and found that fracture callus remodeling and membranous ossification are highly accelerated in STAT1-deficient mice. Additionally, we found that STAT1 suppresses Osterix transcript levels and Osterix promoter activity in vitro, indicating the suppression of Osterix transcription as one of the mechanisms behind the inhibitory effect of STAT1 on osteoblast differentiation. Furthermore, we found that fludarabine, a potent STAT1 inhibitor, significantly increases bone formation in a heterotopic ossification model. These results reveal previously unknown functions of STAT1 in skeletal homeostasis and may have important clinical implications for the treatment of skeletal bone fracture.

Object In this paper, the authors' goal was to elucidate the clinical features and results of decompression surgery for extraforaminal stenosis at the lumbosacral junction. Methods Twenty-eight patients with severe leg pain caused by extraforaminal stenosis at the lumbosacral junction (18 men and 10 women; mean age 68.2 ± 8.9 years) were treated by posterior decompression without fusion using a microendoscope in 19 patients and a surgical microscope or loupe in 9 patients. The decompression procedures consisted of partial resection of the sacral ala, the L-5 transverse process, and the L5–S1 facet joint along the L-5 spinal nerve. The following items were investigated: 1) preoperative neurological findings; 2) preoperative radiological findings, including plain radiographs, CT scans, selective radiculography of L-5; 3) surgical outcome as evaluated using the Japanese Orthopaedic Association scale for low-back pain (JOA score); and 4) need for revision surgery. Results All patients presented with neurological deficits compatible with a diagnosis of L-5 radiculopathy such as weakness of the extensor hallucis longus muscle and sensory disturbance in the L-5 area together with neurogenic claudication. On plain radiographs, 21 patients (75%) and 17 patients (60.7%) exhibited lumbar scoliosis (≥ 5°) and wedging of the L5–S1 intervertebral space (≥ 3°), respectively. The CT scans demonstrated marked osteophyte formation at the posterolateral margin of the L5–S1 vertebral bodies, and a selective L-5 nerve root block was effective in all patients. All patients reported pain relief immediately after surgery. The mean JOA scores were 11.3 ± 3.8 before surgery and 24.3 ± 3.4 at the time of the final follow-up examination; the recovery rate was 68.6 ± 16.5%. The mean estimated blood loss was 66.6 ± 98.6 ml, and the mean surgical time was 135.3 ± 46.5 minutes. No significant difference in the recovery rate of the JOA scores or in the surgical time and blood loss was observed between the 2 surgical approaches. Four patients underwent revision posterior interbody fusion for the recurrence of radicular pain as a result of intraforaminal stenosis in 3 patients and insufficient decompression of the extraforaminal area in the remaining patient at an average of 19.5 months after surgery. Conclusions Extraforaminal stenosis at the lumbosacral junction is a rare but distinct pathological condition causing L-5 radiculopathy. Decompression surgery without fusion using a microendoscope or a surgical microscope/ loupe is a feasible and less invasive surgical option for elderly patients with extraforaminal stenosis at the lumbosacral junction.

Purpose: We investigated the kinematics of nerve growth factor (NGF)mRNA and brain-derived neurotrophic factor (BDNF)mRNA in a skeletal muscle following spinal cord and peripheral nerve injuries by utilizing the reverse-transcription polymerase chain reaction/high-performance liquid chromatography (RT-PCR/HPLC) method. Methods: We made mice models of spinal cord transection and sciatic nerve transection, plus sham and control groups. After RNA extraction from gastrocnemius muscle of mice, RT-PCR was done. We measured the levels of NGFmRNA and BDNFmRNA in a skeletal muscle following spinal cord and peripheral nerve injuries by utilizing the RT-PCR/HPLC method. All values are analyzed and graphed as means ±SED. Bonferroni test (Post-hoc test) was used when two values were compared. Differences were considered statistically significant when p < 0.05. Results: According to the wet muscle weight, at day 7, a significant difference was found between the peripheral lesion and control group, and at days 14 and 28, significant differences were found between the spinal and peripheral lesion and control group. According to the NGFmRNA, in the peripheral nerve injury group, the levels increased up to day 28 and when compared with the control group, the levels were significantly higher at days 14 and 28. According to the BDNFmRNA, levels at days 2, 7, 14, and 28 were significantly lower in the spinal cord injury group than in the control group. However, in peripheral nerve injury group, when compared with the control group, the levels significantly increased at days 7, 14, and 28. Conclusion: We clarified marked differences in chronological changes in neurotrophin kinetics in a skeletal muscle between spinal cord injury and peripheral nerve injury.

Inflammation inevitably follows injury of various tissues, including bone. Transgenic overexpression of Fra-1, a component of the transcription factor activator protein-1 (AP-1), in various tissues progressively and globally enhances bone formation, but little is known about the possible effects of Fra-1/AP-1 on fracture healing. We created a transverse fracture of the mouse tibial diaphysis and examined fracture healing radiologically, histologically, and immunologically. Strikingly, fracture union was delayed even though the bone formation rate in callus was higher in Fra-1 transgenic (Tg) mice. In these mice, chondrogenesis around the fracture site was impaired, resulting in accumulation of fibrous tissue, which interferes with the formation of a bony bridge across the callus. Curiously, immediately after fracture, induction of the inflammatory mediators TNF-alpha, interleukin (IL)-6, and Cox-2 was significantly suppressed in Fra-1 Tg mice followed, by the reduced expression of Sox-9 and BMP-2. Because serum prostaglandin E(2) (PGE(2)) levels were dramatically low in these mice, we administered PGE(2) to the fracture site using a slow-release carrier. The accumulation of fibrous tissue in Fra-1 Tg mice was significantly reduced by PGE(2) administration, and chondrogenesis near the fracture site was partially restored. These data suggest that the Fra-1-containing transcription factor AP-1 inhibits fracture-induced endochondral ossification and bony bridge formation presumably through suppression of inflammation-induced chondrogenesis.

STUDY DESIGN.: A case report. OBJECTIVES.: To report a case of progressive kyphoscoliosis associated with a tethered cord that was corrected by posterior vertebral column resection after complicated untethering surgery. SUMMARY OF BACKGROUND DATA.: There have been few clinical reports on posterior vertebral column resection conducted for severe deformity associated with a tethered cord. METHODS.: A patient with progressive kyphoscoliosis associated with a tethered cord first underwent untethering surgery, resulting in neurologic deterioration. Posterior vertebral column resection was performed to correct the kyphoscoliosis while shortening the spinal column to prevent the spinal cord from stretch injury. RESULTS.: Good correction of kyphoscoliosis was obtained without further neurologic deterioration. The Cobb angles of scoliosis was 103 degrees before surgery and 25 degrees after surgery (correction rate; 75.7%), and that of kyphosis was 90 degrees and 36 degrees , respectively (correction rate; 60.0%). CONCLUSION.: Correction of progressive kyphoscoliosis associated with a tethered cord can be achieved successfully by posterior vertebral column resection even after complicated untethering surgery.

Receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG), a decoy receptor of RANKL, maintain bone mass by regulating the differentiation of osteoclasts, which are bone-resorbing cells. Endochondral bone ossification and bone fracture healing involve cartilage resorption, a less well-understood process that is needed for replacement of cartilage by bone. Here we describe the role of OPG produced by chondrocytes in chondroclastogenesis. Fracture healing in OPG(-/-) mice showed faster union of the fractured bone, faster resorption of the cartilaginous callus, and an increased number of chondroclasts at the chondroosseous junctions compared with that in wild-type littermates. When a cultured pellet of OPG(-/-) chondrocytes was transplanted beneath the kidney capsule, the pellet recruited many chondroclasts. The pellet showed the ability to induce tartrate-resistant acid phosphatase-positive multinucleated cells from RAW 264.7 cells in vitro. Finally, OPG(-/-) chondrocytes (but not wild-type chondrocytes) cultured with spleen cells induced many tartrate-resistant acid phosphatase-positive multinucleated cells. The expression of RANKL and OPG in chondrocytes was regulated by several osteotropic factors including 1,25-dihydroxyvitamin D(3), PTHrP, IL-1alpha, and TNF-alpha. Thus, local OPG produced by chondrocytes probably controls cartilage resorption as a negative regulator for chondrocyte-dependent chondroclastogenesis.

This study evaluated flexion angles and mechanical loads at the knee during weight-bearing deep flexion in patients with knee osteoarthritis (OA). Thirty-eight knees of 26 patients (mean age, 73 years; range, 58-81 years) with medial knee OA and 16 knees of 8 healthy volunteers (mean age, 63.4 years; range, 60-65 years) were enrolled. Patients were subdivided into two groups based on Kellgren and Lawrence OA grade: moderate OA (grade 2, 17 knees) or severe OA (grade 3 or 4, 21 knees). Motion analysis was performed while rising from maximal knee flexion with one leg for each subject. Maximum knee flexion angles and net quadriceps moments in the weight-bearing motion were compared among the two OA groups and healthy subjects. Mean maximum flexion angle in patients was 91+/-9 degrees. Angles were about 30% smaller than passive range of motion (ROM). Mean angles in healthy subjects, moderate OA and severe OA were 102.7+/-5.0 degrees, 95.6+/-7.7 degrees and 86.5+/-7.2 degrees, respectively, and net quadriceps moments during motion were 5.5+/-1.2%BW*Ht, 4.5+/-1.7%BW*Ht and 3.9+/-1.3%BW*Ht, respectively. Angles and moments were significantly lower in OA patients than in healthy subjects. Maximum flexion angles during weight-bearing rising correlated significantly with HSS score (r=0.63; 95% confidence interval, 0.40-0.78) and were significantly lower in severe OA patients compared to moderate OA. This measurement may offer an important clinical index for knee OA.

We have successfully synthesized hydroxyapatite fibers via a homogenous precipitation method. Using these hydroxyapatite fibers, we have produced the apatite fiber scaffolds (AFS) with well-controlled pore sizes (porosity above 95%). The AFS is relatively simple to synthesize, and its porosity and pore size are controllable. The usefulness of AFS as a scaffold for bone regeneration was evaluated by (1) seeding and culturing cells in the AFS in vitro, (2) implanting the AFS seeded with cells inside the subcutaneous tissue of mice. The AFS had biocompatibility to support cell adhesion, proliferation, and differentiation. Ectopic bone formation could be formed in the AFS at 12 weeks after implantation into the subcutaneous tissue. Because of its high interpore connection, pore diameters, and porosity, it was believed that AFS was an effective scaffold that provided a three-dimensional cell culture environment. In both in vitro and in vivo environments, the more porous AFS was more advantageous in cell proliferation, cell adhesion, proliferating capacity, robust cell differentiation, ultimately inducing bone ingrowth inside the scaffolds.

The one-leg standing (OLS) test is one of the balance tests used to diagnose musculoskeletal ambulation disability symptom complex (MARS), a condition newly defined by three professional Japanese medical societies in 2006 to help identify the symptoms of motor organ deterioration and establish preventive strategies. Although many studies have used the OLS test, none has shown conclusively that the test can be used as a practical marker of frailty among elderly people, especially in community settings. Based on the type of epidemiological study -- i.e., descriptive epidemiology and analytical epidemiology (observational and intervention studies) -- we reviewed evidence on three fundamental issues related to the OLS test: (1) testing procedures and reference values; (2) the associations between the OLS time and negative events; (3) improvement of the OLS time by intervention. These issues are key to any discussion of whether the OLS test can be used as a practical marker for predicting frailty in community-dwelling elderly populations.Articles were collected from MEDLINE databases using the search terms "one- leg standing" and the other names included in the same category.Because various procedures are used to carry out the OLS test, the measured values for the OLS time varied widely from study to study. Some observational studies showed that the OLS time is related to negative events such as falls, declines in activity of daily living, and other morbidity. OLS times could be improved by several interventions.This review suggests that the OLS test can be a tool for predicting frailty in community-dwelling elderly populations. However, our review should be interpreted with caution because we did not confirm the evidence level of each of the studies we selected. Further research on this topic is needed.

Lumbar disc herniation (LDH) is one of the most common musculo-skeletal diseases. Recent studies have indicated that LDH has strong genetic determinants, and several susceptibility genes have been reported to associate with LDH; however, its etiology and pathogenesis still remain unclear. KIAA1217 (alias SKT, the human homolog of murine Skt [Sickle tail]) is a good candidate for an LDH susceptibility gene because SKT is specifically expressed in nucleus pulposa of intervertebral discs (IVDs) in humans and mice, and Skt(Gt) mice, which are established through a large-scale gene-trap mutagenesis, exhibit progressive, postnatal onset abnormality of the IVDs. Here, we report the association of SKT with LDH. Using tag SNPs, we examined the association in two independent Japanese case-control populations and found a significant association with SKT rs16924573 in the allele frequency model (p = 0.0015). The association was replicated in a Finnish case-control population (p = 0.026). The combined p value of the two population by meta-analysis is 0.00040 (OR, 1.34; 95% CI, 1.14-1.58). Our data indicate that SKT is involved in the etiology of LDH.

IL-27 was first discovered as a factor supporting initial Th1 immune responses. Subsequent studies revealed that this cytokine has pleiotropic effects, including inhibition of certain immune cells, a regulatory role in hemopoietic stem cell differentiation, and antitumor activities. However, the role of human IL (hIL)-27 in human osteoclast precursors and inflammatory bone disease is unclear. Here, we examined the direct effect of hIL-27 on human osteoclastogenesis. Human bone marrow cells cultured in MethoCult medium containing human (h) GM-CSF, human stem cell factor, and hIL-3 expressed Mac-1, c-kit, and c-Fms. These cells, called hCFU-GMs, also expressed the IL-27 receptor, an IL-27Rα (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-κB ligand induced the differentiation of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) from hCFU-GMs, and hIL-27 inhibited this osteoclastogenesis in a dose-dependent manner. hIL-27 also repressed bone resorption by osteoclasts on a dentine slice. hIL-27 caused a remarkable increase in STAT1 phosphorylation and enhanced the STAT1 protein level. It also inhibited the expression of receptor activator of NF-κB ligand-induced c-Fos and cytoplasmic, calcineurin-dependent 1 NFAT (NFATc1), which are indispensable transcription factors for osteoclastogenesis. Fludarabine, a STAT1 inhibitor, and STAT1 small interfering RNA partially rescued the inhibition of osteoclastogenesis by IL-27. A WSX-1 deficiency caused severe inflammatory bone destruction primed by Escherichia coli cell wall lysate in vivo. Therefore, hIL-27 may act as an anti-inflammatory cytokine in human bone destruction, by inhibiting osteoclastogenesis from hCFU-GMs via STAT1-dependent down-regulation of the transcription factor c-Fos. Our results suggest that hIL-27 may prove useful as a therapeutic target for inflammatory bone destruction.

Retrospective case series.To determine the clinical significance and prognosis of idiopathic syringomyelia.With the widespread use of magnetic resonance imaging, cases of syringomyelia are found occasionally. However, the clinical significance and optimum treatment strategy for idiopathic syringomyelia remain unclear, because there are few reports on details of this condition.The clinical records and magnetic resonance images of 15 patients with idiopathic syringomyelia were reviewed to determine the changes in patient's neurologic status assessed by the Japanese Orthopedic Association scores for cervical myelopathy and the distribution of the syringomyelia on magnetic resonance imaging. Twelve cases were treated conservatively (conservative group) and syringo-subarachnoid shunt was performed in the remaining 3 cases (surgical group). The follow-up period ranged from 7 to 20 years (mean: 10.5 y).The localized type of idiopathic syringomyelia, which extended under 3 vertebras (mean: 2.1 vertebras), was observed in the 12 patients of the conservative group. There were no significant changes in either the size of the syringomyelia or the severity of the neurologic deficits during the follow-up period (mean: 10 y). In contrast, the extended type, which distributed over 4 or more vertebras (mean: 10.2 vertebras), was observed in the 3 patients of the surgical group. Because of severe and progressive neurologic deficits, syringo-subarachnoid shunt was performed and the surgery successfully prevented further neurologic deterioration. The mean Japanese Orthopedic Association score of the surgical group was significantly lower than that of the conservative group, both at the time of the initial examination and at the final follow-up.There are 2 types of idiopathic syringomyelia. One is a "localized" type, which might represents congenital enlargement of the central canal of the spinal cord, and can be managed conservatively. The other is an "extended" type, which causes progressive neurologic dysfunction, and should be treated surgically to prevent further neurologic deterioration. Further study should be needed to clarify the mechanism of the extended type of idiopathic syringomyelia.

The solitary fi brous tumor (SFT) is a rare lesion that arises most commonly in the visceral pleura. It was originally thought to arise from the submesothelial connective tissue. SFT also occurs in other serosal locations. In recent years, however, a variety of nonserosal sites have been described, including the upper respiratory tract, epiglottis, thyroid, soft tissues, orbit, and tibial periosteum. Although SFT presenting as an intradural extramedullary mass lesion with or without a partial intramedullary component has often been reported, SFT restricted within the spinal cord is rare. Following approval from the institutional review board and informed consent from the study participant, a retrospective review of an SFT arising in the cervical spinal cord parenchyma was performed.

Cyclic stretching is pivotal to maintenance of the ligaments. However, it is still not clear when ligament fibroblasts switch on expression of genes related to the mechanotransduction pathway in response to cyclic stretching. This in vitro study investigated, using ligament fibroblasts, the time-dependent changes in distribution and gene expression of beta1 integrin, the cytoskeleton, and collagens after the application of 6% cyclic stretching at a frequency of 0.1 Hz for 3 hr on silicon membranes. We carried out confocal laser scanning microscopy to demonstrate changes in distribution of these components as well as quantitative real-time RT-PCR to quantify levels of these gene expression both during application of cyclic stretching and at 0, 2, 6, 12, and 18 hr after the termination of stretching. Control (unstretched) cells were used at each time point. Within 1 hr of the application of stretching, the fibroblasts and their actin stress fibers became aligned in a direction perpendicular to the major axis of stretch, whereas control (unstretched) cells were randomly distributed. In response to cyclic stretching, upregulation of actin at the mRNA level was first observed within 1 hr after the onset of stretching, while upregulation of beta1 integrin and type I and type III collagens was observed between 2 and 12 hr after the termination of stretching. These results indicate that the fibroblasts quickly modify their morphology in response to cyclic stretching, and subsequently they upregulate the expression of genes related to the mechanotransduction pathway mainly during the resting period after the termination of stretching.

FLT3 ligand (FLT3L) has diverse roles in the hematopoietic system, which include stimulating proliferation of hematopoietic precursors and development of NK cells and dendritic cells. FLT3L is initially synthesized as a membrane-bound protein, which must be cleaved to become a soluble growth factor. However, little is known about the enzyme involved in the proteolytic release of FLT3L. In the current study, we show that shedding of FLT3L is metalloprotease-dependent, and that this proteolytic activity was abolished in fibroblasts lacking TNF-α converting enzyme (TACE) and could be rescued by reintroducing wild-type TACE in these cells. Moreover, we found that cells derived from the thymus of conditional TACE-deficient mice produce less FLT3L, and that serum FLT3L levels in these TACE mutant mice are significantly lower, both after LPS treatment and in the absence of such a challenge, further corroborating the relevance of TACE as FLT3L sheddase in vivo. Considering the involvements of FLT3 and FLT3L in hematopoietic malignancies and stem cell mobilization, the identification of the enzyme involved in FLT3L shedding may have important clinical implications.

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays a critical role in the recruitment and activation of leukocytes. Here, we describe that multinuclear osteoclast formation was significantly inhibited in cells derived from MCP-1-deficient mice. MCP-1 has been implicated in the regulation of osteoclast cell-cell fusion; however defects of multinuclear osteoclast formation in the cells from mice deficient in DC-STAMP, a seven transmembrane receptor essential for osteoclast cell-cell fusion, was not rescued by recombinant MCP-1. The lack of MCP-1 in osteoclasts resulted in a down-regulation of DC-STAMP, NFATc1, and cathepsin K, all of which were highly expressed in normal osteoclasts, suggesting that osteoclast differentiation was inhibited in MCP-1-deficient cells. MCP-1 alone did not induce osteoclastogenesis, however, the inhibition of osteoclastogenesis in MCP-1-deficient cells was restored by addition of recombinant MCP-1, indicating that osteoclastogenesis was regulated in an autocrine/paracrine manner by MCP-1 under the stimulation of RANKL in osteoclasts.

1-Alpha, 25-dihydroxy vitamin D(3) (1alpha,25(OH)(2)D(3)), an active form of vitamin D(3), plays a critical role in calcium and bone metabolism. Although 1alpha,25(OH)(2)D(3) has been used for osteoporosis therapy, the direct role of 1alpha,25(OH)(2)D(3) on human osteoclastogenesis has not been well characterized. Here we show that 1alpha,25(OH)(2)D(3) treatment significantly inhibited human osteoclast formation at the early stage of differentiation in a concentration-dependent manner. 1alpha,25(OH)(2)D(3) inhibited the expression of nuclear factor of activated T cells c1 (NFATc1, also referred as NFAT2), an essential transcription factor for osteoclast differentiation, and upregulated the expression of interferon-beta (IFN-beta), a strong inhibitor of osteoclastogenesis in osteoclast progenitors. Inhibitory effects of 1alpha,25(OH)(2)D(3) on osteoclastogenesis and NFATc1 expression were restored by treatment with an antibody against IFN-beta, suggesting that upregulation of IFN-beta by 1alpha,25(OH)(2)D(3) treatment results in inhibition of NFATc1 expression, in turn interfering with osteoclast formation. Thus, our study may provide a molecular basis for the treatment of human bone diseases by 1alpha,25(OH)(2)D(3) through regulation of the IFN-beta and NFATc1 axis.

1 Laboratory of Statistics, Osaka City University Faculty of Medicine, Osaka, Japan 2 Department of Orthopaedic Surgery, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan 3 Department of Orthopaedic Surgery, Wakayama Medical University, Wakayama, Japan 4 Department of Orthopaedic Surgery, School of Medicine, Fukushima Medical University, Fukushima, Japan 5 Department of Orthopedic Surgery, Nippon Medical School, Tokyo, Japan 6 Department of Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan 7 Department of Orthopaedic Surgery, Iwate Medical University School of Medicine, Morioka, Japan 8 Department of Orthopaedic Surgery, Saitama Medical School. Saitama, Japan 9 Department of Orthopedic Surgery, Yamaguchi University School of Medicine, Yamaguchi, Japan 10 Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan 11 Department of Orthopaedics, Kochi Medical School, Kochi, Japan 12 Department of Orthopaedic Surgery, Hoshigaoka Koseinenkin Hospital, Osaka, Japan 13 National Hospital Organization, Osaka-Minami Medical Center, Osaka, Japan 14 Department of Internal Medicine, Houai Hospital, Osaka, Japan 15 Department of Public Health, Osaka City University Faculty of Medicine, Osaka, Japan

We retrospectively defined the rate and clinical features of tendon entrapment in 693 consecutive patients with 701 distal radius fractures treated in a single hospital. Eight extensor tendons and one flexor tendon were entrapped. All fractures with extensor tendon entrapment were palmarly displaced (Smith type) or epiphyseal. Flexor tendon entrapment was seen in dorsally angulated (Colles type) epiphyseal fracture. The rate of tendon entrapment in acute distal radius fractures was 1.3%. Extensor tendon entrapment in palmarly displaced fractures is more common.

Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor (NF)–κB ligand (RANKL)–mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction. Protein inhibitor of activated STAT3 (PIAS3) was initially identified as a molecule that inhibits DNA binding of STAT3 and regulates many transcription factors through distinct mechanisms. To analyze PIAS3 function in osteoclasts in vivo, we have generated transgenic mice in which PIAS3 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase (TRAP) gene promoter. PIAS3 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation. Overexpression of PIAS3 in RAW264.7 cells suppressed RANKL-induced osteoclastogenesis by inhibiting the expression of c-Fos and NFATc1. Interestingly, PIAS3 inhibits the transcriptional activity of microphthalmiaassociated transcription factor (MITF) independent of sumoylation. Down-regulation of PIAS3 markedly enhances RANKL-mediated osteoclastogenesis in RAW264.7 cells. Furthermore, overexpression of PIAS3 in mouse primary osteoblast (POB), down-regulates RANKL expression induced by interleukin-6 (IL-6) cytokine family, and inhibits osteoclast formation from bone marrow macrophages (BMMs) in vitro coculture system. Down-regulation of PIAS3 leads to the accelerated expression of RANKL in POB stimulated with IL-6 and soluble IL-6 receptor (sIL-6R). Taken together, our results clearly indicate that PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts.

We applied diffusion tensor tractography (DTT), a recently developed MRI technique that reveals the microstructures of tissues based on its ability to monitor the random movements of water molecules, to the visualization of peripheral nerves after injury. The rat sciatic nerve was subjected to contusive injury, and the data obtained from diffusion tensor imaging (DTI) were used to determine the tracks of nerve fibers (DTT). The DTT images obtained using the fractional anisotropy (FA) threshold value of 0.4 clearly revealed the recovery process of the contused nerves. Immediately after the injury, fiber tracking from the designated proximal site could not be continued beyond the lesion epicenter, but the intensity improved thereafter, returning to its pre-injury level by 3 weeks later. We compared the FA value, a parameter computed from the DTT data, with the results of histological and functional examinations of the injured nerves, during recovery. The FA values of the peripheral nerves were more strongly correlated with axon-related (axon density and diameter) than with myelin-related (myelin density and thickness) parameters, supporting the theories that axonal membranes play a major role in anisotropic water diffusion and that myelination can modulate the degree of anisotropy. Moreover, restoration of the FA value at the lesion epicenter was strongly correlated with parameters of motor and sensory functional recovery. These correlations of the FA values with both the histological and functional changes demonstrate the potential usefulness of DTT for evaluating clinical events associated with Wallerian degeneration and the regeneration of peripheral nerves.

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and they are considered a physical barrier to prevent axonal regeneration by producing axonal growth inhibitors, such as chondroitin sulfate proteoglycans. However, the physiological role of reactive astrocytes remains to be elucidated. In this review, we showed that reactive astrocytes play a crucial role in wound healing and functional recovery. At the subacute phase of spinal cord injury (SCI), reactive astrocytes eventually migrated to the lesion epicenter and gradually compacted the infiltrated inflammatory cells and contracted the lesion area, and functional recovery was observed only in this repair phase. Selective deletion of the signal transducer and activator of transcription-3 (STAT3) in reactive astrocytes resulted in their limited migration associated with zinc signaling, markedly widespread damaged area and severe motor deficits. These results suggest that STAT3 is a key regulator of reactive astrocytes migration in the healing process after SCI, providing a beneficial aspect of reactive astrocytes after CNS injury.

Background: Intra-articular injection of hyaluronan (HA) has been suggested to have a disease-modifying effect in osteoarthritis, but little is known about the possible mechanisms. Objective: To investigate the effects of HA species of different molecular mass, including 800 kDa (HA800) and 2700 kDa (HA2700), on the expression of aggrecanases (ie, ADAMTS species), which play a key role in aggrecan degradation. Methods: The effects of HA species on the expression of ADAMTS1, 4, 5, 8, 9 and 15 in interleukin 1α (IL1α)-stimulated osteoarthritic chondrocytes were studied by reverse transcription PCR and real-time PCR. Expression of ADAMTS4 protein and aggrecanase activity and signal transduction pathways of IL1, CD44 and intracellular adhesion molecule 1 (ICAM1) were examined by immunoblotting. Results: IL1α treatment of chondrocytes induced ADAMTS4, and HA800 and HA2700 significantly decreased IL1α-induced expression of ADAMTS4 mRNA and protein. IL1α-stimulated aggrecanase activity in osteoarthritic chondrocytes was reduced by treatment with HA2700 or transfection of small interfering RNA for ADAMTS4. A similar result was obtained when HA2700 was added to explant cultures of osteoarthritic cartilage. HA2700 neither directly inhibited nor bound to ADAMTS4. Downregulation of ADAMTS4 expression by HA2700 was attenuated by treatment of IL1α-treated chondrocytes with antibodies to CD44 and/or ICAM1. The increased phosphorylation of IL1 receptor-associated kinase-1 and extracellular signal-regulated protein kinase1/2 induced by the IL1α treatment was downregulated by enhanced IRAK-M expression after HA2700 treatment. Conclusion: These data suggest that HA2700 suppresses aggrecan degradation by downregulating IL1α-induced ADAMTS4 expression through the CD44 and ICAM1 signalling pathways in osteoarthritic chondrocytes.

The investigations from the aspect of “osteoimmunology”provided a recent advance on bone cell biology1). Various molecules identified to play a crucial role in immune system also play a role in bone system. For example, RANK-RANKL system was originally identified in dendritic cells and T cells2), but these molecules are both essential for osteoclast differentiation and skeletal development3,4). Nuclear factor of activated T cells (NFATc1) was also originally identified in T cells, but plays an essential role in osteoclast differentiation5). Thus bone and immune systems share common molecules. Here we introduce a seven transmembrane receptor protein, dendritic cell specific transmembarne protein (DC-STAMP) as an“osteoimmunology”molecule, which plays a role in both bone and immune systems.

Object This retrospective study was conducted to evaluate the prevalence and clinical consequences of postoperative lamina closure after open-door laminoplasty and to identify the risk factors. Methods Eighty-two consecutive patients with cervical myelopathy who underwent open-door laminoplasty without plates or spacers in the open side (Hirabayashi's original method) were included (62 men and 20 women with a mean age of 62 years and a mean follow-up of 1.8 years). In 67 patients the cause of cervical myelopathy was spondylotic myelopathy, and in 15 it was caused by ossification of posterior longitudinal ligament. Radiographic measurements were made of the anteroposterior diameters of the spinal canal and vertebral bodies from C3–6, and the presence of kyphosis were assessed. Lamina closure was defined as ≥ 10% decrease in the canal-to-body ratio at the final follow-up compared with that immediately after surgery at ≥ 1 vertebral level. The impact of lamina closure on neck pain, patient satisfaction, Japanese Orthopaedic Association scores, and recovery rates were also evaluated. Results The mean canal-to-body ratio at C3–6 was 0.69–0.72 preoperatively, 1.25–1.28 immediately after surgery, and 1.18–1.24 at the final follow-up examination. Lamina closure was observed in 34% of patients and was not associated with sex, age, or cause of myelopathy, but was significantly associated with the presence of preoperative kyphosis (p = 0.014). Between patients with and without lamina closure, there was no significant difference in preoperative (9.7 ± 3.1 vs 10.6 ± 2.5) and postoperative (13.7 ± 2.4 vs 13.1 ± 2.7) Japanese Orthopaedic Association scores, recovery rates (53.9 ± 29.9% vs 44.3 ± 29.5%), neck pain scores (3.5 ± 0.7 vs 3.3 ± 1.0), or patient satisfaction level (4.0 ± 1.4 vs 4.8 ± 1.0). Conclusions Lamina closure at ≥ 1 vertebral level occurred in 34% of patients. Although patients with lamina closure obtained equivalent recovery from myelopathy in a short-term follow-up, they tended to be less satisfied with surgery compared with those who did not have closure. The only significant risk factor identified was the presence of preoperative cervical kyphosis, and preventative methods for lamina closure, therefore, should be considered for patients with preoperative kyphosis.

Synovial sarcoma is a relatively common soft tissue sarcoma with an aggressive clinical course. Although surgery is currently the first treatment modality, improvement of adjuvant chemotherapy is deemed essential to improve the clinical outcome. Nuclear factor-kappaB (NF-kappaB) is constitutively activated in various cancer cells and has emerged as a potential therapeutic molecular target; however, the possible involvement of NF-kappaB in the pathology of sarcomas remains to be clarified. Herein we examined the effects of a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) on two synovial sarcoma-derived cell lines, HS-SY-II and SYO-1. The growth of both cell lines was completely inhibited by DHMEQ and apoptosis was induced at 10 microg/ml. Additionally, we found that DHMEQ showed additive effects when used in combination with other cytotoxic agents. These observations indicate that inhibition of NF-kappaB activity may serve as a potential therapeutic target for synovial sarcoma.

Cartilage disorders of the finger joint may influence hand function. Loss of integrity of the finger joint may severely compromise its stability and may lead to degenerative arthritis. Anatomical reduction of the finger cartilage should be as precise as possible in treating cartilage defects due to trauma and other causes. We have repaired cartilage defects in finger joints by arthroplasty with costal osteochondral grafting in 29 patients (30 joints) since 1997. Three patients underwent total joint reconstruction using costal osteochondral grafting for complete bony ankylosis (1 metacarpophalangeal joint and 2 proximal interphalangeal joints). The purpose of this study was to describe the history, indications, and surgical techniques of the costal osteochondral graft for cartilage disorders or defects in the metacarpophalangeal and proximal interphalangeal joints.

Purpose:Unplanned resection of musculoskeletal sarcoma involves tumor excision without any suspicion of malignancy or regard for the necessity of defining adequate margins. For orthopaedic oncologists, many opportunities arise for management of unplanned resections initially performed by non-specialist surgeons. The puropose of this study is to assess the clinical outcomes and the problems of the patients with unplanned resection of high-grade soft tissue sarcoma.Methods:77 consecutive patients were retrospectively reviewed. Oncological outcomes together with validity and problems of additional treatments were analyzed.Results:Five-year local recurrence-free survival, metastasis-free survival, event-free survival and total survival were 71.55%, 73.2%, 57.5% and 85.9%, respectively. Among adjuvant therapy including additional wide resection, radiotherapy and systemic chemotherapy, only additional wide resection significantly improved oncological outcomes.Conclusion:Additional wide resection appears to be effective in the treatment of high-grade soft tissue sarcomas following primary resection with compromised margins of resection.

Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. In RA synovial tissue, the infiltrating cells such as macrophages, T cells, B cells and dendritic cells play important role in the pathogenesis of RA. Migration of leukocytes into the synovium is a regulated multi-step process, involving interactions between leukocytes and endothelial cells, cellular adhesion molecules, as well as chemokines and chemokine receptors. Chemokines are small, chemoattractant cytokines which play key roles in the accumulation of inflammatory cells at the site of inflammation. It is known that synovial tissue and synovial fluid from RA patients contain increased concentrations of several chemokines, such as monocyte chemoattractant protein-4 (MCP-4)/CCL13, pulmonary and activation-regulated chemokine (PARC)/CCL18, monokine induced by interferon-gamma (Mig)/CXCL9, stromal cell-derived factor 1 (SDF-1)/CXCL12, monocyte chemotactic protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3, and Fractalkine/CXC3CL1. Therefore, chemokines and chemokine-receptors are considered to be important molecules in RA pathology.

Background The Japanese Orthopaedic Association decided to revise the JOA score for low back pain and to develop a new outcome measure. In February 2002, the first survey was performed with a preliminary questionnaire consisting of 60 evaluation items. Based on findings of that survey, 25 items were selected for a draft of the JOA Back Pain Evaluation Questionnaire (JOABPEQ). The second survey was performed to confirm the reliability of the draft questionnaire. This article further evaluates the validity of this questionnaire and establishes a measurement scale. Methods The subjects of this study consisted of 355 patients with low back disorders of any type (201 men, 154 women; mean age 50.7 years). Each patient was asked to fill in a self-administered questionnaire. Superficial validity was checked in terms of the completion rate for filling out the entire questionnaire. Factor analysis was then performed to evaluate the validity of the questionnaire and establish a measurement scale. Results As a result of the factor analysis, 25 items were categorized into five factors. The factors were named based on the commonality of the items: social function, mental health, lumbar function, walking ability, and low back pain. To establish a measurement scale for each factor, we determined the coefficient for each item so the difference between the maximum factor scores and minimum factor scores was approximately 100. We adjusted the formula so the maximum for each factor score was 100 and the minimum was 0. Conclusions We confirmed the validity of the JOA Back Pain Evaluation Questionnaire and est ablished a measurement scale.

To prospectively evaluate signal intensity change on T2-weighted magnetic resonance (MR) images and the time course of T2 values and T2 ratios after reinnervation in various nerve injury models in rats.Institutional animal use and care committee approval was obtained. Thirty male rats made up four groups of rats with an injured left posterior tibial nerve (irreversible neurotmesis, reversible neurotmesis, severe axonotmesis, or moderate axonotmesis) and one control group. There were six rats in each group. Signal intensity changes were seen in the gastrocnemius muscle on the T2-weighted MR images. T2 values were also measured in vivo with the Carr-Purcell-Meiboom-Gill method. Gait function was assessed by calculating the print length factor (PLF). T2 ratios and PLFs on the injured side were compared with those on the unaffected side. Ratios of specific acquisition points within groups were compared by using repeated-measures analysis of variance. Comparisons across the five groups at each acquisition point were performed by using one-way analysis of variance with Scheffe post hoc testing. P.05 indicated a significant difference.The more severe the nerve damage, the higher the signal intensity on T2-weighted MR images. There were significant differences in T2 ratios between the nerve injury groups and the control group (P.05). Changes in T2 values and ratios depended on the degree of nerve injury. In the reversible neurotmesis group, T2 values and ratios began to decrease 28 days after surgery. In the severe and moderate axonotmesis groups, T2 values and ratios began to decrease 14 days after surgery. The starting point of functional recovery also depended on the degree of nerve injury.The degree and prognosis of nerve injury can be evaluated by observing changes in signal intensity on T2-weighted images and the time course of T2 values and ratios.

Objective. Environmental factors are involved in RA pathogenesis and epidemiological studies have suggested that smoking is an environmental risk factor for RA. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the major toxic components in cigarettes. To clarify the biological effects of smoking in RA, we investigated the role of TCDD in RA pathogenesis. Methods. Human synovial tissue was obtained from RA and OA patients and aryl hydrocarbon receptor (AhR) expression in these tissues was evaluated using immunohistochemistry and real-time PCR. Expression of various cytokines was measured by real-time PCR following stimulation of RA synoviocytes with different concentrations of TCDD. To study the role of AhR, we treated RA synoviocytes with � -naphthoflavone, a known AhR antagonist. To evaluate which signal transduction pathways were stimulated by the TCDD–AhR interaction, we used inhibitors of nuclear factor-� B (NF-� B) and extra-cellular stimulus-activated kinase (ERK). Results. Higher AhR mRNA and protein levels were observed in RA synovial tissue than in OA tissue. TCDD up-regulated the expression of IL-1� , IL-6 and IL-8 through binding to AhR, and this effect was transmitted via the NF-� B and ERK signalling cascades. AhR expression in synovial cells was up-regulated by TNF-� . Conclusion. TNF-� activates AhR expression in RA synovial tissue, and that cigarette smoking and exposure to TCDD enhances RA inflammatory processes. TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-� B and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology.

Purpose For the purpose of achieving anatomical reduction as precisely as possible, we performed osteochondral grafting from the costo-osteochondral junction in 16 patients (17 joints) with posttraumatic articular cartilage injury or avascular necrosis in finger joints. The purpose of this study was to review our series of costal osteochondral grafts in order to determine the practicality, effectiveness, and functionality of this grafting technique in a clinical setting. Methods Patients were followed for at least 18 months postoperatively (18–57 months; average, 28 months). The injured joints included 3 metacarpophalangeal, 9 proximal interphalangeal, 3 distal interphalangeal, and 2 thumb interphalangeal joints. The defect accounted for 50% to 100% of the articular surface (average, 63%). Results The average time until bone union of the graft was 58 days. The mean arc of motion was 13° before surgery versus 58° after surgery, with a mean increase of 45°. In 7 patients (8 joints), an extremely small portion (approximately 1 × 1 mm in size and thinner than 0.1 mm) of the implanted cartilage was obtained via biopsy using a scalpel with the consent of the patient at the time of screw removal and was used to prepare histologic specimens, which revealed scattered chondrocytes within the matrix without differences from normal hyaline cartilage in any. The chondrocytes in the grafts appeared viable, and the reconstruction of the joint surface could be confirmed histologically. Conclusions Osteochondral grafting from the costo-osteochondral junction achieves excellent reconstruction of the injured joint without affecting other joints. This technique is particularly beneficial in cases where it is difficult to obtain allograft donors, as is often the case in Japan. Despite these encouraging findings in this small series, we believe that it is necessary to conduct further studies of this method over a longer period. Type of study/level of evidence Therapeutic IV.

Study design Retrospective multi-institutional study Objective To describe the surgical outcomes in patients with ossification of the posterior longitudinal ligament in the thoracic spine (T-OPLL) and to clarify factors related to the surgical outcomes. Summary of background data Detailed analyses of surgical outcomes of T-OPLL have been difficult because of the rarity of this disease. Methods The subjects were 154 patients with T-OPLL who were surgically treated at 34 institutions between 1998 and 2002. The surgical procedures were laminectomy in 36, laminoplasty in 51, anterior decompression via anterior approach in 25 and via posterior approach in 29, combined anterior and posterior fusion in 8, and sternum splitting approach in 5 patients. Instrumentation was conducted in 52 patients. Assessments were made on (1) The Japanese Orthopedic Association (JOA) scores (full score, 11 points), its recovery rates, (2) factors related to surgical results, and (3) complications and their consequences. Results (1) The mean JOA score before surgery was 4.6 +/- 2.0 and, 7.1 +/- 2.5 after surgery. The mean recovery rate was 36.8% +/- 47.4%. (2) The recovery rate was 50% or higher in 72 patients (46.8%). Factors significantly related to this were location of the maximum ossification (T1-T4) (odds ratio, 2.43-4.17) and the use of instrumentation (odds ratio, 3.37). (3) The frequent complications were deterioration of myelopathy immediately after surgery in 18 (11.7%) and dural injury in 34 (22.1%) patients. Conclusion The factors significantly associated with favorable surgical results were maximum ossification located at the upper thoracic spine and use of instrumentation. T-OPLL at the nonkyphotic upper thoracic spine can be treated by laminoplasty that is relatively a safe surgical procedure for neural elements. The use of instrumentation allows correction of kyphosis or prevention of progression of kyphosis, thereby, enhancing and maintaining decompression effect, and its use should be considered with posterior decompression.

Summary Dendritic cells (DCs) have important functions as modulators of immune responses, and their ability to activate T cells is of great value in cancer immunotherapy. The isolation of DCs from the peripheral blood of rhesus and African green monkeys has been reported, but the immune system in the common marmoset remains poorly characterized, although it offers many potential advantages for preclinical studies. In the present study, we devised methods, based on techniques developed for mouse and human DC preparation, for isolating DCs from three major tissue sources in the common marmoset: bone marrow (BM), spleen and peripheral blood. Each set of separated cells was analysed using the cell surface DC-associated markers CD11c, CD80, CD83, CD86 and human leucocyte antigen (HLA)-DR, all of which are antibodies against human antigens, and the cells were further characterized both functionally and morphologically as antigen-presenting cells. BM proved to be an excellent cell source for the isolation of DCs intended for preclinical studies on cell therapy, for which large quantities of cells are required. In the BM-derived CD11c+ cell population, cells exhibiting the characteristic features of DCs were enriched, with the typical DC morphology and the abilities to undergo endocytosis, to secrete interleukin (IL)-12, and to stimulate Xenogenic T cells. Moreover, BM-derived DCs produced the neurotrophic factor NT-3, which is also found in murine splenic DCs. These results suggest that BM-derived DCs from the common marmoset may be useful for biological analysis and for preclinical studies on cell therapy for central nervous system diseases and cancer.